Differential Diagnoses for Thrombocytopenia

The differential diagnosis of thrombocytopenia is organized by mechanism—decreased production, increased destruction, sequestration, and dilution—with pseudothrombocytopenia excluded first because it is a laboratory artifact that mimics true disease. 1

Step 1: Exclude Pseudothrombocytopenia

EDTA-dependent platelet clumping falsely lowers automated platelet counts in approximately 0.1% of samples; repeat the count in a citrate or heparin tube and obtain manual peripheral-smear review by a hematopathologist before proceeding with further workup. 1

Step 2: Categorize by Mechanism

A. Decreased Platelet Production (Bone Marrow Failure)

Malignant Infiltration

Acute leukemia, myelodysplastic syndromes, and metastatic solid tumors infiltrate the marrow and impair megakaryocyte function; bone marrow examination with flow cytometry and cytogenetics is mandatory in patients ≥60 years, those with systemic symptoms (fever, weight loss, bone pain), or any additional cytopenias beyond isolated thrombocytopenia. 1, 2

Aplastic Anemia

Pancytopenia without organomegaly characterizes aplastic anemia; reticulocyte count is low, and bone marrow biopsy shows hypocellularity. 2

Nutritional Deficiencies

Megaloblastic anemia from vitamin B12 or folate deficiency produces macrocytic red cells and hypersegmented neutrophils on smear, with concurrent thrombocytopenia due to ineffective thrombopoiesis. 2

Bone Marrow Suppression

Chronic alcohol use, viral infections (HIV, hepatitis C, EBV, CMV, parvovirus B19), and certain medications (chemotherapy, valproate, linezolid) directly suppress megakaryocyte production. 1, 3, 2
Iron overload in transfusion-dependent patients can impair platelet production. 1

Inherited Thrombocytopenias

MYH9-related disease, Bernard-Soulier syndrome, thrombocytopenia-absent radius (TAR) syndrome, and Wiskott-Aldrich syndrome present with giant platelets (approaching red-cell size) or leukocyte inclusion bodies on smear; family history and platelet morphology provide critical clues. 1
22q11.2 deletion syndrome is associated with large platelets, reduced platelet quality, and characteristically lower counts, though usually mild. 1

B. Increased Platelet Destruction

Immune-Mediated Destruction

Primary Immune Thrombocytopenia (ITP)

Autoimmune destruction of otherwise normal platelets diagnosed only after excluding all secondary causes; typical features include isolated thrombocytopenia, normal physical exam except for bleeding manifestations (petechiae, purpura), and normal-sized or mildly enlarged platelets on smear. 1, 2
Mandatory testing in all adults: HIV antibody, hepatitis C serology, and Helicobacter pylori (urea-breath or stool antigen test), because these infections can be clinically indistinguishable from primary ITP and may precede other symptoms by years. 1, 2
Bone marrow examination is not required in patients with typical ITP features but is mandatory if age ≥60 years, systemic symptoms, organomegaly/lymphadenopathy, additional cytopenias, or atypical smear findings (schistocytes, immature cells, giant platelets). 1, 2

Secondary Immune Thrombocytopenia

HIV-associated thrombocytopenia may be the initial manifestation of HIV infection; routine HIV testing is required regardless of perceived risk. 1, 3, 2
Hepatitis C virus (HCV) causes secondary ITP that can resolve with successful antiviral therapy; HCV serology is mandatory in all adults with suspected ITP. 1, 3, 2
Systemic lupus erythematosus (SLE) produces secondary ITP with concurrent anemia of chronic disease, often presenting with constitutional symptoms, hepatomegaly, or lymphadenopathy; approximately 35% of young adults with primary ITP and high-titer ANA develop a connective-tissue disease within 5 years. 1, 2
Antiphospholipid syndrome causes thrombocytopenia with paradoxical thrombosis rather than bleeding; antiphospholipid antibody testing (anticardiolipin, lupus anticoagulant, anti-β2-glycoprotein-I) should be performed in ITP patients with high-titer ANA. 1
Common variable immune deficiency (CVID) can present initially as ITP; quantitative immunoglobulin measurement should be considered. 1, 2
Lymphoproliferative disorders (chronic lymphocytic leukemia, lymphoma) cause secondary ITP; flow cytometry on bone marrow is indicated when organomegaly or lymphadenopathy is present. 1, 2
Post-infectious ITP typically manifests 1–4 weeks after viral illness (VZV, EBV, CMV, parvovirus B19, hepatitis A, rubella); in children, two-thirds recover spontaneously within 6 months. 1

Drug-Induced Immune Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) typically presents 5–10 days after heparin exposure with moderate thrombocytopenia (30–70 × 10⁹/L) and paradoxical thrombosis risk; calculate the 4T score immediately in any patient who received heparin within the past 3 months, and if ≥4 (intermediate/high probability), discontinue all heparin and obtain anti-PF4 antibody testing without awaiting results. 1
Antibiotics (vancomycin, cefazolin, oxacillin, clindamycin, doxycycline, SMX-TMP), GPIIb-IIIa inhibitors, quinine, sulfonamides, and certain chemotherapies can cause drug-dependent antibodies; onset is typically 5–14 days after drug exposure, and immediate cessation of all suspect drugs is necessary. 1, 4

Non-Immune Destruction

Thrombotic Microangiopathies

Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) cause platelet consumption through microvascular thrombosis; schistocytes on peripheral smear indicate life-threatening thrombotic microangiopathy requiring urgent ADAMTS13 activity, LDH, haptoglobin, and coagulation studies (untreated TTP mortality >90%). 1, 2

Disseminated Intravascular Coagulation (DIC)

Widespread fibrin and platelet deposition in sepsis, malignancy, or major trauma consumes platelets and coagulation factors; basic coagulation studies (PT, aPTT, fibrinogen, D-dimers) should be obtained to evaluate for DIC in patients with severe thrombocytopenia. 1, 2

Mechanical Destruction

Extracorporeal circuits, intra-aortic balloon pumps, and cardiac surgery with cardiopulmonary bypass cause consumption thrombocytopenia with high risk of thrombosis and bleeding complications. 1
Cyanotic congenital heart disease produces mild thrombocytopenia (100,000–150,000/μL) due to polycythemia and hyperviscosity triggering platelet consumption, with platelet counts inversely correlating with hematocrit levels. 1

C. Platelet Sequestration

Hypersplenism

Portal hypertension associated with cirrhosis induces splenomegaly and platelet sequestration; the degree of thrombocytopenia correlates with the extent of splenomegaly and portal pressure. 1
Cirrhosis also leads to decreased thrombopoietin synthesis, resulting in lower platelet production; approximately 80% of patients with cirrhosis have platelet counts below the normal range, while severe thrombocytopenia (<50 × 10⁹/L) is uncommon in compensated disease. 1
Moderate or massive splenomegaly suggests alternative causes beyond primary ITP, including lymphoproliferative disorders or portal hypertension, and mandates bone marrow evaluation with flow cytometry. 1, 2

D. Dilutional Thrombocytopenia

Massive transfusion or fluid resuscitation dilutes circulating platelets; onset within 1–3 days of transfusion suggests hemodilution or non-immune heparin effect. 1, 5

Step 3: Pregnancy-Specific Differentials

Gestational thrombocytopenia is the most common cause of thrombocytopenia in pregnancy, typically presenting with mild thrombocytopenia (platelet count >70,000/μL) and must be distinguished from ITP. 1
Pre-eclampsia and HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) cause thrombocytopenia in pregnant patients; pregnancy testing in individuals of childbearing potential is mandatory to differentiate gestational thrombocytopenia, pre-eclampsia, or HELLP syndrome from primary ITP. 1

Critical Red Flags Requiring Immediate Investigation

Schistocytes on peripheral smear indicate thrombotic microangiopathy (TTP, HUS, DIC) requiring urgent evaluation to prevent catastrophic outcomes. 1, 2
Splenomegaly, hepatomegaly, or lymphadenopathy excludes primary ITP and mandates investigation for HIV, SLE, lymphoproliferative disorders, or chronic liver disease. 1, 2
Constitutional symptoms (fever, unexplained weight loss, night sweats, bone pain) suggest underlying malignancy or infection and require bone marrow examination with flow cytometry and cytogenetics. 1, 2
Anemia or leukopenia beyond isolated thrombocytopenia indicates bone marrow failure or infiltration and necessitates bone marrow evaluation. 1, 2
Giant platelets approaching red-cell size suggest inherited thrombocytopenias (MYH9-related disease, Bernard-Soulier syndrome). 1
Leukocyte inclusion bodies indicate MYH9-related disease. 1, 2
Immature or abnormal white cells raise suspicion for leukemia or myelodysplastic syndrome. 1, 2

Common Pitfalls to Avoid

Never diagnose ITP without personal review of the peripheral-blood smear by a hematopathologist, as automated counters miss pseudothrombocytopenia, giant platelets, or schistocytes. 1
Never omit HIV and HCV testing in adults with suspected ITP, even in low-risk populations, because these infections can masquerade as primary ITP for years. 1, 3, 2
Missing secondary causes of ITP (HIV, HCV, H. pylori, SLE, lymphoproliferative disorders) leads to inappropriate treatment and poor outcomes. 1, 2
Delaying bone marrow examination in patients ≥60 years or with atypical features risks missing life-threatening malignancies. 1, 2
Overlooking medication-induced cytopenias requires comprehensive medication review including prescription drugs, over-the-counter products, herbal supplements, and quinine-containing beverages. 1, 2

What are the differential diagnoses for thrombocytopenia?

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