Disorders of Leukocytes

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Current Diagnosis & Treatment: Pediatrics, 26e
Chapter 30: Hematologic Disorders
DISORDERS OF LEUKOCYTES
NEUTROPENIA
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Increased frequency of infections.
Ulceration of oral mucosa and gingivitis.
Decreased absolute neutrophil count; normal numbers of red cells and platelets.
General Considerations
Neutropenia is an absolute neutrophil (granulocyte) count of less than 1500/μL in childhood, or less than 1100/μL between ages 1 month and 2 years.
During the first few days of life, an absolute neutrophil count of less than 3500/μL may be considered neutropenia in term infants. Neutropenia results
from absent or defective myeloid stem cells; ineffective or suppressed myeloid maturation; altered production of hematopoietic cytokines or
chemokines or abnormalities in their receptors; decreased marrow release; increased neutrophil apoptosis; destruction or consumption; or, in
pseudoneutropenia, from an increased neutrophil marginating pool (Table 30–5). A decrease in neutrophil mass diminishes delivery of these cells to
areas where the balance favors bacterial proliferation and invasion.
Table 30–5.
Classification of neutropenia in childhood.
Congenital neutropenia with abnormalities of stem cells or committed myeloid progenitor cells
Reticular dysgenesis
Chronic idiopathic neutropenia of childhood
Severe congenital neutropenia (SCN 15 and Xlinked)
Cyclic neutropenia
ShwachmanDiamond syndrome
WHIM syndrome
Glycogenosis Ib
ChédiakHigashi syndrome
Cohen syndrome
Barth syndrome
HermanskyPudlak syndrome
Griscelli syndrome
CharcotMarieTooth syndrome
Cartilagehair hypoplasia
Dyskeratosis congenital
Organic acidemias (eg, propionic, methylmalonic)
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Fanconi anemia
Neutropenia with immunodeficiency disorders (SCID, hyperIgM)
Acquired neutropenias affecting stem cells
from absent or defective myeloid stem cells; ineffective or suppressed myeloid maturation; altered production of hematopoietic cytokines or
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chemokines or abnormalities in their receptors; decreased marrow release; increased neutrophil apoptosis; destruction or consumption; or, in
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pseudoneutropenia, from an increased neutrophil marginating pool (Table 30–5). A decrease in neutrophil mass diminishes delivery of these cells to
areas where the balance favors bacterial proliferation and invasion.
Table 30–5.
Classification of neutropenia in childhood.
Congenital neutropenia with abnormalities of stem cells or committed myeloid progenitor cells
Reticular dysgenesis
Chronic idiopathic neutropenia of childhood
Severe congenital neutropenia (SCN 15 and Xlinked)
Cyclic neutropenia
ShwachmanDiamond syndrome
WHIM syndrome
Glycogenosis Ib
ChédiakHigashi syndrome
Cohen syndrome
Barth syndrome
HermanskyPudlak syndrome
Griscelli syndrome
CharcotMarieTooth syndrome
Cartilagehair hypoplasia
Dyskeratosis congenital
Organic acidemias (eg, propionic, methylmalonic)
Osteopetrosis
Fanconi anemia
Neutropenia with immunodeficiency disorders (SCID, hyperIgM)
Acquired neutropenias affecting stem cells
Malignancies (leukemia, lymphoma) and preleukemic disorders
Drugs or toxic substances
Ionizing radiation
Aplastic anemia
Acquired neutropenias affecting committed myeloid progenitors or survival of mature neutrophils
Ineffective myelopoiesis (vitamin B12, folate, and copper deficiency)
Infection
Immune (neonatal alloimmune or autoimmune, autoimmune, or chronic benign neutropenia of childhood)
Hypersplenism
The severity of neutropenia may be characterized by the level of peripheral neutrophils, the number and severity of infections, and the production of
mature neutrophils in the marrow. Also important is whether the neutropenia is acute (< 3 months) or chronic (> 3 months). The most severe types of
chronic neutropenia include reticular dysgenesis (congenital aleukocytosis), Kostmann syndrome or severe congenital neutropenia, SCN (severe
neutropenia with maturation defect in the marrow progenitor cells associated with specific gene defects), Shwachman syndrome (neutropenia with
pancreatic insufficiency), neutropenia with immune deficiency states, cyclic neutropenia, and myelokathexis or dysgranulopoiesis. Genetic mutations
for ChédiakHigashi syndrome (LYST (CHS1), Whim syndrome (CXCR4), SCN 15 (ELANE, GFl1, HAX1, G6PC3, VPS45, as well as WASP and GCSF3R),
Shwachman syndrome (SBDS), and cyclic neutropenia (ELANE) have been identified. Neutropenia may also be associated with storage (GSDIb) and
metabolic diseases, immunodeficiency states, and other disorders. At least 17 genes have been implicated in all these disorders. In many cases,
neutropenia represents the sole manifestation but sometimes the disorder is also associated with multisystem involvement. The most common causes
of acute neutropenia are viral infection or drugs, resulting in decreased neutrophil production in the marrow, increased peripheral turnover, or both.
Severe bacterial infections may be associated with neutropenia. Although not commonly identified, neonatal alloimmune neutropenia can be severe
and associated with infection. Autoimmune neutropenia occurs with chronic benign neutropenia of childhood, immunodeficiency syndromes,
autoimmune disorders, or, in the newborn, as a result of passive transfer of antibody (alloimmune) from the mother to the fetus. Benign ethnic
neutropenia is a common cause of neutropenia in patients of African or Middle Eastern ethnicity and has recently been attributed to single nucleotide
polymorphism in the gene ACKR1/DARC. While peripheral blood neutrophil counts are moderately decreased, patients are not at increased risk for
DISORDERS OF LEUKOCYTES, Rachelle Nuss; Christopher McKinney; Michael Wang Page 2 / 30
infections due to the presence of abundant neutrophils in the tissues. Malignancies, osteopetrosis, marrow failure syndromes, and hypersplenism
usually are not associated with isolated neutropenia.
Clinical Findings
neutropenia represents the sole manifestation but sometimes the disorder is also associated with multisystem involvement. The most common causes
of acute neutropenia are viral infection or drugs, resulting in decreased neutrophil production in the marrow, increased peripheral turnover, or both.
Severe bacterial infections may be associated with neutropenia. Although not commonly identified, neonatal alloimmune neutropenia can be severe
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and associated with infection. Autoimmune neutropenia occurs with chronic benign neutropenia of childhood, immunodeficiency syndromes,
autoimmune disorders, or, in the newborn, as a result of passive transfer of antibody (alloimmune) from the mother to the fetus. Benign ethnic
neutropenia is a common cause of neutropenia in patients of African or Middle Eastern ethnicity and has recently been attributed to single nucleotide
polymorphism in the gene ACKR1/DARC. While peripheral blood neutrophil counts are moderately decreased, patients are not at increased risk for
infections due to the presence of abundant neutrophils in the tissues. Malignancies, osteopetrosis, marrow failure syndromes, and hypersplenism
usually are not associated with isolated neutropenia.
Clinical Findings
A. Symptoms and Signs
Acute severe bacterial or fungal infection is the most significant complication of neutropenia. Although the risk is increased when the absolute
neutrophil count is less than 500/μL, the actual susceptibility is variable and depends on the cause of neutropenia, marrow reserves, and other factors.
The most common types of infection include septicemia, cellulitis, skin abscesses, pneumonia, and perirectal abscesses. In addition to local signs and
symptoms, patients may have chills, fever, and malaise. Sinusitis, aphthous ulcers, gingivitis, and periodontal disease are also significant problems in
chronic neutropenia. In most cases, the spleen and liver are not enlarged. Staphylococcus aureus and gramnegative bacteria are the most common
pathogens.
B. Laboratory Findings
Neutrophils are absent or markedly reduced in the peripheral blood. In most forms of neutropenia or agranulocytosis, the monocytes and
lymphocytes are normal and the red cells and platelets are not affected. The bone marrow usually shows a normal erythroid series, with adequate
megakaryocytes, but a marked reduction in the myeloid cells or a significant delay in maturation of this series may be noted at various stages of
myeloid maturation. Total cellularity may be decreased.
In the evaluation of neutropenia (eg, persistent, intermittent, cyclic), attention should be paid to the duration and pattern of neutropenia, the types of
infections and their frequency, and phenotypic abnormalities on physical examination. A careful family history and blood counts from the parents may
be useful. If an acquired cause, such as viral infection or drug, is not obvious as an acute cause, no other primary disease is present, and the
neutropenia is chronic, WBC counts, white cell differential, and platelet and reticulocyte counts should be completed twice weekly for 6 weeks to
determine the pattern of neutropenia. Bone marrow aspiration and biopsy including cytogenetic analysis are most important to characterize the
morphologic features of myelopoiesis. Measuring the neutrophil counts in response to corticosteroid infusion may document the marrow reserves.
Other tests that aid in the diagnosis include measurement of neutrophil antibodies, immunoglobulin levels, antinuclear antibodies, and lymphocyte
phenotyping to detect immunodeficiency states. Culture of bone marrow may define myeloid progenitors or the presence of inhibitory factors.
Cytokines in plasma or produced by mononuclear cells can be measured directly. Some neutropenia disorders have abnormal neutrophil function, but
severe neutropenia may preclude collection of sufficient cells to complete assays. Analysis for gene mutations noted above may help confirm the
diagnosis of a severe neutropenia syndrome. Increased apoptosis in marrow precursors or circulating neutrophils is a general characteristic described
in several congenital or genetic disorders.
Treatment
Underlying disorders should be identified and treated or associated agents should be eliminated. Infections should be aggressively assessed and
treated. Prophylactic antimicrobial therapy is not indicated for afebrile, asymptomatic patients but may be considered in rare cases with recurrent
infections. Recombinant granulocytecolony–stimulating factor (GCSF) will increase neutrophil counts in most patients; granulocytemacrophage
colonystimulating factor (GMCSF) may be considered but is less extensively used. For patients with neutrophil counts of 500/μL or less GCSF
(Filgrastim) may be started at 3–5 mcg/kg/day subcutaneously or intravenously once a day, and the dose adjusted to keep the absolute neutrophil
count between 500/μL and 10,000/μL. The use of longacting GCSF (pegfilgrastim) has been used in a few patients with chronic neutropenia. In a small
number of patients, GCSF therapy has been shown to be safe for mothers and not teratogenic. Some patients maintain adequate counts with GCSF
given every other day. Treatment will decrease infectious complications but may have little effect on periodontal disease. However, not all patients with
neutropenia syndromes require GCSF (eg, chronic benign neutropenia of childhood). Patients with cyclic neutropenia may have a milder clinical
course as they grow older. Immunizations should be given if the adaptive immune system is normal. Hematopoietic stem cell transplant may be
considered for patients with severe complications, especially those with severe congenital neutropenia refractory to GCSF administration.
Prognosis
The prognosis varies greatly with the cause and severity of the neutropenia. In severe cases with persistent agranulocytosis, the prognosis is poor in
spite of antibiotic therapy but GCSF has the potential to prolong life expectancy. In mild or cyclic forms of neutropenia, symptoms may be minimal and
the prognosis for normal life expectancy excellent. Chronic benign neutropenia of childhood resolves spontaneously in up to 90% of children by 5
years of age. Up to 50% of patients with Shwachman syndrome may develop aplastic anemia, myelodysplasia, or leukemia during their lifetime.
neutropenia syndromes require GCSF (eg, chronic benign neutropenia of childhood). Patients with cyclic neutropenia may have a milder clinical
course as they grow older. Immunizations should be given if the adaptive immune system is normal. Hematopoietic stem cell transplant may be
considered for patients with severe complications, especially those with severe congenital neutropenia refractory to GCSF administration.
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Prognosis
The prognosis varies greatly with the cause and severity of the neutropenia. In severe cases with persistent agranulocytosis, the prognosis is poor in
spite of antibiotic therapy but GCSF has the potential to prolong life expectancy. In mild or cyclic forms of neutropenia, symptoms may be minimal and
the prognosis for normal life expectancy excellent. Chronic benign neutropenia of childhood resolves spontaneously in up to 90% of children by 5
years of age. Up to 50% of patients with Shwachman syndrome may develop aplastic anemia, myelodysplasia, or leukemia during their lifetime.
Patients with other SCNs also have a potential for leukemia, as do patients with neutropenia associated with some immune disorders. Hematopoietic
stem cell transplant may be the only curative therapy for some disorders.
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history. Br J Haematol 2017;179:557–574. doi: 10.1111/bjh.14887
[PubMed: 28875503] .
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[PubMed: 27621310] .
Palmblad J: Ethnic benign neutropenia: a phenomenon finds an explanation. Peditar Blood Cancer 2018;65(12):e27361. doi: 10.1002/pbc.27361
[PubMed: 30117263] .
NEUTROPHILIA
Neutrophilia is an increase in the absolute neutrophil count in the peripheral blood to greater than 7500–8500/μL for infants, children, and adults. To
support the increased peripheral count, neutrophils may be mobilized from bone marrow storage or peripheral marginating pools. Neutrophilia
occurs acutely in association with bacterial or viral infections, inflammatory diseases (eg, juvenile rheumatoid arthritis, inflammatory bowel disease,
Kawasaki disease), surgical or functional asplenia, liver failure, diabetic ketoacidosis, azotemia, congenital disorders of neutrophil function (eg,
chronic granulomatous disease, leukocyte adherence deficiency), and hemolysis. Drugs such as corticosteroids, lithium, and epinephrine increase the
blood neutrophil count. Corticosteroids cause release of neutrophils from the marrow pool, inhibit egress from capillary beds, and postpone
apoptotic cell death. Epinephrine causes release of the marginating pool. Acute neutrophilia has been reported after stress, such as from electric
shock, trauma, burns, surgery, and emotional upset. Tumors involving the bone marrow, such as lymphomas, neuroblastomas, and
rhabdomyosarcoma, may be associated with leukocytosis and the presence of immature myeloid cells in the peripheral blood. Infants with Down
syndrome have defective regulation of proliferation and maturation of the myeloid series and may develop neutrophilia. At times this process may
affect other cell lines and mimic myeloproliferative disorders or acute leukemia.
The neutrophilias must be distinguished from myeloproliferative disorders such as chronic myelogenous leukemia and juvenile chronic myelogenous
leukemia. In general, abnormalities involving other cell lines, the appearance of immature cells on the blood smear, and the presence of
hepatosplenomegaly are important differentiating characteristics.
DISORDERS OF NEUTROPHIL FUNCTION
Neutrophils play a key role in host defenses. Circulating in the laminar flow of blood vessels, they adhere to capillary vascular endothelium adjacent to
sites of infection and inflammation. Moving between endothelial cells, the neutrophil migrates toward the offending agent. Contact with a microbe that
is properly opsonized with complement or antibodies triggers ingestion, a process in which cytoplasmic streaming results in the formation of
pseudopods that fuse around the invader, encasing it in a phagosome. During the ingestion phase, the oxidase enzyme system assembles in the
phagosomal membrane and is activated, taking oxygen from the surrounding medium and reducing it to form toxic oxygen metabolites critical to
microbicidal activity. Concurrently, granules from the two main classes (azurophil and specific) fuse and release their contents into the
phagolysosome. The concentration of toxic oxygen metabolites (eg, hydrogen peroxide, hypochlorous acid, hydroxyl radical) and other compounds
(eg, proteases, cationic proteins, cathepsins, defensins) increases dramatically, resulting in the death and dissolution of the microbe. Complex
physiologic and biochemical processes support and control these functions. Defects in any of these processes may lead to inadequate neutrophil
function and an increased risk of infection.
sites of infection and inflammation. Moving between endothelial cells, the neutrophil migrates toward the offending agent. Contact with a microbe that
is properly opsonized with complement or antibodies triggers ingestion, a process in which cytoplasmic streaming results in the formation of
pseudopods that fuse around the invader, encasing it in a phagosome. During the ingestion phase, the oxidase enzyme system assembles in the
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phagosomal membrane and is activated, taking oxygen from the surrounding medium and reducing it to form toxic oxygen metabolites critical to
microbicidal activity. Concurrently, granules from the two main classes (azurophil and specific) fuse and release their contents into the
phagolysosome. The concentration of toxic oxygen metabolites (eg, hydrogen peroxide, hypochlorous acid, hydroxyl radical) and other compounds
(eg, proteases, cationic proteins, cathepsins, defensins) increases dramatically, resulting in the death and dissolution of the microbe. Complex
physiologic and biochemical processes support and control these functions. Defects in any of these processes may lead to inadequate neutrophil
function and an increased risk of infection.
Classification
Table 30–6 summarizes congenital neutrophil function defects. Recently reported is variant CGD with p40phox deficiency manifested by inflammatory
bowel disease. Also described is a syndrome of severe neutrophil dysfunction and severe infections associated with a mutation in a GTPase signaling
molecule, Rac2 (gene, RAC2). New syndromes of innate immune dysfunction include defects in interferon and interleukin (IL)12 receptor and signaling
pathways, leading to monocyte and macrophage dysfunction and defective tolllike receptor signaling pathways (IL1 receptor–associated kinase 4
[IRAK4] deficiency) associated with recurrent bacterial infections. Leukocyte adhesion deficiency (LAD) III is a disorder characterized by severe
bleeding, impaired leukocyte adhesion, and endothelial inflammation, and is associated with mutations of FERMT3 gene, which encodes for a protein,
Kindlin3, critical for intracellular function of β integrins and perhaps other adhesion strategies. Other congenital or acquired causes of mild to
moderate neutrophil dysfunction include metabolic defects (eg, glycogen storage disease Ib, G6PC3 deficiency, other congenital neutropenia
syndromes (eg, ChediakHigashi syndrome and ShwachmanDiamond syndrome), diabetes mellitus, renal disease, and hypophosphatemia, viral
infections, and certain drugs. Neutrophils from newborn infants have abnormal adherence, chemotaxis, and bactericidal activity. Cells from patients
with thermal injury, trauma, and overwhelming infection have defects in neutrophil motility and bactericidal activity similar to those seen in neonates.
Table 30–6.
Classification of congenital neutrophil function deficits.
Inheritance
Disorder Clinical Manifestations Functional Defect Biochemical Defect (Chromosome;
Gene)
ChédiakHigashi Oculocutaneous albinism, photophobia, Neutropenia. Neutrophils, Gene (CHS1/LYST) deficit Autosomal

syndrome nystagmus, ataxia. Recurrent infections of skin, monocytes, lymphocytes, identified. Alterations in recessive
respiratory tract, and mucous membranes with platelets, and all membrane fusion with (1q42.1.2; CHS1)
grampositive and gramnegative organisms. Many granulecontaining cells have formation of giant
patients die during lymphoproliferative phase giant granules. Most granules. Other
with hepatomegaly, fever, which may be a significant defect is in biochemical abnormalities
viralassociated hemophagocytic syndrome chemotaxis. Also milder in cAMP and cGMP,
secondary to EpsteinBarr virus infection. Older defects in microbicidal microtubule assembly.
patients may develop degenerative CNS disease. activity and degranulation.
Leukocyte Recurrent softtissue infections, including Neutrophilia. Diminished Absence or partial Autosomal

adherence gingivitis, otitis, mucositis, periodontitis, skin adherence to surfaces, deficiency of CD11b/CD18 recessive
deficiency I infections. Delayed separation of the cord in leading to decreased cell surface adhesive (12q22.3; ITGB2)
newborn and problems with wound healing. chemotaxis. glycoprotein. Defect in
expression CD18 (gene,
TGB2)
Leukocyte Recurrent infections, mental retardation, Neutrophilia. Deficient Deficient fucosyl Autosomal

adherence craniofacial abnormalities, short stature. “rolling” interactions with transferase (gene, recessive
deficiency II endothelial cells. Red cells SLC35C1) results in (11p11.2;
have Bombay phenotype. deficient SialylLewisX SLC35C1)
antigen, which interacts
with P selectin. P selectin
on endothelial cells is
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Leukocyte Recurrent severe infections, lifethreatening Neutrophilia. Dysfunctional Mutations in kindlin3 Autosomal

deficiency II endothelial cells. Red cells SLC35C1) results in (11p11.2;
have Bombay phenotype. deficient SialylLewisX
SLC35C1)
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antigen, which interacts
with P selectin. P selectin
on endothelial cells is
required for neutrophil
rolling, a prerequisite for
adherence and diapedesis.
Leukocyte Recurrent severe infections, lifethreatening Neutrophilia. Dysfunctional Mutations in kindlin3 Autosomal

adherence bleeding complications platelet aggregation. impair intracellular recessive
deficiency III activation of integrins (FERMT3)
Chronic Recurrent purulent infections with catalase Neutrophilia. Neutrophils Several molecular defects Xlinked in 60%–

granulomatous positive bacteria and fungi. May involve skin, demonstrate deficient in oxidase components. 65% of cases
disease mucous membranes. Patients also develop deep bactericidal activity but Absent cytochrome b558 (Xp21.1; CYBB)
infections (lymph nodes, lung, liver, bones) and normal chemotaxis and with decreased expression Autosomal
sepsis. ingestion. Defect in the of either (1) or (2): recessive in < 5%
oxidase (Nox2) enzyme 1. gp91phox (gene, of cases (16q24;
system, resulting in absence CYBB) CYBA)
or diminished production of 2. p22phox (gene, CYBA) Autosomal
oxygen metabolites toxic to recessive in 30%
Absent p47phox (gene,
microbes. of cases
NCF1) or p67phox (gene,
(7q11.23; NCF1
NCF2) both are cytosolic
and 1q25; NCF2,
components.
respectively)
Fourth cytosolic
component defect
described, p40phox
deficiency (gene, NCF4)
Myeloperoxidase Generally healthy. Fungal infections when Diminished capacity to Diminished or absent Autosomal

deficiency deficiency associated with systemic diseases (eg, enhance hydrogen myeloperoxidase; recessive (17q22
diabetes in poor control). peroxidemediated posttranslational defect in 23)
microbicidal activity. processing protein.
Decreased killing of Candida.
Specific granule Recurrent skin and deep tissue infections. Neutropenia. Neutrophils Failure to produce specific Autosomal

deficiency have bandshaped or granules or their contents recessive
bilobed nuclei. Decreased during myelopoiesis. (14q11.2; CEBPε)
chemotaxis and bactericidal Defect in transcription
activity. factor (gene, C/EBP
epsilon).
cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; CNS, central nervous system; Nox2, NADPH oxidase 2.
Clinical Findings
Recurrent bacterial or fungal infections are the hallmark of neutrophil dysfunction. Although patients will have infectionfree periods, episodes of
pneumonia, sinusitis, cellulitis, cutaneous and mucosal infections (including perianal or peritonsillar abscesses), and lymphadenitis are frequent. As
with neutropenia, aphthous ulcers of mucous membranes, severe gingivitis, and periodontal disease are also major complications. In general, S
aureus or gramnegative organisms are commonly isolated from infected sites; other organisms may be specifically associated with a defined
neutrophil function defect. In some disorders, fungi account for an increasing number of infections. Deep or generalized infections, such as
osteomyelitis, liver abscesses, pneumonitis, sepsis, meningitis, and necrotic or gangrenous softtissue lesions, occur in specific syndromes (eg,
leukocyte adherence deficiency or chronic granulomatous disease). Patients with severe neutrophil dysfunction may die in childhood from severe
infections and associated complications. Table 30–7 summarizes pertinent laboratory findings.
Table 30–7.
Bleeding assessment.
pneumonia, sinusitis, cellulitis, cutaneous and mucosal infections (including perianal or peritonsillar abscesses), and lymphadenitis are frequent. As
with neutropenia, aphthous ulcers of mucous membranes, severe gingivitis, and periodontal disease are also major complications. In general, S
aureus or gramnegative organisms are commonly isolated from infected sites; other organisms may be specifically associated with a defined
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neutrophil function defect. In some disorders, fungi account for an increasing number of infections. Deep or generalized infections, such as
osteomyelitis, liver abscesses, pneumonitis, sepsis, meningitis, and necrotic or gangrenous softtissue lesions, occur in specific syndromes (eg,
leukocyte adherence deficiency or chronic granulomatous disease). Patients with severe neutrophil dysfunction may die in childhood from severe
infections and associated complications. Table 30–7 summarizes pertinent laboratory findings.
Table 30–7.
Bleeding assessment.
Test Assessment
Prothrombin Time (PT) Clotting function of factors X, VII, V, II, and fibrinogen
Activated partial thromboplastin Clotting function of highmolecularweight kininogen, prekallikrein, and factors XII, XI, IX, VIII, X, V, II, and fibrinogen
time (aPTT)
Complete Blood Count (CBC) Platelet size and number, anemia
Platelet function analyzer100 Platelet functional assessment
(PFA100) or whole blood platelet
aggregometry
Fibrinogen and thrombin time Clotting function of fibrinogen. Dysfibrinogenemia. Thrombin time measures the generation of fibrin from fibrinogen
following conversion of prothrombin to thrombin, as well as the antithrombin effects of fibrin degradation products
and heparin
Euglobulin lysis time (ELT) Fibrinolysis. The ELT is shortened, assess hyperfibrinolysis due to congenital deficiency of the fibrinolytic inhibitors
plasminogen activator inhibitor1 and α2antiplasmin. In ill patients, measurement of fibrin degradation products
may assist in the diagnosis of DIC
Treatment
The mainstay of management of these disorders is anticipation of infections and aggressive attempts to identify the foci and the causative agents.
Surgical procedures to achieve these goals may be both diagnostic and therapeutic. Broadspectrum antibiotics covering the range of possible
organisms should be initiated without delay, switching to specific antimicrobial agents when the microbiologic diagnosis is made. When infections are
unresponsive or they recur, granulocyte transfusions may be helpful.
Chronic management may include prophylactic antibiotics. Trimethoprimsulfamethoxazole and some other antibiotics (eg, rifampin) enhance the
bactericidal activity of neutrophils from patients with chronic granulomatous disease. Some patients with ChédiakHigashi syndrome improve
clinically when given ascorbic acid. Recombinant γinterferon decreases the number and severity of infections in patients with chronic granulomatous
disease. Demonstration of this activity aises the possibility that cytokines, growth factors, and other biologic response modifiers may be helpful in
other conditions in preventing recurrent infections. Bone marrow transplant has been successfully used to cure most major congenital neutrophil
dysfunction syndromes, and reconstitution with normal cells and cell function has been documented. Gene therapy techniques using autologous
hematopoietic stem cells corrected by lentiviral gene insertion or gene editing techniques may provide a future strategy for curing these disorders.
Prognosis
For mild to moderate defects, anticipation and conservative medical management ensure a better outlook. For severe defects, excessive morbidity and
significant mortality still exist. In some diseases, the development of noninfectious complications, such as the lymphoproliferative phase of Chédiak
Higashi syndrome or inflammatory syndromes in chronic granulomatous disease, may influence prognosis.
Ambruso DR: Primary immunodeficiency and other diseases with immune dysregulation. In: Wilmott RW et al (eds): Kendig’s Disorders of the
Respiratory Tract in Children . 9th ed. Philadelphia, PA: Elsevier; 2019:909–922.
Bousfiha A et al: The 2017 IUIS phenotypic classification for primary immunodeficiencies. J Clin Immunol 2018;38(1):129–143. doi: 10.1007/s10875
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For mild to moderate defects, anticipation and conservative medical management ensure a better outlook. For severe defects, excessive morbidity and
significant mortality still exist. In some diseases, the development of noninfectious complications, such as the lymphoproliferative phase of Chédiak
Higashi syndrome or inflammatory syndromes in chronic granulomatous disease, may influence prognosis. Access Provided by:
Ambruso DR: Primary immunodeficiency and other diseases with immune dysregulation. In: Wilmott RW et al (eds): Kendig’s Disorders of the
Respiratory Tract in Children . 9th ed. Philadelphia, PA: Elsevier; 2019:909–922.
Bousfiha A et al: The 2017 IUIS phenotypic classification for primary immunodeficiencies. J Clin Immunol 2018;38(1):129–143. doi: 10.1007/s10875
01704658
[PubMed: 29226301] .
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LYMPHOCYTOSIS
From the first week up to the fifth year of life, lymphocytes are the most numerous leukocytes in human blood. The ratio then reverses gradually to
reach the adult pattern of neutrophil predominance. An absolute lymphocytosis in childhood is associated with acute or chronic viral infections,
pertussis, syphilis, tuberculosis, and hyperthyroidism. Other noninfectious conditions, drugs, and hypersensitivity and serum sickness–like reactions
cause lymphocytosis.
Fever, upper respiratory symptoms, gastrointestinal complaints, and rashes are clues in distinguishing infectious from noninfectious causes. The
presence of enlarged liver, spleen, or lymph nodes is crucial to the differential diagnosis, which includes acute leukemia and lymphoma. Most cases of
infectious mononucleosis are associated with hepatosplenomegaly or adenopathy. The absence of anemia and thrombocytopenia helps to
differentiate these disorders. Evaluation of the morphology of lymphocytes on peripheral blood smear is crucial. Infectious causes, particularly
infectious mononucleosis, are associated with atypical features in the lymphocytes, such as basophilic cytoplasm, vacuoles, finer and lessdense
chromatin, and an indented nucleus. These features are distinct from the characteristic morphology associated with lymphoblastic leukemia.
Lymphocytosis in childhood is most commonly associated with infections and resolves with recovery from the primary disease.
EOSINOPHILIA
Eosinophilia in infants and children is an absolute eosinophil count greater than 300/μL. Marrow eosinophil production is stimulated by the cytokine
IL5. Allergies, particularly those associated with asthma and eczema, are the most common primary causes of eosinophilia in children. Eosinophilia
also occurs in drug reactions, with tumors (Hodgkin and nonHodgkin lymphomas and brain tumors), and with immunodeficiency and histiocytosis
syndromes. Increased eosinophil counts are a prominent feature of many invasive parasitic infections. Gastrointestinal disorders such as chronic
hepatitis, ulcerative colitis, Crohn disease, and milk precipitin disease may be associated with eosinophilia. Increased blood eosinophil counts have
been identified in several families without association with any specific illness. Rare causes of eosinophilia include the hypereosinophilic syndrome,
characterized by counts greater than 1500/μL and organ involvement and damage (hepatosplenomegaly, cardiomyopathy, pulmonary fibrosis, and
central nervous system injury). This is a disorder of middleaged adults and is rare in children. Eosinophilic leukemia has been described, but its
existence as a distinct entity is very rare.
Eosinophils are sometimes the last type of mature myeloid cell to disappear after marrow ablative chemotherapy. Increased eosinophil counts are
associated with graftversushost disease after bone marrow transplant, and elevations are sometimes documented during rejection episodes in
patients who have solid organ grafts.
BLEEDING DISORDERS
Bleeding disorders may occur as a result of (1) quantitative or qualitative abnormalities of platelets, (2) quantitative or qualitative abnormalities in
plasma procoagulant factors, (3) vascular abnormalities, or (4) accelerated fibrinolysis. The coagulation cascade and fibrinolytic system are shown in
Figures 30–4 and 30–5.
Figure 30–4.
The procoagulant system and formation of a fibrin clot. Vascular injury initiates the coagulation process by exposure of tissue factor (TF); the dashed
patients who have solid organ grafts.
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BLEEDING DISORDERS
Bleeding disorders may occur as a result of (1) quantitative or qualitative abnormalities of platelets, (2) quantitative or qualitative abnormalities in
plasma procoagulant factors, (3) vascular abnormalities, or (4) accelerated fibrinolysis. The coagulation cascade and fibrinolytic system are shown in
Figures 30–4 and 30–5.
Figure 30–4.
The procoagulant system and formation of a fibrin clot. Vascular injury initiates the coagulation process by exposure of tissue factor (TF); the dashed
lines indicate thrombin actions in addition to clotting of fibrinogen. The dotted lines associated with VIIa indicate the feedback activation of the VIITF
complex by Xa and IXa. Ca++, calcium; HK, highmolecularweight kininogen; PK, prekallikrein; PL, phospholipid. (Reproduced with permission from
Goodnight SH, Hathaway WE: Disorders of Hemostasis & Thrombosis: A Clinical Guide. 2nd ed. New York, NY: McGraw Hill; 2001.)
Figure 30–5.
The fibrinolytic system. Solid arrows indicate activation; dashed line arrows indicate inhibition. ECM, extracellular matrix; FDP, fibrinogenfibrin
degradation products; MMP, matrix metalloproteinases; PAI, plasminogen activator inhibitor; TAFI, thrombin activatable fibrinolysis inhibitor; tPA,
tissue plasminogen activator; uPA, urokinase; uPAR, cellular urokinase receptor. (Reproduced with permission from Goodnight SH, Hathaway WE:
Disorders of Hemostasis & Thrombosis: A Clinical Guide. 2nd ed. New York, NY: McGraw Hill; 2001.)
The most critical aspect in evaluating the bleeding patient is obtaining detailed personal and family bleeding histories, including bleeding Page 9 / 30
complications associated with birth and the perinatal period, dental interventions, minor procedures, surgeries, and trauma. Excessive mucosal
bleeding is suggestive of a platelet disorder, von Willebrand disease (vWD), dysfibrinogenemia, or vasculitis. Bleeding into muscles and joints may be
associated with a plasma procoagulant factor abnormality. In either scenario, the abnormality may be congenital or acquired. A thorough physical
The fibrinolytic system. Solid arrows indicate activation; dashed line arrows indicate inhibition. ECM, extracellular matrix; FDP, fibrinogenfibrin
degradation products; MMP, matrix metalloproteinases; PAI, plasminogen activator inhibitor; TAFI, thrombin activatable fibrinolysis inhibitor; tPA,
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tissue plasminogen activator; uPA, urokinase; uPAR, cellular urokinase receptor. (Reproduced with permission from Goodnight SH, Hathaway WE:
Disorders of Hemostasis & Thrombosis: A Clinical Guide. 2nd ed. New York, NY: McGraw Hill; 2001.)
The most critical aspect in evaluating the bleeding patient is obtaining detailed personal and family bleeding histories, including bleeding
complications associated with birth and the perinatal period, dental interventions, minor procedures, surgeries, and trauma. Excessive mucosal
bleeding is suggestive of a platelet disorder, von Willebrand disease (vWD), dysfibrinogenemia, or vasculitis. Bleeding into muscles and joints may be
associated with a plasma procoagulant factor abnormality. In either scenario, the abnormality may be congenital or acquired. A thorough physical
examination should be performed with special attention to the skin, oro and nasopharynx, liver, spleen, and joints. Screening and diagnostic
evaluation in patients with suspected bleeding disorders (Table 30–7).
Goodnight SH, Hathaway WE (eds): Disorders of Hemostasis & Thrombosis: A Clinical Guide . 2nd ed. New York, NY: McGrawHill; 2001:41–51.
ABNORMALITIES OF PLATELET NUMBER OR FUNCTION
Thrombocytopenia in the pediatric age range is often immunemediated (eg, ITP, neonatal auto or alloimmune thrombocytopenia) but is also caused
by consumptive coagulopathy (eg, DIC, KasabachMerritt phenomenon), acute leukemias, or rarer disorders such as WiskottAldrich syndrome and
type 2b vWD, and artifactually in automated cytometers (eg, BernardSoulier syndrome), where giant forms may not be enumerated as platelets.
1. Idiopathic Thrombocytopenic Purpura
Otherwise healthy child.
Decreased platelet count.
Petechiae, ecchymoses.
Acute ITP is the most common bleeding disorder of childhood. It occurs most frequently in children aged 2–5 years and often follows infection with
viruses, such as rubella, varicella, measles, parvovirus, influenza, EBV, or HIV. The thrombocytopenia results from clearance of circulating IgM or IgG
coated platelets by the reticuloendothelial system. The spleen plays a predominant role in ITP by sequestering antibodybound platelets. Most patients
recover spontaneously within months. Chronic ITP (> 12 months duration) occurs in 10%–20% of affected patients.
Clinical Findings
Onset of ITP is usually acute, with the appearance of multiple petechiae and ecchymoses. Epistaxis and gingival bleeding are common, while hematuria
and hematochezia are less common. No other physical findings are usually present. Rarely, concurrent infection with EBV or CMV may cause
hepatosplenomegaly or lymphadenopathy.
recover spontaneously within months. Chronic ITP (> 12 months duration) occurs in 10%–20% of affected patients.
Clinical Findings Access Provided by:
Onset of ITP is usually acute, with the appearance of multiple petechiae and ecchymoses. Epistaxis and gingival bleeding are common, while hematuria
and hematochezia are less common. No other physical findings are usually present. Rarely, concurrent infection with EBV or CMV may cause
hepatosplenomegaly or lymphadenopathy.
1. Blood
The platelet count is markedly reduced (usually < 50,000/μL and often < 10,000/μL), and large platelets are present in the peripheral blood smear,
suggesting accelerated new platelet production. The WBC count and differential are normal, and the hemoglobin concentration is preserved unless
hemorrhage has been significant.
2. Bone marrow
Megakaryocyte hyperplasia with normal erythroid and myeloid cellularity.
3. Other laboratory tests
Plateletassociated IgG or IgM, or both, may be demonstrated on the platelets or in the serum. PT and aPTT are normal.
Differential Diagnosis
Table 30–8 lists common causes of thrombocytopenia. ITP remains a diagnosis of exclusion. Family history or the finding of predominantly giant
platelets on the peripheral blood smear is helpful in distinguishing ITP from hereditary thrombocytopenia. Bone marrow examination should be
performed when the history is atypical (ie, the child is not otherwise healthy, or there is a family history of bleeding), if abnormalities other than
purpura and petechiae are present on physical examination, or if other cell lines are abnormal on the CBC. Bone marrow examination prior to
treatment with corticosteroids is usually not required.
Table 30–8.
Common causes of thrombocytopenia.
Increased Turnover Decreased Production
AntibodyMediated Coagulopathy Other Congenital Acquired
Idiopathic Disseminated intravascular Hemolyticuremic syndrome Fanconi anemia Aplastic anemia

thrombocytopenic purpura coagulopathy Amegakaryocytic
thrombocytopenia
Infection Sepsis Thrombotic WiskottAldrich syndrome Leukemia and other

thrombocytopenic purpura malignancies
Immunologic diseases Necrotizing enterocolitis Hypersplenism Thrombocytopenia with Vitamin B12 and folate

Thrombosis Respiratory distress absent radii deficiencies
Cavernous hemangioma syndrome Metabolic disorders Medications
WiskottAldrich syndrome Osteopetrosis
Complications
Severe hemorrhage and bleeding are feared complications of ITP. Intracranial hemorrhage is the most serious complication, occurring in less than 1%
of affected children. The most important risk factors for hemorrhage are a platelet count less than 10,000/μL and mean platelet volume less than 8 fL.
Treatment
A. General Measures
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Complications
Severe hemorrhage and bleeding are feared complications of ITP. Intracranial hemorrhage is the most serious complication, occurring in less than 1%
of affected children. The most important risk factors for hemorrhage are a platelet count less than 10,000/μL and mean platelet volume less than 8 fL.
Treatment
A. General Measures
Observation is recommended for most children in the absence of bleeding regardless of platelet count. NSAIDs such as aspirin, ibuprofen, and
naproxen compromise platelet function and should be avoided. Bleeding precautions (eg, restriction from physical contact activities and use of
helmets) should be observed. Platelet transfusion should be avoided except in circumstances of lifethreatening bleeding, in which case emergent
splenectomy may be considered. In this setting, administration of corticosteroids and IVIG is also advisable.
B. Corticosteroids
Patients with clinically significant but non–lifethreatening bleeding (ie, epistaxis, hematuria, and hematochezia) and those with a platelet count of less
than 10,000/dL may benefit from treatment with corticosteroids. No single dose or dosing regimen has evidence to support its use. Prednisone 2
mg/kg/day (maximum of 60 mg/day) for 14–21 days, or alternatively, prednisone 4 mg/kg/day for 7 days, with a taper to day 14–21 are commonly used
regimens. An initial higher dose (3–5 mg/kg/day) for 3–7 days may lead to faster count recovery. Longterm use of corticosteroids should be avoided
because of toxicity.
C. Intravenous Immunoglobulin
Intravenous immunoglobulin (IVIG) is the treatment of choice for severe, acute bleeding, and may also be used as an alternative or adjunct to
corticosteroid treatment in both acute and chronic ITP. IVIG may be effective when the patient is not responsive to corticosteroids; responses are
prompt and may last for several weeks. A single dose of 0.8–1 g/kg has been recommended. Platelets may be given simultaneously during life
threatening hemorrhage but are rapidly destroyed. Side effects of IVIG are common, including transient neurologic complications in onethird of
patients (eg, headache, nausea, and aseptic meningitis) that mimic intracranial hemorrhage and necessitate radiologic evaluation. A transient
decrease in neutrophil number may also be seen, and hemolytic anemia is rare.
D. AntiRh(D) Immunoglobulin
This polyclonal immunoglobulin binds to the D antigen on RBCs. The splenic clearance of antiD–coated red cells interferes with removal of antibody
coated platelets, resulting in improvement in platelet count. This approach is effective only in Rh(+) patients with a functional spleen who are direct
antiglobulin test (DAT) negative. Approximately 80% of Rh+ children with acute or chronic ITP respond to doses of 50–75 mcg/kg; however, there is no
clear difference between antiD and IVIG in the time to reach a platelet count of 20 × 109/L. Significant hemolysis may occur in up to 5% of patients. The
FDA has provided specific monitoring requirements because of reports of fatal intravascular hemolysis.
E. Splenectomy
Many children with chronic ITP have platelet counts less than 30,000/μL. Corticosteroids, IVIG, and antiD immunoglobulin are typically effective
treatment for acute bleeding. Splenectomy produces a complete response in 70% and partial response in 20% of children with ITP, but it should be
considered only after persistence of significant thrombocytopenia for more than 12 months and the failure of a preferred or alternative secondline
therapy. The risk of overwhelming infection with encapsulated organisms is increased after splenectomy, particularly in the young child. Preoperative
vaccination with polyvalent pneumococcal conjugate and polysaccharide vaccines, meningococcal ACYW conjugate and serotype B vaccines, and H
influenzae b conjugate is recommended. If possible, the splenectomy should be postponed, until age 5 years. For patients younger than 5 years, 125
mg twice daily penicillin prophylaxis should be started postoperatively and continued at least until 5 years of age. Postoperatively, a reactive
thrombocytosis may raise the platelet count to more than 1 million/μL, but it is not associated with thrombosis in children. However, thrombosis is
recognized as a long term potential postsplenectomy complication.
F . Rituximab (AntiCD20 Monoclonal Antibody)
There have been no randomized trials for rituximab in children. The efficacy of treating childhood chronic ITP in several series and case studies has
demonstrated response rates between 26% and 60% but only 20%–30% remain in remission. Because of significant adverse events, this therapy is be
reserved for refractory cases with significant bleeding or as an alternative to splenectomy.
G. New Agents
Thrombopoietin receptor agonists are the only FDAapproved secondline treatments in pediatric ITP. They show high response rates without
F . Rituximab (AntiCD20 Monoclonal Antibody)
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There have been no randomized trials for rituximab in children. The efficacy of treating childhood chronic ITP in several series and case studies has
demonstrated response rates between 26% and 60% but only 20%–30% remain in remission. Because of significant adverse events, this therapy is be
reserved for refractory cases with significant bleeding or as an alternative to splenectomy.
G. New Agents
Thrombopoietin receptor agonists are the only FDAapproved secondline treatments in pediatric ITP. They show high response rates without
immunosuppression and durable responses at the cost of prolonged or indefinite treatment. Two thrombopoietin receptor agonists are now available
for children for the treatment of ITP > 6 months duration not responding to corticosteroids, IVIG, or splenectomy. These are FDAapproved for children
1 year or older. Phase III clinical trials evaluating the use of both eltrombopag and romiplostim demonstrated initial platelet response rate of 75% and
72%, respectively, with increased platelet counts, reduced bleeding and discontinuation of concomitant therapies. While adult studies have shown
adequate safety profiles with use up to 7 years, continued study in children is needed to evaluate longterm adverse effects such as thrombosis and
bone marrow fibrosis, and to confirm efficacy and sustained response.
Prognosis
Eighty percent of children with ITP will achieve a remission. Predictors of developing chronic ITP include female gender, age greater than 10 years at
presentation, insidious onset of bruising, and the presence of other autoantibodies. Treatment with a combination of IVIG and corticosteroids has
been associated with better remission rates at 12 and 24 months after diagnosis than with single agent therapy. Older child and adolescentonset ITP
is associated with an increased incidence of chronic autoimmune diseases or immunodeficiency states. Appropriate screening by history and
laboratory studies is warranted.
Bennett CM: Predictors of remission in children with newly diagnosed immune thrombocytopenia: data from the Intercontinental Cooperative ITP
Study Group Registry II participants. Pediatr Blood Cancer 2018;65(1)
[PubMed: 28792679] .
Neunert CE: Evidencebased management of immune thrombocytopenia: ASH guideline update. Hematology Am Soc Hematol Educ Program
2018;2018(1):568–575
[PubMed: 30504359] .
Provan D: Updated international consensus report on the investigation and management of primary immune thrombocytoipenia. Blood Adv
2019;3(22):3280–3817
[PubMed: 31770441] .
2. Thrombocytopenia in the Newborn
Thrombocytopenia is one of the most common causes of neonatal hemorrhage and should be considered in any newborn with petechiae, purpura, or
other significant bleeding. Defined by a platelet count of less than 150,000/μL, thrombocytopenia occurs in approximately 0.9% of unselected
neonates; however, up to 80% of neonates in a newborn intensive care unit may experience thrombocytopenia; most of these cases are transient.
Several specific entities may be responsible for more severe thrombocytopenia (see Table 30–8). Infection and DIC are the most common causes of
thrombocytopenia in ill fullterm newborns and in preterm newborns. In the healthy neonate, antibodymediated thrombocytopenia (alloimmune or
maternal autoimmune), viral syndromes, hyperviscosity, and majorvessel thrombosis are frequent causes of thrombocytopenia. Management is
directed toward the underlying etiology. Other infants are affected by unknown mechanisms in mothers with preeclampsia. Most of these cases
resolve over several days to a few weeks without treatment, but some are severe enough to warrant platelet transfusions.
A. Thrombocytopenia Associated With Platelet Alloantibodies (Fetal and Neonatal Alloimmune Thrombocytopenia [FNAIT])
FNAIT is the most common cause of thrombocytopenia in well, term infants, with a prevalence of 0.3–1 in 1000 pregnancies. Alloimmunization occurs
when a platelet antigen of the infant from the father differs from that of the mother, and the mother is sensitized by fetal platelets that cross the
placenta into the maternal circulation. In Caucasians, 80% are associated with HPA1a, and 10%–15% HPA5b. Bleeding can vary from minor skin effects
to severe intracranial hemorrhage (1 in 11,000 neonates). Other plateletspecific alloantigens may be etiologic. Unlike in Rh incompatibility, 30%–40%
of affected neonates are firstborn. Thrombocytopenia is progressive over the course of gestation and worse with each subsequent pregnancy. The
presence of antenatal maternal platelet antibodies on more than one occasion and their persistence into the third trimester is predictive of severe
neonatal thrombocytopenia; a weak or undetectable antibody does not exclude thrombocytopenia. Severe intracranial hemorrhage occurs in 10%–
30% of affected neonates as early as 20 weeks’ gestation. Petechiae or other bleeding manifestations are usually present shortly after birth. The
disease is selflimited, and the platelet count normalizes within 4 weeks.
FNAIT is the most common cause of thrombocytopenia in well, term infants, with a prevalence of 0.3–1 in 1000 pregnancies. Alloimmunization occurs
when a platelet antigen of the infant from the father differs from that of the mother, and the mother is sensitized by fetal platelets that cross the
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placenta into the maternal circulation. In Caucasians, 80% are associated with HPA1a, and 10%–15% HPA5b. Bleeding can vary from minor skin effects
to severe intracranial hemorrhage (1 in 11,000 neonates). Other plateletspecific alloantigens may be etiologic. Unlike in Rh incompatibility, 30%–40%
of affected neonates are firstborn. Thrombocytopenia is progressive over the course of gestation and worse with each subsequent pregnancy. The
presence of antenatal maternal platelet antibodies on more than one occasion and their persistence into the third trimester is predictive of severe
neonatal thrombocytopenia; a weak or undetectable antibody does not exclude thrombocytopenia. Severe intracranial hemorrhage occurs in 10%–
30% of affected neonates as early as 20 weeks’ gestation. Petechiae or other bleeding manifestations are usually present shortly after birth. The
disease is selflimited, and the platelet count normalizes within 4 weeks.
If alloimmunization is associated with clinically significant bleeding, transfusion of HPAselected irradiated platelets is preferred if immediately
available; unselected platelets may be used if HPAselected platelets are unavailable, and irradiation should not delay transfusion. If platelets are
unavailable infuse IVIG 1 g/kg. The rise in platelets will occur in 24–72 hours. If thrombocytopenia is not severe (> 30,000/uL) and bleeding is absent,
observation alone may be appropriate.
Intracranial hemorrhage in a previous child secondary to alloimmune thrombocytopenia is a strong risk factor for severe fetal thrombocytopenia and
hemorrhage in a subsequent pregnancy. Amniocentesis or chorionic villus sampling to obtain fetal DNA for platelet antigen typing is sometimes
performed if the father is heterozygous for HPA1a. If alloimmunization has occurred with a previous pregnancy, irrespective of history of intracranial
hemorrhage, screening cranial ultrasound for hemorrhage should begin at 20 weeks’ gestation and be repeated regularly. In addition, if the fetal
platelet count is less than 100,000/μL, the mother should be treated with weekly IVIG with or without corticosteroids. Delivery near term by elective
cesarean section, which is recommended if the fetal platelet count is less than 50,000/μL, results in less severe complications.
B. Thrombocytopenia Associated With ITP in the Mother (Neonatal Autoimmune Thrombocytopenia)
Infants born to mothers with ITP or other autoimmune diseases (eg, antiphospholipid antibody syndrome or systemic lupus erythematosus) may
develop thrombocytopenia as a result of transfer of antiplatelet IgG from the mother. Unfortunately, maternal and fetal platelet counts and maternal
antiplatelet antibody levels are unreliable predictors of bleeding risk. Antenatal corticosteroid administration to the mother is considered if maternal
platelet count falls below 50,000/μL, with or without a concomitant course of IVIG.
Most neonates with autoimmune thrombocytopenia do not develop clinically significant bleeding, and treatment is not often required. The risk of
intracranial hemorrhage is 0.2%–1.5%. If diffuse petechiae or minor bleeding are evident, a 1 to 2week course of oral prednisone, 2 mg/kg/day, may
be helpful. If the platelet count remains consistently less than 20,000/μL or if severe hemorrhage develops, IVIG should be given (1 g/kg daily for 1–2
days). Platelet transfusions are indicated only for lifethreatening bleeding and may be effective only after removal of antibody by exchange
transfusion. The platelet nadir is typically between the fourth and sixth day of life and improves significantly by 1 month; full recovery may take 2–4
months. Platelet recovery may be delayed in breastfed infants because of transfer of IgG by milk.
C. Neonatal Thrombocytopenia Associated With Infections
Thrombocytopenia is commonly associated with severe generalized infections during the newborn period. Between 50% and 75% of neonates with
bacterial sepsis are thrombocytopenic. Intrauterine infections such as rubella, syphilis, toxoplasmosis, HIV, CMV, herpes simplex (acquired intra or
postpartum), enteroviruses, and parvovirus are often associated with thrombocytopenia. In addition to specific treatment for the underlying disease,
platelet transfusions may be indicated in severe cases.
D. KasabachMerritt Phenomenon
A rare but important cause of thrombocytopenia in the newborn is KasabachMerritt phenomenon associated with kaposiform
hemangioendotheliomas, a benign neoplasm with histopathology distinct from that of classic infantile hemangiomas or less often with tufted
angioma. Intense platelet sequestration in the lesion results in thrombocytopenia and may rarely be associated with a DIClike picture and hemolytic
anemia. The bone marrow typically shows megakaryocytic hyperplasia in response to the thrombocytopenia. Corticosteroids and vincristine or
steroids and sirolimus are treatment options if significant coagulopathy is present, a vital structure is compressed, or the lesion is cosmetically
unacceptable. Depending on the site, embolization may be an option. Surgery is often avoided because of the high risk of hemorrhage.
Lieberman L: Fetal and neonatal alloimmune thrombocytopenia: recommendations for evidencebased practice, an international approach. Br J
Haematol 2019;185(3):549–562
[PubMed: 30828796] .
Mahajan R, Margolin J, Iacobas I: KasabachMerritt phenomenon: classic presentation and management options. Clin Med Insights Blood Disord
2017;10:1–5
[PubMed: 28579853] . Page 14 / 30
Lieberman L: Fetal and neonatal alloimmune thrombocytopenia: recommendations for evidencebased practice, an international approach. Br J
Access Provided by:
Haematol 2019;185(3):549–562
[PubMed: 30828796] .
Mahajan R, Margolin J, Iacobas I: KasabachMerritt phenomenon: classic presentation and management options. Clin Med Insights Blood Disord
2017;10:1–5
[PubMed: 28579853] .
3. Disorders of Platelet Function
Individuals with platelet function defects typically develop abnormal bruising and mucosal bleeding similar to that occurring in persons with
thrombocytopenia. The PFA100, which can evaluate platelet dysfunction and vWD, has replaced the template bleeding time in many institutions but is
not unanimously endorsed. Although laborintensive, platelet aggregometry remains important in selected clinical situations for in vitro assessment of
platelet function. It uses platelet activators, such as adenosine diphosphate, collagen, arachidonic acid, and ristocetin. Unfortunately, none of these
screening tests of platelet function uniformly predicts clinical bleeding severity.
Platelet dysfunction may be inherited or acquired, with the latter being more common. Acquired disorders of platelet function may occur secondary to
uremia, cirrhosis, sepsis, myeloproliferative disorders, congenital heart disease, and viral infections. Many pharmacologic agents decrease platelet
function. The most common offending agents in children are aspirin and other NSAIDs, synthetic penicillins, and valproic acid. In acquired platelet
dysfunction, the PFA100 closure time is prolonged with collagenepinephrine, while normal with collagenADP.
The inherited disorders are due to defects in plateletvessel interaction, plateletplatelet interaction, platelet granule content or release (including
defects of signal transduction), thromboxane and arachidonic acid pathway, and plateletprocoagulant protein interaction. Individuals with hereditary
platelet dysfunction have a prolonged bleeding time, but may have normal platelet number and morphology by light microscopy. PFA100 closure time
is typically prolonged with both collagenADP and collagenepinephrine.
Congenital causes of defective plateletvessel wall interaction include BernardSoulier syndrome, which is characterized by increased platelet size and
decreased platelet number. This autosomal recessive disorder is a deficiency or dysfunction of glycoprotein IbVIX complex on the platelet surface
resulting in impaired von Willebrand factor (vWF) binding, and hence impaired platelet adhesion to the vascular endothelium.
Glanzmann thrombasthenia is an example of severe plateletplatelet dysfunction. In this autosomal recessive disorder, glycoprotein IIbIIIa is deficient
or dysfunctional. Platelets do not bind fibrinogen effectively and exhibit impaired aggregation. As in BernardSoulier syndrome, acute bleeding is
treated with platelet transfusion and recombinant factor VIIa.
Disorders involving platelet granule content include storage pool disease and Quebec platelet disorder. In individuals with storage pool disease,
plateletdense granules lack adenosine diphosphate and adenosine triphosphate and are decreased in number by electron microscopy. These
granules are also deficient in HermanskyPudlak, ChédiakHigashi, and WiskottAldrich syndromes. Whereas deficiency of a second granule class, α
granules, results in the gray platelet syndrome. Quebec platelet disorder is characterized by a normal platelet αgranule number, but with abnormal
proteolysis of αgranule proteins and deficiency of platelet αgranule multimerin. αGranule abnormality in this disorder also results in increased
serum levels of urokinasetype plasminogen activator. Epinephrineinduced platelet aggregation is markedly impaired.
Platelet dysfunction has also been observed in other congenital syndromes, such as Down and Noonan syndromes, without a clear understanding of
the molecular defect.
Treatment
Acute bleeding in many individuals with acquired or selected congenital platelet function defects responds to therapy with desmopressin acetate,
likely due to an induced release of vWF from endothelial stores and/or upregulated expression of glycoprotein IbVIX on the platelet surface. If this
therapy is ineffective or if the patient has BernardSoulier syndrome or Glanzmann syndrome, the mainstay of treatment for bleeding episodes is
platelet transfusion, preferably with HLA type–specific platelets. Recombinant VIIa, which has variable efficacy and may be helpful in platelet
transfusionrefractory patients, is FDAapproved for patients with Glanzmann syndrome.
Sharma R: Congenital disorders of platelet funtion and number. Pediatr Clin North Am 2018;65(3):561–578
[PubMed: 29803283] .
INHERITED BLEEDING DISORDERS Page 15 / 30
Table 30–9 lists normal values for coagulation factors. The more common factor deficiencies are discussed in this section. Individuals with bleeding
disorders should avoid exposure to medications that inhibit platelet function. Participation in contact sports should be considered in the context of
transfusionrefractory patients, is FDAapproved for patients with Glanzmann syndrome.
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Sharma R: Congenital disorders of platelet funtion and number. Pediatr Clin North Am 2018;65(3):561–578
[PubMed: 29803283] .
INHERITED BLEEDING DISORDERS
Table 30–9 lists normal values for coagulation factors. The more common factor deficiencies are discussed in this section. Individuals with bleeding
disorders should avoid exposure to medications that inhibit platelet function. Participation in contact sports should be considered in the context of
the severity of the bleeding disorder.
Table 30–9.
Physiologic alterations in measurements of the hemostatic system.
Normal Fetus (20 Preterm (25–32 Term Infant (6 Pregnancy Exercise Aging (70–

Measurement
Adults wk) wk) Infant mo) (term) (acute) 80 y)
Platelets
Count μL/103 250 107–297 293 332 – 260 ↑ 18%–40% 225
Size (fL) 9.0 8.9 8.5 9.1 – 9.6 ↑ –
Aggregation N + ↓ ↓ – ↑ ↓ 15% –
ADP
Collagen N ↓ ↓ ↓ – N ↓ 60% N
Ristocetin N – ↑ ↑ – – ↓ 10% –
BT (min) 2–9 – 3.6±2 3.4±1.8 – 9.0±1.4 – 5–6
Procoagulant system
PTT* 1 4.0 3 1.3 1.1 1.1 ↓ 15% ↓
PT* 1.00 2.3 1.3 1.1 1 0.95 N –
TCT* 1 2.4 1.3 1.1 1 0.92 N –
Fibrinogen, 278 (0.61) 96 (50) 250 (100) 240 (150) 251 (160) 450 (100) ↓ 25% ↑ 15%

mg/dL
II, U/mL 1(0.7) 0.16 (0.10) 0.32 (0.18) 0.52 (0.25) 0.88 (0.6) 1.15 (0.68–1.9) – N
V, U/mL 1.0 (0.6) 0.32 (0.21) 0.80 (0.43) 1.00 (0.54) 0.91 (0.55) 0.85 (0.40–1.9) – N
VII, U/mL 1.0 (0.6) 0.27 (0.17) 0.37 (0.24) 0.57 (0.35) 0.87 (0.50) 1.17 (0.87–3.3) ↑ 200% ↑ 25%
VIIIc, U/mL 1.0 (0.6) 0.50 (0.23) 0.75 (0.40) 1.50 (0.55) 0.90 (0.50) 2.12 (0.8–6.0) ↑ 250% 1.50
vWF, U/mL 1.0 (0.6) 0.65 (0.40) 1.50 (0.90) 1.60 (0.84) 1.07 (0.60) 1.7 ↑ 75–200% ↑
IX, U/mL 1.0 (0.5) 0.10 (0.05) 0.22 (0.17) 0.35 (0.15) 0.86 (0.36) 0.81–2.15 ↑ 25% 1.0–1.40
X, U/mL 1.0 (0.6) 0.19 (0.15) 0.38 (0.20) 0.45 (0.3) 0.78 (0.38) 1.30 – N

XI, U/mL 1.0 (0.6) 0.13 (0.08) 0.2 (0.12) 0.42 (0.20) 0.86 (0.38) 0.7 – N
XII, U/mL 1.0 (0.6) 0.15 (0.08) 0.22 (0.09) 0.44 (0.16) 0.77 (0.39) 1.3 (0.82) – ↑ 16%

vWF, U/mL 1.0 (0.6) 0.65 (0.40) 1.50 (0.90) 1.60 (0.84) 1.07 (0.60) 1.7 ↑ 75–200% ↑
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IX, U/mL 1.0 (0.5) 0.10 (0.05) 0.22 (0.17) 0.35 (0.15) 0.86 (0.36) 0.81–2.15 ↑ 25% 1.0–1.40
X, U/mL 1.0 (0.6) 0.19 (0.15) 0.38 (0.20) 0.45 (0.3) 0.78 (0.38) 1.30 – N
XI, U/mL 1.0 (0.6) 0.13 (0.08) 0.2 (0.12) 0.42 (0.20) 0.86 (0.38) 0.7 – N
XII, U/mL 1.0 (0.6) 0.15 (0.08) 0.22 (0.09) 0.44 (0.16) 0.77 (0.39) 1.3 (0.82) – ↑ 16%
XIII, U/mL 1.04 (0.55) 0.30 0.4 0.61 (0.36) 1.04 (0.50) 0.96 – –
PreK, U/mL 1.12 (0.06) 0.13 (0.08) 0.26 (0.14) 0.35 (0.16) 0.86 (0.56) 1.18 – ↑ 27%
HK, U/mL 0.92 (0.48) 0.15 (0.10) 0.28 (0.20) 0.64 (0.50) 0.82 (0.36) 1.6 – ↑ 32%
Anticoagulant system
AT, U/mL 1.0 0.23 0.35 0.56 1.04 1.02 ↑ 14% N
α2MG, U/mL 1.05 (0.79) 0.18 (0.10) – 1.39 (0.95) 1.91 (1.49) 1.53 (0.85) – –
C1IN, U/mL 1.01 – – 0.72 1.41 – – –
PC, U/mL 1.0 0.10 0.29 0.50 0.59 0.99 N N
Total PS, U/mL 1.0 (0.6) 0.15 (0.11) 0.17 (0.14) 0.24 (0.1) 0.87 (0.55) 0.89 – N
Free, PS, U/mL 1.0 (0.5) 0.22 (0.13) 0.28 (0.19) 0.49 (0.33) – 0.25 – –
Heparin 1.01 0.10 (0.06) 0.25 (0.10) 0.49 (0.33) 0.97 (0.59) – – ↓ 15%
Cofactor II, (0.73)
U/mL
TFPI, ng/mL 73 21 20.6 38 – – – –
Fibrinolytic system
Plasminogen, 1.0 0.20 0.35 (0.20) 0.37 (0.18) 0.90 1.39 ↓ 10% N

U/mL
tPA, ng/mL 4.9 – 8.48 9.6 2.8 4.9 ↑ 300% N
α2AP, U/mL 1.0 1.0 1.0 0.74 (0.5) 0.83 (0.65) 1.11 (0.83) 0.95 N N
PAI1, U/mL 1.0 – 1.5 1.0 1.07 4.0 ↓ 5% N
Overall N ↑ ↑ ↓ – ↓ ↑ ↓
fibrinolysis
Except as otherwise indicated values are mean ±2 standard deviation (SD) or values in parentheses are lower limits (–2 SD or lower range); +, positive or present; ↓,
decreased; ↑, increased; N, normal or no change;* values as ratio or subject/mean of reference range; α2MG, α2macroglobulin; α2AP, α2antiplasmin; ADP,
adenosine diphosphate; AT, antithrombin; BT, bleeding time; C1IN, C1 esterase inhibitor; HK, highmolecularweight kininogen; PAI, plasminogen activator inhibitor;
PC, protein C; PreK, prekallikrein; PS, protein S; PT, prothrombin time; PTT, partial thromboplastin time; TCT, thrombin clotting time; TFPI, tissue factor pathway
inhibitor; tPA, tissue plasminogen activator; vWF, von Willebrand factor. Overall fibrinolysis is measured by euglobulin lysis time.
Reproduced with permission from Goodnight SH, Hathaway WE: Disorders of Hemostasis & Thrombosis: A Clinical Guide. 2nd ed. New York, NY: McGraw Hill; 2001.
Except as otherwise indicated values are mean ±2 standard deviation (SD) or values in parentheses are lower limits (–2 SD or lower range); +, positive or present; ↓,
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decreased; ↑, increased; N, normal or no change;* values as ratio or subject/mean of reference range; α2MG, α2macroglobulin; α2AP, α2antiplasmin; ADP,
adenosine diphosphate; AT, antithrombin; BT, bleeding time; C1IN, C1 esterase inhibitor; HK, highmolecularweight kininogen; PAI, plasminogen activator inhibitor;
PC, protein C; PreK, prekallikrein; PS, protein S; PT, prothrombin time; PTT, partial thromboplastin time; TCT, thrombin clotting time; TFPI, tissue factor pathway
inhibitor; tPA, tissue plasminogen activator; vWF, von Willebrand factor. Overall fibrinolysis is measured by euglobulin lysis time.
Reproduced with permission from Goodnight SH, Hathaway WE: Disorders of Hemostasis & Thrombosis: A Clinical Guide. 2nd ed. New York, NY: McGraw Hill; 2001.
1. Factor VIII Deficiency (Hemophilia A)
Bruising, softtissue bleeding, hemarthrosis.
Prolonged aPTT.
Reduced factor VIII activity.
Factor VIII (FVIII) activity is reported in units per milliliter, with 1 U/mL equal to 100% of the factor activity found in 1 mL of normal plasma. The normal
range for FVIII activity is 0.50–1.50 U/mL (50%–150%). Hemophilia A occurs predominantly in males as an Xlinked disorder. Onethird of cases are due
to a spontaneous mutation. The incidence of FVIII deficiency is 1:5000 male births.
Clinical Findings
Persons with hemophilia who have less than 1% FVIII activity have severe hemophilia A and have frequent spontaneous bleeding episodes involving
skin, mucous membranes, joints, muscles, and viscera. In contrast, patients with mild hemophilia A (5%–40% FVIII activity) mainly bleed at times of
trauma or surgery. Those with moderate hemophilia A (1% to < 5% FVIII activity) typically have intermediate bleeding manifestations but their
treatment should be similar to patients with severe hemophilia. The most crippling aspect of FVIII deficiency is the development of recurrent
hemarthroses that incites joint destruction, and the sequelae of intracranial hemorrhage.
Individuals with hemophilia A have a prolonged aPTT, except in some cases of mild deficiency. The PT is normal. The diagnosis is confirmed by a
decreased FVIII activity with normal vWF activity. In twothirds of families of people with hemophilia (PwH), the females are carriers and may manifest
symptomatic bleeding. Carriers of hemophilia can be diagnosed by DNA sequencing, and their bleeding severity by factor activity. In a male fetus or
newborn with a family history of hemophilia A, cord blood sampling for FVIII activity is accurate.
Complications
Intracranial hemorrhage is the leading diseaserelated cause of death among persons with hemophilia. Most intracranial hemorrhages in moderate to
severe deficiency are spontaneous and not associated with trauma. Hemarthroses begin early in childhood and, when recurrent, can result in joint
destruction (ie, hemophilic arthropathy). Large intramuscular hematomas can lead to compartment syndrome with resultant neurologic compromise
or pseudotumors. Although these complications are most common in severe hemophilia A, they may occur in individuals with moderate or mild
disease. Acquired neutralizing antibodies to FVIII are a potential serious complication after treatment with FVIII concentrate. These antibodies develop
in up to 30% of patients with severe hemophilia A, and especially in patients with absent or large deletions in the FVIII gene. Inhibitors may be
desensitized with regular FVIII infusion (immune tolerance therapy). The bispecific monoclonal antibody emicizumab is approved for all patients with
hemophilia A, is the standard of care for prophylaxis in patients with a FVIII inhibitor. Therapy that bypasses the FVIII inhibitor with recombinant factor
VIIa and/or FEIBA (factor eight inhibitor bypassing agent) is used to treat acute hemorrhage in patients with hemophilia A and a hightiter inhibitor.
FEIBA is contraindicated for FVIII inhibitor patients using emicizumab.
In prior decades, therapyrelated complications in hemophilia A have included factorrelated infection with HIV, hepatitis B virus, and hepatitis C virus.
Through stringent donor selection, implementation of sensitive screening assays, use of heat or chemical methods for viral inactivation, and
development of recombinant products, the risk of these infections is effectively eliminated. Inactivation methods do not eradicate viruses lacking a
lipid envelope; therefore, transmission of parvovirus and hepatitis A remains a concern with the use of plasmaderived products. Immunization with
hepatitis A and hepatitis B vaccines is recommended for all hemophilia patients.
hemophilia A, is the standard of care for prophylaxis in patients with a FVIII inhibitor. Therapy that bypasses the FVIII inhibitor with recombinant factor
VIIa and/or FEIBA (factor eight inhibitor bypassing agent) is used to treat acute hemorrhage in patients with hemophilia A and a hightiter inhibitor.
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FEIBA is contraindicated for FVIII inhibitor patients using emicizumab.
In prior decades, therapyrelated complications in hemophilia A have included factorrelated infection with HIV, hepatitis B virus, and hepatitis C virus.
Through stringent donor selection, implementation of sensitive screening assays, use of heat or chemical methods for viral inactivation, and
development of recombinant products, the risk of these infections is effectively eliminated. Inactivation methods do not eradicate viruses lacking a
lipid envelope; therefore, transmission of parvovirus and hepatitis A remains a concern with the use of plasmaderived products. Immunization with
hepatitis A and hepatitis B vaccines is recommended for all hemophilia patients.
Treatment
The general aim of management is to raise the FVIII activity to prevent or stop bleeding (see Table 30–8). Some patients with mild FVIII deficiency may
respond to desmopressin via release of endothelial stores of FVIII and vWF into plasma; however, many patients still require administration of
exogenous FVIII to achieve hemostasis. The in vivo halflife of infused standard halflife FVIII is 6–14 hours but varies among PwH. Non–lifethreatening,
non–limbthreatening hemorrhage is treated with 20–30 U/kg of FVIII, to achieve a plasma FVIII activity of 40%–60%. Joint hemarthrosis and life or
limbthreatening hemorrhage is treated with 50 U/kg of FVIII, targeting 100% FVIII activity. Subsequent doses are determined according to the site and
extent of bleeding, and clinical response to FVIII infusion. In circumstances of poor clinical response, recent change in bleeding frequency, or comorbid
illness, monitoring the plasma FVIII activity response is recommended. For most instances of non–lifethreatening hemorrhage in experienced PwH
with moderate or severe hemophilia A, treatment can be administered at home, provided adequate intravenous access and management with the
hemophilia treatment center.
Prophylactic FVIII infusions prevent the development of arthropathy in severe and moderate hemophilia, and are the standard of care in pediatric
hemophilia. Extended halflife FVIII concentrates that are approved by the FDA have decreased infusion frequency while maintaining low bleeding
rates. In addition, multiple nonfactor replacement strategies (eg, emicizumab [FDA approved for prophylaxis in hemophilia A for all ages and severities
with or without inhibitor], fitusiran, concizumab) are emerging that may replace FVIII for prophylaxis. Along with gene therapy, which is in phase 3
clinical trial(s), they look to reshape the lives and outcomes of PwH.
Prognosis
The development of innovative, safe, and effective therapies for hemophilia A has resulted in improved longterm survival in recent decades. In
addition, comprehensive care managed through hemophilia treatment centers has greatly improved quality of life and level of function.
2. Factor IX Deficiency (Hemophilia B, Christmas Disease)
The mode of inheritance and clinical manifestations of FIX (FIX)deficiency are the same as those of FVIII deficiency. Hemophilia B is 15%–20% as
prevalent as hemophilia A. FIX deficiency is associated with a prolonged aPTT but normal PT and thrombin time. However, the aPTT is slightly less
sensitive to FIX deficiency than FVIII deficiency. Diagnosis of hemophilia B is made by assaying FIX activity, and severity is determined similar to
hemophilia A.
The mainstay of treatment in hemophilia B is exogenous FIX. Unlike FVIII, about 50% of the administered dose of FIX distributes into the extravascular
space. Therefore, 1 U/kg of plasmaderived FIX concentrate or recombinant FIX is expected to increase plasma FIX activity by approximately 1%. FIX
typically has a halflife of 18–22 hours in vivo. In contrast to severe FVIII deficiency, only 1%–3% of persons with FIX deficiency develop a FIX inhibitor,
but patients may be at risk for anaphylaxis when receiving exogenous FIX. The prognosis for persons with FIX deficiency is comparable to that of
patients with FVIII deficiency. Extended halflife factor concentrates have changed treatment of severe and moderate hemophilia B. Gene therapy and
nonfactor replacement technologies are in phase 3 clinical trial.
Croteau S: 2021 clinical trials update: Innovations in hemophilia therapy. Am J Hematol 2021;96(1):128–144
[PubMed: 33064330] .
Srivastava A: Guidelines for the management of hemophilia. Haemophilia 2013 Jan;19(1):e1–47
[PubMed: 22776238] .
3. Factor XI Deficiency (Hemophilia C)
Factor XI (FXI) deficiency is a genetic, autosomal coagulopathy, typically of mild to moderate clinical severity. Cases of FXI deficiency account for less
than 5% of all persons living with hemophilia. Homozygous individuals generally bleed at surgery or following severe trauma, and at hyperfibrinolytic
sites, but do not commonly have spontaneous hemarthroses. In contrast to FVIII and FIX deficiencies, FXI activity is least predictive of bleeding risk.
Pathologic bleeding may be seen in heterozygous individuals with FXI activity as high as 60%. The aPTT is often considerably prolonged. In individuals
with deficiency of both plasma and plateletassociated FXI, the PFA100 may also be prolonged. Management typically consists of perioperative
[PubMed: 22776238] .
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3. Factor XI Deficiency (Hemophilia C)
Factor XI (FXI) deficiency is a genetic, autosomal coagulopathy, typically of mild to moderate clinical severity. Cases of FXI deficiency account for less
than 5% of all persons living with hemophilia. Homozygous individuals generally bleed at surgery or following severe trauma, and at hyperfibrinolytic
sites, but do not commonly have spontaneous hemarthroses. In contrast to FVIII and FIX deficiencies, FXI activity is least predictive of bleeding risk.
Pathologic bleeding may be seen in heterozygous individuals with FXI activity as high as 60%. The aPTT is often considerably prolonged. In individuals
with deficiency of both plasma and plateletassociated FXI, the PFA100 may also be prolonged. Management typically consists of perioperative
prophylaxis and episodic therapy for acute hemorrhage. Treatment includes infusion of fresh frozen plasma (FFP); platelet transfusion may also be
useful for acute hemorrhage in patients with deficiency of plateletassociated FXI. Desmopressin has been used in some cases, as well as rFVIIa, and
antifibrinolytic therapy is common.
James P: Rare bleeding disorders—bleeding assessment tools, laboratory aspects and phenotype and therapy of FXI deficiency. Haemophilia 2014
May;20 (Suppl 4):71–75
[PubMed: 24762279] .
4. Other Inherited Bleeding Disorders
Other hereditary single clotting factor deficiencies are rare and generally autosomal. Homozygous individuals with a deficiency or structural
abnormality of prothrombin, factor V, factor VII, or factor X may have excessive bleeding.
Persons with dysfibrinogenemia (ie, structurally or functionally abnormal fibrinogen) may develop recurrent venous thromboembolic episodes or
bleeding. Immunologic assay of fibrinogen is normal, but clotting assay may be low and the thrombin time prolonged. The PT and aPTT may be
prolonged.
Afibrinogenemia resembles hemophilia clinically but has an autosomal recessive inheritance. Affected patients experience a variety of bleeding
manifestations, including mucosal bleeding, ecchymoses, hematomas, hemarthroses, and intracranial hemorrhage, especially following trauma. Fatal
umbilical cord hemorrhage has been reported. The PT, aPTT, and thrombin time are all prolonged. A severely reduced fibrinogen concentration in an
otherwise well child is confirmatory of the diagnosis. As in dysfibrinogenemia, fibrinogen concentrates are used for surgical prophylaxis and for acute
hemorrhage.
Menegatti M: Treatment of rare factor deficiencies other than hemophilia. Blood 2019 Jan 31;133(5):415–424
[PubMed: 30559262] .
VON WILLEBRAND DISEASE
Easy bruising and epistaxis from early childhood.
Menorrhagia.
Prolonged PFA100 (or bleeding time), normal platelet count, absence of acquired platelet dysfunction.
Reduced amount or abnormal activity of vWF.
von Willebrand disease (vWD) is the most common inherited bleeding disorder among Caucasians, with a prevalence as high as 1%. vWF is a multimeric
plasma protein that binds FVIII and facilitates platelet adhesion to damaged endothelium. An estimated 70%–80% of all patients with vWD have type 1
vWD, caused by a partial quantitative deficiency of vWF. vWD type 2 involves a qualitative deficiency of (ie, dysfunctional) vWF, and vWD type 3 is
characterized by a nearly complete deficiency of vWF. vWD is most often transmitted as an autosomal dominant trait, but it can be autosomal recessive.
The disease can also be acquired, developing in association with hypothyroidism, Wilms tumor, cardiac disease, renal disease, or systemic lupus
erythematosus, and in individuals receiving valproic acid. Acquired vWD is most often caused by the development of an antibody to vWF or increased
turnover of vWF.
von Willebrand disease (vWD) is the most common inherited bleeding disorder among Caucasians, with a prevalence as high as 1%. vWF is a multimeric
Access Provided by:
plasma protein that binds FVIII and facilitates platelet adhesion to damaged endothelium. An estimated 70%–80% of all patients with vWD have type 1
vWD, caused by a partial quantitative deficiency of vWF. vWD type 2 involves a qualitative deficiency of (ie, dysfunctional) vWF, and vWD type 3 is
characterized by a nearly complete deficiency of vWF. vWD is most often transmitted as an autosomal dominant trait, but it can be autosomal recessive.
The disease can also be acquired, developing in association with hypothyroidism, Wilms tumor, cardiac disease, renal disease, or systemic lupus
erythematosus, and in individuals receiving valproic acid. Acquired vWD is most often caused by the development of an antibody to vWF or increased
turnover of vWF.
Clinical Findings
Mucocutaneous bleeding, increased bruising, and excessive epistaxis is often present. Prolonged bleeding occurs with trauma or at surgery.
Menorrhagia is often a presenting finding in females.
PT is normal and aPTT is prolonged if factor VIII is decreased. Prolongation of the PFA100 is usually present. Platelet number may be decreased in type
2b vWD. FVIII and vWF antigen are decreased in types 1 and 3 but may be normal in type 2 vWD. vWF activity (eg, ristocetin cofactor, collagen binding,
GP1bM/R) is decreased in all types. Complete laboratory classification also requires vWF multimer or collagen binding assay, and measurement of VWF
propeptide for VWD 1C. The diagnosis requires confirmatory laboratory testing.
Treatment
Desmopressin acetate can be given intravenously or subcutaneously to release vWF from endothelial stores in many patients with vWD types 1 and 2 to
prevent or halt bleeding. In responding patients, the increase in vWF and FVIII in the plasma can be two to fivefold. Because response to vWF is variable
among patients, FVIII and vWF activities are typically measured before, 30–60 minutes post, and 4 hours after desmopressin administration to
document response. Desmopressin causes fluid retention which can result in hyponatremia; therefore, fluid restriction should be discussed. Because
release of stored vWF is limited, tachyphylaxis often occurs after two to three administered doses of desmopressin.
If further therapy is indicated, vWFreplacement therapy (plasma derived or recombinant VWF) is recommended; such therapy is also used in patients
with type 1 or 2a vWD who exhibit suboptimal laboratory response to desmopressin, and for all individuals with type 2b or 3 vWD. Antifibrinolytic
agents (eg, εaminocaproic acid and tranexamic acid) are useful for control of mucosal bleeding. Oral or intrauterine contraceptive therapy may be
helpful for menorrhagia.
Prognosis
With the availability of effective treatment and prophylaxis for bleeding, life expectancy in vWD is normal.
http://practicalhemostasis.com (Excellent Practical source for Laboratory Hemostasis). Accessed June 31, 2019.
James PD: ASH USTH NHF WFH 2021 guidelines on the diagnosis of von Willebrand disease. Blood Adv 2021;5(1):280–300
[PubMed: 33570651] .
O’Brien SH: von Willebrand disease in pediatrics: evaluation and management. Hematol Oncol Clin North Am 2019 Jun; 33(3):425–438
[PubMed: 31030811] .
ACQUIRED BLEEDING DISORDERS
1. Disseminated Intravascular Coagulation
Presence of a disorder known to trigger DIC.
Evidence for consumptive coagulopathy (prolonged aPTT, PT, or thrombin time; increase in FSPs [fibrinfibrinogen split products]; decreased
fibrinogen or platelets).
ACQUIRED BLEEDING DISORDERS Access Provided by:
1. Disseminated Intravascular Coagulation
Presence of a disorder known to trigger DIC.
Evidence for consumptive coagulopathy (prolonged aPTT, PT, or thrombin time; increase in FSPs [fibrinfibrinogen split products]; decreased
fibrinogen or platelets).
Disseminated intravascular coagulation (DIC) is an acquired coagulopathy characterized by tissue factor–mediated coagulation activation in the host.
DIC involves dysregulated, excessive thrombin generation, with consequent intravascular fibrin deposition and consumption of platelets and
procoagulant factors. Microthrombi, composed of fibrin and platelets, produce tissue ischemia and endorgan damage. The fibrinolytic system is
frequently activated in DIC, leading to plasminmediated destruction of fibrin and fibrinogen. These fibrinfibrinogen degradation products (FDPs)
exhibit anticoagulant and plateletinhibitory functions. While DIC commonly accompanies severe infection, other conditions known to trigger DIC
include endothelial damage (eg, endotoxin, virus), tissue necrosis (eg, burns), diffuse ischemic injury (eg, shock, hypoxia acidosis), and systemic
release of tissue procoagulants (eg, certain cancers, placental disorders).
Clinical Findings
Signs of DIC may include (1) complications of shock, often including endorgan dysfunction; (2) diffuse bleeding tendency (eg, hematuria, melena,
purpura, petechiae, persistent oozing from needle punctures or other invasive procedures); and (3) evidence of thrombosis (eg, small and large vessel
thrombosis, purpura fulminans).
Tests that are sensitive, easiest to perform, useful for monitoring, and reflect the hemostatic capacity of the patient are the PT, aPTT, platelet count,
fibrinogen, and FDPs (including Ddimer). The PT and aPTT are typically prolonged, and the platelet count and fibrinogen concentration may be
decreased. However, in children the fibrinogen level may be normal until late in the course. Levels of FSPs are increased. Elevated levels of Ddimer, a
crosslinked fibrin degradation byproduct, may be helpful in monitoring the degree of activation of both coagulation and fibrinolysis. However, D
dimer is nonspecific and may be elevated in the context of a triggering event (eg, severe infection) without concomitant DIC. Often, physiologic
inhibitors of coagulation, especially antithrombin III, protein C, and protein S are consumed, predisposing to thrombosis. The specific laboratory
abnormalities in DIC may vary with the triggering event and the course of illness.
DIC can be difficult to distinguish from the coagulopathy of liver disease (ie, hepatic synthetic dysfunction), especially when the latter is associated with
thrombocytopenia secondary to portal hypertension and hypersplenism. Generally, factor VII activity is decreased markedly in liver disease due to
deficient synthesis of this protein, which has the shortest halflife among the procoagulant factors, but only mildly to moderately decreased in DIC (due
to consumption). Factor VIII activity is often normal or even increased in liver disease but decreased in DIC.
Treatment
A. Therapy for Underlying Disorder
The most important aspect of therapy in DIC is the identification and treatment of the triggering event. If the pathogenic process underlying DIC is
reversed, often no other therapy is needed for the coagulopathy.
B. Replacement Therapy for Consumptive Coagulopathy
Replacement of consumed procoagulant factors with FFP, cryoprecipitate, unactivated prothrombin complex concentrates (PCCs), and platelets is
warranted in the setting of DIC with hemorrhagic complications, or as periprocedural bleeding prophylaxis. Infusion of 10–15 mL/kg FFP typically
raises procoagulant factor activities by approximately 10%–15%. Cryoprecipitate can also be given as a rich source of fibrinogen, factor VIII, vWF, and
factor XIII; one bag of cryoprecipitate per 3 kg in infants or one bag of cryoprecipitate per 6 kg in older children typically raises plasma fibrinogen
concentration by 75–100 mg/dL.
The most important aspect of therapy in DIC is the identification and treatment of the triggering event. If the pathogenic process underlying DIC is
reversed, often no other therapy is needed for the coagulopathy.
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B. Replacement Therapy for Consumptive Coagulopathy
Replacement of consumed procoagulant factors with FFP, cryoprecipitate, unactivated prothrombin complex concentrates (PCCs), and platelets is
warranted in the setting of DIC with hemorrhagic complications, or as periprocedural bleeding prophylaxis. Infusion of 10–15 mL/kg FFP typically
raises procoagulant factor activities by approximately 10%–15%. Cryoprecipitate can also be given as a rich source of fibrinogen, factor VIII, vWF, and
factor XIII; one bag of cryoprecipitate per 3 kg in infants or one bag of cryoprecipitate per 6 kg in older children typically raises plasma fibrinogen
concentration by 75–100 mg/dL.
C. Anticoagulant Therapy for Coagulation Activation
Continuous intravenous infusion of unfractionated heparin is sometimes given in order to attenuate coagulation activation and consequent
consumptive coagulopathy. The rationale for heparin therapy is to maximize the efficacy of, and minimize the need for, replacement of procoagulants
and platelets; however, clinical evidence demonstrating benefit of heparin in DIC is lacking. Prophylactic doses of unfractionated heparin or low
molecularweight heparin (LMWH) in critically ill and nonbleeding patients with DIC may be considered for prevention of venous thromboembolism.
D. Specific Factor Concentrates
A nonrandomized pilot study of antithrombin concentrate in children with DIC and associated acquired antithrombin deficiency demonstrated
favorable outcomes, suggesting that replacement of this consumed procoagulant may be beneficial. Protein C concentrate has also shown promise in
two small pilot studies of meningococciassociated DIC with purpura fulminans.
2. Liver Disease
The liver is the major synthetic site of prothrombin, fibrinogen, highmolecularweight kininogen, and factors V, VII, IX, X, XI, XII, and XIII. Plasminogen
and the physiologic anticoagulants (antithrombin III, protein C, and protein S) are synthesized in the liver, as is α2antiplasmin, a regulator of
fibrinolysis. Deficiency of factor V and the vitamin K–dependent factors (II, VII, IX, and X) is most often a result of decreased hepatic synthesis, and is
manifested by a prolonged PT and often a prolonged aPTT. Extravascular loss and increased consumption of clotting factors may also contribute to PT
and aPTT prolongation. Fibrinogen production is often decreased, or an abnormal fibrinogen (dysfibrinogen) containing excess sialic acid residues
may be synthesized, or both. Hypofibrinogenemia or dysfibrinogenemia is associated with prolongation of thrombin time and reptilase time. FSPs and
Ddimers may be present because of increased fibrinolysis, particularly in the setting of chronic hepatitis or cirrhosis. Thrombocytopenia secondary to
hypersplenism may occur. DIC and the coagulopathy of liver disease also mimic vitamin K deficiency; however, vitamin K deficiency has normal factor V
activity. Treatment of acute bleeding in the setting of coagulopathy of liver disease consists of replacement with FFP or PCCs and platelets.
Desmopressin may shorten the bleeding time and aPTT in patients with chronic liver disease, but its safety is not well established. Recombinant VIIa
also is efficacious for lifethreatening refractory hemorrhage.
3. Vitamin K Deficiency
The newborn period is characterized by physiologically depressed activity of the vitamin K–dependent factors (II, VII, IX, and X). If vitamin K is not
administered at birth, a bleeding diathesis previously called hemorrhagic disease of the newborn, now termed vitamin K deficiency bleeding (VKDB),
may develop. Outside of the newborn period, vitamin K deficiency may occur as a consequence of inadequate intake, excess loss, inadequate
formation of active metabolites, or competitive antagonism.
One of three patterns is seen in the neonatal period:
1. Early VKDB of the newborn occurs within 24 hours of birth, most often manifested by cephalohematoma, intracranial hemorrhage, or intra
abdominal bleeding. Although occasionally idiopathic, it is most often associated with maternal ingestion of drugs that interfere with vitamin K
metabolism (eg, warfarin, phenytoin, isoniazid, and rifampin). Early VKDB occurs in 6%–12% of neonates born to mothers who take these
medications without receiving vitamin K supplementation. The disorder is often life threatening.
2. Classic VKDB occurs at 24 hours to 7 days of age and usually is manifested as gastrointestinal, skin, or mucosal bleeding. Bleeding after
circumcision may occur. Although occasionally associated with maternal drug usage, it most often occurs in well infants who do not receive vitamin
K at birth and are solely breastfed.
3. Late neonatal VKDB occurs on or after day 8. Manifestations include intracranial, gastrointestinal, or skin bleeding. This disorder is often
associated with fat malabsorption (eg, in chronic diarrhea) or alterations in intestinal flora (eg, with prolonged antibiotic therapy). Like classic
VKDB, late VKDB occurs almost exclusively in breastfed infants.
The diagnosis of vitamin K deficiency is suspected based on the history, physical examination, and laboratory results. The PT is prolonged out of
proportion to the aPTT (also prolonged). The thrombin time becomes prolonged late in the course. The platelet count is normal. This laboratory
2. Classic VKDB occurs at 24 hours to 7 days of age and usually is manifested as gastrointestinal, skin, or mucosal bleeding. Bleeding after
circumcision may occur. Although occasionally associated with maternal drug usage, it most often occurs in well infants who do not receive vitamin
Access Provided by:
K at birth and are solely breastfed.
3. Late neonatal VKDB occurs on or after day 8. Manifestations include intracranial, gastrointestinal, or skin bleeding. This disorder is often
associated with fat malabsorption (eg, in chronic diarrhea) or alterations in intestinal flora (eg, with prolonged antibiotic therapy). Like classic
VKDB, late VKDB occurs almost exclusively in breastfed infants.
The diagnosis of vitamin K deficiency is suspected based on the history, physical examination, and laboratory results. The PT is prolonged out of
proportion to the aPTT (also prolonged). The thrombin time becomes prolonged late in the course. The platelet count is normal. This laboratory
profile is similar to the coagulopathy of acute liver disease, but with normal fibrinogen level and absence of hepatic transaminase elevation. The
diagnosis of vitamin K deficiency is confirmed by a demonstration of noncarboxylation of specific clotting factors in the absence of vitamin K in the
plasma and by clinical and laboratory responses to vitamin K. Intravenous or subcutaneous treatment with vitamin K should be given immediately and
not withheld while awaiting test results. In the setting of severe bleeding, additional acute treatment with FFP or PCCs may be indicated.
4. Uremia
Uremia is frequently associated with acquired platelet dysfunction. Bleeding occurs in approximately 50% of patients with chronic renal failure. The
bleeding risk conferred by platelet dysfunction associated with metabolic imbalance may be compounded by decreased vWF activity and procoagulant
deficiencies (eg, factor II, XII, XI, and IX) due to increased urinary losses of these proteins in some settings of renal insufficiency. In accordance with
platelet dysfunction, uremic bleeding is typically characterized by purpura, epistaxis, menorrhagia, or gastrointestinal hemorrhage. Acute bleeding
may be managed with infusion of desmopressin acetate, factor VIII concentrates containing vWF, or cryoprecipitate with or without coadministration of
FFP. Severe anemia increases the potential for bleeding; therefore, red blood cell transfusion may be required. Recombinant VIIa may be useful in
refractory bleeding.
Rajagopal R: Disseminated intravascular coagulation in paediatrics. Arch Dis Child 2017;102:187–193
[PubMed: 27540263] .
Shearer MJ: Vitamin K deficiency bleeding (VKDB) in early infancy. Blood Rev 2009;23:49–59
[PubMed: 18804903] .
VASCULAR ABNORMALITIES ASSOCIATED WITH BLEEDING
1. Immunoglobulin A Vasculitis (HenochSchönlein Purpura)
Purpuric cutaneous rash.
Migratory polyarthritis or polyarthralgia.
Intermittent abdominal pain.
Nephritis.
Immunoglobulin A vasculitis, which is the most common type of small vessel vasculitis in children, primarily affects boys 2–7 years of age. Occurrence is
highest in the spring and fall, and upper respiratory infection precedes the diagnosis in twothirds of children.
Leukocytoclastic vasculitis in immunoglobulin A vasculitis principally involves the small vessels of the skin, gastrointestinal tract, and kidneys, with
deposition of IgA immune complexes. The most common and earliest symptom is palpable purpura, which results from extravasation of erythrocytes
into the tissue surrounding the involved venules. Antigens from group A βhemolytic streptococci and other bacteria, viruses, drugs, foods, and insect
bites have been proposed as inciting agents.
Clinical Findings
Skin involvement may start urticarial; progress to maculopapules; and coalesce to a symmetrical, palpable purpuric rash distributed on the legs,
Leukocytoclastic vasculitis in immunoglobulin A vasculitis principally involves the small vessels of the skin, gastrointestinal tract, and kidneys, with
deposition of IgA immune complexes. The most common and earliest symptom is palpable purpura, which results from extravasation of erythrocytes
Access Provided by:
into the tissue surrounding the involved venules. Antigens from group A βhemolytic streptococci and other bacteria, viruses, drugs, foods, and insect
bites have been proposed as inciting agents.
Clinical Findings
Skin involvement may start urticarial; progress to maculopapules; and coalesce to a symmetrical, palpable purpuric rash distributed on the legs,
buttocks, and elbows. New lesions may continue to appear for 2–4 weeks and may extend to involve the entire body. Twothirds of patients develop
migratory polyarthralgia or polyarthritis, primarily of the ankles and knees. Intermittent, sharp abdominal pain occurs in approximately 50% of
patients, and hemorrhage and edema of the small intestine can often occur. Intussusception may develop. Approximately 25%–50% develop renal
involvement in the second or third week of illness with either a nephritic or, less commonly, nephrotic picture, often with high blood pressure.
Testicular torsion may also occur. Neurologic symptoms are possible due to small vessel vasculitis.
The platelet count is normal or elevated, and other screening tests of hemostasis and platelet function are typically normal. Urinalysis frequently
reveals hematuria, and sometimes proteinuria. Stool may be positive for occult blood. The antistreptolysin O (ASO) titer is often elevated and the
throat culture positive for group A βhemolytic streptococci. Serum IgA may be elevated.
The rash of septicemia (especially meningococcemia) may be similar to skin involvement in immunoglobulin A vasculitis, although the distribution
tends to be more generalized. The possibility of trauma should be considered in any child presenting with purpura. Other vasculitides should also be
considered. The lesions of thrombotic thrombocytopenic purpura (TTP) are not palpable.
Treatment
Generally, treatment is supportive. NSAIDs may be useful for arthritis. Corticosteroid therapy may provide symptomatic relief for severe
gastrointestinal or joint manifestations but does not alter skin or renal manifestations. If culture for group A βhemolytic streptococci is positive or if
the ASO titer is elevated, a course of penicillin is warranted.
Prognosis
The prognosis for recovery is generally good, although symptoms frequently (25%–50%) recur over a period of several months. In patients who
develop renal manifestations, microscopic hematuria may persist for years. Progressive renal failure occurs in fewer than 5% of patients with
immunoglobulin A vasculitis, with an overall fatality rate of 3%.
Key NS: Vascular hemostasis. Haemophilia 2010 Jul;16(Suppl 5):146
[PubMed: 20590874] .
Ozen S: European consensusbased recommendations for diagnosis and treatment of immunoglobulin A vasculitis—the SHARE initiative.
Rheumatology (Oxford) 2019 Sep 1;58(9):1607–1616
[PubMed: 30879080] .
2. Collagen Disorders
Mild to lifethreatening bleeding occurs with some types of EhlersDanlos syndrome, the most common inherited collagen disorder. EhlersDanlos
syndrome is characterized by joint hypermobility, skin extensibility, and easy bruising. Coagulation abnormalities may sometimes be present,
including platelet dysfunction and deficiencies of coagulation factors VIII, IX, XI, and XIII. However, bleeding and easy bruising, in most instances,
relates to fragility of capillaries and compromised vascular integrity. EhlersDanlos syndrome types 4 and 6 are associated with at risk for aortic
dissection and spontaneous rupture of aortic aneurysms. Surgery should be avoided for patients with EhlersDanlos syndrome, as should medications
that induce platelet dysfunction.
Jesudas R: An update on the new classification of EhlersDanlos syndrome and review of the causes of bleeding in this population. Haemophilia
2019;25(4):558–566
Page 25 / 30
[PubMed: 31329366] .
including platelet dysfunction and deficiencies of coagulation factors VIII, IX, XI, and XIII. However, bleeding and easy bruising, in most instances,
relates to fragility of capillaries and compromised vascular integrity. EhlersDanlos syndrome types 4 and 6 are associated with at risk for aortic
Access Provided by:
dissection and spontaneous rupture of aortic aneurysms. Surgery should be avoided for patients with EhlersDanlos syndrome, as should medications
that induce platelet dysfunction.
Jesudas R: An update on the new classification of EhlersDanlos syndrome and review of the causes of bleeding in this population. Haemophilia
2019;25(4):558–566
[PubMed: 31329366] .
THROMBOTIC DISORDERS
Uncommon in children, thrombotic disorders are recognized with increasing frequency because of heightened physician awareness and improved
survival in pediatric intensive care settings.
Clinical Findings
Initial evaluation of the child who has thrombosis includes an assessment for potential provoking factors, as well as a family history of thrombosis and
early cardiovascular or cerebrovascular disease.
A. Clinical Risk Factors
Clinical risk factors are present in more than 90% of children with acute venous thromboembolism (VTE). These conditions include the presence of an
indwelling vascular catheter, cardiac disease, infection, trauma, surgery, immobilization, collagenvascular or chronic inflammatory disease, renal
disease, sickle cell anemia, and malignancy. Prospective findings employing serial radiologic evaluation as screening indicate that the risk of VTE is
nearly 30% for shortterm central venous catheters placed in the internal jugular veins. Retrospective data suggest that approximately 8% of children
with cancer develop symptomatic VTE.
1. Inherited Thrombophilia (Hypercoagulable) States
A. PROTEIN C DEFICIENCY
Protein C is a vitamin K–dependent protein activated by thrombin bound to thrombomodulin, which inactivates activated factors V and VIII. In addition,
activated protein C promotes fibrinolysis. Two phenotypes of hereditary protein C deficiency exist. Heterozygous individuals with autosomal dominant
protein C deficiency often present with VTE as young adults, but the disorder may manifest during childhood or in later adulthood. In mild protein C
deficiency, anticoagulant prophylaxis is typically limited to periods of increased prothrombotic risk. Homozygous or compound heterozygous protein
C deficiency is rare and phenotypically severe. Affected children generally present within the first 12 hours of life with purpura fulminans (Figure 30–6)
and/or VTE. Prompt protein C replacement by infusion of protein C concentrate or FFP every 6–12 hours, along with therapeutic heparin
administration, is recommended. Subsequent management requires chronic therapeutic anticoagulation, often with routine protein C concentrate
infusion. Recurrent VTE is common, especially during periods of subtherapeutic anticoagulation or in the presence of conditions associated with
increased prothrombotic risk.
Figure 30–6.
Purpura fulminans in an infant with severe protein C deficiency.
increased prothrombotic risk.
Figure 30–6.
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Purpura fulminans in an infant with severe protein C deficiency.
B. PROTEIN S DEFICIENCY
Protein S is a cofactor for protein C. Neonates with homozygous protein S deficiency have a course similar to those with homozygous or compound
heterozygous protein C deficiency. Lifelong anticoagulation therapy is indicated in homozygous/severe deficiency, or in heterozygous individuals who
have experienced recurrent VTE. Efforts must be made to distinguish these conditions from acquired deficiency, which can be antibodymediated or
secondary to an increase in C4bbinding protein induced by inflammation.
C. ANTITHROMBIN DEFICIENCY
Antithrombin, which is the most important physiologic inhibitor of thrombin, also inhibits activated factors IX, X, XI, and XII. Antithrombin deficiency is
transmitted in an autosomal dominant pattern and associated with VTE, typically with onset in adolescence or young adulthood. Therapy for acute VTE
is therapeutic anticoagulation. The efficiency of heparin may be significantly diminished in the setting of severe antithrombin deficiency, and it often
requires supplementation with antithrombin concentrate. Patients with homozygous/severe deficiency or recurrent VTE are maintained on lifelong
anticoagulation.
D. FACTOR V LEIDEN MUTATION
An amino acid substitution in the gene coding for factor V results in factor V Leiden, a factor V polymorphism that is resistant to inactivation by
activated protein C. The most common cause of activated protein C resistance in Caucasians, factor V Leiden is present in approximately 5% of the
Caucasian population, 20% of Caucasian adults with deep vein thrombosis (DVT), and 40%–60% of those with a family history of VTE. VTE occurs in
both heterozygous and homozygous individuals. For heterozygous individuals, thrombosis is typically triggered by a clinical risk factor (or else
develops in association with additional thrombophilia traits), whereas in homozygous people it is often spontaneous. Population studies suggest that
the risk of incident VTE is increased two to sevenfold in the setting of heterozygous factor V Leiden, 35fold among heterozygous individuals taking the
oral contraceptives, and 80fold in those homozygous for factor V Leiden.
E. PROTHROMBIN MUTATION
The 20210 glutamine to alanine mutation in the prothrombin gene is a relatively common polymorphism in Caucasians that enhances its activation to
thrombin. In heterozygous form, this mutation is associated with a two to threefold increased risk for incident VTE. This mutation also appears to
modestly increase the risk for recurrent VTE.
F. OTHER INHERITED DISORDERS
Qualitative abnormalities of fibrinogen (dysfibrinogenemias) are usually inherited in an autosomal dominant manner. Most individuals with
dysfibrinogenemia are asymptomatic. Some patients experience bleeding, while others develop venous or arterial thrombosis. The diagnosis is Page 27 / 30
suggested by a prolonged thrombin time with a normal fibrinogen concentration. Hyperhomocysteinemia, which can be inherited or acquired, is
associated with an increased risk for both arterial and venous thromboses. In children, it may be a risk factor for ischemic arterial stroke.
E. PROTHROMBIN MUTATION
The 20210 glutamine to alanine mutation in the prothrombin gene is a relatively common polymorphism in Caucasians that enhances its activation to
Access Provided by:
thrombin. In heterozygous form, this mutation is associated with a two to threefold increased risk for incident VTE. This mutation also appears to
modestly increase the risk for recurrent VTE.
F. OTHER INHERITED DISORDERS
Qualitative abnormalities of fibrinogen (dysfibrinogenemias) are usually inherited in an autosomal dominant manner. Most individuals with
dysfibrinogenemia are asymptomatic. Some patients experience bleeding, while others develop venous or arterial thrombosis. The diagnosis is
suggested by a prolonged thrombin time with a normal fibrinogen concentration. Hyperhomocysteinemia, which can be inherited or acquired, is
associated with an increased risk for both arterial and venous thromboses. In children, it may be a risk factor for ischemic arterial stroke.
Hyperhomocysteinemia is uncommon in the setting of dietary folate supplementation (as in the United States) and observed almost uniquely in cases
of renal insufficiency or metabolic disease (eg, homocystinuria). Methylene tetrahydrofolate reductase receptor mutations do not appear to constitute
a risk factor for thrombosis in US children unless homocysteine is elevated.
Lipoprotein(a) is a lipoprotein with homology to plasminogen. In vitro studies suggest that lipoprotein(a) may both promote atherosclerosis and
inhibit fibrinolysis. Some evidence suggests that elevated plasma concentrations of lipoprotein(a) are associated with an increased risk of VTEs and
recurrent ischemic arterial stroke in children.
Increased factor VIII activity is a risk factor for incident VTE and is common among children with acute VTE. Most elevations in factor VIII are acquired
and may persist, but may also be inherited.
2. Acquired Disorders
A. ANTIPHOSPHOLIPID ANTIBODIES
The development of antiphospholipid antibodies is the most common form of acquired thrombophilia in children. Antiphospholipid antibodies, which
include the lupus anticoagulant, anticardiolipin antibodies, and β2glycoprotein1 antibodies (among others), can be present in acute childhood VTE.
The lupus anticoagulant is detected in vitro by its inhibition of phospholipiddependent coagulation assays (eg, aPTT, dilute Russell viper venom time,
hexagonal phase phospholipid neutralization assay), whereas immunologic techniques (eg, enzymelinked immunosorbent assays) are often used to
detect anticardiolipin and β2glycoprotein1 antibodies. While common in patients with autoimmune diseases such as systemic lupus erythematosus,
antiphospholipid antibodies may also develop following certain drug exposures, infection, acute inflammation, and lymphoproliferative diseases. VTE
and antiphospholipid antibodies may predate other signs of lupus. Viral illness is a common precipitant in children, and in many cases, the inciting
infection may be asymptomatic.
When an antiphospholipid antibody persists for 12 weeks following the acute thrombotic event, the diagnosis of antiphospholipid syndrome (APS) is
confirmed. Optimal duration of anticoagulation in this setting is unclear. Current pediatric treatment guidelines recommend a 3month to lifelong
course.
B. DEFICIENCIES OF INTRINSIC ANTICOAGULANTS
Acquired deficiencies of proteins C and S and antithrombin may becaused by specific antibodies (eg, protein S antibodies in varicella) or by excessive
consumption, such as during sepsis, DIC, majorvessel or extensive VTE, and post–bone marrow transplant sinusoidal obstruction syndrome (formerly
termed hepatic venoocclusive disease). Pilot studies in children have suggested a possible therapeutic role for antithrombin or protein C concentrates
in sepsisassociated DIC (eg, meningococcemia) and severe posttransplant sinusoidal obstruction syndrome.
C. ACUTE PHASE REACTANTS
As part of the acute phase response, elevations in plasma fibrinogen concentration, plasma factor VIII, and platelet count may occur, all of which may
contribute to an acquired prothrombotic state. Reactive thrombocytosis is rarely associated with VTEs in children when the platelet count is less than 1
million/μL.
B. Symptoms and Signs
Presenting features of thrombosis vary with the anatomic site, extent of vascular involvement, degree of vasoocclusion, and presence of endorgan
dysfunction. The classic presentation of deep venous thrombosis of an upper or lower extremity is pain with acute or subacute extremity swelling,
while pulmonary embolism commonly presents as dyspnea and pleuritic chest pain, and cerebral sinovenous thrombosis (CSVT) often includes severe
or persistent headache, with or without neurologic deficit in otherwise well children. Arterial thrombosis of the lower extremity (eg, neonatal umbilical
artery catheter–associated) as well as vasospasm without identified thrombosis, often manifests with diminished distal pulses and dusky discoloration
of the limb.
C. Laboratory Findings
A comprehensive laboratory investigation for thrombophilia (ie, hypercoagulability) remains controversial with wide variation of practice. Recent
trends favor thrombophilia testing in infants, children, and adolescents with unprovoked thrombosis, and in neonates/children with non–catheter
related thrombosis and stroke. There are insufficient data to recommend routine thrombophilia testing in neonates or children with catheterrelated
while pulmonary embolism commonly presents as dyspnea and pleuritic chest pain, and cerebral sinovenous thrombosis (CSVT) often includes severe
or persistent headache, with or without neurologic deficit in otherwise well children. Arterial thrombosis of the lower extremity (eg, neonatal umbilical
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artery catheter–associated) as well as vasospasm without identified thrombosis, often manifests with diminished distal pulses and dusky discoloration
of the limb.
C. Laboratory Findings
A comprehensive laboratory investigation for thrombophilia (ie, hypercoagulability) remains controversial with wide variation of practice. Recent
trends favor thrombophilia testing in infants, children, and adolescents with unprovoked thrombosis, and in neonates/children with non–catheter
related thrombosis and stroke. There are insufficient data to recommend routine thrombophilia testing in neonates or children with catheterrelated
thrombosis. When indicated, thrombophilia testing can include: evaluation for intrinsic anticoagulant deficiency (proteins C and S and antithrombin),
procoagulant factor excess (eg, factor VIII), proteins and genetic mutations mediating enhanced procoagulant activity or reduced sensitivity to
inactivation (antiphospholipid antibodies; factor V Leiden, prothrombin 20210 polymorphisms), biochemical mediators of endothelial damage
(homocysteine), and markers or regulators of fibrinolysis (eg, Ddimer, plasminogen activator inhibitor1, and lipoprotein[a]). Interpretation of
procoagulant factor and intrinsic anticoagulant levels should recognize the agedependent normal values. Among VTE risk factors, antiphospholipid
antibodies and elevated levels of homocysteine and lipoprotein(a) have also been demonstrated as risk factors for arterial thrombotic ischemic events.
D. Imaging
Appropriate radiologic imaging is essential for objective documentation of thrombosis and to delineate the type (venous vs arterial), degree of
occlusion, and extent (proximal and distal termini) of thrombosis. Depending on site, typical imaging modalities include compression ultrasound with
Doppler, computed tomographic (CT) venography, magnetic resonance venography, and conventional angiography.
Treatment
Current guidelines for the treatment of firstepisode VTE in children are largely based on adult experience and include therapeutic anticoagulation for
at least 3 months. During the period of anticoagulation, bleeding precautions should be followed, as previously described (see Treatment under
Idiopathic Thrombocytopenic Purpura, earlier). Initial therapy for acute VTE employs continuous intravenous unfractionated heparin or subcutaneous
injections of LMWH for at least 7 days, monitored by antiXa activity level to maintain safe and therapeutic anticoagulant levels of 0.3–0.7 or 0.5–1.0
IU/mL, respectively. Subsequent extended anticoagulant therapy is given with LMWH or daily oral warfarin, the latter agent monitored by the PT to
maintain an international normalized ratio (INR) of 2.0–3.0. During warfarin treatment, the INR optimally should be within the therapeutic range before
discontinuation of heparin. Warfarin pharmacokinetics are affected by acute illness, numerous medications, and changes in diet, and can necessitate
frequent monitoring. In children, warfarin dose is determined by age and weight. LMWH offers the advantage of infrequent need for monitoring but is
far more expensive than warfarin. Anatomic contributions to venous stasis (eg, mastoiditis or depressed skull fracture as risk factors for cerebral sinus
venous thrombosis or congenital left iliac vein stenosis in DVT of proximal left lower extremity with MayThurner anomaly) should be addressed to
optimize response to anticoagulation. In cases of limb or lifethreatening VTEs, including massive proximal pulmonary embolus, and in cases of
progressive VTE despite therapeutic anticoagulation, thrombolytic therapy (eg, tissuetype plasminogen activator) may be considered. In adolescent
females, estrogencontaining contraceptives are relatively contraindicated in those with prior VTE if not using anticoagulation, particularly if an
additional genetic cause for impairment of protein C pathway is disclosed.
Direct oral anticoagulants are now firstline therapy for adult acute VTE and for extended anticoagulation. Phase 3 clinical trials in infants and children
are ongoing. One direct oral anticoagulant, rivaroxaban is approved for the treatment of VTE in children.
Prognosis
Registries and cohort studies have suggested that recurrent VTE occurs in approximately 10% of children within 2 years. Persistent thrombosis is
evident following completion of a standard therapeutic course of anticoagulation in up to 30% of children, with unclear clinical importance.
Approximately one in four children with DVT involving the extremities develop postthrombotic syndrome (PTS), a condition of venous insufficiency of
varying severity characterized by chronic skin changes, edema, and dilated collateral superficial venous formation. PTS is often accompanied by
functional limitation (pain with activities or at rest), venous stasis ulcers, and cellulitis. Complete venoocclusion and elevated levels of factor VIII and D
dimer at VTE diagnosis are prognostic factors for PTS among children with DVT affecting the limbs. The presence of homozygous anticoagulant
deficiencies, multiple thrombophilia traits, or persistent antiphospholipid antibodies following VTE diagnosis has been associated with increased risk
of recurrent VTE, leading to consideration of extended anticoagulation in these instances. In cerebral sinus venous thrombosis failure to provide
antithrombotic therapy has been associated with adverse neurologic outcome.
3. SARSCoV2 Vaccines & Thrombosis
A very small minority of people receiving one of two recombinant adenoviral vaccines encoding SARSCoV2 spike protein and a single person receiving
the Moderna mRNA vaccine have developed VTE, and cerebral sinus venous thrombosis. This vaccineinduced immune thrombotic thrombocytopenia
(VITT) is associated with thrombocytopenia and a positive PL4heparin ELISA, and as such resembles heparininduced thrombotic thrombocytopenia
(HITT), a fulminant thrombophilic condition. An urgent hematology consult is needed. Heparin should be avoided. And the initial evaluation should
deficiencies, multiple thrombophilia traits, or persistent antiphospholipid antibodies following VTE diagnosis has been associated with increased risk
of recurrent VTE, leading to consideration of extended anticoagulation in these instances. In cerebral sinus venous thrombosis failure to provide
antithrombotic therapy has been associated with adverse neurologic outcome. Access Provided by:
3. SARSCoV2 Vaccines & Thrombosis
A very small minority of people receiving one of two recombinant adenoviral vaccines encoding SARSCoV2 spike protein and a single person receiving
the Moderna mRNA vaccine have developed VTE, and cerebral sinus venous thrombosis. This vaccineinduced immune thrombotic thrombocytopenia
(VITT) is associated with thrombocytopenia and a positive PL4heparin ELISA, and as such resembles heparininduced thrombotic thrombocytopenia
(HITT), a fulminant thrombophilic condition. An urgent hematology consult is needed. Heparin should be avoided. And the initial evaluation should
include: CBC with platelet count and peripheral smear, imaging for thrombosis based on signs/symptoms, PF4ELISA (HIT assaydraw blood prior
to any therapies), fibrinogen, and Ddimers.
Bussell JB: Thrombosis with Thrombocytopenia Syndrome (also termed Vaccineinduced Thrombotic Thrombocytopenia). American Society of
Hematology COVID19 Resources. https://www.hematology.org/covid19/vaccineinducedimmunethromboticthrombocytopenia
Monagle P: American Society of Hematology 2018 Guidelines for management of venous thromboembolism: treatment of pediatric venous
thromboembolism. Blood Adv 2018 Nov 27;2(22):3292–3316
[PubMed: 30482766] .
Witmer C: Treatment of venous thromboembolism in pediatric patients. Blood 2020;135(5):335–343
[PubMed: 31917400] .

Disorders of Leukocytes

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Universidad

Chédiak­Higashi Oculocutaneous albinism, photophobia, Neutropenia. Neutrophils, Gene (CHS1/LYST) deficit Autosomal

Leukocyte Recurrent soft­tissue infections, including Neutrophilia. Diminished Absence or partial Autosomal

Leukocyte Recurrent infections, mental retardation, Neutrophilia. Deficient Deficient fucosyl Autosomal

Leukocyte Recurrent severe infections, life­threatening Neutrophilia. Dysfunctional Mutations in kindlin­3 Autosomal

Leukocyte Recurrent severe infections, life­threatening Neutrophilia. Dysfunctional Mutations in kindlin­3 Autosomal

Chronic Recurrent purulent infections with catalase­ Neutrophilia. Neutrophils Several molecular defects X­linked in 60%–

Myeloperoxidase Generally healthy. Fungal infections when Diminished capacity to Diminished or absent Autosomal

Specific granule Recurrent skin and deep tissue infections. Neutropenia. Neutrophils Failure to produce specific Autosomal

Antibody­Mediated Coagulopathy Other Congenital Acquired

Idiopathic Disseminated intravascular Hemolytic­uremic syndrome Fanconi anemia Aplastic anemia

Infection Sepsis Thrombotic Wiskott­Aldrich syndrome Leukemia and other

Immunologic diseases Necrotizing enterocolitis Hypersplenism Thrombocytopenia with Vitamin B12 and folate

Normal Fetus (20 Preterm (25–32 Term Infant (6 Pregnancy Exercise Aging (70–

Count μL/103 250 107–297 293 332 – 260 ↑ 18%–40% 225

Size (fL) 9.0 8.9 8.5 9.1 – 9.6 ↑ –

BT (min) 2–9 – 3.6±2 3.4±1.8 – 9.0±1.4 – 5–6

PTT* 1 4.0 3 1.3 1.1 1.1 ↓ 15% ↓

PT* 1.00 2.3 1.3 1.1 1 0.95 N –

TCT* 1 2.4 1.3 1.1 1 0.92 N –

Fibrinogen, 278 (0.61) 96 (50) 250 (100) 240 (150) 251 (160) 450 (100) ↓ 25% ↑ 15%

II, U/mL 1(0.7) 0.16 (0.10) 0.32 (0.18) 0.52 (0.25) 0.88 (0.6) 1.15 (0.68–1.9) – N

V, U/mL 1.0 (0.6) 0.32 (0.21) 0.80 (0.43) 1.00 (0.54) 0.91 (0.55) 0.85 (0.40–1.9) – N

VII, U/mL 1.0 (0.6) 0.27 (0.17) 0.37 (0.24) 0.57 (0.35) 0.87 (0.50) 1.17 (0.87–3.3) ↑ 200% ↑ 25%

VIIIc, U/mL 1.0 (0.6) 0.50 (0.23) 0.75 (0.40) 1.50 (0.55) 0.90 (0.50) 2.12 (0.8–6.0) ↑ 250% 1.50

vWF, U/mL 1.0 (0.6) 0.65 (0.40) 1.50 (0.90) 1.60 (0.84) 1.07 (0.60) 1.7 ↑ 75–200% ↑

IX, U/mL 1.0 (0.5) 0.10 (0.05) 0.22 (0.17) 0.35 (0.15) 0.86 (0.36) 0.81–2.15 ↑ 25% 1.0–1.40

X, U/mL 1.0 (0.6) 0.19 (0.15) 0.38 (0.20) 0.45 (0.3) 0.78 (0.38) 1.30 – N

XII, U/mL 1.0 (0.6) 0.15 (0.08) 0.22 (0.09) 0.44 (0.16) 0.77 (0.39) 1.3 (0.82) – ↑ 16%

IX, U/mL 1.0 (0.5) 0.10 (0.05) 0.22 (0.17) 0.35 (0.15) 0.86 (0.36) 0.81–2.15 ↑ 25% 1.0–1.40

X, U/mL 1.0 (0.6) 0.19 (0.15) 0.38 (0.20) 0.45 (0.3) 0.78 (0.38) 1.30 – N

XI, U/mL 1.0 (0.6) 0.13 (0.08) 0.2 (0.12) 0.42 (0.20) 0.86 (0.38) 0.7 – N

XII, U/mL 1.0 (0.6) 0.15 (0.08) 0.22 (0.09) 0.44 (0.16) 0.77 (0.39) 1.3 (0.82) – ↑ 16%

XIII, U/mL 1.04 (0.55) 0.30 0.4 0.61 (0.36) 1.04 (0.50) 0.96 – –

PreK, U/mL 1.12 (0.06) 0.13 (0.08) 0.26 (0.14) 0.35 (0.16) 0.86 (0.56) 1.18 – ↑ 27%

HK, U/mL 0.92 (0.48) 0.15 (0.10) 0.28 (0.20) 0.64 (0.50) 0.82 (0.36) 1.6 – ↑ 32%

AT, U/mL 1.0 0.23 0.35 0.56 1.04 1.02 ↑ 14% N

α2­MG, U/mL 1.05 (0.79) 0.18 (0.10) – 1.39 (0.95) 1.91 (1.49) 1.53 (0.85) – –

C1IN, U/mL 1.01 – – 0.72 1.41 – – –

PC, U/mL 1.0 0.10 0.29 0.50 0.59 0.99 N N

Total PS, U/mL 1.0 (0.6) 0.15 (0.11) 0.17 (0.14) 0.24 (0.1) 0.87 (0.55) 0.89 – N

Free, PS, U/mL 1.0 (0.5) 0.22 (0.13) 0.28 (0.19) 0.49 (0.33) – 0.25 – –

Heparin 1.01 0.10 (0.06) 0.25 (0.10) 0.49 (0.33) 0.97 (0.59) – – ↓ 15%

Plasminogen, 1.0 0.20 0.35 (0.20) 0.37 (0.18) 0.90 1.39 ↓ 10% N

tPA, ng/mL 4.9 – 8.48 9.6 2.8 4.9 ↑ 300% N

α2­AP, U/mL 1.0 1.0 1.0 0.74 (0.5) 0.83 (0.65) 1.11 (0.83) 0.95 N N

PAI­1, U/mL 1.0 – 1.5 1.0 1.07 4.0 ↓ 5% N

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ChédiakHigashi Oculocutaneous albinism, photophobia, Neutropenia. Neutrophils, Gene (CHS1/LYST) deficit Autosomal

Leukocyte Recurrent softtissue infections, including Neutrophilia. Diminished Absence or partial Autosomal

Leukocyte Recurrent severe infections, lifethreatening Neutrophilia. Dysfunctional Mutations in kindlin3 Autosomal

Leukocyte Recurrent severe infections, lifethreatening Neutrophilia. Dysfunctional Mutations in kindlin3 Autosomal

Chronic Recurrent purulent infections with catalase Neutrophilia. Neutrophils Several molecular defects Xlinked in 60%–

AntibodyMediated Coagulopathy Other Congenital Acquired

Idiopathic Disseminated intravascular Hemolyticuremic syndrome Fanconi anemia Aplastic anemia

Infection Sepsis Thrombotic WiskottAldrich syndrome Leukemia and other

α2MG, U/mL 1.05 (0.79) 0.18 (0.10) – 1.39 (0.95) 1.91 (1.49) 1.53 (0.85) – –

α2AP, U/mL 1.0 1.0 1.0 0.74 (0.5) 0.83 (0.65) 1.11 (0.83) 0.95 N N

PAI1, U/mL 1.0 – 1.5 1.0 1.07 4.0 ↓ 5% N