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Hematology - Thrombocytopenia - Fast Facts | NEJM Resident 360

Isolated thrombocytopenia is a deficiency of platelets in the blood and one of the most common disorders encountered in the inpatient setting. A thorough history and examination is required to identify and treat the underlying cause. Management may initially be guided by the severity of symptoms, which can range from mild bruising to significant bleeding.

Etiology

The following table lists common causes of thrombocytopenia:

Common Etiologies of Thrombocytopenia

Decreased Production	Increased Destruction	Other Special Populations
Bone-Marrow Suppression

Chemotherapy

Radiotherapy

Drug-induced

Chronic alcohol use

Bone-Marrow Failure

Aplastic anemia

Paroxysmal nocturnal hemoglobinuria

Myelodysplastic syndrome

Malignancy

Metastatic cancer

Primary hematologic cancer

Nutritional

B₁₂ deficiency

Folate deficiency

Infection

HIV

Hepatitis C virus

Epstein–Barr virus

Parvovirus

Other viral infections | Connective Tissue Disorders

Systemic lupus erythematosus (SLE)

Antiphospholipid syndrome

Rheumatoid arthritis

Other Immune Disorders

Immune thrombocytopenia purpura (ITP)

Heparin-induced thrombocytopenia (HIT)

Post-transfusion purpura

Non-immune Disorders

Disseminated intravascular coagulopathy (DIC)

Thrombotic thrombocytopenic purpura (TTP)

Hemolytic-uremic syndrome (HUS)

| Pregnancy

Gestational thrombocytopenia

HELLP syndrome*

Preeclampsia/eclampsia

Acute fatty liver

ICU Patients

Sepsis

Dilutional

Cirrhosis

DIC

Cardiac Patients

Bypass surgery

HIT

Glycoprotein IIb/IIIa inhibitors

Splenomegaly

Sequestration

|

* HELLP syndrome (hemolysis, elevated liver enzymes, low platelet) is a severe form of preeclampsia.

Workup

Algorithm for the Workup of Thrombocytopenia

Abbreviations: WBC, white blood cell; TTP, thrombotic thrombocytopenic purpura; HUS, hemolytic–uremic syndrome; DIC, disseminated intravascular coagulopathy; RBC, red blood cell; LDH, lactate dehydrogenase; PT, prothrombin time; aPTT, activated partial-thromboplastin time; BM, bone marrow; DAT, direct antiglobulin test; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; CXR, chest x-ray; ITP, immune thrombocytopenic purpura; DITP, drug-induced immune thrombocytopenic purpura; HCV, hepatitis C virus; HIT, heparin-induced thrombocytopenia; GT, gestational thrombocytopenia
(Republished with permission of American Society of Hematology, from How to Approach Thrombocytopenia. Hematology Am Soc Hematol Educ Program 2012.)

Immune Thrombocytopenia Purpura (ITP)

Diagnosis

ITP is a diagnosis of exclusion and defined as a platelet count <100,000 per mm³ in the absence of other causes.

• Primary ITP is an acquired autoimmune disorder classified by the time elapsed since diagnosis:

  • new diagnosis (<3 months)

  • persistent (3–12 months)

  • chronic (>12 months)

• Causes of secondary ITP are summarized in the following table:

(Source: Immune Thrombocytopenia. N Engl J Med 2019.)

• Drug-induced ITP (DITP): A frequently updated list of drugs that can cause ITP can be found here.

Treatment

The American Society of Hematology (ASH) guidelines recommend treatment of ITP in patients with severe bleeding or low platelet counts (<30,000 per mm³). Treatment for episodes of severe bleeding can range from platelet transfusions to other supportive measures (e.g., tranexamic acid).

The numerous options for the treatment of ITP are summarized in the following table:

Dosages, Efficacy, and Adverse Effects of Various Treatments for ITP

Agent	Dosage	Onset of Action	Durability of Effect	Side Effects and Cautions
Glucocorticoids
Prednisone or prednisolone*	1–2 mg per kilogram of body weight orally for 1–2 wk, followed by gradual tapering; rapid tapering if no response	1–2 wk	Response with treatment in 60 to 80% of patients; sustained response after dis- continuation in 30–50% of patients	Weight gain, insomnia, acne, mood changes, cushingoid appearance, glucose intolerance, osteoporosis, increased risk of infection (particularly with prolonged use of prednisone or prednisolone), gastrointestinal symptoms, neuropsychiatric symptoms (particularly with dexamethasone)
Dexamethasone*	20–40 mg orally for 4 days every 2–4 wk; maximum of 4 cycles		Response with treatment in 60 to 80% of patients; sustained response after dis- continuation in 30–50% of patients	Weight gain, insomnia, acne, mood changes, cushingoid appearance, glucose intolerance, osteoporosis, increased risk of infection (particularly with prolonged use of prednisone or prednisolone), gastrointestinal symptoms, neuropsychiatric symptoms (particularly with dexamethasone)
Immune globulin*	0.4 g per kilogram of body weight intravenously for up to 5 days or 1g per kilogram for 1–2 days	1–4 days	Transient response lasting 1–4 wk in ≤80% of patients; treatment can be repeated	Headache, aseptic meningitis, renal failure, volume overload (may need to spread out over 4 days if cardiac function is impaired)
Thrombopoietin-receptor agonists†
Eltrombopag*	25–75 mg orally daily	1–2 wk	Response achieved and maintained in 40–60% of patients receiving continu- ing therapy; response maintained after discontinuation in 10–30% of patients	Gastrointestinal symptoms, transaminitis, cataract, possible increased risks of thrombosis and myelofibrosis; should be taken 4 hr after and 2 hr before food containing cations (e.g., iron, and calcium from milk or other dairy products)
Romiplostim*	1–10 μg per kilogram, sub- cutaneously once weekly	1–2 wk	Response achieved and maintained in 40–60% of patients receiving continuing therapy; response maintained after discontinuation in 10–30% of patients	Headache, muscle aches, possible increased risks of thrombosis and myelofibrosis
Avatrombopag*	5–40 mg orally daily	1–2 wk	Response achieved in 65% of patients with- in 8 days after treatment	Headache, arthralgia, possible increased risk of thrombosis
Immunomodulators†
Rituximab	375 mg per square meter of body-surface area intra- venously weekly for 4 wk or 1 g administered twice with 2 wk between doses; lower doses (100–200 mg) weekly for 4 wk have also been shown to be effective	1–8 wk	Sustained response in 60% of patients at 6 mo and 30% at 2 yr; treatment can be repeated	Infusion-related side effects (chills, upper respiratory discomfort, bronchospasm), neutropenia, hypogammaglobulinemia, serum sickness; increased risks of infections and progressive multifocal leukoencephalopathy (very rare); should not be used in patients with evidence of active HBV infection (HBV surface antigen) or previous HBV infection (antibodies against hepatitis B core antigen)
Fostamatinib*	50–150 mg orally twice daily	1–2 wk	Response achieved and maintained in 18–43% of patients receiving continuing therapy	Hypertension, nausea, diarrhea, transaminitis
Azathioprine	1–2 mg per kilogram orally (maximum, 150 mg daily)	6–12 wk	Response in 30–60% of patients	Weakness, sweating, neutropenia, transaminitis, increased risk of cancer
Mycophenolate mofetil	500 mg orally twice daily for 2 wk, with gradual increase to 1 g twice daily	4–8 wk	Response in 30–60% of patients	Headache, gastrointestinal symptoms, fungal skin infections, teratogenic in pregnancy, increased risk of cancer
Danazol	400–800 mg orally daily	3–6 months	Response in 30–60% of patients	Hirsutism, acne, amenorrhea, transaminitis; this androgenic agent should not be used in patients with prostate cancer
Dapsone	75–100 mg orally daily	3 wk	Response in 30–60% of patients	Gastrointestinal symptoms, methemogloblinuria, rash, hemolytic anemia (in patients with glucose-6-phosphate dehydrogenase deficiency)

* This agent is approved by the Food and Drug Administration for use in patients with ITP.

† These agents are used in patients in whom glucocorticoids have failed.
(Source:  Immune Thrombocytopenia. N Engl J Med 2019.)

Heparin-Induced Thrombocytopenia (HIT)

HIT is an acquired immune-mediated drug reaction wherein the patient develops an antibody to the complex of heparin and platelet factor 4 (PF4). Although thrombocytopenia is a key feature, antibody binding to the heparin–PF4 complex leads to platelet activation and significant risk of thrombosis, both arterial and venous (about 50% of patients with HIT develop thrombosis).

HIT most often occurs 5 to 14 days after initiating heparin therapy. However, HIT can develop infrequently either earlier (after a recent previous exposure to heparin) or much later after heparin exposure.

Diagnosis

• The 4T Scoring System is used to evaluate the pretest probability of HIT.

• The PF4 antibody test is the most sensitive test available, but false positives are common due to the low threshold used for a positive test to maximize sensitivity.

• Optical density (OD): Always ask the lab for the OD in order to assess the likelihood of true HIT.

• Many labs use an OD cutoff of 0.4 for a positive test, but most patients with an OD of 0.4 do not have HIT.

• An OD >1.5 is almost always a true positive.

• If the OD is equivocal but there is a high clinical suspicion for HIT, the serotonin-release assay (SRA) can be ordered (only after consultation with a hematologist); although SRA is usually the most specific test, it is less sensitive than the PF4 test for HIT.

The following flowchart describes the recommended approach to diagnosis and management of HIT:

Diagnosis of HIT

(Source: Heparin-Induced Thrombocytopenia. N Engl J Med 2015.)

Management

If HIT is suspected based on the 4T score and high clinical suspicion:

• All heparin should be stopped (including flushes for intravascular lines [e.g., intravenous or central venous catheters] that often contain heparin to prevent line clots) and a workup should be performed (as described in the algorithm above).

• If a patient is on warfarin at the time of diagnosis, hold warfarin and administer vitamin K to reverse (warfarin may increase risk of thrombosis in HIT via depletion of protein C).

• The most common alternative agents for anticoagulation therapy in patients diagnosed with HIT are the direct thrombin inhibitors argatroban and bivalirudin; subcutaneous fondaparinux (which has no heparin cross-reactivity) can also be used. Direct oral anticoagulants (DOACs) are increasingly being used as off-label options in clinically stable individuals.  

  • Argatroban or fondaparinux are preferred for urgent surgery and nonurgent cardiac surgery.

  • Avoid argatroban with liver dysfunction.

  • Avoid bivalirudin and fondaparinux in patients with renal dysfunction.

  • DOACs should not be used in patients who require IV anticoagulation, have life or limb threatening thrombosis, or have hepatic dysfunction (Child-Pugh Class B and C).

• Guidelines on DOAC use and dosing recommendations for HIT and HITT are available from the American Society of Hematology.

Medications Used for Treatment of Heparin-Induced Thrombocytopenia

Agent	Clearance	Half-Life	Antidote	Dosing Regimen	Monitoring
Argatroban	Hepatobiliary	40–50 min	No	Intravenous infusion of 2.0 µg per kilogram of body weight
per minute (no bolus); decrease
initial infusion to 0.5–1.2 µg
per kilogram per minute
in patients with liver disease
or critical illness or
after cardiac surgery	Adjust dose to maintain activated partial thromboplastin time at 1.5–3.0 times baseline value (maximum 10 µg per kilogram per minute)
Bivalirudin	Enzymatic and renal	25 min	No	Dose not established; 0.15–2.0 mg per kilogram per hour (no bolus) has been suggested	Adjust dose to maintain activated partial thromboplastin time at 1.5–2.5 times baseline value
Fondaparinux	Renal	17–20 hr	No	5.0 mg subcutaneously once daily for patients <50 kg; 7.5 mg for 50–100 kg; 10.0 mg for >100 kg	None required
Danaparoid
(not available in the U.S.)	Renal	24 hr	No	Intravenous bolus (1500 U
if patient <60 kg; 2250 U if
60 to <75 kg; 3000 U if 75 to 90 kg; 3750 U if >90 kg) followed by intravenous infusion of 400 U per hour for 4 hr, 300 U per hour for 4 hr, then 150–200 U per hour	Adjust to anti-Xa activity of 0.5–0.8 U per milliliter (with use of danaparoid standard curve)

Risk for thrombosis: Patients with HIT are at high risk for thrombosis. Therefore, upper- and lower-extremity ultrasounds are reasonable to rule out occult thrombosis, since this will affect treatment duration.

Clots can occur in odd locations in patients with HIT, including distal veins (a common presentation is a cold, blue toe after cardiac surgery) or the adrenal veins (leading to adrenal hemorrhage). Consider HIT in a patient with adrenal hemorrhage, thrombocytopenia, and recent heparin exposure.

Risk of clotting can persist for >30 days in patients with HIT. Therefore, anticoagulation therapy, usually with warfarin, should be started once the patient is stabilized and platelets have risen to ≥150,000 per mm³. DOACs could also be considered in this setting.

• Continue non-warfarin anticoagulation therapy until platelets are >150,000 per mm³ and bridge to warfarin.

• Duration of treatment is approximately one month if no thrombosis is present and 3 months if thrombosis is present.

• Heparinoid medications should be avoided in these patients indefinitely.

Disseminated Intravascular Coagulation (DIC)

DIC is a broadly defined diagnosis that includes many different pathophysiological mechanisms. All cases of DIC are characterized by a consumptive coagulopathy driven by thrombotic microangiopathy. DIC causes the fibrinolytic system to be overactivated, usually secondary to abnormal thrombin generation. Clinical presentation is variable and reflects consequences of small-vessel thrombosis that may present as dyspnea, chest pain, stroke, or individual organ failure combined with coagulation defects.

(Source: How I Treat Disseminated Intravascular Coagulation. Blood 2018.)

Diagnosis

No single test for DIC exists. The diagnosis must always be considered in patients with the risk factors and conditions mentioned above. The common laboratory profile is:

• elevated international normalized ratio (INR) and D-dimer levels (D-dimer levels increase with age and must be interpreted with caution)

• low platelets and fibrinogen

The ISTH DIC score can help determine if current laboratory changes are compatible with overt DIC 

Workup

(Source: Bleeding and Coagulopathies in Critical Care. N Engl J Med 2014.)

Management

Primary management of DIC involves treating the underlying illness. Supportive care is directed at coagulation abnormalities.

Platelet transfusion may be indicated along with administration of cryoprecipitate as a source of fibrinogen. If international normalized ratio (INR), partial thromboplastin time (PTT), or both >2.5 ULN remain abnormal after administration of cryoprecipitate and the patient is still bleeding, fresh frozen plasma can be administered. Always administer vitamin K when using products that include coagulation factors, such as cryoprecipitate or fresh frozen plasma. Hypocalcemia may result from transfusion of multiple blood products and calcium replacement therapy may be needed. 

When DIC presents predominantly as excessive coagulation activation (thrombotic DIC), administration of low-dose unfractionated heparin can be considered, although evidence of its efficacy is sparse.

No conclusive evidence supports repletion of specific anticoagulant proteins or clotting factors.

Thrombotic Thrombocytopenic Purpura–Hemolytic Uremic Syndrome (TTP-HUS)

TTP and HUS are consumptive thrombocytopenias associated with microangiopathic hemolysis and a spectrum of clinical findings. Both TTP and HUS are rare diagnoses, but must be ruled out in all patients with thrombocytopenia. The presence of fragmented RBCs (schistocytes) on the peripheral-blood smear should raise the suspicion of these conditions.

Peripheral-Blood Smear Consistent with Microangiopathic Hemolytic Anemia

A peripheral-blood smear showed numerous schistocytes (arrows).
(Source: Thrombotic Thrombocytopenic Purpura. N Engl J Med 2019.)

The following algorithm summarizes the evaluation of patients presenting with microangiopathic hemolytic anemia and thrombocytopenia:

Algorithm for the Evaluation of Children and Adults Presenting with Microangiopathic Hemolytic Anemia and Thrombocytopenia

(Source: Syndromes of Thrombotic Microangiopathy. N Engl J Med 2014.)

Treatment: TTP is a clinical emergency. Mortality is as high as 90% without treatment but can be reduced to 10%–20% with proper treatment. Treatment includes the following:

• daily therapeutic plasma exchange (TPE) until resolution of symptoms, recovery of platelet count, and cessation of hemolysis

• steroids if the patient is presumed autoimmune (most cases)

• rituximab in patients experiencing relapse or continue to have refractoriness to steroids and TPE

• caplacizumab, an anti–von Willebrand factor humanized, bivalent variable-domain-only immunoglobulin fragment, can also be considered

• recombinant ADAMTS13 is currently being studied for treatment of acquired TTP and is used in congenital TTP

• if TPE is not available, FFP should be given to temporize; platelets should not be administered

Reviews of treatment options for the various thrombotic microangiopathies can be found here and here.

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