[ Critical Care CHEST Reviews ]

Hematology Emergencies in Critically

Ill Adults
Benign Hematology
Jenna Spring, MD; and Laveena Munshi, MD

Hematologic conditions (malignant or benign) may progress to acute critical illness requiring
prompt recognition and intensive management. This review outlines diagnostic considerations
and approaches to management for intensivists of common benign hematologic emergencies,
including the following: thrombotic thrombocytopenic purpura, atypical hemolytic uremic
syndrome, disseminated intravascular coagulopathy, catastrophic antiphospholipid antibody
syndrome, hemophagocytic lymphohistiocytosis, acute chest syndrome associated with sickle
cell disease, and hyperhemolysis syndrome. CHEST 2022; 161(5):1285-1296

KEY WORDS: antiphospholipid syndrome; disseminated intravascular coagulation; hematologic

emergencies; hemophagocytic lymphohistiocytosis; thrombotic thrombocytopenic purpura

Hematologic emergencies represent thrombocytopenic purpura (TTP), atypical

important causes of critical illness that, if
not promptly recognized and treated, may
become imminently life-threatening.
Although these conditions require expert
consultation with a hematologist, it is
essential for the intensivist to have an
approach to the initial management of these
complex patients. Delays in recognition,
diagnosis, and treatment may result in
worse outcomes. The current review focuses
on the diagnosis and management of
hematologic emergencies that arise in the
absence of an underlying hematologic
malignancy, including important
considerations for the intensivist. This
review includes thrombotic
hemolytic uremic syndrome (aHUS),
disseminated intravascular coagulopathy
(DIC), hemophagocytic
lymphohistiocytosis (HLH), catastrophic
antiphospholipid syndrome (CAPS), acute
chest syndrome associated with sickle cell
disease (SCD), and hyperhemolysis
syndrome. These topics were chosen
because they represent either commonly
encountered emergencies or rarer
presentations that when missed can
become imminently life-threatening. The
full scope of hematologic emergencies,
including malignant causes that are
addressed in a separate review, is outlined
in Table 1.

ABBREVIATIONS: aHUS = atypical hemolytic uremic syndrome; APS =
antiphospholipid syndrome; CAPS = catastrophic antiphospholipid
syndrome; DIC = disseminated intravascular coagulation; HbS = he-
moglobin S; HLH = hemophagocytic lymphohistiocytosis; IVIG = IV
immunoglobulin; SCD = sickle cell disease; ST-HUS = Shiga toxin-
associated hemolytic uremic syndrome; TMA = thrombotic micro-
angiopathy; TPE = therapeutic plasma exchange; TTP = thrombotic
thrombocytopenic purpura; vWF = von Willebrand factor
AFFILIATIONS: From the Interdepartmental Division of Critical Care
Medicine (J. Spring and L. Munshi), Department of Medicine, and
Institute of Health Policy, Management and Evaluation (L. Munshi),
University of Toronto, Toronto, ON, Canada; and the Sinai Health
System and University Health Network (J. Spring and L. Munshi),
Toronto, ON, Canada.
CORRESPONDENCE TO: Laveena Munshi, MD; email: Laveena.munshi@
sinaihealth.ca
Copyright Ó 2022 American College of Chest Physicians. Published by
Elsevier Inc. All rights reserved.
DOI: https://doi.org/10.1016/j.chest.2021.12.650

chestjournal.org 1285
TABLE 1 ] Hematologic Emergencies
Benign Hematology Malignant Hematology
 Acute chest syndrome in sickle cell disease  Acute promyelocytic leukemia
 Acquired hemophilia  Complications following hematopoietic stem cell
 Autoimmune hemolytic anemia transplantation
 Catastrophic antiphospholipid syndrome  Febrile neutropenia and neutropenic sepsis
 Hemophagocytic lymphohistiocytosis  Hypercalcemia
 Hyperhemolysis syndrome  Hyperleukocytosis and leukostasis
 Thrombotic microangiopathy, including thrombocytopenic  Hyperviscosity syndrome
purpura, atypical hemolytic uremic syndrome, and disseminated  Malignant spinal cord compression
intravascular coagulopathy  Superior vena cava syndrome
 Toxicities of novel therapies
 Tumor lysis syndrome

Thrombotic Thrombocytopenic Purpura also have other findings in keeping with intravascular
TTP is the most frequently diagnosed thrombotic hemolysis, including elevated indirect bilirubin,
microangiopathy (TMA) in adults. It can lead to reticulocyte count, and lactate dehydrogenase with low
multiorgan failure and death due to microvascular haptoglobin. Coombs test results should be negative.
occlusion and ischemia. TTP is a relatively rare Although fever, neurologic symptoms, and occasionally
condition caused by a deficiency in ADAMTS13, which renal failure are clinical manifestations of TTP, they are
is a protein that usually cleaves von Willebrand factor not required for the diagnosis. Cardiac manifestations or
(vWF). This is primarily caused by the development of elevated troponins at the time of diagnosis are associated
antibodies that inhibit ADAMTS13, although rare with worse outcomes.8
genetic forms of TTP exist. In the absence of
Laboratory evidence of reduced ADAMTS13 activity
ADAMTS13 activity, large multimers of vWF arise and
(< 10%) may help to confirm the diagnosis.9 However,
bind platelets, leading to the formation of microthrombi
and shearing of RBCs.1 TTP is usually idiopathic but
may be associated with underlying diseases such as TABLE 2 ] Presenting Signs and Symptoms in TTP3,5,6
autoimmune conditions, infection (including HIV),
Organ System Manifestations
malignancy, or pregnancy and is more common in
women, with a typical age of onset between 40 and 50 CNS Altered mental status,
memory loss, visual
years.2,3 Historically, the mortality was 80%4; however, changes, numbness,
with early recognition and prompt initiation of headache, focal neurologic
contemporary treatments, mortality rates have decreased deficits, stroke, seizures,
coma
substantially to 10% to 20%.5
Cardiac Syncope, chest pain,
myocardial infarction,
Clinical Presentation and Diagnosis
hypertension, congestive
Patients with TTP may present with a variety of signs and heart failure, arrhythmia,
ECG abnormalities, elevated
symptoms (Table 2).3,5,6 The historic classic pentad of
cardiac enzymes, cardiac
TTP is fever, neurologic symptoms, hemolytic anemia, arrest
thrombocytopenia, and acute kidney injury. However, GI Abdominal pain, nausea,
this is uncommonly seen, occurring in < 10% of cases and vomiting, diarrhea,
often a late manifestation of more severe disease.7 Given pancreatitis, colitis,
elevated liver enzymes,
that early recognition and prompt initiation of treatment liver necrosis
are associated with improved outcomes, suspicion should Renal Acute kidney injury
be raised for TMA and possibly TTP when profound
Hematologic Bleeding, bruising,
thrombocytopenia (platelet counts < 30
109/L) and microangiopathic hemolytic
hemolytic anemia with schistocytosis on a peripheral anemia, schistocytes,
thrombocytopenia, purpura
blood smear are present with a normal prothrombin time
and partial thromboplastin time. These findings should Other Fever, generalized malaise,
jaundice
raise suspicion for TTP and prompt a consultation with a
hematology specialist and rapid workup. Patients may TTP ¼ thrombotic thrombocytopenic purpura.

1286 CHEST Reviews [ 161#5 CHEST MAY 2022 ]

these results can take several days to obtain, and
treatment should not be delayed in the interim.
Calculating the PLASMIC score (Table 3) may be a
helpful adjunct to clinical judgment, with high
sensitivity when the score is five or higher and excellent
negative predictive value.10,11 Diagnoses that are
important to distinguish from TTP include aHUS, DIC,
CAPS, Evans syndrome (immune thrombocytopenia
with autoimmune hemolysis), heparin-induced
thrombocytopenia, and HELLP (hemolysis, elevated
liver enzymes, and low platelets) syndrome in pregnant
patients.
Management
Any patient with a presumed or confirmed diagnosis of
TTP should undergo emergent consultation with a
hematologist and initiation of therapeutic plasma
exchange (TPE). TPE is performed by using fresh frozen
plasma or solvent/detergent plasma. Time to TPE
should occur ideally within 6 h of suspicion of TTP, if
feasible.12 Most patients will require ICU admission
either due to the severity of their illness or to facilitate
the prompt initiation of this therapy. A specialized
center with an apheresis program should be contacted
urgently. If TPE is not immediately available, under the
guidance of a hematologist, transfusion of fresh frozen
plasma to transiently replace ADAMTS13 can be
considered until definitive treatment is arranged,
particularly in the setting of neurologic symptoms. If
ADAMTS13 testing has not yet been conducted, it is
recommended that a sample be obtained to send for
testing prior to the initiation of TPE or administration of
fresh frozen plasma.
The mechanism of benefit for TPE in TTP is believed to
be the removal of autoantibodies and replacement of
ADAMTS13 along with the elimination of large vWF
multimers from the circulation. Corticosteroids should
also be administered early in the disease course.6,13 This
is generally at a dose of prednisone 1 mg/kg/d; however,
TABLE 3 ] PLASMIC Score for TTP10
Components
Platelets < 30
10 /L 9
Each component is awarded 1 point
Evidence of hemolysisa
No active cancer
No previous solid organ or stem cell transplant
MCV < 90 fL
INR < 1.5
Creatinine < 176 mmol/L
INR ¼ international normalized ratio; MCV ¼ mean corpuscular volume; TTP ¼ thrombotic thrombocytopenic purpura.
a
Evidence of hemolysis is defined by reticulocyte count > 2.5%, undetectable haptoglobin, or indirect bilirubin. > 34.2 mmol/L.
chestjournal.org
pulse steroids for 3 days may be considered in the setting
of severe disease or neurologic manifestations.6
Rituximab in addition to TPE is also recommended for
patients with a first presentation of TTP, with evidence
to suggest that rituximab may reduce relapse rates and
may be associated with reduced mortality when given
early.13-15 Timing and dosing of rituximab should be
coordinated with the apheresis team and pharmacist.
More recently, caplacizumab has also been
recommended as a potential treatment for TTP with
guidance from hematology experts familiar with its
use.13 Caplacizumab is an anti-vWF immunoglobulin
that prevents interaction between vWF and platelets and
has been shown to result in faster recovery of platelets
and lower recurrence rates.16
Neurologic recovery often occurs very early following
treatment initiation (24 h), followed by improvement in
hemolytic parameters (1-2 days) and platelet recovery
(> 2-3 days). Treatment response is determined by
normalization of the platelet count and hemolytic
parameters (hemoglobin and lactate dehydrogenase).
TPE should continue until 2 days after platelet count
and lactate dehydrogenase normalize, with a median of 7
to 10 sessions often required.6
There has been significant concern surrounding the risks
associated with platelet transfusions in TTP following
early reports of devastating outcomes after platelet
administration. In general, it is recommended to avoid
platelet transfusions outside of major bleeding or the
need for an invasive procedure or intervention.17
However, in the era of contemporary treatments, the
degree of harm from platelet transfusions in the setting
of TTP remains unclear.18-20
Atypical Hemolytic Uremic Syndrome
aHUS is a rare TMA and is seen less frequently than
TTP. It is a complement-mediated TMA that can be
challenging to recognize and diagnose. Distinct from
Scoring Interpretation
0-4 ¼ Low risk
5 ¼ Moderate risk
6-7 ¼ High risk
1287
HUS associated with Shiga toxin-producing Escherichia
coli (ST-HUS), which is more frequently seen in
children, aHUS is caused by dysregulated complement
activity that leads to endothelial injury, damage to RBCs,
platelet activation, and microthrombi formation.21,22
More than one-half of cases are associated with
genetic mutations in the complement cascade,
although this fact may not be diagnostically helpful
in the emergent setting.23 Compared with TTP,
aHUS is generally associated with more severe renal
dysfunction, and prognosis overall is poor, with death
or progression to end-stage renal disease in one-half
of patients.24
Clinical Presentation and Diagnosis
Patients with aHUS will also present with the classic
TMA features of hemolytic anemia, thrombocytopenia,
and schistocytes on peripheral smear. Clinical symptoms
alone are unreliable to distinguish aHUS from TTP or
other causes of TMA. Although renal failure is more
common in aHUS, and neurologic symptoms are more
frequently described in TTP, this is not true in all cases.
The most helpful distinguishing feature from TTP is the
presence of a normal ADAMSTS13 level in aHUS, which
may take days to confirm.25 Similarly, the presence or
absence of GI symptoms does not reliably differentiate
between ST-HUS and aHUS. However, ST-HUS can
typically be ruled out via a negative stool culture and
immunoassay for Shiga toxin.
There are also numerous other causes of TMA that
should be considered depending on the presenting
features and clinical scenario. A diagnostic approach is
outlined in Figure 1.26-31 However, this is not an
exhaustive list, and both TTP and aHUS may be
triggered by underlying illnesses that can independently
cause TMA such as malignancy and infection. When
aHUS is suspected, genetic tests aimed at identifying
abnormal complement proteins can also be performed
to confirm the diagnosis with the caveat that these
results may take weeks to obtain and 50% of patients
may not have an identifiable variant.32 Tests for
antibodies to complement factor H should also be
conducted.25 Given the diagnostic complexities, early
consultation with a hematologist is critical to making an
accurate and timely diagnosis.
Management
Definitive treatment for aHUS requires inhibition of
complement activation. However, given the challenge
differentiating aHUS from TTP and demonstrated
1288 CHEST Reviews
efficacy of TPE in some cases of aHUS,33 TPE should
still be offered as first-line therapy while awaiting the
results of the diagnostic work up, including
ADAMSTS13 testing.
For the past decade, the mainstay of treatment for aHUS
has been eculizumab, which is a monoclonal antibody
that acts as a terminal complement inhibitor by binding
to C5.21 Ravulizumab, a longer acting C5 inhibitor, has
also recently been found to be safe and effective and is
now being used in some centers.34 The optimal duration
of treatment is unknown, and patients often remain on
anticomplement therapy in excess of 1 year with risk of
relapse following discontinuation.35
Disseminated Intravascular Coagulopathy
DIC is a consumptive coagulopathy characterized by
overactivation of the coagulation pathway and
disordered fibrinolysis that results in diffuse
microvascular thrombosis and end-organ dysfunction.
The most common cause of DIC in critically ill patients
is sepsis, with evidence of DIC in up to one-third of
patients.36,37 However, it is also associated with a wide
variety of other underlying illnesses that are frequently
seen in the ICU, including cancer, major trauma, burns,
pancreatitis, and peripartum complications in pregnant
patients.38 Recognizing DIC is essential because it is
associated with high mortality rates and requires early
identification of the underlying cause.
Clinical Presentation
DIC can manifest with both bleeding and thrombotic
complications. Small vessel thromboses predominate,
but patients may also develop overt venous and arterial
thromboembolic complications.39 Bleeding often
manifests as oozing from puncture sites, indwelling
lines, or drains, although life-threatening pulmonary,
GI, and intracranial bleeding can occur. Patients may
also develop acute kidney injury and evidence of liver
dysfunction. Purpura fulminans is an extreme cutaneous
presentation associated with infections such as
meningococcemia and Streptococcus pneumoniae that
results in widespread and rapidly progressive skin
necrosis with a high risk of multiorgan failure and
death.40
The diagnostic criteria are outlined in Figure 2.41 In
addition, schistocytes may be seen on peripheral smear,
and antithrombin levels are characteristically low.42 DIC
can typically be separated from other causes of TMA,
such as TTP, on the basis of abnormal coagulation
parameters. Differentiating DIC from the coagulopathy
[ 161#5 CHEST MAY 2022 ]
 Figure 1 – Diagnostic approach in a
Patient Presenting with Evidence of patient presenting with TMA.26-31
TMA DIC ¼ disseminated intravascular
• Severe thrombocytopenia • Anemia • coagulation; HELLP ¼ hemolysis,
elevated liver enzymes, low platelets;
• Schistocytes on peripheral smear •
HSCT ¼ hematopoietic stem cell trans-
plantation; HUS ¼ hemolytic uremic
YES syndrome; MCTD ¼ mixed connective
tissue disease; PT ¼ prothrombin time;
YES PTT ¼ partial thromboplastin time;
TTP ADAMSTS13 < 10% SLE ¼ systemic lupus erythematosus;
TMA ¼ thrombotic microangiopathy.
NO

YES
Shiga toxin-associated HUS Positive Shiga toxin

NO

Other Causes of Thrombotic Microangiopathy

Cause Features

Suspect in any patient with TMA, normal ADAMSTS13,

Atypical HUS negative Shiga toxin, and no alternate cause. Renal failure may
be a predominant manifestation

In addition to features of TMA, patient will have elevated

DIC
PT/PTT, low fibrinogen, elevated D dimer

TMA in a patient with known or suspected systemic bacterial

Infection-Related
or viral infection

Consider in patients with metastatic breast, lung, prostate,

Malignancy-
gastric, or unknown primary cancer. Also described in
Associated
hematologic malignancy and patients post-HSCT

Autoimmune- Known or suspected autoimmune disease (SLE, systemic

Associated sclerosis, Sjögren’s, MCTD, and vasculitis)

Recent administration of a medication known to cause TMA

Drug-Induced such as quinine, sirolimus, tacrolimus, mitomycin, interferon,
and cyclosporine, etc

Can be associated with HELLP syndrome and severe

Pregnancy-Related
preeclampsia

Malignant Extreme elevation in BP with or without

Hypertension concomitant renal dysfunction

caused by hepatic failure can be challenging, although
factor VIII levels may help (they should be low in DIC
but not in liver dysfunction).
Management
The primary consideration when managing a patient
with DIC is identifying and treating the underlying
cause. The decision to administer blood products to
correct coagulopathy depends largely on the patient’s
bleeding risk. For actively bleeding patients, or those at
high risk of bleeding, platelet count should be
maintained > 50
109/L.43 However, prophylactic
platelet transfusion in lower risk patients should be
reserved until the platelet count falls to < 10 to 20

109/L. Fresh frozen plasma may be administered to
correct an elevated prothrombin time or activated
partial thromboplastin time, but again this decision
should be based on bleeding risk, with the addition of
cryoprecipitate or fibrinogen concentrate as needed to
maintain the fibrinogen level > 1 g/L. The addition of
tranexamic acid can also be considered in the case of
active bleeding or need for invasive procedures.37 For
patients presenting with overt thrombosis or purpura
fulminans, anticoagulation with unfractionated heparin

chestjournal.org 1289

First, a potential cause for DIC must be present such as infection,
malignancy, trauma, or pregnancy complications
Platelet Count
Prothrombin Time
Fibrinogen
Fibrin Marker
(ie, D-dimer)
Score interpretation: ≥ 5 is in keeping with a diagnosis of DIC
Units: Platelet count = 109 /L; PT = seconds; fibrinogen = g/L
Figure 2 – Diagnostic criteria for DIC.41 DIC ¼ disseminated intravascular coagulopathy.
should be pursued. All other patients with an acceptable
bleeding risk should receive VTE prophylaxis.
Hemophagocytic Lymphohistiocytosis
HLH is a severe, life-threatening inflammatory
syndrome caused by overactivation of macrophages,
natural killer cells, and cytotoxic T lymphocytes. The
resultant cytokine storm can lead to multiorgan
failure and death. HLH may be primary or
secondary. Secondary HLH is associated with an
underlying condition, including hematologic
malignancies, viral infections, underlying
autoimmune disorders, or solid organ or stem cell
transplantation. In adults, it is more common in
men, with an average age of onset of around 50
years.44 Historically, prognosis was very poor.
However, with rapid recognition and prompt
initiation of treatment, 5-year survival exceeds
50%.45
Clinical Presentation and Diagnosis
Patients with HLH may present with a syndrome that is
very difficult to differentiate clinically from the
dysregulated immune response seen in severe sepsis. The
presentation is often nonspecific and typically includes
fever, splenomegaly, elevated ferritin, and cytopenias
occurring concurrently with end-organ dysfunction.
Because of the challenge in distinguishing HLH from
other causes of critical illness, it may frequently be
underdiagnosed in the ICU setting.46
The most commonly used diagnostic criteria, HLH-
2004, were initially developed for pediatric HLH and
require that five of eight diagnostic criteria be present
1290 CHEST Reviews
Diagnosis of DIC
< 50 = 2 50–100 = 1 > 100 = 0
>6=2 3–6 = 1 <3=0
<1=1 >1=0
Strongly Moderately
Normal = 0
increased = 3 increased = 2
(Table 4).47 An alternative scoring system, known as the
HScore, estimates the risk of HLH based on nine
variables and was developed for adults.48 Both
frameworks are reliable diagnostic tools in critically ill
patients, with elevated ferritin levels as an effective
screening tool.49 If a diagnosis of HLH is suspected,
concurrent investigations for the underlying precipitant
should be pursued. This often necessitates consultation
with hematologists, infectious disease experts, or
rheumatologists based on the potential underlying
condition.
Management
The treatment of HLH centers on intensive
immunosuppression to mitigate the inflammatory
response while concurrently treating the underlying
disease. The recommended protocol was developed for
pediatrics, with dose adjustment in adults.50 The
treatment regimen for primary HLH includes
corticosteroids, etoposide, cyclosporine, and intrathecal
methotrexate for patients with neurologic
involvement.51 Once HLH is confirmed, in the setting of
severe disease or a deteriorating critically ill patient,
urgent expert consultation with a hematologist is
recommended to initiate immunosuppressive treatment
even while awaiting identification of the underlying
precipitant. In the setting of secondary HLH, when an
underlying diagnosis is identified, treatment should be
targeted to the underlying condition. If a patient
presents with severe critical illness with HLH confirmed
yet there is a lack of clarity on whether it is primary or
secondary, expert consultation is recommended to
discuss empiric initiation of corticosteroids/etoposide
while waiting for a definitive diagnoses.
[ 161#5 CHEST MAY 2022 ]
TABLE 4 ] Diagnostic Criteria for HLH
HLH-2004 Criteria47
Diagnosis of HLH can be made if patients have $ 5 of the following criteria:
 Fever
 Splenomegaly
 Cytopenias (at least two): hemoglobin < 90 g/L, neutrophils < 1
109/L,
platelets
< 100
109/L
 Elevated triglycerides ($ 3.0 mmol/L) or low fibrinogen (# 1.5 g/L)
 Evidence of hemophagocytosis in lymph nodes, spleen, or bone marrow
 Low or absent natural killer cell activity
 Ferritin $ 500 mg/L
 Soluble CD25 $ 2,400 U/mL
HScore48
Criteria Points
Underlying immunosuppression No ¼ 0
Yes ¼ 18
Temperature,  C < 38.4 ¼ 0
38.4-39.4 ¼ 33
> 39.4 ¼ 49
Organomegaly No ¼ 0
Hepatomegaly or splenomegaly ¼ 23
Hepatomegaly and splenomegaly ¼ 38
No. of cytopenias 1 cell line ¼ 0
2 cell lines ¼ 24
3 cell lines ¼ 34
Ferritin, ng/mL < 2,000 ¼ 0
2,000-6,000 ¼ 35
> 6,000 ¼ 50
Triglyceride, mmol/L < 1.5 ¼ 0
1.5-4 ¼ 44
> 4 ¼ 64
Fibrinogen, g/L > 2.5 ¼ 0
# 2.5 ¼ 30
Aspartate aminotransferase, IU/L < 30 ¼ 0
$ 30 ¼ 19
Hemophagocytosis on bone marrow No ¼ 0
Yes ¼ 35

As the HScore increases, the likelihood of hemophagocytic lymphohistiocytosis (HLH) increases. An HScore cutoff of 168 has been shown to have a sensitivity
of 100% and a specificity of 94% in critically ill patients.49

Catastrophic Antiphospholipid Syndrome with a superimposed trigger, such as infection, surgery,

Antiphospholipid syndrome (APS) is an autoimmune
disorder associated with venous and arterial thromboses.
It is most frequently seen in patients with lupus or other
autoimmune conditions but may be discovered
incidentally in a small proportion of patients with
thrombotic events as well as adverse events during
pregnancy. CAPS involves simultaneous thromboses in
multiple organs with microvascular involvement
resulting in organ failure. CAPS occurs in approximately
1% of patients with APS and has a high mortality rate
despite treatment.52 It is believed to result from an
underlying susceptibility to thrombosis in combination
trauma, or cancer that leads to a systemic inflammatory
response.53 CAPS most commonly occurs in women, with
a mean age of onset of around 40 years.54 For 50% of
patients, CAPS may be the first presentation of APS.
Clinical Presentation and Diagnosis
For patients presenting with CAPS, the kidneys are the
most commonly involved organ.54 However, pulmonary,
CNS, and cardiac manifestations are also seen. The
range of organ involvement is outlined in
Figure 3.52,54-56 On bloodwork, patients may be found to
have thrombocytopenia and evidence of

chestjournal.org 1291
 Organ
Clinical Manifestations
System
CNS Headaches, stroke, seizures, encephalopathy
Myocardial infarction, congestive heart failure,
Cardiac
Libman Sacks endocarditis, valvulopathy
ARDS, pulmonary embolism, pulmonary
Pulmonary
edema, alveolar hemorrhage
Liver failure, jaundice, hepatomegaly, elevated
GI
liver enzymes, GI bleeding, ileus
Acute kidney injury, hypertension, proteinuria,
Renal
hematuria
Livedo reticularis, cutaneous ulcers or
Skin
necrosis, purpura
Figure 3 – Clinical manifestations and diagnosis of CAPS.52,54-56 CAPS ¼ catastrophic antiphospholipid antibody syndrome.
microangiopathic hemolytic anemia (schistocytes,
thrombocytopenia, and signs of hemolysis). However,
the degree of schistocytosis is usually much less than
that seen in TTP.52 DIC may also be present.
CAPS can be challenging to diagnose, and a high index
of suspicion must be maintained, particularly in patients
presenting with microvascular thromboses in the
context of known APS or another underlying
autoimmune condition. The diagnosis is based on the
occurrence of thrombotic complications across at least
three organ systems or tissues within a 1-week period in
a patient with antiphospholipid antibodies and small
vessel thromboses on pathology.55,56 Antiphospholipid
antibodies include lupus anticoagulant and
anticardiolipin antibodies, which should be present on
two occasions at least 6 weeks apart. It is important to
note that antiphospholipid antibodies by themselves are
not diagnostic, and they may be common in critically ill
patients, especially those with an underlying
malignancy.52,57
Management
Given the rarity of this syndrome with a mortality rate of
around 30%, a multidisciplinary approach to
management for patients with CAPS is critical, including
consultation with hematology and rheumatology.52
Patients frequently develop multiorgan failure and
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Diagnosis
Definite CAPS is defined by the presence of all
four of the following criteria:
1. Involvement of at least 3 organs, systems
or tissues
2. Manifestations develop within 1 week
3. Confirmation of small vessel occlusion on
pathology
4. Presence of antiphospholipid antibodies
present on two occasions at least 6
weeks apart
• Lupus anticoagulant and/or
• Anticardiolipin antibodies
Probable CAPS is defined by the following:
• All four criteria but only two organs involved
• All four criteria except for laboratory
confirmation of antiphospholipid antibodies
on two occasions 6 weeks apart
• Criteria 1, 2, and 4
• Criteria 1, 3, and 4 and the occurrence of a
third thrombotic event despite
anticoagulation 1-4 weeks following
presentation
require ICU admission. It is also crucial to identify and
treat the underlying precipitant whenever possible. Once
patients are admitted to the ICU, care should be taken to
avoid any unnecessary arterial cannulation or
instrumentation wherever possible as this may induce
additional thromboses.58
The available evidence for the treatment of CAPS is
limited. However, first-line therapy typically includes
systemic anticoagulation with IV unfractionated heparin
combined with steroids and plasmapheresis or IV
immunoglobulin (IVIG).59 The dose of corticosteroids
used varies in the literature, but pulse doses of 500 to
1,000 mg of methylprednisolone IV daily for 3 days are
frequently recommended upfront.60 The addition of
plasmapheresis or IVIG has been associated with
improved outcomes in retrospective cohorts and is
recommended in current guidelines.59,61 In patients with
lupus, cyclophosphamide should also be considered.52
Additional treatments such as eculizumab and rituximab
have been used in some patients with refractory disease
but are not recommended as standard of care.
Acute Chest Syndrome in Sickle Cell Disease
SCD is an inherited hemoglobinopathy defined by the
presence of hemoglobin S (HbS). Deoxygenation of HbS
leads to the characteristic sickle shape along with
[ 161#5 CHEST MAY 2022 ]
hemolysis and microvascular thrombosis with multiple
complications. Acute chest syndrome, characterized
by abnormalities on chest radiograph in conjunction
with respiratory symptoms or fever, is a frequent
cause of ICU admission and early death in patients
with SCD.62 It is most commonly caused by viral or
bacterial infections, fat embolism, or pulmonary
infarction and frequently occurs in conjunction with a
vaso-occlusive pain crisis in adults.63 Fluid overload
from IV hydration and hypoventilation in association
with pain or opiate administration are other potential
precipitants and may exacerbate the severity of
respiratory failure.64 Patients who have homozygous
SCD are at the highest risk, but it can also be seen in
other sickle cell phenotypes.65 Mortality rates in adults
with acute chest syndrome may be as high as 9%, and
up to one in five adults may require mechanical
ventilation.63
Clinical Presentation and Diagnosis
Acute chest syndrome may be the reason for admission
to the hospital, or the onset may occur within 1 to
3 days of an acute pain crisis that prompted
Diagnosis
The diagnosis of ACS can be made if there is a new
segmental infiltrate on chest radiograph AND
one of the following:
• Fever (T ≥ 38.5°C)
• Hypoxemia: more than 2% increase in SpO2 or PaO2
< 60 mm Hg
• Tachypnea, or increased work of breathing
• Cough, chest pain, rales or wheeze
Disease Severity
Disease severity is based on degree of hypoxemia, imaging
findings, and transfusion needs.
Severe or very severe disease is characterized by the
presence of one of the following features:
• Respiratory failure: SpO2 < 85% on room
air or ≤ 90% despite maximal supplemental oxygen,
PaO2 < 60 mm Hg or PCO2 > 50 mm Hg, ARDS
• Infiltrates in three or more lobes on chest radiograph
• Need for simple transfusion or exchange
transfusion to keep HbA ≥ 70%
Figure 4 – Approach to diagnosis and treatment of ACS.64,68 ACS ¼ acute chest syndrome; HbS ¼ hemoglobin S; SpO2 ¼ blood oxygen saturation.
chestjournal.org
admission.66 Common symptoms in adults include
fever, cough, chest pain, sternal or rib pain, and
shortness of breath.63 Pain in the extremities and
abdomen may also be present in a significant number of
patients. On chest radiograph, patients may have
multilobar infiltrates as well as pleural effusions.67 To
meet criteria for diagnosis of acute chest syndrome,
patients must have a new infiltrate on chest radiograph
in addition to fever or respiratory symptoms (Fig 4).64,68
Bronchoscopy is not routinely indicated outside of a
specific clinical question. However, if bronchoscopy is
performed, the presence of > 5% of lipid-laden alveolar
macrophages is highly suggestive of fat emboli as a
precipitant.69
Other life-threatening diagnoses can be challenging to
distinguish from acute chest syndrome due to
significant overlap in the clinical presentation. These
include pulmonary embolism, pneumonia, and acute
coronary syndrome. A CT pulmonary angiogram
and cardiac enzyme evaluation should be ordered
based on clinical suspicion. Patients with SCD are also
prone to other pulmonary complications such as
reactive airway disease and pulmonary hypertension,
Initial Investigations
In all patients:
• CBC, creatinine, liver profile, reticulocyte count,
group and screen
• Hemoglobin electrophoresis to determine levels of HbS
• Chest radiograph, electrocardiogram
• Blood cultures, sputum cultures, nasopharyngeal swab for
respiratory viruses
Based on clinical suspicion or specific clinical question:
• CT pulmonary angiogram
• Cardiac enzymes
Treatment
Supportive care:
• Ensure excellent pain control
• Encourage incentive spirometry
• Prescribe standing bronchodilators if there is evidence of
bronchospasm or history of asthma
• Start empiric antibiotics for pneumonia, including atypical
coverage
• Maintain adequate hydration
Transfusion strategy: Expert consultation recommended
• Mild disease = No transfusion
• Moderate disease = Simple transfusion or exchange
transfusion
• Severe disease = Exchange transfusion
1293
which could further exacerbate their acute respiratory
failure.
Management
Intensive supportive care and close monitoring are
essential for patients with acute chest syndrome (Fig 4).
The threshold to consult ICU and hematology should be
low, particularly in patients with severe disease. Pain
must be urgently and adequately treated, and patients
should be encouraged to use incentive spirometry where
available.70 Empiric antibiotics with atypical coverage
are recommended for all patients, even those with
negative culture results.64
Transfusion to increase oxygen-carrying capacity and
decrease the HbS fraction should be considered in all
patients with acute chest syndrome and hypoxemia.64
Patients with severe disease should undergo exchange
transfusion to target a hemoglobin level of 100 to 110
g/L with an HbS fraction < 30%.64,71 Exchange
transfusion involves removing the patient’s RBCs and
replacing them, which can be done either manually or
with the use of an apheresis machine. This process
results in improved hemoglobin levels while also
removing a proportion of the RBCs containing HbS. In
patients with multiple alloantibodies, decision-making
surrounding transfusion can be challenging, and expert
consultation with hematology is important.
Post-Transfusion Hyperhemolysis Syndrome
Hyperhemolysis syndrome is a hemolytic transfusion
reaction characterized by destruction of both the
patient’s RBCs and transfused RBCs leading to a drop in
hemoglobin level. Although hyperhemolysis is most
commonly described in SCD, it can also occur in
patients with other hemoglobinopathies and
hematologic disorders.72 Complement and macrophage
activation are believed to play a role, but the underlying
pathophysiology and risk factors are not well
understood. Hyperhemolysis is essential to recognize, as
further attempts at transfusion may only worsen the
hemolysis and, in severe cases, it can be fatal.73
Clinical Presentation and Diagnosis
Hallmarks of hyperhemolysis include a decrease in
hemoglobi following transfusion, laboratory evidence of
hemolysis (elevated lactate dehydrogenase, elevated
bilirubin, and low haptoglobin), elevated ferritin, and
low reticulocyte count. Fever and pain are also common.
Both acute (ie, in the first week following transfusion)
and delayed reactions have been described. When a
1294 CHEST Reviews
delayed reaction occurs, the patient’s direct antiglobulin
test result will typically be positive with new
alloantibodies present.74
Management
Given that hyperhemolysis is rare, evidence for
treatment is lacking. Standard management includes
IVIG and pulse steroids. The following regimen has
been suggested: IVIG 0.4 g/kg IV daily for 5 days with
methylprednisolone 500 mg IV daily for 2 days.75
Subsequent doses of IVIG and steroids may be
considered when there is evidence of ongoing hemolysis.
Additional therapies that have been used successfully in
case reports include tocilizumab, eculizumab, and
rituximab.76-78 Patients are also frequently given
erythropoietin.73 Recurrent episodes were previously
believed to be rare but a case-control analysis reported
recurrence in 50% of patients.73
Patients with hyperhemolysis may present with critical
illness if the degree of hemolysis results in impaired
oxygen delivery and lactic acidosis. In these settings,
enhancing oxygen delivery through other pathways in
the oxygen delivery equation and minimizing excess
oxygen consumption (eg, treating fever) while
simultaneously conserving blood may be necessary (eg,
minimizing blood draws, using pediatric tubes).
Synthetic blood products such as Hemopure
(Hemoglobin Oxygen Therapeutics LLC) have also been
used with success in these settings.79 Consultation with a
hematologist is recommended.
Conclusions
Emergencies in benign hematology that may be
encountered in critically ill patients represent a broad
range of complex presentations. Although many of these
diseases may not be frequently seen in daily ICU
practice, the ability to urgently recognize them and
initiate supportive care while awaiting expert
hematology consultation can be lifesaving.
Acknowledgments
Financial/nonfinancial disclosures: None declared.
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