CHAPTER 131
DISEASES OF PLATELET NUMBER: IMMUNE
THROMBOCYTOPENIA, NEONATAL ALLOIMMUNE
THROMBOCYTOPENIA, AND POSTTRANSFUSION PURPURA
Donald M. Arnold, Michelle P. Zeller, James W. Smith, and Ishac Nazy
Platelets are anucleate cells that are required for primary hemostasis.
Platelets have a life span of 7–10 days in the circulation, after which
time they are cleared by the cells of the reticuloendothelial system
(RES), including the spleen. Platelet production is stimulated by
thrombopoietin (TPO), a hormone that is constitutively secreted by
the liver. TPO binds to c-Mpl, its receptor on platelets, hematopoietic
progenitor cells, and bone marrow (BM) megakaryocytes. When
bound to c-Mpl, TPO is internalized, degraded, and removed from
the circulation; thus when the platelet count is low, free TPO levels
are high, and more platelets are produced. In contrast, when platelet
counts are high, circulating TPO levels are low, and platelet produc-
tion declines. This primitive feedback system is very effective at
maintaining the platelet count at a stable level. Recent evidence in
mice has shown that the Ashwell-Morell receptor on murine hepato-
cytes binds platelets that have lost sialic acid residues on their surface.
Binding activates a JAK-STAT signaling pathway, resulting in
increased hepatic TPO mRNA expression and TPO production. The
role of this pathway in normal human thrombopoiesis is not yet
known.
Immune-mediated platelet disorders disrupt normal regulation
of platelet number because of antibody-mediated or cell-mediated
platelet destruction or platelet underproduction. Antibodies that
target self (autoimmune) or nonself (alloimmune) antigens on plate-
lets can cause severe thrombocytopenia. Immune thrombocytopenia
(ITP) is an autoimmune disorder characterized by antibodies directed
against platelet glycoproteins (GPs). Neonatal alloimmune thrombo-
cytopenia (NAIT) is a thrombocytopenic syndrome caused by platelet
alloantibodies. Posttransfusion purpura (PTP) has features of both
alloantibody- and autoantibody-mediated processes. These platelet
disorders have related immunologic features with distinct clinical
characteristics (Table 131.1). The pathophysiology, clinical manifes-
tations, and management of these disorders are discussed in this
chapter.
IMMUNE THROMBOCYTOPENIA
ITP is a common autoimmune disease characterized by a low platelet
count that can be associated with an increased risk of bleeding.
Increased platelet destruction resulting from platelet autoantibodies
is a hallmark of ITP. Recently, however, it has become evident that
relative platelet underproduction is also an important mechanism for
the thrombocytopenia in ITP. Conventional treatments, including
corticosteroids, intravenous immunoglobulin (IVIg), immunosup-
pressant drugs, and splenectomy are aimed at preventing platelet
destruction. TPO receptor agonists are medications that work by
increasing platelet production. They represent the most significant
advance in ITP management since the first description of IVIg as a
treatment for ITP in the early 1980s. TPO receptor agonists have
been shown to be effective in clinical trials1,2 and were the catalyst
for several key initiatives in ITP including the standardization of
terminology (2009)3 and the development of the American Society
of Hematology (ASH) Guidelines on diagnosis and management of
ITP (2011).4
1944
Epidemiology
The natural history of ITP is different in children and adults. For the
majority of children, ITP presents acutely and resolves within several
weeks, often in the absence of intervention. Seasonal variability sug-
gests that viral infections may trigger the disease in many children.
Conversely, adult-onset ITP tends to be insidious in onset and is
characterized by a chronic or remitting and relapsing course.
Incidence and Prevalence of Immune
Thrombocytopenia in Children
The incidence of acute ITP in children is estimated at 1.9–6.4 per
100,000 per year. Nearly 70% of childhood ITP occurs between the
ages of 1 and 10 years with the peak prevalence between 4 and 6 years.
Most studies in children report an overall male predominance in early
childhood and equalization or reversal to female predominance in older
children. Reported prevalence estimates are 12.6 per 100,000 for girls
and 9.3 per 100,000 for boys in the older age groups.
Incidence and Prevalence of Immune
Thrombocytopenia in Adults
Incidence estimates for adult-onset ITP are reported to be between
1.6 and 3.9 per 100,000 per year. A retrospective analysis from the
United Kingdom described a bimodal distribution for men, with
peak incidences before the age of 18 years and between 75 and 84
years of age. Relatively stable incidence rates were found in women
up to the age of 60 years with a steady increase thereafter. The inci-
dence of ITP has been reported to double in patients over 60 years
of age.
The overall prevalence of ITP in adults has been estimated at 9.5
per 100,000, and ranges from 4.1 per 100,000 in younger ages
(19–24 years) to 16 per 100,000 in older age groups (55–64 years).
Male and female prevalence rates are 16.6 and 27.2 per 100,000
adults, respectively, for those 18–64 years of age, with prevalence rates
increasing significantly after the age of 65 years. The female predomi-
nance is attenuated in older age groups and may revert to a male
predominance after the age of 65 years. Indeed, the prevalence of ITP
in older men is reported to be as high as 38.3 per 100,000. Increasing
incidence and prevalence rates may reflect a true rise in disease fre-
quency with age or ascertainment bias because of the higher likeli-
hood of discovering incidental thrombocytopenia with more frequent
medical visits in older individuals.
Pathophysiology
ITP is caused by increased platelet destruction and impaired platelet
production. Until recently, the pathogenesis of immune-mediated
thrombocytopenia was mainly attributed to platelet-reactive autoan-
tibodies; however, it is now evident that the pathophysiology of ITP
 Chapter 131 Diseases of Platelet Number 1945

TABLE Antibody-Mediated Thrombocytopenic Disorders Caused by Autoantibodies (Immune Thrombocytopenia), Alloantibodies

131.1 (Neonatal Alloimmune Thrombocytopenia) or Potentially Both (Posttransfusion Purpura)
Immune Thrombocytopenia Neonatal Alloimmune Thrombocytopenia Posttransfusion Purpura
Immune reaction Autoimmune Alloimmune Features of both allo- and autoimmunity
Incidence 5 per 100,000 population 40 per 100,000 births (or 1 per 2500) 1 per 100,000 blood transfusions
Principal antigenic target GPIIb/IIIa HPA-1a HPA-1a plus autoantigens
Nature of the antibody Intermittent Persistent (past 1 year) Persistent often at high titers
Mode of sensitization Autoantibody Alloantibody Features of allo- and autoantibodies
Sensitizing event Mostly unknown; some viral Exposure to fetal platelet antigens early Blood transfusion (RBCs or platelets)
illnesses, chronic infection in first pregnancy 5–10 days earlier
Bleeding frequency Uncommon Common Very common
Epidemiology Higher incidence in children Majority affects fetus or newborn Almost all are HPA-1bb women
and elderly adults; female carrying the HPA-1a antigen sensitized by previous transfusion or
predominance in early pregnancy
adulthood
GP, Glycoprotein; HPA, human platelet antigen; RBC, red blood cell.

is more complex and involves alterations in cellular immunity and
immune-mediated megakaryocyte injury.
The antibody hypothesis began with the observation that blood
from patients with ITP was able to cause a reduction in platelet count
levels in other individuals. In one of the first experiments, William
Harrington infused blood from ITP patients into normal volunteers
and observed a decrease in the platelet counts in most recipients.5 The
circulating factor in blood responsible for this effect was later identi-
fied as an immunoglobulin (Ig) that bound to the surface of platelets.
In further studies, investigators were able to quantify platelet-associated
IgG (PAIgG) on or inside platelets. PAIgG was not able to discriminate
between immune and non-ITP and eventually assays were developed
to detect antibodies directed against specific platelet GPs, specifically
GPIIb/IIIa or GPIb/IX. GP-specific assays exhibited improved speci-
ficity but had limited sensitivity (50%–66%) since many patients with
ITP had no detectable antibody. Autoantibodies against platelet GPs
target those cells for rapid opsonization and clearance in the RES,
particularly the spleen. Peptides from phagocytosed platelets may be
processed and presented to specific T cells, which in turn stimulate B
cells to produce additional platelet autoantibodies. This process,
known as epitope spreading, may explain why patients have circulating
autoantibodies targeting a variety of platelet antigens. Other proposed
mechanisms of antibody-induced platelet destruction are complement
activation and platelet apoptosis.
In ITP, platelet production does not compensate for the increased
platelet destruction, suggesting that BM megakaryocyte growth and/
or ability to produce platelets are impaired. Evidence supporting
reduced platelet production in ITP derives from radiolabeled autolo-
gous platelet studies demonstrating normal or reduced platelet
turnover; and from clinical studies that have consistently demon-
strated the capacity of TPO receptor agonists to increase platelet
counts in patients with severe thrombocytopenia. Megakaryocytes
also express GP receptors, which may render them targets of ITP
autoantibodies. Indeed, in vitro studies demonstrated suppression of
megakaryocyte growth and maturation when the cells were incubated
with IgG from ITP patients.
In addition to the effect of autoantibodies, cytotoxic T cells from
ITP patients may have direct cytolytic effects on platelets. Some
patients with active ITP but without detectable platelet autoantibod-
ies had CD8+ T cells that induced platelet lysis in vitro. In contrast,
CD8+ T cells from patients in remission did not show significant
platelet reactivity. Furthermore, compared with cells from controls,
CD3+ cells from ITP patients exhibited increased expression of genes
involved in cell-mediated cytotoxicity including tumor necrosis
factor-α (TNF-α), perforin, and granzyme A and B, and CD8+ T
cells exhibited increased expression of FasL (Fas–Fas ligand) and
TNF-α.
In the broadest sense, autoimmunity develops because of a break-
down in regulatory checkpoints that occurs during development or
maturation of the immune system. Although the precise events that
trigger the loss of self-tolerance to platelet GPs are largely unknown,
patients with ITP have been shown to exhibit several immune altera-
tions to platelet antigens including dysfunctional cellular immunity
because of T-helper (Th)0/Th1 polarization, decreased regulatory
T-cell function, and autoreactive platelet-specific cytotoxic T cells. In
addition, ITP patients may have increased circulating levels of cyto-
kines and soluble factors that promote the survival of self-reactive T
and B cells, including B-cell activating factor, a proliferation-inducing
ligand, and B-cell lymphoma-2 interacting mediator of cell death.
Reduced levels of proapoptotic cytokines that regulate self-reactive
T-cells, including Fas, interferon-γ, interleukin-2 receptor β (IL2RB),
Bax, and caspases 8 and A20, have also been demonstrated.
Primary and Secondary Immune Thrombocytopenia
Primary ITP, which was previously known as idiopathic but is now
referred to as immune thrombocytopenia (Table 131.2) occurs for
unknown reasons. Secondary ITP is important to recognize because
treatment of the underlying cause is often necessary to increase the
platelet count. Examples are ITP occurring in the setting of infection,
pregnancy, drugs, or lymphoproliferative disease.
Infection may stimulate the formation of platelet reactive autoan-
tibodies. Cross-reactive antibodies (molecular mimicry) have been
described in Helicobacter pylori, human immunodeficiency virus
(HIV), and hepatitis C virus (HCV) infections. Molecular mimicry
between the highly antigenic H. pylori CagA protein and platelet
antigens is the suspected mechanism of H. pylori–associated ITP. In
most patients, H. pylori can be successfully eradicated with a 1–2
week course of clarithromycin (500 mg twice daily), amoxicillin
(1000 mg twice daily), and a proton pump inhibitor (e.g., pantopra-
zole 40 mg twice daily); however, the effect of H. pylori eradication
on the platelet count is variable. In a metaanalysis that included 788
patients, H. pylori eradication resulted in platelet counts that were 34
× 109/L higher than those in untreated control participants and 52
× 109/L higher than those in treated patients whose H. pylori was not
eradicated. Another systematic review evaluating 696 patients
reported that 42.7% of treated patients achieved platelet counts above
100 × 109/L; however, the effect was highly dependent on geographic
location with the beneficial effect mainly observed in patients from
Japan. Evidence-based guidelines for the investigation and manage-
ment of ITP recommend against routine screening for H. pylori in
patients presenting with ITP because of the low yield of testing and
the low likelihood of a platelet count increase with H. pylori
 1946 Part XII Hemostasis and Thrombosis

Standardized Terminology and Definitions for Immune

TABLE Thrombocytopenia Proposed by the International
131.2 Working Group (Vicenza Consensus Conference)
in 2009
Terminology Definition
ITP Immune thrombocytopenia (rather than
idiopathic or immune
thrombocytopenic purpura)
Platelet threshold for ITP <100 × 109/L
diagnosis
Primary ITP ITP with no associated cause (diagnosis
of exclusion)
Secondary ITP ITP in the setting of an underlying
cause such as drugs, HIV, or SLE
Newly diagnosed ITP Designation for patients at diagnosis
(rather than “acute” ITP).
Persistent ITP Sustained or recurrent thrombocytopenia
lasting 3–12 months
Chronic ITP Thrombocytopenia lasting >12 months
Complete response Achievement of a platelet count of
≥100 × 109/L in the absence of
bleeding
Response Achievement of a platelet count of
≥30 × 109/L and at least a twofold
increase from baseline in the absence
of bleeding
Refractory ITP Failure to achieve a response or relapse
after splenectomya and requirement
for treatment(s) to minimize the risk
of clinically significant bleeding
a
Splenectomy failure may not be applicable in children.
HIV, Human immunodeficiency virus; ITP, immune thrombocytopenia;
SLE, systemic lupus erythematosus.
eradication. Testing may be warranted in countries where H. pylori
infection is endemic, particularly those where the response rates to
eradiation therapy are high.
ITP also may present for the first time or relapse in pregnancy.
Although mild ITP may be difficult to differentiate from incidental
thrombocytopenia of pregnancy, pregnancy-related vascular disorders
must be excluded.6 Incidental thrombocytopenia of pregnancy (also
called gestational thrombocytopenia) represents a physiologic change in
platelet count. Pregnancy-related vascular disorders include pre-
eclampsia, microangiopathy caused by HELLP syndrome (character-
ized by hemolysis, elevated liver enzymes, and a low platelet count),
and acute fatty liver. Platelet counts tend to be mildly reduced and
hypertension is common.
Pregnancy-associated ITP may present early in pregnancy and
thrombocytopenia can be severe. Typically, platelet counts increase
after ITP-specific therapies such as IVIg or corticosteroids. In con-
trast, incidental thrombocytopenia of pregnancy, which occurs late
in pregnancy, is associated with a mild reduction in platelet count
and does not respond to immune-modulating therapy. Platelet count
thresholds for instituting treatment are the same as those for women
with ITP who are not pregnant. In the absence of bleeding, treatment
should be considered when the platelet count decreases to less than
20 × 109/L. Vaginal deliveries are thought to be safe for mothers with
ITP, even if the platelet count is very low, and most clinicians try to
maintain the count above 20–30 × 109/L. Epidural anesthesia is not
recommended with platelet counts below 70–80 × 109/L; however,
this practice is operator driven and based on little evidence. IVIg and
corticosteroids are generally safe in pregnancy, but corticosteroids can
be associated with hypertension, gestational diabetes, intrauterine
growth restriction, and other pregnancy-associated morbidities.
Splenectomy is rarely performed during pregnancy because most
women can successfully be managed with less aggressive treatments.
Immunosuppressant medications, such as azathioprine, have been
used in pregnancy but should be reserved for refractory pregnancy-
associated ITP with bleeding. There is a risk of severe thrombocyto-
penia in the newborn because of passive transfer of maternal
antiplatelet autoantibodies. This can occur in 10% of newborns.
Clinical and Laboratory Features
Thrombocytopenia
Thrombocytopenia is the defining feature of ITP. The international
working group on standardization of terminology in ITP established
a platelet count below 100 × 109/L as the cutoff for the diagnosis (see
Table 131.2).3 The rationale behind this threshold was that patients
with mild thrombocytopenia (100–150 × 109/L) have a low risk
(approximately 7%) of developing persistent thrombocytopenia
(platelets less than 100 × 109/L); platelet counts slightly below 150
× 109/L may be normal for certain ethnic groups; and mild throm-
bocytopenia may be caused by physiologic processes, such as preg-
nancy. Nonetheless, primary ITP remains a diagnosis of exclusion,
and as such, investigations are directed towards ruling out nonim-
mune causes, including pseudothrombocytopenia, myelodysplastic
syndromes, thrombotic microangiopathies, splenomegaly, or heredi-
tary thrombocytopenia; and secondary immune causes such as
infection, concomitant autoimmune disease, or lymphoproliferative
disorders.
Clinical Outcomes: Mortality, Bleeding and
Quality of Life
Patients with ITP most commonly present with asymptomatic
thrombocytopenia. Although some patients bleed with platelet
counts less than 30 × 109/L, many do not. Bleeding symptoms
characteristic of ITP (“platelet-type bleeding”) include skin bleeding
(i.e., bruises, nonpalpable purpura, or petechiae), oral hemorrhagic
blood blisters or oral petechiae, epistaxis, menorrhagia, or gastro-
intestinal bleeding. The most severe complication is intracerebral
hemorrhage (ICH).
In a systematic review of prospective studies, the incidence of ICH
was 1.4% for adults (95% confidence interval [CI], 0.9–2.1) and
0.4% for children (95% CI, 0.2–0.7).7 The proportion of patients
with severe (non-ICH) bleeding was 9.6% for adults (95% CI,
4.1–17.1) and 20.2% for children (95% CI, 10.0–32.9). Risk factors
for severe bleeding include severe thrombocytopenia, previous bleed-
ing, and older age.
Chronic ITP has been associated with a risk of death that is up
to four times higher than that in the general population. ITP patients
are more likely to die of bleeding, infection, and hematologic malig-
nancies. Some deaths are attributable to adverse effects of treatment
rather than the disease. Quality of life is affected, at least in part,
because of the prevalence of fatigue that appears to be independent
of platelet count levels.
Investigations of Patients With Suspected Immune
Thrombocytopenia
Patients presenting with newly identified thrombocytopenia require
a careful history and physical examination to uncover the underlying
cause of the thrombocytopenia and to assess the risk of bleeding. A
complete blood count and review of the blood film is required (Fig.
131.1). HIV and HCV testing should be performed in any patient
suspected of having ITP. There are insufficient data to support routine
screening for antinuclear antibodies or antiphospholipid antibodies
unless other signs and symptoms of systemic lupus erythematosus or
antiphospholipid syndrome are present. BM aspiration and biopsy
should be reserved for patients with abnormalities affecting other cell
 Chapter 131 Diseases of Platelet Number 1947

A B

C D
Fig. 131.1 BLOOD FILM EXAMINATIONS FROM PATIENTS WITH THROMBOCYTOPENIA.
(A) Pseudothrombocytopenia showing marked platelet clumping. (B) Schistocytes (fragmented red blood cells)
and reticulocytosis in a patient with thrombotic thrombocytopenic purpura. (C) Macrothrombocyte (left panel)
and neutrophil-containing cytoplasmic inclusions (Döhle bodies, right panel) in a patient with May-Hegglin
anomaly. (D) A patient with immune thrombocytopenia with low platelets and postsplenectomy Howell-Jolly
bodies (arrows).

lines such as anemia, leukopenia, or macrocytosis. Most patients with

typical ITP do not require BM examination. Quantitative Ig levels
may be useful in children to exclude common variable immune
deficiency and thyroid testing can uncover subclinical hypothyroid-
ism if surgery is planned.

First-Line Therapy
Corticosteroids with or without IVIg are first-line treatments for
patients with newly diagnosed ITP. Second-line therapies include
rituximab, splenectomy, TPO receptor agonists, or immunosuppres-
sant medications. ASH guidelines for the management of ITP were
developed using GRADE methodology to assess the level of evidence
associated with each recommendation.4 Aligned with these guidelines,
the authors recommend a treatment approach starting with those that Fig. 131.2 STAIRCASE MODEL OF IMMUNE THROMBOCYTOPE-
are least toxic (Fig. 131.2). NIA TREATMENT. Therapies build on each other, often cumulatively, in a
stepwise fashion starting from the least toxic. After a period of observation,
corticosteroid-based treatment is the accepted first-line therapy. Splenectomy,
Observation rituximab, and thrombopoietin receptor agonists may be reasonable second-
line therapies. Rituximab is not currently licensed for immune thrombocy-
One of the ASH 2014 Choosing Wisely recommendations is that topenia. Thrombopoietin (TPO) receptor agonists are indicated for immune
patients with ITP should not be treated unless they are bleeding or thrombocytopenia (IVIg) patients who have failed to respond to other thera-
have very low platelet counts.8 Most patients with platelet counts pies, including splenectomy. (Modified with permission from Arnold DM, Kelton
above 30 x 109/L and no bleeding can be managed safely with JG: Current options for the treatment of idiopathic thrombocytopenic purpura. Semin
observation alone. This is especially true for children with ITP who Hematol 44:S12, 2007.)
are at low risk of serious bleeding. Furthermore, in up to 80% of
cases, childhood ITP resolves within 6 months with no treatment. If
 1948 Part XII Hemostasis and Thrombosis
First-Line Therapy
An 8-year-old girl is brought to the emergency department because
her mother noticed bruising on her legs. She has had a sore throat
and fever for the past 7 days but is otherwise well and not taking any
medications. On physical examination, there are a few small bruises
on her legs but no petechiae on her skin or purpura in her mouth.
Neurologic examination findings are normal, and the spleen is not
palpable. The platelet count is 23 × 109/L. The presumed diagnosis is
ITP without significant bleeding; thus the decision is made to observe
the child in the hospital with no specific treatment. The next day, the
platelet count is 33 × 109/L. On day 2, it is 37 × 109/L, and the child
is discharged home. One week later, the platelet count is 66 × 109/L,
and 1 month later, it is up to 155 × 109/L.
patients present with bleeding, such as epistaxis or mucosal hemor-
rhage, treatment is required. For adults, a period of observation may
be reasonable if there is no evidence of bleeding and the platelet count
is above 20 × 109/L; however, most adults will require treatment
because spontaneous remissions are rare. To reflect current practice,
the ASH 2011 guidelines recommend using a platelet count below
30 × 109/L as the threshold for starting treatment.
Corticosteroids
The conventional starting dose of prednisone is 1–2 mg per kg for
2–4 weeks followed by tapering over a several week period once the
platelet count improves. In general, 60% to 70% of adults with acute
ITP achieve an initial response with corticosteroids. Sustained platelet
count responses (platelet count >100 × 109/L at 6 months) with
corticosteroids are infrequent in practice, but have been reported to
be as high as 47% in some studies. The risk of relapse increases with
longer duration of follow up. Low-dose prednisone (0.5 mg/kg per
day followed by a taper) may be as effective as the conventional dose
for initial ITP treatment, but long-term remissions are rare. The
optimal duration of prednisone treatment and the optimal tapering
schedule have yet to be established.
High-dose dexamethasone, typically administered at a dose of
40 mg/day for 4 consecutive days, is also effective. In one study that
included 125 adults with ITP, approximately 40% of patients had a
sustained response that lasted 2–5 years.9 Repeated cycles of high-
dose dexamethasone (once per month for 6 months) may result in
even higher rates of durable remissions, although this effect may
simply reflect the total corticosteroid exposure. High-dose dexa-
methasone is associated with side effects that may limit the use of
this treatment including hypertension, muscle weakness, insomnia,
and impaired cognition. In a systematic review of randomized trials
comparing high dose dexamethasone and prednisone in adults with
previously untreated ITP (n = 533), treatment with dexamethasone
resulted in improved overall (79% vs. 59%; P = .048) and complete
platelet count response (64% vs. 36%; P = .040) without excess
toxicity.9a Sustained responses at 6 months were not different between
groups, but platelet count responses occurred more rapidly with high
dose dexamethasone.
Intravenous Immunoglobulin and Anti-D
The predominant mechanism of action of high-dose IVIg and anti-D
is thought to be via RES blockade. Individuals with low plasma IgG
levels exhibit more rapid clearance of sensitized red blood cells (RBCs)
(indicating enhanced RES capacity) than those with high levels of
plasma IgG, such as those achieved with high-dose IVIg. A competitive
model of RES clearance would also explain why anti-D administration
to Rhesus (Rh)-positive individuals is effective in improving platelet
counts in patients with ITP. Thus IgG-sensitized RBCs compete
for Fc receptor occupancy. Other potential mechanisms of action
of IVIg or anti-D include antiidiotypic antibodies, stimulation of
proinflammatory and antiinflammatory cytokines, upregulation or
downregulation of various Fc receptors, and the induction of soluble
immune complexes. In a mouse model of ITP, transfer of IVIg-primed
dendritic cells recapitulated the effect of IVIg.
Based on the results of a metaanalysis of randomized controlled
trials that included 410 children, the probability of achieving a
platelet count above 20 × 109/L at 48 hours was higher with IVIg
than corticosteroids (relative risk for corticosteroids, 0.74; 95% CI,
0.65–0.85).10 Similar results have been observed in adults. Common
side effects of IVIg include headache, hypertension, and chills.
Hemolysis, thrombosis, renal impairment, and neutropenia are rare
complications.
Anti-D (50–75 IU/kg) and IVIg have similar efficacy in children.
Hemolysis is expected with anti-D administration, and rarely, intra-
vascular hemolysis can be severe or even fatal. Consequently, the
United States Food and Drug Administration has issued a black box
warning about the use of anti-D for the treatment of ITP, and the
drug has been removed from certain European markets. In general,
the use of anti-D is restricted to nonsplenectomized patients who are
Rh-positive and have a negative direct antiglobulin test.
Second-Line Therapy
Splenectomy
Splenectomy was first proposed as a treatment for ITP in 1913
and was subsequently shown to be an effective means of rapidly
increasing the platelet count in most ITP patients. In a systematic
review, approximately two-thirds of patients achieved a platelet count
response after splenectomy, usually within days.11 Despite the high
success rate with splenectomy, patients (and physicians) are often
reluctant to undertake an invasive procedure such as splenectomy,
when pharmacologic alternatives are available. Only younger age
has been identified as a predictor of splenectomy success, although
some investigators have found a correlation between prior response
to IVIg and a splenic pattern on radiolabeled platelet sequestration
studies.
With currently available minimally invasive surgical techniques,
complications after splenectomy are uncommon. The overall mortal-
ity rate is approximately 1% with open surgery and about 0.2% after
laparoscopic splenectomy. The most frequent perioperative complica-
tions include pneumonia, subphrenic abscess or pleural effusion
(4%), major bleeding (1.5%), and thromboembolism (1%). With
laparoscopic techniques, patients have less postoperative pain, shorter
hospital stays, and fewer wound complications.
Because the spleen is involved in clearance of encapsulated bacte-
ria, asplenic individuals are at risk for infection with Streptococcus
pneumoniae, Neisseria meningitides, and Haemophilus influenzae type
b. Therefore all patients undergoing splenectomy should receive
vaccinations against these bacteria at least 2 weeks before surgery.
Poor compliance and vaccine failures contribute to the ongoing risk
of serious postsplenectomy infections. The lifetime risk of over-
whelming postsplenectomy infection is estimated to be 1% to 3%
with the risk being higher in children younger than 15 years of age
and in patients with hematologic malignancies. Although the risk of
an infection requiring hospitalization was highest in the first 90 days
after splenectomy in a cohort of 3812 splenectomized patients in
Denmark, this risk remained 2.5 times higher than that in the general
population even after 90 days.
The ITP International Working Group and the revised ASH
guidelines consider splenectomy an acceptable second-line therapy
for ITP. However, the former group considers splenectomy equal to
other medical options, whereas the ASH guidelines favor splenectomy
(grade 1B evidence) over rituximab or TPO receptor agonists (grade
2C evidence). Splenectomy leads to a high rate of durable remission.
In a systematic review, 1731 (66%) of 2623 adults with ITP achieved
a complete response following splenectomy at a median follow up of
28 months (range 1–153 months) and this response rate was main-
tained for 10 years or more after splenectomy.

Disadvantages of splenectomy include a lack of validated
predictors of response, surgical risk with 30-day mortality, and
complication rates of 0.2% and 9.6% for laparoscopic splenectomy,
respectively, and 1.0% and 12.9% for open splenectomy, respectively,
and an increased risk of postsplenectomy infection, and vascular
thrombosis.
Rituximab
Rituximab has been widely used in patients with various autoimmune
diseases, including ITP. Rituximab is an anti-CD20 monoclonal
antibody that targets and destroys CD20+ B lymphocytes, some of
which are likely involved in autoantibody production. Data correlat-
ing cellular profiles with clinical outcomes suggest that the efficacy
of rituximab reflects improvement in T-cell function and reversion of
T-cell abnormalities; processes downstream to its direct effect on
B-cell depletion. The effects of rituximab on platelets and autoanti-
bodies require further investigations.
In a systematic review of 19 observational studies that enrolled
313 ITP patients of whom 46.2% were not splenectomized, rates of
complete response (platelet count >150 × 109/L) and overall response
(platelet count >50 × 109/L) with rituximab after a median follow
up of 9.5 months were 43.6% (95% CI, 29.5–57.7) and 62.5% (95%
CI, 52.6–72.5), respectively.12 The typical rituximab regimen was
375 mg/m2 administered by intravenous infusion once weekly for 4
consecutive weeks. The median time to response was 5.5 weeks, and
responses lasted a median of 10.5 months. Other observational
studies have reported lower rates of durable remission, ranging from
24% at 12 months to 35% at 57 months. A metaanalysis of five
randomized trials demonstrated that complete platelet count response
was more frequent with rituximab plus standard of care than with
standard of care alone (relative risk 1.4, 95% CI, 1.1–1.8); however,
there was limited evidence for sustained platelet count responses
beyond 6–12 months.13
In a prospective observational study that included 60 nonsplenec-
tomized adult patients with ITP who had a median of two prior
therapies, 24 (40%) achieved a platelet count above 50 × 109/L and
at least twice their baseline value at 1 year, and 20 (33%) maintained
their platelet count response at 2 years with rituximab treatment. In
a follow-up study of 72 adults and 66 children with chronic ITP who
achieved an initial response to rituximab, 21% to 26% maintained a
treatment-free response for at least 5 years.14 Low-dose rituximab
(100 mg per week for 4 weeks) has been shown to be effective in ITP,
but the frequency of durable responses is uncertain.
Minor infusion-related side effects of rituximab occur in approxi-
mately 30% of patients with ITP and include hypotension, rash, sore
throat, fever, and rigors. Severe or fatal infusion reactions are rare in
patients treated for autoimmune diseases. Serum sickness, which is
characterized by arthropathy, fever, and low serum complement
levels, may be more common in children than in adults and often
necessitates treatment interruption. Progressive multifocal leukoen-
cephalopathy (PML) is a rapidly fatal neurologic syndrome caused
by reactivation of latent JC virus in the brain. Rare reports have
linked PML with rituximab treatment.
Rituximab also interferes with the response to polysaccharide
vaccines. This is of potential concern in patients who may subse-
quently undergo splenectomy and supports the practice of adminis-
tering immunizations before initiating rituximab therapy.
The 2011 ASH treatment guidelines gave rituximab a weak (grade
2C) recommendation for patients who have failed corticosteroids,
IVIg, or splenectomy.
Thrombopoietin Receptor Agonists
Drugs aimed at increasing platelet production by stimulating the
c-Mpl receptor have been investigated for the treatment of thrombo-
cytopenia. Initial studies with pegylated recombinant human mega-
karyocyte growth and development factor were halted because of the
Chapter 131 Diseases of Platelet Number 1949
development of cross-reactive antibodies against endogenous TPO,
which led to severe and sustained thrombocytopenia in some healthy
volunteers. These findings prompted the development of second-
generation TPO receptor agonists that have no homology to endog-
enous TPO. Two such drugs are now approved for the treatment of
patients with chronic ITP, romiplostim (Nplate, Amgen) and eltrom-
bopag (Promacta/Revolade, GlaxoSmithKline). These agents increase
the platelet count in most ITP patients including those with refrac-
tory disease. The effect on platelet count is generally sustained as long
as the TPO receptor agonists are administered; when they are stopped,
platelet counts tend to fall rapidly to baseline levels.
Romiplostim (administered as a once-weekly subcutaneous injec-
tion) is a synthetic peptibody consisting of four peptides linked to an
IgG Fc fragment. The molecule binds the c-Mpl receptor at the same
location as endogenous TPO and stimulates megakaryocyte prolifera-
tion and platelet production through intracellular JAK/STAT and
mitogen-activated protein kinase signaling. In a phase III trial, a
durable platelet count response (defined as the achievement of a
platelet count of 50 × 109/L or higher for 6 or more of the last 8
weeks of treatment) was achieved in 41 of 83 patients (49.4%)
receiving romiplostim compared with 1 of 42 (2.4%) patients receiv-
ing a placebo.15 In a subsequent randomized trial that compared
romiplostim plus standard of care with standard of care alone,
romiplostim was associated with more platelet count responses, fewer
treatment failures, fewer splenectomies, less bleeding, and better
quality of life.2 Weekly doses of romiplostim ranged between 1 and
10 μg/kg; however, most patients achieved a suitable response with
a dose of 3 μg/kg. Weekly doses were titrated up or down to maintain
the platelet count in the appropriate range (30–100 × 109/L).
Eltrombopag (administered as an oral daily tablet, 50–75 mg
daily) is a small molecule, nonpeptide TPO receptor agonist. Eltrom-
bopag also activates the c-Mpl receptor, but unlike romiplostim,
eltrombopag binds to the transmembrane domain of the receptor and
does not compete with circulating TPO for binding. In a phase III
trial, eltrombopag was associated with an eightfold increase in platelet
count response compared with placebo throughout the 6-month
treatment period.16 The time to response was 1–2 weeks (similar to
romiplostim) and there was minimal need for dose titration. Durable
responses were achieved in 57 of 95 patients (60%) receiving main-
tenance eltrombopag and in only 4 of 39 patients (10%) receiving
placebo.
In a recent systematic review that summarized the data from
randomized trials comparing TPO receptor agonists with standard of
care in ITP patients, the authors concluded that although romiplos-
tim and eltrombopag increased the platelet count response, neither
agent significantly lowered the rate of severe, life-threatening, or fatal
bleeding. These findings highlight the need for studies that evaluate
patient focused outcomes.
TPO receptor agonists are generally well tolerated but have been
associated with headache, fatigue, and insomnia. The development
of BM reticulin in patients with ITP was an early concern; however,
this problem was rarely encountered in prospective studies and the
changes improved with discontinuation of the medication. TPO
receptor agonists have also been associated with thromboembolic
events (independent of platelet count), although the strength of this
association remains uncertain. One study of eltrombopag in patients
with advanced liver disease was ended early because of an increase in
portal vein thrombosis. Eltrombopag has been associated with serum
liver function test abnormalities in approximately 10% of patients.
Treatment-related serious adverse events were infrequent even after
prolonged exposure to romiplostim (n = 292) or eltrombopag (n =
299). Thromboembolic events occurred in 6.5% of patients on
romiplostim and 4% of patients on eltrombopag.
Long-Term Follow-Up
The best treatment for patients with ITP who fail to respond to
first-line therapy remains controversial and depends on the severity
of symptoms, side effect profile, and patient preference. Splenectomy
has been used for many years and is the treatment option most likely
to be associated with durable remissions. Rituximab may achieve a
 1950 Part XII Hemostasis and Thrombosis
platelet count response in up to 60% of patients, but responses are
rarely sustained past 6–12 months. TPO receptor agonists (romip-
lostim or eltrombopag) are associated with a platelet count response
in up to 60% of patients as long as treatment is maintained. These
drugs are generally well tolerated; however, long-term safety data
beyond 5 years are not yet available and long-term maintenance
therapy is expensive since either agent costs approximately $3,000
per month.
Treatment of Refractory Immune Thrombocytopenia
As suggested by the International Working Group on standardization
of terminology in ITP, the term refractory ITP is used to define
patients who have failed splenectomy or relapsed thereafter and either
exhibit severe thrombocytopenia or have a risk of bleeding that neces-
sitates therapy (see Table 131.2).3
Evidence to help guide management of patients with chronic
refractory ITP after splenectomy is limited, and treatment has been
mainly unsatisfactory. However, TPO receptor agonists provide a
new and effective option for this challenging group of patients. The
overarching principle of therapy for this population is to prevent
bleeding with the achievement of a stable, although not necessarily
normal, platelet count, and that combination therapy may be more
effective than single agent treatment for achievement of this goal.
In randomized trials, nonsplenectomized patients with ITP tended
to show better platelet count responses to TPO receptor agonists
than splenectomized patients; however, the difference was small, and
response rates in splenectomized patients approached 50%. Although
some patients included in the trials had failed up to five prior thera-
pies, the results may not be applicable to all patients with refractory
ITP seen in clinical practice.
Before the availability of TPO receptor agonists, a systematic review
identified rituximab, azathioprine, and cyclophosphamide as the agents
most often associated with complete responses in patients with refrac-
tory ITP. Good response rates have also been reported with a combina-
tion of cyclosporine, azathioprine, and mycophenolate (CellCept).
Similarly, a combination of IVIg, intravenous methylprednisolone,
vincristine, or intravenous anti-D followed by maintenance therapy
with danazol and azathioprine have shown good response rates. Other
treatment options include low-dose or alternate-day corticosteroids,
repeated doses of IVIg, high-dose chemotherapy, or dapsone. High-
dose chemotherapy followed by stem cell transplantation has also been
used successfully in this population, but with the advent of TPO
receptor agonists, transplantation is no longer used.
NEONATAL ALLOIMMUNE THROMBOCYTOPENIA
NAIT is an uncommon but serious thrombocytopenic disorder that
can cause fetal or neonatal bleeding resulting in death or disability.
It is important to recognize this disorder because treatment may
prevent recurrence in subsequent pregnancies. With NAIT, intra-
cranial bleeding can occur during the neonatal period or in utero, in
which case the diagnosis is first suspected after abnormal fetal ultra-
sonography. The incidence of NAIT has been estimated to range
from 1 : 1000–1 : 5000 births; however, it is often underdiagnosed.
Clinical Presentation
Thrombocytopenia may be severe in infants affected by NAIT and
often the platelet count is less than 10–20 × 109/L shortly after birth.
The differential diagnosis is broad and includes septicemia, hypoxia,
and birth trauma, among other factors (Table 131.3). Typically,
NAIT presents as severe thrombocytopenia, possibly with associated
bleeding, in an otherwise healthy neonate with no other explanation
for the low platelet count. The thrombocytopenia often worsens
hours or days after delivery, likely reflecting increased RES function
in the newborn, particularly within the lungs. Without treatment,
TABLE Differential Diagnosis of Thrombocytopenia in
131.3 Newborns
Perinatal Hypoxemia
Placental Insufficiency
Congenital Infection
Sepsis
Toxoplasmosis
Rubella
Cytomegalovirus
Autoimmune
Maternal immune thrombocytopenia
Maternal systemic lupus erythematosus
Disseminated Intravascular Coagulation
Maternal Drug Exposure
Congenital Heart Disease
Hereditary Thrombocytopenia
MYH9 macrothrombocytopenia (including May-Hegglin anomaly)
Thrombocytopenia absent radii syndrome
Amegakaryocytic thrombocytopenia
Wiskott-Aldrich syndrome
Fanconi anemia
Hemangioma with Thrombocytopenia
Kasabach-Merritt syndrome
Bone marrow Infiltration
Congenital leukemia
thrombocytopenia may last for days, but occasionally, it can be severe
and can persist for many weeks. Bleeding symptoms range from
petechiae and bruising to gastrointestinal or intracranial hemorrhage.
Bleeding occurs in up to 20% of neonates with NAIT and can occur
early in pregnancy. For infants with severe thrombocytopenia, mor-
tality estimates of 10% have been reported and infants with intra-
cranial bleeding may be left with developmental delays and permanent
neurologic deficits.
Pathophysiology
Fetal and neonatal thrombocytopenia in NAIT reflects the clearance
of IgG-sensitized fetal platelets by maternal alloantibodies directed
against fetal/paternal platelet-specific antigens. The syndrome can be
considered analogous to the destruction of fetal RBCs in hemolytic
disease of the newborn (HDN) but with several differences. Perhaps
most importantly, NAIT often presents in a first pregnancy, possibly
because of early maternal sensitization to paternally derived antigens
expressed on fetal platelets. In contrast, it is uncommon for HDN to
occur in a first pregnancy without previous sensitization to the Rh
antigen. This difference suggests that unlike RBCs, transplacental
passage of fetal platelets or platelet antigens into the maternal circula-
tion occurs early in pregnancy. Another difference is that pregnant
women at risk for HDN (e.g., those who are Rh negative) can be
identified early by screening and treatment with anti-Rh immune
globulin reduces the risk of sensitization. To date, screening programs
for NAIT have not been widely implemented because women at risk
are not readily identifiable before sensitization has occurred, and
therapies to prevent maternal alloimmunization are not currently
available. Screening programs for NAIT continue to be an active area
of research (see box on Neonatal Alloimmune Thrombocytopenia
Versus Hemolytic Disease of the Newborn).
Laboratory Investigation of Suspected Neonatal
Alloimmune Thrombocytopenia
The diagnosis of NAIT is established by documenting the presence
of platelet-specific antigen incompatibility between mother and infant
(or mother and father) and the presence of maternal antiplatelet allo-
antibodies directed against the incompatible antigen (Fig. 131.3).17
 Chapter 131 Diseases of Platelet Number 1951

Diagnosis of Neonatal Alloimmune Thrombocytopenia (NAIT)

Testing for Human Platelet Antigens (HPA) and Antibodies

Exclude other causes Request samples from

Affected Neonate
of thrombocyotpenia mother and father for
laboratory investigation
(platelets <100x109/L)
Suspect NAIT of NAIT

Plasma / Serum
Platelets
Leucocytes-DNA

Maternal Phenotyping and

antiplatelet target for maternal Genotyping
antibody antibody testing

Incompatible for
Incompatible for Incompatible for Compatible for
HPA antigen
HPA antigen HPA-1a antigen HPA antigens
other than HPA-1a
and and and
and
antibody present antibody absent antibody absent
antibody absent

NAIT confirmed NAIT probable NAIT possible NAIT unlikely

Assess risk of NAIT in future children

by amniocyte genotyping
when the father is heterozygous

As currently practised at the McMaster University Platelet Immunology Reference Laboratory 2017
Fig. 131.3 DIAGNOSTIC TESTING ALGORITHM FOR INVESTIGATION OF NEONATAL ALLO-
IMMUNE THROMBOCYTOPENIA AND MANAGEMENT RECOMMENDATIONS BASED ON
RESULTS OF TESTING. This algorithm is currently used by the McMaster University Platelet Immunology
Reference Laboratory, 2017. Maternal blood samples are tested for platelet antigens (phenotyping and poly-
merase chain reaction genotyping) and platelet alloantibodies. Amniocentesis and fetal genotyping are recom-
mended when the father is known to be heterozygous for the incompatible antigen. HPA, Human platelet
antigen; NAIT, neonatal alloimmune thrombocytopenia. (Modified from Arnold DM, Smith JW, Kelton JG:
Diagnosis and management of neonatal alloimmune thrombocytopenia. Transfus Med Rev 22:255, 2008, with
permission.)

Neonatal Alloimmune Thrombocytopenia Versus Hemolytic Disease of
the Newborn
NAIT can be viewed as the platelet equivalent of HDN with some impor-
tant differences: (1) maternal sensitization by fetal platelet antigens can
occur early in the first trimester, (2) NAIT can affect first pregnancies,
(3) women at risk for NAIT are not easily identifiable before sensitization
and thus are not amenable to universal screening programs, and (4) a
specific therapy that targets prevention of platelet antigen sensitization
is lacking (e.g., Rh-immune globulin that target RBC antigen exposure).
Consequently, diagnosis requires allele-specific genotyping using
polymerase chain reaction technology to identify a maternal–fetal
(or maternal–paternal) antigenic mismatch. Serologic confirmation
for the complete array of maternal alloantibodies is more difficult
for two reasons. First, the technology is complex and relatively few
laboratories perform these tests. In general, most commercial assays
detect platelet alloantibodies directed against only a limited number
of antigens. This limitation necessitates the use of more specific
assays, such as monoclonal antibody immobilization of platelet
antigen assays or antigen capture assays.18 Even these tests are limited
by the lack of monoclonal antibodies required to capture the different
target proteins that express the alloantigens (e.g., human platelet
antigen (HPA)-15 on CD109). An alternative method uses radioim-
munoprecipitation, which can detect all of the known alloantibodies
described to date. Second, for unknown reasons, up to 25% of
HPA-1a–negative women with NAIT have no detectable antibodies
using currently available laboratory methods. Recent studies have
used surface plasmon resonance to identify alloantibodies in women
suspected of having NAIT, but who tested negative in conventional
immunoassays. Low affinity anti–HPA-1a antibodies were detected
in some, suggesting that standard immunoassays may be limited in
their capacity to detect such antibodies.19 Low-incidence platelet-
specific alloantigens expressed on platelets only from the paternal
lineage may account for fetomaternal incompatibility. Detection of
alloantibodies in these cases requires that maternal serum be tested
against paternal platelets whenever possible.
Alloantibodies recognize epitopes on platelet GPs that are defined
by genetic polymorphisms. To date, all of these antigens are the result
of single nucleotide polymorphisms or in-frame deletions of the
codon. Consequently, platelet typing using genetic analysis is
 1952 Part XII Hemostasis and Thrombosis
relatively straightforward. The majority of platelet alloantigens occur
on GPIIIa, which is the most abundant platelet GP (50,000–75,000
copies per platelet). GPIIIa, also known as β3, forms a heterodimer
with platelet GPIIb to form the integrin α2β3, which serves as the
binding site for fibrinogen and enables platelet aggregation.
The most common platelet alloantigen implicated in NAIT is
HPA-1a. This important alloantigen is defined by a leucine (HPA-
1a) to proline (HPA-1b) substitution at amino acid 33 on GPIIIa.
Maternal incompatibility to HPA-1a is implicated in more than 80%
of women with NAIT. These women lack the common HPA-1a
antigen (i.e., their genotype is HPA-1bb) and during pregnancy they
are immunized with fetal HPA-1a antigen inherited from the father.
The next most commonly implicated antigens in NAIT are HPA-
5a5b on GPIa/IIa and HPA-15a15b on the glycosylphosphatidylinosi-
tol–anchored protein, CD109. Only 6 of the 28 platelet antigen systems
have been defined by maternal alloantibodies against both alleles; these
include the HPA 1, 2, 3, 4, 5, and 15 systems. There are a number of
other low-frequency alleles, the majority of which are expressed on
platelet GPIIb/IIIa and are usually found within a single family.
Although maternal immunization to low-frequency antigens is impli-
cated in some cases of NAIT, these antigens account for a minority of
the NAIT cases that remain unresolved after investigation for common
HPA antigens.20 Frequently, discrepancies in human leukocyte antigen
(HLA) and ABO, which are also expressed on platelets, are found during
the course of investigations for NAIT; however, their significance is
uncertain. A database of genetically confirmed alloantigens is maintained
by the European Bioinformatics Institute (http://www.ebi.ac.uk).
Management
Management of Infants After Delivery
When NAIT is suspected and depending on the platelet count,
treatment should be initiated even before confirmatory test results are
available. It is important to appreciate that moderate or severe
thrombocytopenia at birth (20–50 × 109/L) can worsen over the next
few days. Treatment should be initiated immediately if thrombocy-
topenia is severe (platelets <50 × 109/L); if there are petechiae or
purpura; or if there is evidence of serious bleeding, such as intra-
cranial bleeding on cranial ultrasonography. The initial treatment is
platelet transfusion along with high-dose IVIg (1–2 g/kg).21 Ideally,
platelet products for transfusions should be alloantigen compatible;
however, if these are unavailable, random donor platelets can be used
because they often produce adequate increases in the platelet count.22
Antenatal Management of the Mother
Women with a previously affected infant with NAIT are at high risk
of having another affected infant. Consequently, careful management
in subsequent pregnancies is required. Similar to HDN, the disorder
is often more severe in subsequent pregnancies than it is in the first.
The exception is if the father is heterozygous for the implicated
platelet antigen, in which case antigenic testing can be performed by
amniocentesis to determine if the fetus is at risk and whether treat-
ment is required.
Antenatal treatment options for at-risk mothers during subsequent
pregnancies range from careful observation, to IVIg with or without
corticosteroids, to fetal blood sampling (FBS) and intrauterine
platelet transfusion. Invasive strategies that include FBS are associated
with a high rate of complications, including fetal death and premature
labor; thus a noninvasive approach is often recommended.
The mainstay of antenatal therapy for women with a previously
affected infant is high-dose IVIg (1–2 g/kg) administered weekly
throughout pregnancy starting at 18–22 weeks of gestation. A sys-
tematic review summarizing the results of four randomized trials that
included 206 women compared weekly IVIg with a variety of other
therapies, including alternate dosing of IVIg or IVIg plus corticoster-
oids.23 Although no definitive conclusions could be drawn, most
clinicians use IVIg for antenatal treatment. Corticosteroids (predni-
sone or dexamethasone) given in combination with IVIg should be
considered for mothers at high risk, such as those with a previously
affected infant with intracranial hemorrhage or severe thrombocyto-
penia or if the response to IVIg is suboptimal.
Fetal Monitoring During Pregnancy
Serial ultrasonography is indicated for fetal surveillance. This provides
a simple, noninvasive method for identifying fetal bleeds at an early
stage. FBS by percutaneous cannulation of the umbilical or intrahepatic
vein may be a way of capturing high-risk fetuses, identifying those who
require treatment, and monitoring response to therapy. However, FBS
is technically challenging and is associated with significant morbidity
and mortality. In one study, 6% of FBS procedures were associated
with complications, including fetal death from exsanguination and
premature induction of labor.24 Furthermore, a platelet transfusion
protocol based on the detection of fetal thrombocytopenia would
necessitate frequent FBS procedures because of the short (7-day) life
span of transfused platelets. Because the risks associated with FBS
exceed the benefits, routine FBS is not recommended.
Mode of Delivery
There is no evidence that planned cesarean section is safer than uncom-
plicated vaginal delivery for infants with NAIT. Nonetheless, planned
cesarean section delivery can ensure that personnel and resources,
including antigen-compatible platelet transfusions, are readily available.
Population Screening for Neonatal Alloimmune
Thrombocytopenia
Universal NAIT screening programs for all pregnant women are not
currently available because of the difficulty in early identification of
at-risk women and the lack of specific and proven treatments. Screen-
ing algorithms also have to account for the large difference in numbers
of women lacking an antigen and those who will later develop NAIT.
About 2% of women will be identified as HPA-1bb, whereas only 1
in 20 of these will have an affected child because of HPA-1a immu-
nization. One study screened 100,448 pregnant women and offered
those with HPA-1a antibodies early cesarean section together with
compatible platelet transfusions.25 This approach identified 161
affected infants, of whom three (6%) died or had an intracranial
bleed, compared with 10 of 51 infants (20%) born to mothers who
were not screened. These results are encouraging, and additional
studies of NAIT screening programs are ongoing.
POSTTRANSFUSION PURPURA
PTP is a rare thrombocytopenic syndrome that is provoked by an
immune-mediated reaction against HPAs, most frequently HPA-1a.
PTP presents 5–10 days following exposure to platelets or platelet
antigenic material in blood transfusions with profound thrombocy-
topenia and clinically significant bleeding.
Epidemiology
PTP is rare with an estimated incidence of 1–2 per 100,000 transfu-
sions. Data from the Serious Hazards of Transfusion surveillance
program from the United Kingdom have shown that the incidence
of PTP has decreased in the last decade (Fig. 131.4).26 Reasons for
this trend may be related to universal leukoreduction, which was
implemented in the United Kingdom in 1999. The average annual
incidences of PTP in the years preceding 1996–99 and following the
implementation of universal leukoreduction between 2000 and 2005

Fig. 131.4 CONFIRMED CASES OF POSTTRANSFUSION PURPURA REPORTED BY THE UK
SERIOUS HAZARDS OF TRANSFUSION (SHOT) SURVEILLANCE PROGRAM. Universal leukore-
duction began in the United Kingdom in late 1999 and coincided with a decrease in new cases of posttransfu-
sion purpura. (From www.shotuk.org.)
Clinical Presentation of Posttransfusion Purpura
On postoperative day 8 after spinal surgery, a 43-year-old woman has
a platelet count of 3 × 109/L. During the operation, she received 3
units of non–leuko-reduced packed RBCs because of intraoperative
bleeding. She is receiving intravenous ampicillin and prophylactic
doses of the low-molecular-weight heparin dalteparin. On physical
examination, she has extensive oral mucosal purpura and petechiae
on both lower extremities. HIT testing results (anti-PF4/heparin
enzyme-linked immunosorbent assay and serotonin release assay) are
negative. The ampicillin is stopped, and she is treated with IVIG (2 g/
kg) and platelet transfusions. Three days later, the platelet count is 4
× 109/L, and the patient develops melena. The presumed diagnosis
is posttransfusion purpura; therefore, HPA-1a–negative platelets
and high-dose parenteral corticosteroids are administered, and daily
plasma exchange is initiated. One week later, the thrombocytopenia
and bleeding symptoms resolve. Platelet antibody testing reveals the
presence of anti–HPA-1a antibodies.
were 10.3 and 2.3 cases per year, respectively. Since the implementa-
tion of universal leukoreduction, there has also been a shift from red
cell concentrates to platelet concentrates as the inciting transfusion
event, which may be attributable to the reduction in platelet con-
tamination of red cell products with leukoreduction methods. A
recent study estimated that the frequency of PTP corresponds to 1.8
per 100,000 transfusions.27 In this study, platelet containing transfu-
sions posed a significantly higher risk than RBC transfusions.
Approximately 85% of PTP episodes occur in women, the major-
ity of whom had a history of pregnancy. In a report of 61 patients,
the sensitizing event among women was pregnancy alone in 58%,
pregnancy and/or transfusion in 34%, and transfusion alone in 7.5%.
Males had associated transfusion histories in 55%, with some having
no known exposure. PTP has not been reported in children.
Clinical Presentation
PTP presents with severe thrombocytopenia (platelets <10 x 109/L) and
bleeding, which may include petechiae, purpura, mucosal hemorrhage,
hematuria, and rarely ICH. The thrombocytopenia is often refractory
to platelet transfusions even with antigen-negative platelets. Mortality
because of severe thrombocytopenia and bleeding has been estimated
to be 5% to 20%. The thrombocytopenia occurs 5–10 days after blood
transfusion and typically resolves within weeks, but occasionally can
be prolonged and severe and can persist for months. Other causes of
Chapter 131 Diseases of Platelet Number 1953
thrombocytopenia with similar clinical presentation include primary
ITP, drug-induced ITP, sepsis, disseminated intravascular coagulation,
and thrombotic thrombocytopenic purpura; however, association with
transfusion and bleeding severity suggest a diagnosis of PTP. Patients
with PTP may present with features that overlap with heparin-induced
thrombocytopenia (HIT), and positive HIT testing in the context of
anti–HPA antibodies has been reported; however, thrombocytopenia
is typically less severe with HIT and bleeding is rare.
Diagnosis
Most patients with PTP lack the common HPA-1a platelet antigen
and are homozygous for HPA-1b. These patients develop anti-HPA
1a antibodies from sensitizing events such as previous pregnancies or
transfusions. Anti–HPA 1a antibodies may persist for many years in
these patients. In addition, platelet antibodies with specificities other
than HPA-1a may also be found.28
Pathophysiology
Platelets contain abundant amounts of GPIIb/IIIa; thus even small
numbers of platelets or platelet microparticles contained within RBC
concentrates can be immunogenic and can lead to the development
of PTP. Genotypic analyses have shown that HLA-II alleles
DRβ3*0101 and DQβ1*0201 are commonly associated with this
disorder. This is similar to NAIT: the frequency of immunization
depends on platelet alloantigen discrepancy plus the presence of
certain immune response genes.
The most intriguing feature of PTP is that the patient’s own
antigen-compatible platelets are destroyed. Furthermore, platelet
reactive antibodies can be eluted from both antigen-positive and
antigen-negative platelets. Although the mechanism is still poorly
understood, theories to explain this “innocent bystander” phenom-
enon include immune complex formation, passive antigen adsorp-
tion, and autoantibody formation. As discussed later, some of these
mechanisms may be overlapping.
Immune complexes can form if the anti–HPA-1a antibodies bind
soluble antigen. Alternatively, platelet alloantigens contained within
the transfused blood product may be passively adsorbed onto autolo-
gous platelets, converting them from antigen negative to antigen
positive and rendering them targets for immune destruction. Immune
complexes may then bind to platelets through Fc-receptors causing
platelet destruction. Anti–HPA-1a antibodies have been shown to
 1954 Part XII Hemostasis and Thrombosis
induce platelet activation through release of platelet-derived RANTES
(regulated on activation, normal, T-cell expressed and secreted), a
proinflammatory and immunomodulatory chemokine involved in
multiple immunologic processes, including Ig synthesis and regula-
tion of Th1/Th2 cytokine homeostasis. In some patients with PTP,
the alloantibodies have been shown to interfere with cell-fibrinogen
interaction, thereby increasing the risk of bleeding.
The stimulation of specific anti–HPA alloantibodies could in turn
initiate the formation of platelet-reactive autoantibodies. Production
of pan-reactive antibodies has been shown to correspond with the
period of greatest thrombocytopenia and serologic analyses of PTP
cases demonstrated the presence of reactive IgG and IgM antibodies
against GPIIb/IIIa, GPIX, and GPIa/IIa; however, only HPA-specific
IgG antibodies persisted.29 The presence of autoantibodies can help
to explain the destruction of both donor and recipient platelets.
Management
Treatment of PTP should be initiated even before serologic test results
for anti–HPA-antigens are available. The primary goal of treatment
is to abbreviate the period of severe thrombocytopenia and minimize
the risk of bleeding. Multiple treatments are often administered
simultaneously or in rapid succession because of the desperate nature
of the disorder when it is severe.
Patients with PTP require admission to hospital for close obser-
vation, supportive treatments, and rapid management of bleeding
symptoms should they occur. Nonessential transfusions should be
discontinued. The mainstay of therapy is high dose IVIg, which is
followed by a platelet count increase after 3–4 days.30 High-dose
corticosteroids have also been tried as a means of inhibiting RES
phagocytosis and reducing IgG synthesis. Patients with bleeding
should be transfused with HPA-compatible platelets. While awaiting
the results of antigen typing, HPA-1a–negative platelet transfusions
can be administered to reduce further antibody production. Patients
with PTP may be at increased risk of transfusion reactions such as
fever, dyspnea, and allergic reactions. Plasma exchange should be con-
sidered in patients who do not respond to IVIg and corticosteroids.
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counts and bleeding during treatment of chronic idiopathic thrombocy-
topenic purpura: a randomised, double-blind, placebo-controlled trial.
Lancet 373:641, 2009.
2. Kuter DJ, Rummel M, Boccia R, et al: Romiplostim or standard
of care in patients with immune thrombocytopenia. N Engl J Med
363(20):1889–1899, 2010.
3. Rodeghiero F, Stasi R, Gernsheimer T, et al: Standardization of termi-
nology, definitions and outcome criteria in immune thrombocytopenic
purpura of adults and children: report from an international working
group. Blood 113(11):2386–2393, 2009.
4. Neunert C, Lim W, Crowther M, et al: The American Society of
Hematology 2011 evidence-based practice guideline for immune
thrombocytopenia. Blood 117(16):4190–4207, 2011.
5. Harrington WJ, Minnich V, Hollingsworth JW, et al: Demonstration of
a thrombocytopenic factor in the blood of patients with thrombocyto-
penic purpura. J Lab Clin Med 38(1):1–10, 1951.
6. Burrows RF, Kelton JG: Fetal thrombocytopenia and its relation to
maternal thrombocytopenia. N Engl J Med 329(20):1463–1466, 1993.
7. Neunert C, Noroozi N, Norman G, et al: Severe bleeding events in
adults and children with primary immune thrombocytopenia: a system-
atic review. J Thromb Haemost 13(3):457–464, 2015.
8. Hicks LK, Bering H, Carson KR, et al: Five hematologic tests and
treatments to question. Hematology Am Soc Hematol Educ Program
2014(1):599–603, 2014.
9. Cheng Y, Wong RS, Soo YO, et al: Initial treatment of immune throm-
bocytopenic purpura with high-dose dexamethasone. N Engl J Med
349(9):831–836, 2003.
9a. Mithoowani S, Gregory-Miller K, Goy J, et al: High-dose dexa-
methasone compared with prednisone for previously untreated primary
immune thrombocytopenia: a systematic review and meta-analysis.
Lancet Haematol 3(10):e489–e496, 2016.
10. Beck CE, Nathan PC, Parkin PC, et al: Corticosteroids versus intravenous
immune globulin for the treatment of acute immune thrombocytopenic
purpura in children: a systematic review and meta-analysis of randomized
controlled trials. J Pediatr 147(4):521–527, 2005.
11. Kojouri K, Vesely SK, Terrell DR, et al: Splenectomy for adult patients
with idiopathic thrombocytopenic purpura: a systematic review to assess
long-term platelet count responses, prediction of response, and surgical
complications. Blood 104(9):2623–2634, 2004.
12. Arnold DM, Dentali F, Crowther MA, et al: Systematic review: efficacy
and safety of rituximab for adults with idiopathic thrombocytopenic
purpura. Ann Intern Med 146(1):25–33, 2007.
13. Chugh S, Lim W, Crowther MA, et al: Rituximab plus standard of care
for treatment of primary immune thrombocytopenia: a systematic review
and meta-analysis. Lancet Haematol 2:e75–e81, 2015.
14. Patel VL, Mahevas M, Lee SY, et al: Outcomes 5 years after response to
rituximab therapy in children and adults with immune thrombocytope-
nia. Blood 119(25):5989–5995, 2012.
15. Kuter DJ, Bussel JB, Lyons RM, et al: Efficacy of romiplostim in patients
with chronic immune thrombocytopenic purpura: a double-blind ran-
domised controlled trial. Lancet 371(9610):395–403, 2008.
16. Cheng G, Saleh MN, Marcher C, et al: Eltrombopag for management of
chronic immune thrombocytopenia (RAISE): a 6-month, randomised,
phase 3 study. Lancet 377(9763):393–402, 2011.
17. Arnold DM, Smith JW, Kelton JG: Diagnosis and management of neonatal
alloimmune thrombocytopenia. Transfus Med Rev 22(4):255–267, 2008.
18. Warner MN, Moore JC, Warkentin TE, et al: A prospective study of
protein-specific assays used to investigate idiopathic thrombocytopenic
purpura. Br J Haematol 104(3):442–447, 1999.
19. Bakchoul T, Bertrand G, Krautwurst A, et al: The implementation of
surface plasmon resonance technique in monitoring pregnancies with
expected fetal and neonatal alloimmune thrombocytopenia. Transfusion
53(9):2078–2085, 2013.
20. Ghevaert C, Rankin A, Huiskes E, et al: Alloantibodies against low-
frequency human platelet antigens do not account for a significant
proportion of cases of fetomaternal alloimmune thrombocytopenia:
evidence from 1054 cases. Transfusion 49(10):2084–2089, 2009.
21. Mueller-Eckhardt C, Kiefel V, Grubert A, et al: 348 cases of suspected
neonatal alloimmune thrombocytopenia. Lancet 1(8634):363–366, 1989.
22. Kiefel V, Bassler D, Kroll H, et al: Antigen-positive platelet transfusion
in neonatal alloimmune thrombocytopenia (NAIT). Blood 107(9):3761–
3763, 2006.
23. Rayment R, Brunskill SJ, Soothill PW, et al: Antenatal interventions for
fetomaternal alloimmune thrombocytopenia. Cochrane Database Syst Rev
(5):CD004226, 2011.
24. Berkowitz RL, Kolb EA, McFarland JG, et al: Parallel randomized trials
of risk-based therapy for fetal alloimmune thrombocytopenia. Obstet
Gynecol 107(1):91–96, 2006.
25. Kjeldsen-Kragh J, Killie MK, Tomter G, et al: A screening and inter-
vention program aimed to reduce mortality and serious morbidity
associated with severe neonatal alloimmune thrombocytopenia. Blood
110(3):833–839, 2007.
26. Williamson LM, Stainsby D, Jones H, et al: The impact of universal
leukodepletion of the blood supply on hemovigilance reports of post-
transfusion purpura and transfusion-associated graft-versus-host disease.
Transfusion 47(8):1455–1467, 2007.
27. Menis M, Forshee RA, Anderson SA, et al: Posttransfusion purpura
occurrence and potential risk factors among the inpatient US elderly,
as recorded in large Medicare databases during 2011 through 2012.
Transfusion 55(2):284–295, 2015.
28. Woelke C, Eichler P, Washington G, et al: Post-transfusion purpura
in a patient with HPA-1a and GPIa/IIa antibodies. Transfus Med
16(1):69–72, 2006.
29. Taaning E, Tonnesen F: Pan-reactive platelet antibodies in post-
transfusion purpura. Vox Sang 76(2):120–123, 1999.
30. Mueller-Eckhardt C, Kiefel V: High-dose IgG for post-transfusion
purpura-revisited. Blut 57(4):163–167, 1988.

THROMBOCYTOPENIA CAUSED BY PLATELET DESTRUCTION,
HYPERSPLENISM, OR HEMODILUTION
Thrombocytopenia is defined as a platelet count below the lower
limit of the normal range (≈150 × 109/L). Sometimes an expanded
definition of thrombocytopenia is appropriate. For example, an
abrupt drop in the platelet count can signify the onset of a platelet-
destructive process such as heparin-induced thrombocytopenia (HIT)
or bacteremia even if the platelet count remains above 150 × 109/L.
This is especially relevant in the second or third week after surgery
because patients usually have platelet counts that peak at levels 2–3
times greater than their usual preoperative value (postoperative
thrombocytosis).
In the clinical evaluation of a patient with thrombocytopenia, three
questions must be asked. First, could the patient have pseudothrom-
bocytopenia? Second, what is the most likely explanation for the
thrombocytopenia? And third, what are the risks posed by the caus-
ative disorder and the severity of the thrombocytopenia? For example,
severe thrombocytopenia caused by drug-dependent antibodies or
platelet-reactive autoantibodies is often associated with bleeding. By
contrast, thrombocytopenia caused by HIT antibodies or attributable
to disseminated intravascular coagulation (DIC) secondary to adeno-
carcinoma is associated with thrombosis. Often, the underlying cause
of the thrombocytopenia (e.g., bacteremia, cancer, cirrhosis), rather
than the thrombocytopenia itself, poses the greater risk.
Thrombocytopenia can be caused by any of four general mecha-
nisms: (1) platelet underproduction, (2) increased platelet destruction
or consumption, (3) platelet sequestration, and (4) hemodilution.
Platelet underproduction usually occurs in association with under-
production of other blood cell lines, which results in bicytopenia
or pancytopenia. Thrombocytopenia caused by increased platelet
destruction develops when the rate of platelet loss surpasses the ability
of the bone marrow (BM) to produce platelets and may be caused
by immune or nonimmune mechanisms (Table 132.1). Thrombocy-
topenia from platelet sequestration is caused by redistribution of
platelets from the circulation into an enlarged splenic vascular bed.
Hemodilution is characterized by a decrease in the number of plate-
lets, as well as red blood cells (RBCs) and white blood cells (WBCs)
as a result of the administration of colloid, crystalloid, or platelet-
poor blood products.
In the postoperative period, platelet count changes reflect several
processes, including initial hemodilution (immediate platelet count
decrease) and increased platelet consumption (first 2–4 days), at which
point the platelet count begins to rise because of increased platelet
production; when the platelet count reaches its postoperative peak—
usually about 14 days after surgery—platelet production decreases
somewhat, and the platelet count returns to baseline (Fig. 132.1).1 In
addition to usual mechanisms, the differential diagnosis of thrombo-
cytopenia in pregnancy includes some unique causes (Table 132.2).
APPROACH TO PATIENTS WITH THROMBOCYTOPENIA
History and Physical Examination
Certain information should be ascertained, including (1) the location
and severity of bleeding (if any); (2) the temporal profile of the
hemostatic defect (acute, chronic, or relapsing), particularly the
temporal relationship with potential proximate triggers (e.g., new
CHAPTER 132
Theodore E. Warkentin
drug, recent infection); (3) the presence of symptoms of a secondary
illness, such as a neoplasm, infection, or an autoimmune disorder
such as systemic lupus erythematosus (SLE); (4) history of recent
medication use, alcohol ingestion, or transfusion; (5) presence of risk
factors for certain infections, particularly human immunodeficiency
virus (HIV) infection or viral hepatitis; and (6) family history of
thrombocytopenia.
As part of the physical examination, evidence of hemostatic
impairment should be sought, as well as secondary causes of throm-
bocytopenia. The signs of platelet-related bleeding include petechiae
and purpura. Petechiae typically occur in the dependent regions of
the body or on traumatized areas. Spontaneous mucous membrane
bleeding (wet purpura), epistaxis, and gastrointestinal bleeding
indicate a more serious hemostatic defect. Although petechiae are
common in patients whose platelet counts are less than 10–20 ×
109/L, most patients with platelet counts over 50 × 109/L have no
signs of hemostatic impairment. The physical examination may
provide an explanation for the thrombocytopenia. For example,
enlarged lymph nodes may indicate a viral infection, such as infec-
tious mononucleosis or HIV infection, or a neoplastic process. An
enlarged spleen raises the possibility of hypersplenism.
Timing of Onset and Severity of Thrombocytopenia
Many thrombocytopenic disorders, particularly those involving an
immune pathogenesis, exhibit characteristic temporal features that can
aid in the diagnosis. For example, if the platelet count begins to fall
5–10 days (median, 6–7 days) after starting a new drug or after a blood
transfusion and reaches a nadir of less than 20 × 109/L a few days later,
the diagnosis of drug-induced immune thrombocytopenia (D-ITP) or
posttransfusion purpura (PTP), respectively, should be considered (Fig.
132.2).2 Patients with these disorders typically have mucocutaneous
bleeding and are at risk for fatal intracranial hemorrhage.
A similar temporal profile is also characteristic of typical-onset
HIT, although there the platelet count only falls below 20 × 109/L
in only 10% of affected patients (see Fig. 132.2); in approximately
80% of patients, the platelet count nadir ranges from 20–150 ×
109/L, and in the remainder, the platelet count nadir never falls below
150 × 109/L despite a large reduction in the platelet count. When
the platelet count falls abruptly after drug administration, the pos-
sibility of rapid-onset thrombocytopenia caused by preexisting drug-
dependent antibodies should be considered, as is well described with
HIT. Indeed, so-called rapid-onset HIT is the presenting feature of
this adverse drug reaction in 25% to 30% of cases.3 Rapid-onset
thrombocytopenia is also a feature of glycoprotein (GP) IIb/IIIa
antagonist-induced ITP.
Occasionally, thrombocytopenia worsens in the first few days after
surgery; this can occur with multiorgan system failure (e.g., cardio-
genic or septic shock) (see Fig. 132.2). If the patient develops con-
comitant DIC and hypotension, there is high risk for ischemic limb
injury secondary to microvascular thrombosis (“symmetric peripheral
gangrene”), especially if the patient has “shock liver” (ischemic hepa-
titis), which is a risk factor for severe depletion of protein C, an
important endogenous anticoagulant.4,5 If the platelet count falls to
very low levels and is accompanied by microangiopathic hemolysis,
1955
1956 Part XII Hemostasis and Thrombosis

TABLE
Mechanisms of Platelet Destruction or Consumption
132.1
Type of Thrombocytopenia Specific Example(s)
Immune Mediated
Autoantibody-mediated platelet destruction by RES Primary and secondary idiopathic (immune) ITPa
Alloantibody-mediated platelet destruction by RES NAIT,a PTP,a PAT; alloimmune platelet transfusion refractorinessa
Drug-dependent, antibody-mediated platelet destruction by RES Drug-induced immune ITP (e.g., vancomycin) (see Fig. 132.5)
Platelet activation by binding of IgG Fc of drug-dependent IgG to platelet HIT
FcγIIa receptors
Non–Immune Mediated
Platelet activation by thrombin or proinflammatory cytokines DICa; septicemia or systemic inflammatory response syndromes
Platelet destruction via ingestion by macrophages (hemophagocytosis) Infections, certain malignant lymphoproliferative disorders
Platelet destruction through platelet interactions with altered vWFb TTP,a HUSa
Platelet losses on artificial surfaces CPB,a use of intravascular catheters
Decreased platelet survival associated with cardiovascular diseases Congenital and acquired heart disease, cardiomyopathy, PE
a
See Chapter 131 for a discussion of thrombocytopenia in these disorders.
b
Although platelet destruction is not directly caused by antibodies, immune mechanisms can explain altered vWF (e.g., autoimmune clearance of vWF-cleaving
metalloprotease).
CPB, Cardiopulmonary bypass surgery; DIC, disseminated intravascular coagulation; HIT, heparin-induced thrombocytopenia; HUS, hemolytic uremic syndrome;
IgG, immunoglobulin G; ITP, idiopathic (immune) thrombocytopenic purpura; NAIT, neonatal alloimmune thrombocytopenia; PAT, passive alloimmune thrombocytopenia;
PE, pulmonary embolism; PTP, posttransfusion purpura; RES, reticuloendothelial system; TTP, thrombotic thrombocytopenic purpura; vWF, von Willebrand factor.

1 2 3 4
Acute thrombocytopenia
Increased platelet Decreased platelet
Steady state (hemodilution/increased production production
Surgery platelet consumption)

Surgery 4
Liver
Platelet count

3
1 1
Postoperative thrombocytosis Thrombopoietin
(platelet count peak, day ~14) Megakaryocyte
2
Platelet

0 5 10 15 20 25
Days after surgery
Fig. 132.1 POSTSURGERY PLATELET COUNT CHANGES. Initial platelet count declines result from
hemodilution and increased platelet consumption, with the platelet count nadir occurring between days 1 to
4 (median, day 2). There is constitutive production of thrombopoietin (TPO) by the liver. TPO binds to
platelets and megakaryocytes via a specific receptor (c-Mpl, not shown), and receptor-bound TPO is removed
from circulation and degraded. The level of circulating TPO is thus inversely related to the mass of platelets
and megakaryocytes. In early postsurgery thrombocytopenia, fewer TPO binding sites are available, resulting
in high free TPO levels, which stimulates megakaryocyte proliferation and differentiation and leads to increased
platelet production. With subsequent thrombocytosis, the high platelet mass acts as a “sink” for removing
TPO, with decreased stimulus for platelet production. Thus after acute postsurgery thrombocytopenia, TPO
levels rise about twofold, leading to increased platelet production that begins on days 2–4, with resulting
thrombocytosis that generally peaks at approximately day 14 (postoperative thrombocytosis) and returns to
baseline by about day 21. (Reprinted, with modifications, with permission, from Arnold DM, Warkentin TE: Throm-
bocytopenia and thrombocytosis. In Wilson WC, Grande CM, Hoyt DB, editors: Trauma: Critical care, vol 2, New York,
2007, Informa Healthcare, p 983).
 Chapter 132 Thrombocytopenia Caused by Platelet Destruction, Hypersplenism, or Hemodilution 1957

the possibility of postoperative thrombotic thrombocytopenic
purpura (TTP) should be considered.6
Mild to moderate platelet count decreases that occur soon after
transfusion of blood products are common and can be explained by
hemodilution; however, a marked platelet count fall after transfusion
may be the result of passive alloimmune thrombocytopenia (PAT) or
sepsis because of contaminated blood products (see Fig. 132.2).
Other characteristic temporal features of thrombocytopenia
include postenterohemorrhagic Escherichia coli–associated hemolytic
uremic syndrome (HUS); thrombocytopenia and microangiopathic
hemolysis that begin approximately 1 week after a prodromal diar-
rheal illness; and fungemia-associated thrombocytopenia (onset, 1–3
weeks after complex illness involving indwelling catheters and broad-
spectrum antibiotic usage). In contrast, thrombocytopenia of insidi-
ous onset that progresses over several years suggests chronic liver
disease, with evolution to portal hypertension and associated spleno-
megaly (e.g., cirrhosis secondary to alcohol or hepatitis C) or a slowly
progressive BM disorder (e.g., myelodysplasia).

TABLE Differential Diagnosis of Thrombocytopenia in Laboratory Evaluation

132.2 Pregnancy
Incidental thrombocytopenia of pregnancy (gestational
Laboratory evaluation of patients with thrombocytopenia is sum-
thrombocytopenia)
marized in Table 132.3 (also see Chapter 129). The blood film is
Preeclampsia or eclampsiaa
examined to exclude pseudothrombocytopenia, which is character-
DIC secondary to:
ized by in vitro platelet clumping. This phenomenon, which is
Abruptio placentae
evident in approximately one in 1000 blood samples, is most often
Endometritis
caused by naturally occurring GPIIb/IIIa (αIIbβ3)-reactive autoanti-
Amniotic fluid embolism
bodies that induce aggregation of platelets in the presence of the
Retained fetus
calcium-chelating anticoagulant ethylenediamine tetraacetic acid
Preeclampsia or eclampsiaa
(EDTA). Because the platelet aggregates are not counted by the
Peripartum or postpartum thrombotic microangiopathy
electronic particle counter, the automated platelet count appears
TTP
falsely low. The correct platelet count usually can be determined by
HUS
collecting the blood into sodium citrate or heparin or by performing
a
the count on nonanticoagulated finger prick samples; maintaining
Preeclampsia or eclampsia usually is not associated with overt DIC.
DIC, Disseminated intravascular coagulation; HUS, hemolytic uremic syndrome;
the blood sample at 37°C often attenuates platelet clumping. EDTA-
TTP, thrombotic thrombocytopenic purpura. dependent pseudothrombocytopenia has no pathologic significance
other than potentially placing a patient in jeopardy for inappropriate

Transfusion of
blood product
500
Heparin bolus

400 Normal platelet count

nadir after major surgery
Platelet count (× 109/L)

300

200 Rapid- Bacterial

onset HIT contamination
Typical-onset
100 HIT
Sepsis, multiorgan failure
PAT
Postsurgery TTP D-ITP, PTP
0
0 1 2 3 4 5 6 7 8 9 10
Postoperative day (day 0 = day of surgery)
Fig. 132.2 TIMING OF ONSET AND SEVERITY OF THROMBOCYTOPENIA: IMPLICATIONS
FOR DIFFERENTIAL DIAGNOSIS. The usual postoperative platelet count nadir is seen between postopera-
tive days 1 to 3 (inclusive). Early and progressive platelet count declines often reflect severe postoperative
complications such as sepsis and multiorgan failure; severe thrombocytopenia can (rarely) indicate postsurgery
thrombotic thrombocytopenic purpura. Thrombocytopenic disorders that begin approximately 1 week after
surgery are often immune mediated: moderate thrombocytopenia can indicate heparin-induced thrombocy-
topenia (HIT), both “typical onset” or (if heparin is not being given) “delayed onset”; very severe thrombo-
cytopenia can indicate drug-induced immune thrombocytopenia (D-ITP) or (rarely) posttransfusion purpura.
An abrupt decline in platelet count after receiving a heparin bolus in a patient who has received heparin within
the past 7–100 days can indicate “rapid-onset” HIT; thrombocytopenia that begins abruptly after transfusion
of a blood product can indicate sepsis from bacterial contamination or (rarely) passive alloimmune thrombo-
cytopenia caused by transfusion of platelet-reactive alloantibodies. D-ITP, Drug-induced immune thrombo-
cytopenia; HIT, heparin-induced thrombocytopenia; PAT, passive alloimmune thrombocytopenia; PTP,
posttransfusion purpura; TTP, thrombotic thrombocytopenic purpura. (Reprinted, with permission, from Grein-
acher A, Warkentin TE: Acquired non-immune thrombocytopenia. In: Marder VJ, Aird WC, Bennett JS, et al, editors:
Hemostasis and thrombosis: Basic principles and clinical practice, ed 6, Philadelphia, 2013, Lippincott Williams &
Wilkins, p 796.)
1958 Part XII Hemostasis and Thrombosis

TABLE Laboratory Tests Used to Investigate a Patient With treatment for thrombocytopenia that does not exist. A much less
132.3 Thrombocytopenia common (one in 10,000 blood samples) antibody-mediated pseudo-
thrombocytopenic disorder is platelet satellitism, in which rosette-like
Test Rationale clusters of platelets surround neutrophils. This entity is produced by
Common Tests immunoglobulin G (IgG) antibodies that recognize EDTA-induced
CBC Isolated thrombocytopenia usually is cryptic epitopes on both platelet GPIIb/IIIa and neutrophil FcγIII
caused by platelet destruction, but receptors.
involvement of all cell lines BM examination can be helpful for assessment of platelet produc-
suggests underproduction or tion, particularly if megakaryocytes are reduced in number or
sequestration abnormal in appearance. Examination of the BM can be diagnostic
in some disorders (e.g., leukemia, metastatic tumor, Gaucher disease,
Examination of the blood film Pseudothrombocytopenia (platelet
megaloblastic anemia).
clumps)
Elevated platelet-associated IgG (PAIgG) can be detected in
Toxic changes and granulocyte “left
patients with either immune or non-ITP; therefore, this assay is not
shift” suggest septicemia
useful diagnostically. In contrast, GP-specific platelet antibody assays,
Atypical lymphocytes suggest viral
such as the monoclonal antibody immobilization of platelet antigens
infection
(MAIPA) assay or antigen capture enzyme immunoassay, are relatively
RBC fragments suggest TTP or HUS
specific for detection of autoimmune thrombocytopenic disorders.
Parasites (e.g., in malaria)
These assays can also be adapted for detection of drug-dependent
White cell inclusions suggest
GP-reactive antibodies.
hereditary macrothrombocytopenia
When the mechanism of chronic thrombocytopenia is unclear, an
Blood cultures Bacteremia, fungemia autologous platelet survival study using 111In-labeled platelets may be
ANA test Systemic lupus erythematosus informative. Three patterns can be seen: (1) normal platelet survival
and recovery (underproduction), (2) marked reduction in the platelet
Direct antiglobulin test Exclude immune hemolysis
life span (increased destruction), and (3) reduced recovery but a
accompanying ITP (Evans
normal or near-normal life span (sequestration). However, platelet
syndrome)
survival studies are rarely performed.
Coagulation Assays
aPTT, PT (INR), thrombin DIC
time, fibrinogen, D-dimer Therapy
assay
LA assay (nonspecific aPL antibody syndrome The risk of bleeding in patients with thrombocytopenia can be
inhibitor), anticardiolipin reduced by avoiding drugs that impair hemostasis (e.g., alcohol,
and anti-β2-glycoprotein I antiplatelet agents, anticoagulants) and invasive procedures (e.g.,
assays intramuscular injections). If drug-induced thrombocytopenia is sus-
Serum protein ITP associated with pected, as many medications as possible, especially those started
electrophoresis; IgG, IgM, lymphoproliferative disorder within the preceding 5–14 days, should be stopped. Life-threatening
IgA levels (monoclonal); hypersplenism bleeding episodes should be treated with platelet transfusion regard-
associated with chronic hepatitis less of the mechanism of the thrombocytopenia.
(polyclonal) The underlying cause and anticipated natural history of the
thrombocytopenic disorder influence the decision about prophylactic
HIV serologic studies HIV-associated thrombocytopenia platelet transfusion. As a general rule, patients with chronic throm-
BM aspiration, biopsy Assess megakaryocyte numbers and bocytopenic disorders characterized by increased platelet destruction
morphology; exclude primary BM (e.g., chronic ITP) or chronic underproduction (e.g., aplastic anemia
disorder or myelodysplasia) can tolerate long periods of severe thrombocyto-
Specialized Tests penia without major bleeding. In addition, prophylactic platelet
GP-specific platelet antibody Relatively specific assay for primary transfusions can trigger alloimmunization against human leukocyte
assays (e.g., MAIPA) and secondary ITP antigen (HLA) or platelet antigens, thereby jeopardizing future thera-
peutic platelet transfusions. Consequently, prophylactic platelet
Drug-dependent increase in Specific assay for D-ITP
transfusions are seldom indicated for such patients except when they
platelet-associated IgG
are at risk of bleeding because of trauma or major surgery. When
Drug-dependent platelet HIT platelets are given, the platelet count should be maintained above 50
activation test (e.g., × 109/L. Invasive procedures such as thoracentesis, paracentesis, and
platelet serotonin release liver biopsy are not usually associated with excess bleeding if the
assay) or PF4–heparin (or platelet count is greater than 50 × 109/L.
PF4-polyanion) ELISA Prophylactic platelet transfusions should not be given to patients
Radionuclide platelet life Define the mechanism of with strongly suspected or confirmed HIT, TTP, or HUS because
span study with imaging thrombocytopenia; identify an they may exacerbate platelet-mediated thrombotic complications,
(e.g., 111In platelet survival “accessory” spleen postsplenectomy and, particularly with HIT, mucocutaneous bleeding is uncommon.
study) However, bleeding in the setting of severe thrombocytopenia may
ANA, Antinuclear antibody; aPL, antiphospholipid; aPTT, activated partial
justify platelet transfusion even in these disorders.
thromboplastin time; BM, bone marrow; CBC, complete blood count;
DIC, disseminated intravascular coagulation; D-ITP, drug-induced immune
thrombocytopenia; ELISA, enzyme-linked immunosorbent assay; ANATOMY AND PHYSIOLOGY
GP, glycoprotein; HIT, heparin-induced thrombocytopenia; HIV, human
immunodeficiency virus; HUS, hemolytic uremic syndrome;
IgG, immunoglobulin G; INR, international normalized ratio; ITP, idiopathic The Spleen: Anatomy and Function
(immune) thrombocytopenic purpura; LA, lupus anticoagulant;
MAIPA, monoclonal antibody immobilization of platelet antigens; PF4, platelet The spleen is a small, well-perfused organ that receives about 5% of
factor 4; PT, prothrombin time; RBC, red blood cell; TTP, thrombotic
thrombocytopenic purpura.
the total cardiac output. In adults, the spleen weighs between 150
and 200 g and measures approximately 11 cm in length.
 Chapter 132 Thrombocytopenia Caused by Platelet Destruction, Hypersplenism, or Hemodilution 1959

The anatomy of the spleen is uniquely suited for its function;
progressive branching of the splenic artery into trabecular and central
arteries helps separate the plasma from the cellular elements (see
Chapter 160). The central arteries arise perpendicularly from the
trabecular arteries and skim the plasma layer from the cells. Soluble
antigens in the plasma are delivered to the white pulp, where phago-
cytic cells process them and antibody production is initiated.
A cell-rich, hemoconcentrated fraction of the blood is delivered
to the red pulp. Some of this blood flows directly to the splenic veins
(the closed system), but most moves into the splenic cords (the open
system). Here, the cellular elements percolate through a meshwork
of reticulum fibers, reticuloendothelial cells, and supporting cells to
reach the splenic sinuses. The cells enter the sinuses by passing
through narrow fenestrations in the basement membrane of the
endothelial cells lining the sinuses. The blood exits through the
splenic vein into the portal system. Because the veins in the portal
system lack valves, any increase in portal pressure is transmitted to
the splenic microcirculation.
The spleen plays a number of important roles. It is the largest
lymphoid organ in the body and contributes to host defense by
clearing microorganisms and antibody-coated cells. The spleen is also
important for antibody synthesis, especially antibodies directed
against soluble antigens. The filtering function of the spleen includes
(1) culling (removal of damaged or senescent cells and bacteria), (2)
pitting (removal of RBC inclusion bodies or parasites), and (3)
remodeling (reticulocyte sequestration and maturation). The spleen
also serves as a reservoir of platelets (accommodating about one-third
of the platelet mass in normal individuals). By contrast, the human
spleen contains less than 2% of the total RBC mass, although in some
animals (dogs and cats), the spleen is a much more important RBC
reservoir.
Physiologic Platelet Sequestration
Radiolabeled platelet studies have shown that approximately 30% of
the total platelet mass exists as a freely exchangeable pool in the
spleen. Because the normal platelet life span is 9–10 days, platelets
spend approximately one-third of their lives, or 3 days, within the
spleen. In patients with hypersplenism, up to 90% of the platelets
can be found in the spleen.
After labeled platelets are injected, there is accumulation in both
the liver and the spleen. An initial, irreversible phase of hepatic
uptake occurs. This equilibrates during the first 5 minutes and may
reflect hepatic clearance of platelets damaged during the labeling
procedure. Simultaneously, there is a slow increase in activity over the
spleen that peaks in about 20 minutes. Splenic platelet uptake is thus
dependent on input (spleen blood flow) and output (clearance).
The splenic platelet pool size can be decreased and the platelet
count increased with intravenous infusions of epinephrine in normal
persons and in patients with splenomegaly. By contrast, isoprenaline
increases the splenic pool size. Splenic blood flow increases with
increasing spleen size, although perfusion (flow per unit of tissue
volume) falls. Blood flow can be increased in some inflammatory
disorders (e.g., SLE) without an increase in spleen size. A marked
increase or decrease in splenic perfusion alters the proportion of
platelets within the spleen.
Fig. 132.3 shows why approximately 30% of the platelets
are normally present in the spleen.1 Because about 5% of cardiac
output goes to the spleen and because the average splenic transit time
(i.e., the time for the platelet to pass through the spleen) is approxi-
mately 10 minutes—compared with the usual average time of
1 minute for a platelet to make a complete circulatory pass—
approximately one-third of the platelets are within the spleen

95%

5% 5%-25%
~1 min

Normal transit time Normal transit time

(~10 min) (~10 min)

Normal spleen

Hypersplenism
Fig. 132.3 PHYSIOLOGIC AND PATHOLOGIC PLATELET SPLENIC SEQUESTRATION. Normally,
about 5% of cardiac output is to the spleen; however, a platelet that enters the spleen spends about 10 minutes
there (splenic transit time = 10 min). In contrast, it usually takes only about 1 minute for a platelet to make
a circulatory pass elsewhere. Thus about one-third of the platelets at any one time are located within the spleen:
(5% × 10 min):(95% × 1 min), or an approximate 1 : 2 ratio. In hypersplenism, the splenic blood flow can
increase by a factor of 5, that is, from 5% to 25% of total blood flow per minute. Thus, even without increase
in splenic transit time, up to 70% or more of the platelets can be exchangeably sequestered within the spleen.
(From Arnold DM, Warkentin TE: Thrombocytopenia and thrombocytosis. In: Wilson WC, Grande CM, Hoyt DB, editors:
Trauma: Critical care, vol. 2, New York, 2007, Informa Healthcare USA, p 983.)
 1960 Part XII Hemostasis and Thrombosis

(i.e., 5% × 10 min/95% × 1 min, or a ratio of 50 : 95, or ≈1 : 2). TABLE Differential Diagnosis of Splenomegaly and
With hypersplenism, the splenic blood flow can increase up to fivefold 132.4 Hypersplenism
(i.e., from 5% to 25% of total blood flow). Thus even without an
increase in splenic transit time, 70% or more of the platelets can be Infections
exchangeably sequestered within the spleen. Acute
The most important determinant of the splenic platelet pool is Viral (viral hepatitis, infectious mononucleosis, CMV infection)
the spleen size. The measurement of spleen size can thus be helpful Bacterial (septicemia, salmonellosis, brucellosis, splenic abscess)
in predicting the degree of thrombocytopenia expected from excess Parasite (toxoplasmosis)
platelet pooling in the spleen. For example, if 90% of the platelet Subacute and Chronic
pool is in the spleen (i.e., 10% outside the spleen), the platelet count Subacute bacterial endocarditis
will be reduced by sevenfold because normally, 70% of platelets lie Tuberculosis
outside the spleen. Consequently and as a general rule, even if the Malaria
spleen is massively enlarged, severe thrombocytopenia (<20 × 109/L) Kala-azar
is rare. On the other hand, mild thrombocytopenia may be explained Fungal disease
by mild splenomegaly that may not be detectible on physical exami- Inflammation
nation but can be seen with imaging studies. Felty syndrome
SLE
Serum sickness
PATHOLOGIC PLATELET SEQUESTRATION: Rheumatic fever
HYPERSPLENISM Sarcoidosis
ALPS
Definition Congestive Splenomegaly
Intrahepatic
Hypersplenism is a syndrome characterized by splenomegaly and any Cirrhosis
or all of the following cytopenias: anemia, leukopenia, or thrombo- Extrahepatic
cytopenia. Implicit in the definition is that the cytopenias will correct
Portal vein obstruction
after splenectomy. Although splenomegaly is almost always present
Splenic vein obstruction
in hypersplenism, many patients with splenomegaly do not have
Hepatic vein occlusion (Budd-Chiari syndrome)
hypersplenism. Hypersplenism usually is the result of an identifiable
pathologic process, but rarely, the cause of the splenomegaly remains Chronic Passive Congestion
elusive, and the hypersplenism is termed primary. Heart failure
Hematologic Disorders
RBC disorders: hemolytic anemias, thalassemia, sickle cell disorders
Pathogenesis Neoplasia
Malignant
A list of disorders producing splenomegaly and hypersplenism is MPDs
presented in Table 132.4. An increase in the size of the spleen can be Myeloid metaplasia
caused by several mechanisms. Increased workload of the spleen can Polycythemia rubra vera
be caused by immunologic stress (infection, inflammation, or an Essential thrombocythemia
autoimmune disorder) or by increased RBC removal (RBC mem- Chronic leukemia
brane disorders, hemoglobinopathies). Portal hypertension also Chronic myeloid leukemia
increases the size of the spleen, producing congestive splenomegaly. Chronic lymphocytic leukemia
Benign and malignant infiltrative disorders may increase splenic size Hairy cell leukemia
(infiltrative splenomegaly) and cause hypersplenism. Some of these Lymphoma
disorders produce thrombocytopenia by more than just hypersplen- Acute leukemia
ism (e.g., BM infiltration with tumor, immune-mediated platelet Malignant histiocytosis
clearance). Thus the demonstration of an enlarged spleen does not Benign
necessarily mean that the cytopenias are caused solely by Hamartoma
hypersplenism. Hemangioma
Thrombocytopenia of hypersplenism is caused primarily by Lymphangioma
increased splenic platelet pooling. A massively enlarged spleen can Fibroma
hold more than 90% of the total platelet mass. In the absence of Storage Diseases
altered platelet production, the total body platelet mass usually is
Gaucher disease
normal, and the platelet life span is near normal. Usually, the splenic
Niemann-Pick disease
transit time remains normal (≈10 minutes), but the absolute number
Miscellaneous
of platelets retained within the enlarged spleen is increased. All of
these platelets remain part of the exchangeable pool. In hypersplen- Amyloidosis
ism, the thrombocytopenia is moderately severe (platelet counts of Cysts
50 × 109/L to 150 × 109/L). Severe thrombocytopenia (<20 × 109/L) ALPS, Autoimmune lymphoproliferative syndrome; CMV, cytomegalovirus;
suggests another diagnosis. Therefore it is unusual for patients with MPD, myeloproliferative disorder; RBC, red blood cell; SLE, systemic lupus
erythematosus.
hypersplenism to have evidence of hemostatic impairment attribut-
able to thrombocytopenia or to need specific interventions to raise
the platelet count. Plasma volume expansion occurs in hypersplen-
ism, but hemodilution plays a relatively minor role in the thrombo- Diagnosis
cytopenia. In some patients with advanced liver disease, impaired
hepatic production of thrombopoietin may contribute to thrombo- Thrombocytopenia is likely to be caused by hypersplenism when
cytopenia in addition to hypersplenism. (1) splenomegaly is present, (2) the thrombocytopenia is mild to
The neutropenia of hypersplenism is caused by an increase in the moderate in severity, (3) a moderately reduced neutrophil count
marginated granulocyte pool, a portion of which is located in the and low-normal hemoglobin levels are found, and (4) there is no or
spleen. The neutropenia of hypersplenism is usually asymptomatic. minimal evidence of impaired hematopoiesis on BM examination.
 Chapter 132 Thrombocytopenia Caused by Platelet Destruction, Hypersplenism, or Hemodilution
Ultrasonography, computed tomography, and radionuclide imaging
are of comparable sensitivity for documenting splenomegaly, and an
imaging study should be performed if splenomegaly is not evident
on physical examination. The mean platelet volume is often slightly
decreased in hypersplenism, but this finding is not sufficiently specific
to be diagnostically useful. An 111In-labeled platelet survival study
can be diagnostic of hypersplenism, demonstrating reduced platelet
recovery and a normal platelet life span. Determining the cause of
the splenomegaly is usually the most important issue.
Therapy
Several maneuvers can improve or correct the cytopenias attributable
to hypersplenism, including total or partial splenectomy; partial
splenic embolization; and in patients with congestive splenomegaly,
surgical or transjugular intrahepatic portosystemic shunting. However,
cytopenias secondary to hypersplenism and thrombocytopenia in
particular, are almost never of sufficient severity to justify such treat-
ment. Consequently the decision to perform one of these interven-
tions usually depends on other considerations. For example,
splenectomy should be considered for relief of pain or early satiety
associated with massive splenomegaly (e.g., in myelo- or lymphopro-
liferative disorders) or for splenomegaly of unknown origin (for
investigation of possible splenic lymphoma).
Short-term complications from splenectomy include infections,
bleeding, and thromboembolism. The major long-term risk associ-
ated with splenectomy is overwhelming septicemia; this risk can be
reduced by vaccination. All patients should be vaccinated against
pneumococci, meningococci, and Haemophilus species at least 2
weeks before elective splenectomy. Moreover, “booster” doses of
pneumococcus and meningococcus vaccines are recommended after
5 years.7 Splenectomy for congestive hypersplenism in the setting of
portal hypertension is associated with high morbidity and mortality
rates. Splenectomy is also associated with high morbidity (50%) and
mortality (10%–15%) rates in myeloid metaplasia and does not alter
the natural history of this disorder. Thus splenectomy is usually
performed for palliation of intractable symptoms.
Splenectomy in Gaucher disease usually corrects the cytopenias,
relieves abdominal discomfort, and improves growth in children.
Partial, rather than total, splenectomy has been used in an attempt
to avoid shifting the deposition of glucocerebroside from the spleen
to the bones. Often, however, splenomegaly and hypersplenism recur
after partial splenectomy. Enzyme replacement therapy can reduce
the morbidity from hypersplenism (see Chapter 53).
DRUG-INDUCED THROMBOCYTOPENIC SYNDROMES
Many drugs can cause thrombocytopenia. Some drugs (e.g., antican-
cer chemotherapeutic agents, valproic acid) cause dose-dependent
thrombocytopenia, generally through myelosuppressive mechanisms.
An important disorder encountered by hematologists is unexpected
thrombocytopenia caused by immunologic (idiosyncratic)
mechanisms.8–10 The frequency of these reactions varies considerably
among drugs and ranges from very rare (<1 : 10,000) for commonly
used drugs such as acetaminophen, indomethacin, naproxen, quinine
or quinidine, and trimethoprim-sulfamethoxazole (TMP-SMX) to
common (1%–5%) for other drugs such as gold and unfractionated
heparin (UFH).
Immunologic drug-induced thrombocytopenia can occur through
different mechanisms (Fig. 132.4). For example, thrombocytopenia
can occur when the Fab terminus of the pathogenic IgG binds to a
complex composed of drug (or drug metabolite) and a platelet
membrane component (typically, platelet GPIIb/IIIa or GPIb/IX/V).
The Fc portions of the pathogenic IgG molecules do not bind to
platelets but interact with Fc receptors on phagocytic cells of the
reticuloendothelial system, which ingest the platelets, leading to
accelerated platelet clearance. Severe thrombocytopenia (platelet
counts <20 × 109/L) is typically observed. This mechanism is
1961
exemplified by quinine- and quinidine-induced thrombocytopenia.
A complicating issue (discussed later in this chapter) is that quinine
can also rarely cause thrombocytopenia with a clinical picture of
microangiopathic hemolysis11 and/or DIC.
Sometimes the Fab terminus binds to a neoepitope on platelet
GPIIb/IIIa induced by the drug, and the drug itself is not part of the
neoepitope. This mechanism is exemplified by the GPIIb/IIIa recep-
tor antagonists, eptifibatide and tirofiban, which bind to the Arg-Gly-
Asp recognition site on GPIIb/IIIa, forming a neoepitope to which
the “fiban-dependent” antibodies bind.
Another distinct form of drug-induced thrombocytopenia is
exemplified by HIT (see Chapter 133). In this disorder, the Fab
portion of the pathogenic IgG binds to platelet factor 4 (PF4), an
α-granule protein that is immunogenic when complexed to heparin
or certain other polyanions. The Fc portions of the IgG molecules
bind to platelet FcγIIa receptors, initiating intense platelet activation
(see Fig. 132.4). Perhaps because HIT is a platelet activation syn-
drome or because of the relatively low number of HIT antibodies
that bind to platelet surfaces, the thrombocytopenia is typically mild
to moderate rather than severe (see Fig. 133.3 in Chapter 133).
DRUG-INDUCED IMMUNE THROMBOCYTOPENIA
A large number of drugs can cause a syndrome that mimics acute
ITP (D-ITP); however, there are relatively few drugs for which causa-
tion is well established on both clinical and serologic grounds (Table
132.5).10,12–14 Typically, severe thrombocytopenia (platelet count
usually <20 × 109/L), together with petechiae and purpura, develop
within approximately 1 week (although occasionally much longer)
after initiation of therapy with the responsible drug. D-ITP is much
less common than HIT. For example, a relatively “common” cause of
this syndrome is TMP-SMX (co-trimoxazole), even though it occurs
in only approximately one in 25,000 patients who receive this drug
combination.
Important exceptions to these generalizations occur with D-ITP
that results from GPIIb/IIIa receptor antagonists; these reactions are
relatively common (affecting about 0.5%–1% of patients) and usually
occur within hours of first use as a result of preexisting, naturally
occurring antibodies. Another exception is carbimazole-induced
thrombocytopenia, in which mild thrombocytopenia is explained by
the presence of relatively small quantities of the platelet GP target
(platelet endothelial cell adhesion molecule-1 [PECAM-1]) on the
platelet surface. Besides the atypical immune-mediated syndromes of
HIT and GPIIb/IIIa antagonist thrombocytopenia, the most common
drugs (in absolute terms) implicated in the causation of classic D-ITP
syndrome are quinine (outpatients) and vancomycin (inpatients).15
Pathogenesis
Drug-dependent binding of the Fab component of IgG to platelet
GP leads to platelet destruction. This occurs because the IgG-
sensitized platelets are recognized by Fc receptors of phagocytic cells.
For quinine- and quinidine-induced ITP, both the GPIIb/IIIa and
GPIb/IX/V complexes have been implicated as targets for the drug-
dependent IgG (see Fig. 132.4). By contrast, for sulfa antibiotic- and
naproxen-induced ITP, the GPIIb/IIIa complex is predominantly
involved. Sometimes, drug metabolites form the antigen rather than
the parent drug. A trimolecular complex is formed among IgG Fab,
the drug (or metabolite), and the platelet GP. In contrast to HIT,
platelet Fc receptors are not involved in D-ITP pathogenesis. Drug-
dependent IgG binding is remarkably heterogeneous with respect to
binding affinity, number of binding sites per platelet, and the range
of drug concentrations required. A study of quinine-induced ITP
identified two different types of antibodies: quinine-dependent
antibodies that bound to platelets in the presence of drug and
quinine-specific antibodies that reacted with quinine-conjugated
albumin.16 The pathophysiologic implications of this latter group of
antibodies remain unclear.
 1962 Part XII Hemostasis and Thrombosis

Drug-induced antibody production

Platelet clearance by
phagocytic cells
(See enlargement below)

Ibα Monocyte
B lymphocyte IIb
IIb

Ibα IIIa IIIa

Ibβ
IX

V
Ibβ
IX
Platelet

Neoepitope
Drug–glycoprotein complex (ligand-induced bonding site)
e.g., quinine ( ) e.g., eptifibatide ( )
Autoantibody
GPIbα, GPIX, GPIIb, and GPIIIa implicated
(e.g., gold)
Platelet activation Drug binds to GPIIb/IIIa
GPV implicated exposing a neoepitope ( )
on GPIIIa

Procoagulant
HIT
platelet-derived
microparticles IgG recognizes PF4 ( ) Bound to heparin ( )

FcγIIa receptor ( ) clustering causes platelet activation

Fig. 132.4 MECHANISMS OF DRUG-INDUCED IMMUNE THROMBOCYTOPENIA. Four immune

thrombocytopenic syndromes are illustrated. On the bottom of the schematic platelet, heparin-induced
thrombocytopenia (HIT) is illustrated, indicating that immunoglobulin G (IgG) antibodies bind to complexes
of platelet factor 4 (PF4) and heparin, with the Fc regions of the antibodies binding to the platelet FcγIIa
receptors, resulting in platelet activation (including generation of procoagulant, platelet-derived microparticles).
On the top of the schematic platelet, three mechanisms are illustrated that lead to increased platelet clearance
by phagocytic cells. From left to right, these are (1) autoantibody-induced immune thrombocytopenia (e.g.,
gold-induced antiglycoprotein V [GPV] antibodies). (2) Drug-dependent antibodies reactive against drug (or
drug metabolite)–platelet glycoprotein complex(es) (e.g., quinine-induced thrombocytopenia in which drug-
dependent antibodies against GPIbα, GPIX, GPIIb, and GPIIIa have been implicated, resulting in an
antibody/drug/glycoprotein ternary complex), and (3) antibodies against neoepitope(s) formed in the presence
of a drug (e.g., eptifibatide-induced immune thrombocytopenia caused by formation of ligand-induced
binding site elsewhere on the GPIIb/IIIa complex after eptifibatide binding). Note that preexisting (naturally
occurring) antibodies can explain abrupt-onset thrombocytopenia in a patient receiving eptifibatide for the
first time.

The fundamental mechanism that accounts for antibody forma-
tion in a small proportion of patients is unknown. One group has
proposed that drug-dependent platelet-reactive antibodies are derived
from a pool of naturally occurring autoantibodies with inherently
weak (nonpathologic) affinity for certain platelet membrane GPs.8,16
However, if a certain drug is able to enhance antibody–antigen interac-
tion, and if B cells expressing such antibodies are induced to proliferate
and undergo affinity maturation in such a patient, the resulting
antibody can destroy the platelets in the presence of the drug.
Clinical Features
Patients with D-ITP typically present with petechiae, purpura, and
severe thrombocytopenia (platelet count often <20 × 109/L). Systemic
symptoms, such as fever and chills, may occur in patients with
abrupt-onset thrombocytopenia. Usually, the thrombocytopenia
becomes clinically apparent 1–2 weeks after initiation of the drug,
but the thrombocytopenia can start after a patient has been taking a
drug for several years. Typically, the platelet count begins to rise in a
few days after discontinuation of the implicated drug, but occasion-
ally several weeks are required for recovery, possibly because of the
generation of drug-independent IgG (platelet autoantibodies).
Sometimes drug exposure is relatively obscure. Among outpa-
tients, the physician needs to inquire about potential exposure to
quinine. Quinine is widely available: for example, as an ingredient in
tonic water, as an additive to street drugs, and in some countries as
therapy for leg cramps. Vancomycin is a relatively common cause of
D-ITP in hospitalized inpatients; most often this occurs after the
usual intravenous administration, but some reports have implicated
exposure via orthopedic cement or with peritoneal administration of
vancomycin.
 Chapter 132 Thrombocytopenia Caused by Platelet Destruction, Hypersplenism, or Hemodilution 1963

Rarely, distinct drug-dependent IgG molecules destroy RBCs or several that the patient is receiving) is most likely to explain a diag-
WBCs in addition to platelets. For example, both platelet- and nosis of D-ITP.10,12–14 The clinician should focus on drugs that have
leukocyte-reactive quinidine-dependent IgG molecules have been been started 5–10 days before the onset of the platelet count decrease
detected in a patient with quinidine-induced bicytopenia. Sometimes (Fig. 132.5A). Also, with drugs such as quinine, in which there may
the immune process is directed against a pluripotent hematopoietic be intermittent exposure (e.g., consumption of gin and tonic), a very
stem cell, resulting in pancytopenia accompanied by BM aplasia or recent exposure (previous 1 or 2 days) usually explains the abrupt
hypoplasia (e.g., gold-, carbamazepine-, or quinidine-induced pancy- onset of symptomatic thrombocytopenia.
topenia). A BM aspirate should be performed in patients with sus- After the physician has identified one or more potential agents,
pected drug-induced bicytopenia or pancytopenia because a the next step is to determine whether these drugs have previously
hypoplastic BM may be indicative of drug-induced aplastic anemia. been implicated as causes of D-ITP. The box Search Strategies When
Investigating Patient With Possible Drug-Induced Immune Throm-
bocytopenic Purpura includes some strategies for identifying drugs
Diagnosis implicated in D-ITP.
Demonstration of drug-dependent binding of IgG to platelets in
A high index of clinical suspicion is required to make the diagnosis. vitro can be important for diagnosis (see Fig. 132.5B). Labeled
Moreover, clinicians need to evaluate which drug (often among Ig-specific probes (e.g., phase II assays) or GP capture techniques
(phase III assays) can be used (see Table 132.3). In other cases, D-ITP
test results are negative, but the diagnosis still seems likely based on
clinical features and supporting literature (see Fig. 132.6).
TABLE List of Drugs Implicated in Drug-Induced Immune There are certain caveats in diagnostic testing. First, metabolites
132.5 Thrombocytopenia must sometimes be used instead of the parent drug to detect the IgG.
Drugs Common to All Three Lists12–14 Second, the target drug (or metabolite) must be included in the wash
Quinine, quinidine, rifampin, trimethoprim-sulfamethoxazole, buffer used in these assays. Third, despite these maneuvers, the sen-
vancomycin sitivity of in vitro assays is relatively low, and the diagnosis of D-ITP
George12 Reese13 Arnold14 must often be made on clinical grounds. Sometimes the diagnosis is
Acetaminophen Abciximab a
Abciximaba confirmed by inadvertent or deliberate reexposure to the suspected
Alprenolol Acetaminophen Carbamazepine drug. However, deliberate drug challenge is not often performed
Aminoglutethimide Amiodarone Ceftriaxone because of its potential risk.
Aminosalicylic acid Ampicillin Eptifibatideb A novel approach to identify drug-dependent platelet-reactive
Amiodarone Carbamazepine Ibuprofen antibodies was reported by investigators at the Milwaukee Blood
Amphotericin B Eptifibatideb Mirtazapine Center.20 They used nonobese diabetic/severe combined immunode-
Amrinone Ethambutol Oxaliplatin ficient (NOD/SCID) mice (which lack xenoantibodies, thereby
Chlorothiazide Haloperidol Penicillin allowing infused human platelets to circulate) to identify drug-
Chlorpromazine Ibuprofen Suramin dependent antibodies in patient sera, including antibodies that only
Cimetidine Irinotecan Tirofibanb recognize drug metabolites (presumably, mice produce the same or
Danazol Naproxen Heparinc similar drug metabolites as humans, which are recognized by the
Diatrizoate meglumine Oxaliplatin drug-dependent antibodies).
Diazepam Phenytoin
Diazoxide Piperacillin
Diclofenac Ranitidine
Digoxin Simvastatin Search Strategies When Investigating a Patient With Possible
Ethambutol Sulfisoxazole Drug-Induced Immune Thrombocytopenic Purpura
Haloperidol Tirofibanb
Interferon-α Valproic acid Four sources of information as to whether a drug has been implicated
Iopanoic acid as a cause of D-ITP:
• PubMed search (http://www.ncbi.nlm.nih.gov/pubmed): [name of
Levamisole
drug] and [thrombocytopenia]. By way of example, the author
Lithium encountered a patient who developed severe thrombocytopenia
Meclofenamate 5 days after starting treatment with mirtazapine (Fig. 132.6).
Methyldopa Searching [mirtazapine] and [thrombocytopenia] in December
Minoxidil 2014 identified two reports17,18 of mirtazapine-induced D-ITP
Nalidixic acid syndrome.
Naphazoline • Drug-induced thrombocytopenia website (http://www.ouhsc.edu/
Nitroglycerin platelets/ditp.html): Investigators at the University of Oklahoma
Oxprenolol published a comprehensive survey of drugs implicated in
D-ITP using clinical criteria12; a website maintained by these
Sulfasalazine
investigators is updated every 2 years.
Sulfisoxazole • Database from drug-dependent platelet-reactive antibody
Tamoxifen testing at the BloodCenter of Wisconsin, 1995–2010 (http://
Thiothixene www.ouhsc.edu/platelets/InternetPostingLab2_18_11Frames.htm):
Tolmetin the BloodCenter of Wisconsin maintains a website reporting
a
Subtype of D-ITP where patient’s antibodies (either naturally occurring or that its experience in detecting drug-dependent platelet-reactive
are formed after treatment with abciximab) bind to platelet GPIIb/IIIa antibodies.19
subsequent to binding of abciximab (chimeric human-murine Fab that • Combined approach that uses clinical criteria,12 laboratory
recognizes GPIIb/IIIa) to platelets. criteria,19 and Adverse Event Reporting System.13 Table 132.5
b
Subtype of D-ITP caused by fiban-dependent antibodies (either naturally- (middle column) lists two dozen drugs (including those drugs
occurring or that are formed after treatment with eptifibatide or tirofiban) that identified by two other comprehensive reviews12,14) for which
recognize neoepitopes on platelet GPIIb/IIIa that form subsequent to binding of convincing clinical and laboratory evidence exists.13 To review
fiban drug to GPIIb/IIIa.
c
HIT is considered a distinct subtype of D-ITP disorder, given its unusual
the comprehensive list of all drugs investigated in this study,13
pathogenesis centered on IgG-induced platelet activation. interested readers can consult the online supplemental
D-ITP, Drug-induced immune thrombocytopenia; HIT, heparin-induced table (http://bloodjournal.hematologylibrary.org/content/
thrombocytopenia. suppl/2010/06/08/blood-2010-03-276691.DC1/TableS1.pdf).
1964 Part XII Hemostasis and Thrombosis

66 F: Admission for prosthetic valve endocarditis

300

Plt
250
tfns
Platelet count (mean × 109/L) 200 IVIg
x2
150
Nadir
100 4 × 109/L

50

0
Heparin Heparin
Ranitidine Omeprazole
Carbamazepine, phenytoin Carbamazepine, valproate
Gentamicin and vancomycin Teicoplanin
Digoxin Digoxin

–2 0 2 4 6 8 10 12 14 16
A Days after starting multiple drugs

Normal serum Normal serum

60 + buffer 60 + drug (vancomycin)
Events

Events

40 40

20 20

0 0
1 10 100 1000 1 10 100 1000
Fluorescence Fluorescence

Patient serum Patient serum

60 + buffer 60 + drug (vancomycin)
Events

Events

40 40

20 20

0 0
1 10 100 1000 1 10 100 1000
B Fluorescence Fluorescence
Fig. 132.5 DRUG-INDUCED IMMUNE THROMBOCYTOPENIA (D-ITP) SECONDARY TO VAN-
COMYCIN. A, Timeline of D-ITP. A 66-year-old woman was admitted for prosthetic valve endocarditis 5
months after undergoing mitral valve replacement. The initiation of multiple new drugs and the onset 6 days
later of progressively severe thrombocytopenia (platelet count nadir, 4 × 109/L on day 9) suggested D-ITP
syndrome. However, the timing fit several drugs (ranitidine, carbamazepine, phenytoin, gentamicin, vanco-
mycin, and digoxin). B, Drug-dependent binding of antibodies was demonstrated using patient serum and
vancomycin. Also, test results for heparin-induced thrombocytopenia antibodies was negative. Thus the
diagnosis of vancomycin-induced D-ITP syndrome was made based on clinical and serological grounds. The
patient received treatment with high-dose intravenous immunoglobulin (IVIG) and platelet transfusions. Plt
tfns, Platelet transfusions.
 Chapter 132 Thrombocytopenia Caused by Platelet Destruction, Hypersplenism, or Hemodilution 1965

Trauma (burn)-
associated
thrombo- Postoperative Resolution of Mirtazapine-induced
1800 cytopenia thrombocytosis thrombocytosis thrombocytopenia

1600
MIRTAZAPINE:
1400 tetracyclic antidepressant of the
piperazine-azapine group
Platelet count × 109/L 1200

1000

800 Abrupt unexpected

platelet count fall
600

400
High-dose IVIG
200

0
Platelet count nadir
Debridement Mirtazapine (12 × 109/L)

–20 –15 –10 –5 0 5 10 15 20

Days after starting mirtazapine
Fig. 132.6 DRUG-INDUCED IMMUNE THROMBOCYTOPENIA (D-ITP) SECONDARY TO MIR-
TAZAPINE. The onset of severe thrombocytopenia (platelet count nadir, 12 × 109/L) on day 6 of mirtazapine
therapy implicated this tetracyclic antidepressant of the piperazine-azapine group as a cause of drug-induced
immune thrombocytopenia (D-ITP) syndrome. The very rapid platelet count fall (which was already manifest
on day 5 of mirtazapine therapy) is explained by reduced platelet production (because the patient’s platelet
count was declining from postoperative thrombocytosis). Although in vitro testing for mirtazapine-dependent
antibodies was negative, the low sensitivity of these assays does not rule out mirtazapine as the cause of
D-ITP syndrome, particularly in a high pretest probability scenario such as this. IVIg, Intravenous
immunoglobulin.

Management high-dose IVIg. Some patients with persisting thrombocytopenia

As many drugs as possible should be discontinued in patients with
suspected D-ITP. If further drug treatment is necessary, an alternate,
immunologically non–cross-reactive substitute should be used.
Spontaneous improvement in the platelet count usually begins within
a few days of discontinuing the offending drug, although in some
cases, complete recovery may take 2 weeks or longer. Platelet transfu-
sions should be given to patients with life-threatening bleeding.
High-dose intravenous immunoglobulin (IVIg), 1 g/kg given over
6–8 hours, with a second dose 1 or 2 days later if required, may be
helpful in some situations. Corticosteroids appear to be relatively
ineffective for treatment of D-ITP.
GOLD-INDUCED THROMBOCYTOPENIA
Gold-induced ITP occurs in as many as 1% to 3% of treated
patients. A genetic predisposition is suggested by the association
with HLA-DR3, which is found in approximately 85% of affected
patients. The thrombocytopenia typically occurs during the first 20
weeks of therapy before a total of 1000 mg of gold has been given.
Rarely, the thrombocytopenia begins much later, sometimes several
months after discontinuation of the gold. Although the onset of
thrombocytopenia is typically abrupt, regular platelet count monitor-
ing is important because an early diagnosis can be made in some
patients. The thrombocytopenia often persists for several months
after discontinuation of the gold, probably because of gold-induced
autoimmune thrombocytopenia (drug-independent gold-induced
autoantibodies against gold-induced antiglycoprotein V [GPV] have
been implicated) (see Fig. 132.4). Although most patients will even-
tually respond to corticosteroids, immediate, albeit often transient,
correction of severe thrombocytopenia can usually be achieved with
benefit from splenectomy or use of gold-chelating agents (dimercap-
rol, N-acetylcysteine). The disorder is rarely encountered because the
use of gold to treat rheumatic disorders has declined.
DRUG-INDUCED AUTOIMMUNE THROMBOCYTOPENIA
Certain drugs other than gold have been reported to initiate auto-
immune thrombocytopenia (e.g., levodopa, procainamide). Because
the pathogenic antibodies are by definition drug independent,
however, it is difficult to establish causation. The mumps–measles–
rubella (MMR) vaccine can rarely (≈1 : 40,000) cause a severe but
generally self-limited thrombocytopenia that is clinically and sero-
logically indistinguishable from childhood acute ITP; MMR vaccina-
tion of unimmunized children with ITP and revaccination of children
with prior ITP does not lead to recurrent thrombocytopenia.
DRUG-INDUCED IMMUNE THROMBOCYTOPENIA OF
RAPID ONSET
A rapid onset of thrombocytopenia (within hours) can occur if a
patient with preexisting drug-dependent antibodies is (re)exposed to
the drug. This situation is relatively common in HIT (≈25% of
patients identified)3 because repeated treatment with heparin is
common and heparin use itself can result in the complication (HIT-
associated thrombosis) that might lead to further use of heparin.
Because HIT antibodies are transient, however, rapid-onset HIT
occurs in patients with recent heparin exposures, usually within the
past 100 days.3 By contrast, repeated episodes of quinine-induced
thrombocytopenia of abrupt onset can occur many months or
even years apart because these antibodies persist for much longer.
 1966 Part XII Hemostasis and Thrombosis
Thrombocytopenia of rapid onset is commonly seen with GPIIb/IIIa
receptor antagonists (see next section).
THROMBOCYTOPENIA CAUSED BY GLYCOPROTEIN IIB/
IIIA RECEPTOR ANTAGONISTS
Several thrombocytopenic syndromes have been reported with use of
GPIIb/IIIa receptor antagonists (abciximab, eptifibatide, tirofiban)
administered during percutaneous coronary intervention (e.g., angio-
plasty, stenting): (1) rapid-onset, severe thrombocytopenia within 12
hours of drug administration (in 0.4%–2% of patients), (2) rapid-
onset pseudothrombocytopenia (in approximately 1% of patients
exposed to abciximab [ReoPro]), (3) rapid-onset thrombocytopenia
within 12 hours of a second exposure to a GPIIb/IIIa antagonist, and
(4) delayed-onset thrombocytopenia beginning 5–7 days after drug
administration (rare).21 The frequency of rapid-onset thrombocyto-
penia is higher among patients who receive a second course of therapy,
especially if it follows the initial exposure by only a few weeks.
Thrombocytopenia is typically severe (median platelet count nadir,
about 5 × 109/L to 10 × 109/L), but clinical effects vary dramatically,
ranging from absence of petechiae or other signs of bleeding (in 50%
of patients) to fatal hemorrhage (in less than 5%). Some patients
develop anaphylactoid reactions accompanying the abrupt platelet
count declines. The antibodies may cause thrombosis in some
patients, likely because the pathogenic antibodies also activate
platelets.21
These syndromes are caused by at least three mechanisms. First,
antibodies of IgG (and possibly IgM) class can bind to neoepitopes
on the GPIIb/IIIa complex generated by these drugs (or their metabo-
lites), that is, ligand-induced binding sites (see Fig. 132.4). Up to 5%
of humans and nonhuman primates have naturally occurring IgG
antibodies that will bind to GPIIb/IIIa receptors in the presence of
drug, which could explain why rapid-onset thrombocytopenia occurs
so frequently with these agents. A second mechanism is applicable to
abciximab, a chimeric Fab fragment comprised of murine GPIIb/
IIIa-reactive sequences and human framework sequences. Interest-
ingly, although a high frequency of normal persons (74%) have
antibodies that recognize platelets coated with abciximab, these
“normal” antibodies were shown to differ from those detected in
patients in whom thrombocytopenia developed after a second expo-
sure to abciximab: whereas the pathogenic antibodies recognized
murine sequences within abciximab, the “normal” (nonpathogenic)
antibodies were specific for the carboxyl terminus (papain cleavage
site) of Fab fragments prepared from normal human IgG. Drug-
dependent antibodies can also be generated about 1 week after
exposure. The antibodies differ among patients with respect to the
precise neoepitopes recognized and display variable degrees of cross-
reactivity among the different GPIIb/IIIa receptor antagonists
(“fibans”); this explains why a repeat treatment course with another
GPIIb/IIIa receptor antagonist may not necessarily cause thrombo-
cytopenia. A third mechanism involves eptifibatide-dependent anti-
bodies that activate platelets via their FcγIIa receptors.21
Some naturally occurring antibodies only bind to GPIIb/IIIa
when the calcium concentration is low, thus explaining
pseudothrombocytopenia—falsely low platelet count estimates
caused by ex vivo aggregation of platelets in blood samples collected
into calcium-chelating anticoagulants, especially EDTA. The rare
syndrome of delayed-onset thrombocytopenia after brief exposure
might result from high-titer GPIIb/IIIa-reactive antibodies that bind
even in the absence of the drug.
Platelet transfusions are indicated in patients who are bleeding,
although their efficacy has not been established. Platelet transfusions
are most likely to be effective for the treatment of abciximab-induced
thrombocytopenia because the drug binds so tightly to GPIIb/IIIa
that little abciximab is free to bind to the transfused platelets. Platelet
transfusions are not indicated in pseudothrombocytopenia, which
underscores the importance of reviewing the blood film when a
low platelet count is reported after treatment with one of these
agents.
Approach to Patients With Thrombocytopenia Following Percutaneous
Coronary Intervention
Four diagnoses should be considered in patients who develop thrombo-
cytopenia within minutes or a few hours after a PCI and have received
one or more of the following agents: (1) platelet GPIIb/IIIa inhibitor
(e.g., abciximab, eptifibatide, tirofiban), (2) heparin, or (3) iodinated
contrast agent.
• GPIIb/IIIa inhibitor–induced pseudothrombocytopenia. The patient
has no symptoms or signs of bleeding, and platelet aggregates
are seen in the blood film. The platelet count is falsely reported
as low by the automated particle counter, which fails to count
aggregated platelets. No treatment is required.
• GPIIb/IIIa inhibitor–induced thrombocytopenia. The platelet count
falls abruptly, often to profoundly reduced levels (typical nadir,
<20 × 109/L). Hemostatic impairment is variable, ranging from
petechiae to fatal hemorrhages; occasionally, patients develop
anaphylactoid reactions or even associated thrombosis. Treatment
involves stopping all platelet antagonists and anticoagulants and
giving platelets if the patient has signs of bleeding. Prophylactic
platelet transfusions can also be considered if the platelet count
is very low (e.g., <10 × 109/L). Testing for drug-dependent
antibodies can be accomplished using flow cytometry or ELISA.
• Rapid-onset HIT. In patients who have preexisting HIT antibodies
because of recent heparin exposure (generally within the
past 100 days), rapid-onset HIT can occur when heparin is
given during PCI. This is much less common than GPIIb/IIIa
inhibitor–induced thrombocytopenia or pseudothrombocytopenia,
so presumptive treatment of HIT with a nonheparin anticoagulant
is rarely indicated in this situation. The platelet count nadir
is usually much higher than with GPIIb/IIIa inhibitor–induced
thrombocytopenia.
• Radiocontrast-induced ITP. Very rarely, patients who have
previously received iodinated contrast can develop abrupt-onset,
severe thrombocytopenia after exposure to contrast during
PCI. Platelet transfusions (with or without high-dose IVIg) are
appropriate for a bleeding patient.
ELISA, Enzyme-linked immunosorbent assay; HIT, heparin-induced thrombocy-
topenia; ITP, induced thrombocytopenia; IVIg, intravenous immunoglobulin; PCI,
percutaneous coronary intervention.
Various in vitro assays using flow cytometry or enzyme-linked
immunosorbent assay (ELISA) have been developed to detect these
antibodies. Because some pathogenic antibodies are naturally occur-
ring, it is theoretically possible to identify patients at high risk for
rapid-onset thrombocytopenia in elective situations (see box on
Approach to Patients With Thrombocytopenia Following Percutane-
ous Coronary Interventions).
MISCELLANEOUS DRUG-INDUCED
THROMBOCYTOPENIC SYNDROMES
Drug-Induced Thrombotic Microangiopathy
Several drugs can trigger a syndrome of thrombocytopenia, fragmen-
tation hemolysis, and renal failure known as drug-induced thrombotic
microangiopathy (TMA). This syndrome has been established for
quinine,11 in which multiple quinine-dependent antibodies reactive
against platelets, RBCs, leukocytes, and endothelial cells have been
reported. Although TMA has been reported with ticlopidine and
clopidogrel, a recent systematic review22 failed to confirm this
association.
Although a similar syndrome may be caused by mitomycin,
gemcitabine, cyclosporine, and tacrolimus, it should be noted that
many patients who receive these drugs have an underlying illness
(e.g., gastric adenocarcinoma, BM transplantation, collagen vascular
disease) that itself can be complicated by TMA; moreover, high
cumulative doses of the implicated drug have usually been received,
suggesting a nonimmune (e.g., toxic) pathogenesis.11 Furthermore,
 Chapter 132 Thrombocytopenia Caused by Platelet Destruction, Hypersplenism, or Hemodilution
these patients tend to be less responsive to plasma exchange than
those with idiopathic TTP.
Drug-Induced Disseminated Intravascular Coagulation
On rare occasions, quinine causes severe thrombocytopenia accom-
panied by marked coagulation abnormalities indicative of DIC. This
syndrome overlaps that of quinine-induced thrombotic microangi-
opathy, and the explanation for the prominent coagulopathy is
unknown. Although all patients with HIT have biochemical evidence
of increased thrombin generation, only about 10% to 20% have overt
DIC; however, these patients often present with large and small vessel
thrombosis.
Nonidiosyncratic Drug-Induced Thrombocytopenia
Most antineoplastic drugs produce dose-dependent pancytopenia
because of their effect on hematopoietic cells, including megakaryo-
cytes and their progenitor cells. Typically, the platelet count nadir
occurs at a predictable time after treatment, and the count then
quickly recovers. Unexpectedly severe or prolonged thrombocytope-
nia in patients receiving chemotherapy should suggest alternate
explanations (e.g., idiosyncratic thrombocytopenia caused by another
drug).
Mild to moderate thrombocytopenia develops in approximately
20% of patients who take valproic acid (an antiepileptic agent);
bleeding symptoms are uncommon. The mechanism of thrombocy-
topenia in this setting is unknown, but the condition appears to be
nonidiosyncratic because the risk of thrombocytopenia correlates
strongly with serum concentrations of valproic acid metabolite.
Amrinone is another agent that can cause mild, dose-dependent
thrombocytopenia.
Rapid Nonimmune Drug-Induced Thrombocytopenia
Some drugs produce rapid but generally mild and transient drops in
the platelet count. These drugs include heparin, protamine, bleomy-
cin, hematin, desmopressin (particularly in patients with type 2B von
Willebrand disease), and porcine factor VIII. The mechanisms for
thrombocytopenia in these syndromes are obscure.
Drug Hypersensitivity Reactions
Mild to moderate thrombocytopenia is sometimes observed in
patients with systemic drug hypersensitivity reactions. Co-morbid
clinical features can include generalized rash, fever, cholestasis, and
leukopenia. Allopurinol, isoniazid, sulfasalazine, and phenothiazine
drugs, among others, have been implicated in these reactions.
Thrombocytopenia Secondary to Biologic
Response Modifiers
Use of purified or recombinant biologic response modifiers such as
interferon, interleukin-2, and certain colony-stimulating factors has
resulted in severe, reversible thrombocytopenia in some patients.
Antilymphocyte globulins can also produce severe thrombocytopenia.
OTHER CAUSES OF DESTRUCTIVE THROMBOCYTOPENIA
Incidental Thrombocytopenia of Pregnancy
Maternal thrombocytopenia occurs in 4% to 8% of pregnancies.23
Most affected women are healthy and have no history of thrombo-
cytopenia, and their thrombocytopenia is incidentally detected by
1967
routine blood testing. The cause of the mild reduction in platelet
count (approximately 75 × 109/L to 150 × 109/L) is believed to
represent a leftward shift in the normal platelet count range during
pregnancy related to one or more of hemodilution, reduced platelet
production, or increased platelet turnover.23 This condition is benign
and is not associated with an increased risk for maternal bleeding or
neonatal thrombocytopenia. Accordingly, no special maneuvers are
indicated in these women, and the route of delivery should be
determined by obstetric indications. Epidural anesthesia is believed
to be safe if the platelet count is at least 75 × 109/L.
Preeclampsia and Eclampsia
Preeclampsia is characterized by the onset of hypertension and pro-
teinuria during pregnancy, especially in a primigravida near term.
Preeclampsia complicates approximately 5% of pregnancies, and the
frequency is higher in black women. Thrombocytopenia occurs in up
to 50% of preeclamptic patients, and its severity generally parallels
that of the underlying preeclampsia.23 A subset of patients with
preeclampsia has microangiopathic hemolysis, elevated liver enzymes,
and low platelets, widely known as the HELLP syndrome. This
condition usually indicates severe preeclampsia and is associated with
a higher risk of fetal and maternal complications, including maternal
hepatic rupture. Repeated clinical and laboratory assessment of these
patients is important because this syndrome can mimic other life-
threatening complications of pregnancy, such as overt DIC, TTP,
septicemia, and acute fatty liver of pregnancy.
Increased platelet destruction is the mechanism for the thrombo-
cytopenia in preeclampsia. However, activation of the coagulation
system is relatively modest, suggesting that thrombin generation may
not be a major driver of the thrombocytopenia. Endothelial dysfunc-
tion (e.g., impaired nitric oxide synthesis) is a potential explanation
for increased platelet turnover in preeclampsia.
Pharmacologic control of hypertension and rapid delivery are the
treatments for preeclampsia and usually result in resolution of the
thrombocytopenia within a few days. If delivery is not an option,
treatment with bed rest and aggressive antihypertensive therapy has
been reported to result in an improved platelet count. However, the
clinical course is markedly variable, and some patients develop life-
threatening organ failure. Plasmapheresis has been used in some
patients, especially if there is evidence of thrombotic microangiopathy
and organ dysfunction. Plasma exchange is appropriate for patients
whose clinical picture has features suggesting TTP.
Infection
Infection is a common cause of thrombocytopenia, occurring in
approximately 50% to 75% of patients with bacteremia or fungemia
and in almost all patients with septic shock or DIC. Even when
caused by bacteremia, the thrombocytopenia is generally mild to
moderate in severity and is usually not accompanied by significant
coagulation abnormalities or bleeding. The likelihood of laboratory
evidence for DIC increases as the platelet count falls below 50 ×
109/L. The mechanisms for thrombocytopenia in septicemia in the
absence of DIC are uncertain but could include chemokine-induced
macrophage ingestion of platelets (hemophagocytosis) and direct
activation of platelets by endogenous mediators of inflammation
(e.g., platelet-activating factor) or certain microbial products. In rare
situations, platelet-reactive autoantibodies are implicated. Various
explanations for thrombocytopenia in different types of infection are
listed in Table 132.6.
Unexplained thrombocytopenia in a hospitalized patient warrants
studies to exclude infection, such as blood cultures. Prompt recogni-
tion and treatment of the infection constitute the most important
therapy because platelet count recovery tends to parallel the resolu-
tion of the infection. Prophylactic platelet transfusions are generally
not required unless the platelet count falls below 10 × 109/L or
comorbid clinical features increase the likelihood of serious bleeding
 1968 Part XII Hemostasis and Thrombosis

TABLE Mechanisms for Thrombocytopenia Complicating immune complexes containing IgM antiidiotype antibodies (which
132.6 Infections could explain the paradox of high levels of platelet-associated IgG and
IgM with low serum levels of platelet-reactive antibodies). Anti-HIV
Mechanism for Thrombocytopenia Selected Example(s)a therapy (e.g., zidovudine, HAART) often raises the platelet count
Increased Platelet Destruction in patients with HIV-associated thrombocytopenia. Most patients
DIC Meningococcemia with HIV-associated thrombocytopenia respond to conventional
treatments for ITP, including corticosteroids, splenectomy, IVIg, and,
Hemophagocytosis Septicemia, EBV infection
particularly, anti-D.
Platelet-reactive autoantibodies Varicella, subacute bacterial
(acute) endocarditis (rare)
Platelet-reactive autoantibodies HIV infection Systemic Lupus Erythematosus
(chronic)
Immune-mediated thrombocytopenia, which occurs in as many as
HUS Verocytotoxin-producing
25% of patients with SLE, is associated with a twofold increased risk
Escherichia coli, Shigella spp.,
of organ damage events. Many different types of platelet–IgG interac-
HIV infection
tions are described (e.g., antiglycoprotein, antiglycolipid, β2-
Antibodies against platelet- Malaria glycoprotein I [β2GPI]–containing immune complexes). In addition,
adsorbed microbial antigens antithrombopoietin, anti–c-Mpl (thrombopoietin receptor), and
Hypersplenism anti-CD40 ligand autoantibodies have been reported. Multiple causes
Acute Disseminated Mycobacterium for thrombocytopenia—increased platelet destruction, hypersplen-
avium infection in HIV ism, and even impaired platelet production related to antibody-
infection induced megakaryocytic hypoplasia—have been reported. The
Chronic Viral chronic active hepatitis, predominant explanation for thrombocytopenia in SLE remains
malaria unknown.
Decreased Platelet Production
Several thrombocytopenic syndromes are seen in patients with
SLE. For many patients, the thrombocytopenia is chronic, resembling
Replacement of BM by Ehrlichiosis, tuberculosis
ITP, and is the predominant clinical manifestation of the lupus.
granulomas
Often, these patients have a prolonged bleeding time despite mild
Infection of megakaryocytes HIV infection thrombocytopenia. Some thrombocytopenic patients with SLE have
Transient virus-induced aplasia Parvovirus B19 infection antiphospholipid (aPL) antibodies and are at increased risk for
(erythroblastopenia thrombotic rather than bleeding complications (see Chapter 141).
predominates) Acute, severe thrombocytopenia can be a prominent feature in
Multiple Mechanisms patients with a severe multisystem exacerbation of lupus. Rarely,
Platelet destruction plus Recurrent malaria patients with SLE develop an illness that closely resembles TTP or
hypersplenism HUS; these patients should be treated with plasma exchange. Throm-
bocytopenia as a feature of SLE-associated, viral-induced macrophage
Increased platelet destruction, Chronic HIV infection activation syndrome has been reported.
decreased platelet production, Treatment of the thrombocytopenia of SLE is similar to that of
hypersplenism ITP (see Chapter 131). Corticosteroids constitute the first line of
a
References can be found in Hoffman R, Benz EJ Jr, Shattil SJ, et al, eds: therapy, but many patients do not respond or require high doses.
Hematology: Basic Principles and Practice, ed 3. New York, 2000, Churchill High-dose IVIg may be useful in patients who are bleeding to tran-
Livingstone. BM, Bone marrow; DIC, disseminated intravascular coagulation;
EBV, Epstein-Barr virus; HIV, human immunodeficiency virus; HUS, hemolytic siently increase the platelet count. Before resorting to splenectomy,
uremic syndrome. one could try danazol (an attenuated androgen) in doses of
200–800 mg/day. Higher doses can cause hepatitis. Typically, several
weeks of treatment are required before a benefit is seen. Splenectomy
is probably as effective in achieving platelet count remission in SLE
as in ITP. Patients with refractory thrombocytopenia sometimes
(e.g., concomitant coagulopathy, an invasive procedure, uremic benefit from more aggressive therapies, such as azathioprine,
platelet dysfunction). The use of heparin for patients with septic intermittent-pulse cyclophosphamide, plasmapheresis synchronized
shock and DIC is controversial. However, heparin may be of benefit with pulse cyclophosphamide, cyclosporine, thrombopoietin mimet-
in patients with clinical evidence of DIC and microvascular throm- ics, or rituximab.
bosis (e.g., acral tissue ischemia or necrosis). The possibility of
acquired protein C deficiency complicating acute DIC should also
be considered in septic patients with purpura fulminans, such as that Antiphospholipid Syndrome
secondary to meningococcemia, or preceding “shock liver,”4,5 in
whom treatment with heparin24 and plasma could be beneficial. Antiphospholipid syndrome (APS; see Chapter 141) is characterized
Vitamin K administration is reasonable, although it will not help in by occurrence of one or more clinical events (e.g., venous, arterial or
the absence of vitamin K deficiency. small vessel thrombosis, pregnancy loss, preterm delivery for patients
Thrombocytopenia in patients infected with HIV poses a special with severe preeclampsia or placental insufficiency) associated with
diagnostic problem because there are many potential explanations IgG, IgM, or IgA antibodies that recognize a complex of one or more
for the thrombocytopenia. These include immune platelet destruc- protein cofactors (e.g., β2GPI, annexin V, prothrombin, protein C,
tion, impaired platelet production secondary to HIV infection protein S) bound to negatively charged phospholipid. Many patients
of megakaryocytes, drug-induced myelosuppression (commonly (30%–50%) with this syndrome have thrombocytopenia, which is
implicated drugs include zidovudine, ganciclovir, and TMP-SMX), typically mild and intermittent; approximately 15% have auto-
HIV-associated thrombotic microangiopathy, hypersplenism, and immune hemolysis. The APS should be considered in patients who
BM infiltration by tumor or opportunistic infections. Platelet kinetic develop idiopathic lower limb or abdominal vein (mesenteric, renal,
studies have shown a complex interaction of decreased platelet produc- adrenal) thrombosis, cerebral venous (dural sinus) thrombosis, cardiac
tion, increased platelet destruction, and splenic platelet sequestration. valvulitis, nonatheromatous arterial thrombosis (especially throm-
Immune mechanisms for platelet destruction include antibodies that botic stroke in a patient younger than 50 years of age), dermal
cross-react with GPIIb/IIIa complexes (“molecular mimicry”) and microvascular thrombosis (acrocyanosis, digital ulceration or
 Chapter 132 Thrombocytopenia Caused by Platelet Destruction, Hypersplenism, or Hemodilution
gangrene, livedo reticularis), or acute multiorgan failure associated
with DIC or widespread thrombosis of the microvasculature (cata-
strophic APS).
The mechanism of the prothrombotic tendency in patients with
APS remains elusive, but interference with endothelial cell function,
impaired fibrinolysis, antibody-mediated platelet activation, forma-
tion of endothelial microparticles, interference with thrombin and
factor Xa degradation by antithrombin, disturbance in the protein C
anticoagulant pathway or anticoagulant activity of β2GPI have all
been described. Disruption of the antithrombotic annexin V anti-
thrombotic “shield” by aPL antibodies has been proposed to explain
pregnancy losses through placental vascular thrombosis. Evidence
indicates that thrombocytopenia in patients with APS is associated
with platelet GP-reactive autoantibodies.
aPL antibodies are detected by either of two methods: (1) solid-
phase ELISA with purified phospholipids (usually cardiolipin) as
target antigens or (2) a “functional” assay for so-called lupus antico-
agulant (LA) activity, shown by demonstrating inhibition of certain
phospholipid-dependent coagulation assays, such as the activated
partial thromboplastin time or the Russell viper venom time.
Although aPL antibodies are frequently detected in patients with
SLE, they can also be found in patients with other autoimmune
disorders, malignancy, or infections or as a complication of certain
drugs (e.g., procainamide). Often no associated condition is identi-
fied (“primary” APS). aPL antibodies of low titer are sometimes found
in normal persons, particularly elderly individuals, or during normal
pregnancy. Autoantibody “cluster” studies show that anticardiolipin,
LA, and anti–double-stranded DNA antibodies occur together more
often than with other SLE-associated autoantibodies (e.g., anti-Sm,
anti-Ro, anti-RNP).
There are intriguing parallels between the APS and HIT: in both
disorders, the antibodies are directed at a protein target (β2GPI and
PF4, respectively) bound to a negatively charged species (anionic
phospholipid and heparin, respectively). For both, high-titer IgG
antibodies that result in a positive “functional” test result (LA activity
and HIT-IgG–induced platelet activation, respectively) are most
likely to be associated with clinical disease. Both disorders are char-
acterized by the paradox of thrombocytopenia associated with
increased risk for venous and arterial thrombosis.
To help physicians diagnose the APS, clinical and laboratory cri-
teria have been developed. The laboratory criteria include the pres-
ence of anticardiolipin, anti-β2GPI, or LA antibodies (moderate- to
high-titer IgG or IgM) on two or more occasions at least 12 weeks
apart. The major clinical criteria are thrombosis and complications
of pregnancy. Thrombosis can involve large arteries or veins or small
vessels within any organ. The complications of pregnancy include one
or more unexplained deaths of normal fetus(es) after week 10 of
gestation or premature births (before 34 weeks) or more than three
spontaneous abortions before week 10 of gestation. Some experts
advocate for thrombocytopenia to be included within the criteria for
APS.25
Specific treatment for the thrombocytopenia is not usually
required. For many patients, long-term anticoagulant or antiplatelet
therapy, or both, are needed to prevent recurrent thrombosis. For
patients with recurring pregnancy losses and aPL antibodies, random-
ized trials have documented the benefit of low-dose aspirin com-
bined with either low-dose UFH or low-molecular-weight heparin
(LMWH).
Malignancy
Thrombocytopenia complicating malignant disorders most frequently
results from antineoplastic treatment or BM replacement by tumor.
However, certain thrombocytopenic syndromes have been associated
with malignancy, including autoimmune thrombocytopenia, DIC,
and thrombotic microangiopathy.
ITP attributable to platelet GP-reactive autoantibodies can
complicate neoplastic lymphoproliferative diseases such as Hodgkin
disease, non-Hodgkin lymphoma, chronic lymphocytic leukemia,
1969
and multiple myeloma. Sometimes the thrombocytopenia responds
to treatment of the neoplasm, although in some patients (par-
ticularly those with Hodgkin disease), the thrombocytopenia is
indistinguishable from ITP and is not related to the activity of the
lymphoma.
DIC occurs with certain malignancies, particularly adenocarci-
noma of the pancreas, stomach, lung, colon, breast, and prostate.
Some patients present with venous or, less commonly, arterial throm-
bosis as the first clinical manifestation of their malignancy. In these
patients, the presence of thrombocytopenia is an important clue that
should prompt investigations for DIC, such as measurement of
fibrinogen or D-dimer levels. In the author’s experience, the platelet
count typically rises to normal or even elevated levels with heparin
therapy because heparin ameliorates the DIC process; however, recur-
rent thrombocytopenia and thrombosis can occur within hours of
discontinuing the heparin therapy.26 Cancer patients with DIC and
venous thrombosis are also at increased risk for warfarin-associated
venous limb gangrene.26 The role of various tumor-associated proco-
agulant substances—such as “cancer procoagulant” (a 68-kDa cysteine
proteinase that activates factor X independently of tissue factor/factor
VIIa) and cancer-associated tissue factor (which is expressed on tumor
cells, as well as circulating microparticles)—suggest pathophysiologic
parallels with microthrombosis in HIT because both cancer-associated
DIC and acute HIT are risk factors for phlegmasia cerulean dolens
and venous limb gangrene during anticoagulation with warfarin.
Thus cancer patients with DIC should receive heparin (especially
LMWH) rather than warfarin anticoagulation (see box on Diagnostic
Considerations in the Patient With Limb Ischemia and Thrombocy-
topenia in Chapter 133). DIC with hemorrhagic manifestations is
characteristically seen in some patients with prostate cancer and in
many patients with acute promyelocytic leukemia. It is crucial to
recognize promyelocytic leukemia because treatment with all-trans-
retinoic acid produces differentiation of the malignant cells, thereby
rapidly reducing the life-threatening bleeding risks attributable to
hyperfibrinolysis.
A destructive thrombocytopenic disorder that resembles HUS or
TTP has been described in patients with advanced cancer. In some
patients, mitomycin, gemcitabine, or other drugs may have contrib-
uted to the microangiopathy. DIC is not usually present. Some
patients respond transiently to plasmapheresis, but for many, response
to any therapy is poor.
Macrophage Activation (Hemophagocytic) Syndrome
The macrophage activation (or hemophagocytic) syndrome comprises
a heterogeneous group of disorders characterized by variable cytope-
nias and morphologic evidence of macrophage phagocytosis of RBCs,
granulocytes, and platelets; hyperferritinemia, hypercytokinemia, and
sepsis-like features are characteristic, with potential for evolution to
fatal multiple organ failure.27 Some adult patients have an aggressive
disease characterized by high fever, weight loss, prominent hepato-
splenomegaly, severe pancytopenia, elevated liver enzymes, and often
a terminal infection. Both T- and B-cell lymphomas can explain such
a dramatic syndrome. However, similar patients with fulminant
illness have been described after otherwise unremarkable bacterial or
viral infections (particularly those caused by Epstein-Barr virus). In
children, the high mortality rate associated with hemophagocytic
lymphohistiocytosis warrants aggressive treatment, including anti-
neoplastic chemotherapy and BM transplantation. Nonneoplastic
but nonetheless severe hemophagocytosis can be seen in patients with
certain infections (e.g., babesiosis, ehrlichiosis, HIV infection), as
well as in patients with rheumatologic disorders (SLE, Still disease,
ankylosing spondylitis). Laboratory indicators of macrophage activa-
tion syndrome include markedly elevated ferritin,28 high levels of
soluble CD163 and CD25, and morphologic evidence of hemo-
phagocytosis. Treatment should be directed at the underlying illness.
Early administration of corticosteroids and high-dose IVIg appears
to benefit some patients with nonneoplastic macrophage activation
syndrome.
 1970 Part XII Hemostasis and Thrombosis

60 54.9
After cardiac surgery
50
After orthopedic surgery
Patients (%) 40 38.4
31.6
30 25.5 26.7
Potentially abnormal
20 on or after day 5
13.0
10 4.3 3.8
0.4 1.4
0
1 2 3 4 5 >6
A Days of postoperative nadir

300 300
Platelet count (× 109/L)

200 200

Hemodilution Day 3 nadir

100 Day 2 nadir 100
Hemodilution

0 0
0 1 2 3 4 5 0 1 2 3 4 5
B Days after cardiac surgery C Days after cardiac surgery
Fig. 132.7 EARLY POSTOPERATIVE PLATELET COUNT DECLINES. (A) Distribution of early post-
operative count nadirs. For both orthopedic and cardiac surgery patients, day 2 represents the most common
day for the postoperative platelet count nadir to occur (data exclude day 0); beyond postoperative day 4, it is
likely that a superimposed thrombocytopenic disorder is occurring. (B and C) Representative postcardiac
surgery platelet count declines. Both patients illustrate early hemodilution effects (day 0) and subsequent
additional early platelet count declines with nadirs of day 2 (B) and day 3 (C). Neither patient received platelet
transfusions. (From Greinacher A, Warkentin TE: Acquired non-immune thrombocytopenia. In: Marder VJ, Aird WC,
Bennett JS, et al, editors: Hemostasis and thrombosis: Basic principles and clinical practice, ed 6. Philadelphia, 2013,
Lippincott Williams & Wilkins, p 796.)

Solid Organ and Bone Marrow Transplantation
Thrombocytopenia commonly occurs during episodes of solid organ
allograft rejection. It is possible that platelet activation and deposition
in the transplanted organ vasculature contribute to the rejection
process. Antirejection therapies can also cause thrombocytopenia
through increased platelet destruction (antilymphocyte globulin) or
BM suppression (azathioprine). Posttransplantation HUS develops in
approximately 5% of renal transplant recipients and in even fewer
recipients of liver or heart transplants. Although cyclosporine is
sometimes implicated in HUS, it can usually be safely resumed after
recovery.
Early, severe thrombocytopenia caused by BM-ablative therapy
invariably accompanies BM transplantation (BMT). Platelet count
recovery to greater than 50 × 109/L is more rapid (16 vs. 35
days) in patients receiving autologous mobilized peripheral blood
progenitor cells than in those undergoing autologous BMT. Severe
persistent thrombocytopenia despite recovery of RBCs and WBCs
is relatively common after BMT or peripheral blood transplanta-
tion; autoimmune thrombocytopenia has been implicated in some
patients. Late-onset thrombocytopenia after BMT that responds to
corticosteroids, IVIg, and splenectomy also has been attributed to
autoimmune thrombocytopenia. Rarely, transplantation-associated
alloimmune thrombocytopenia can be caused by donor–recipient
incompatibility involving platelet-specific alloantigens such as PlA1
(HPA-1a) or Bra (HPA-5b).
A syndrome of thrombocytopenia, RBC fragmentation, and renal
impairment can occur in as many as 10% of patients undergoing
BMT, usually beginning 3–12 months after transplantation (BMT-
associated thrombotic microangiopathy). The pathogenesis remains
obscure; reduced ADAMTS13 (a disintegrin and metalloproteinase
with thrombospondin 13) levels have not been implicated. The
hematologic abnormalities can be mild and remit spontaneously,
although patients often have residual azotemia and hypertension.
More severely affected patients do not usually benefit from plasma-
pheresis. The syndrome has a poor overall prognosis, and many
patients die irrespective of any intervention.
Cardiopulmonary Bypass Surgery
Excess bleeding is a common problem in patients who undergo heart
surgery using cardiopulmonary bypass. Many of these patients receive
blood transfusions, and approximately 5% require reoperation for
postoperative bleeding.
Thrombocytopenia and transient platelet dysfunction (see Chapter
159) are observed in virtually every patient. Typically, the platelet
count falls by 30% to 70%, primarily as a result of hemodilution but
also because of bleeding and losses within the extracorporeal perfu-
sion device. Because patients invariably receive heparin during cardiac
surgery and have often received heparin in the remote or recent past,
immune HIT is frequently considered in the differential diagnosis
of early-onset and persisting postcardiac surgery thrombocytopenia;
however, HIT is an unlikely explanation for thrombocytopenia even
when anti-PF4/heparin antibodies are positive.29
The bleeding time increases markedly during heart surgery (to
greater than 30 minutes) but usually improves to less than 15 minutes
shortly after surgery and to normal several hours later. By contrast,
the thrombocytopenia persists for 3–4 days followed by recovery of
the platelet count to values exceeding the preoperative baseline.
 Chapter 132 Thrombocytopenia Caused by Platelet Destruction, Hypersplenism, or Hemodilution
The pathogenesis and clinical significance of the hemostatic defect
in these patients remain uncertain, but the explanation is probably
multifactorial. Studies have described transient, intrinsic defects in
platelet function. These defects include decreased in vitro platelet
aggregation, decreased platelet surface membrane proteins, selective
depletion of platelet α-granules, and evidence of in vivo platelet
activation and platelet vesiculation. The platelet dysfunction in heart
surgery is also attributable to an extrinsic platelet defect resulting from
thrombin inhibition by the high doses of heparin. Furthermore, an
important role for hyperfibrinolysis in the pathogenesis of bleeding
is shown by elevated D-dimer levels in bleeding patients, as well as
the efficacy of antifibrinolytic agents in the prevention and treatment
of heart surgery–associated bleeding. Other factors in some patients
include residual heparin effect after bypass (including heparin
rebound) and preoperative use of aspirin and/or clopidogrel. Treat-
ment of platelet dysfunction after cardiopulmonary bypass is discussed
in Chapter 159.
THROMBOCYTOPENIA ASSOCIATED WITH
CARDIOVASCULAR DISEASE
Congenital Cyanotic Heart Disease
Thrombocytopenia caused by a decrease in platelet life span occurs
in some patients with severe cyanotic congenital heart disease and is
approximately related to the severity of the polycythemia. Bleeding
occurs in a few patients and can be related to platelet function defects,
coagulopathy, or hyperfibrinolysis. Reducing the hematocrit by
phlebotomy sometimes helps to correct the hemostatic defects.
Valvular Heart Disease
Increased platelet turnover is common in valvular heart disease, and
some patients have mild thrombocytopenia. The pathogenesis of the
platelet consumption is not well understood, but the defect could be
related to increased platelet–von Willebrand factor (vWF) interac-
tions at high shear. Indeed, high-molecular-weight multimers of vWF
are reduced in some of these patients, which explains why bleeding
from gastrointestinal angiodysplasia in patients with aortic stenosis
(Heyde syndrome) typically resolves after aortic valve replacement.30
Thrombocytopenia secondary to consumptive coagulopathy can be
seen in intracardiac thrombosis associated with valvular heart disease.
Pulmonary Vascular Disorders
Disorders characterized by pulmonary hypertension can be accompa-
nied by thrombocytopenia, the pathogenesis of which is poorly
defined. Thrombocytopenia can occur in association with pulmonary
embolism, possibly as a result of DIC. When evaluating such patients,
the clinician should inquire about current or recent heparin exposure
because HIT and pulmonary embolism are strongly associated.
HEMODILUTION AND PLATELET CONSUMPTION
AFTER SURGERY
Platelet count declines of 30% to 70% occur universally after
major surgery and reflect the combined effects of hemodilution
and increased platelet consumption. Such hemodilution-associated
thrombocytopenia is especially prominent after cardiac surgery and is
proportional to the amount of fluids (crystalloid, colloid, blood prod-
ucts) administered. The platelet count fall is abrupt and is evident a
few hours after surgery. Dilutional coagulopathy also occurs, which
is responsible for the minor to moderate increases in coagulation test
results that occur transiently after surgery.
Perioperative hemodilution is also usually accompanied by
increased platelet consumption related to the effects of surgery. This
1971
helps to explain why the postsurgery platelet count usually continues
to decline over the next 1–3 days, with the postoperative nadir (lowest
platelet count value) usually occurring at a median of postoperative
day 2, with a range between postoperative days 1–4 (Fig. 132.7).2
Subsequently, there is a rise in the platelet count that peaks at
approximately day 14 at levels often 2–3 times the patient’s preopera-
tive baseline before it returns to baseline over the next 2 weeks (≈day
28). As described earlier in this chapter (see Fig. 132.1), these platelet
count changes reflect thrombopoietin physiology.
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