What are the causes of thrombocytopenia (low platelet count)?

Causes of Thrombocytopenia

Major Mechanistic Categories

Thrombocytopenia results from four primary mechanisms: decreased platelet production, increased platelet destruction, splenic sequestration, or dilution/clumping 1, 2, 3.

Decreased Platelet Production

Bone marrow disorders represent the most critical category requiring urgent exclusion, particularly in patients over 60 years:

• Malignant infiltration: Myelodysplastic syndromes, acute leukemias, and metastatic malignancies directly impair megakaryocyte function 1, 2, 3
• Bone marrow failure syndromes: Aplastic anemia and bone marrow fibrosis reduce platelet production 2, 3
• Nutritional deficiencies: Megaloblastic anemia from B12 or folate deficiency affects platelet production 2
• Chronic suppression: Alcohol use, iron overload, certain medications, and viral infections (particularly hepatitis C and HIV) chronically suppress bone marrow function 3
• Inherited thrombocytopenias: Thrombocytopenia-absent radius syndrome, Wiskott-Aldrich syndrome, MYH9-related disease, and 22q11.2 deletion syndrome affect platelet production from birth 1, 2, 3

Increased Platelet Destruction

Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterized by immunologic destruction of otherwise normal platelets, diagnosed only after excluding all secondary causes 1, 2, 3.

Secondary immune thrombocytopenia occurs with multiple associated conditions 1, 2, 3:

• Autoimmune disorders: Antiphospholipid syndrome, systemic lupus erythematosus, and other rheumatologic conditions 1, 3
• Infections: HIV, hepatitis C, and H. pylori are the most important infectious causes requiring routine screening in adults 1, 2, 3
• Lymphoproliferative disorders: Chronic lymphocytic leukemia and lymphomas 1, 3
• Drug-induced thrombocytopenia: Numerous medications can trigger immune-mediated platelet destruction 1, 2, 3
• Common variable immune deficiency: ITP can be the presenting feature 1, 3
• Post-vaccination or post-transfusion: Recent vaccinations or blood transfusions 2, 3

Heparin-induced thrombocytopenia (HIT) typically presents with moderate thrombocytopenia (30-70 × 10⁹/L) occurring 5-10 days after heparin initiation, evaluated using the 4T score based on degree of thrombocytopenia, timing, presence of thrombosis, and absence of other causes 1, 3.

Thrombotic microangiopathies cause both thrombocytopenia and thrombosis 1:

• Disseminated intravascular coagulation (DIC)
• Antiphospholipid syndrome
• Thrombotic thrombocytopenic purpura (TTP)

Pregnancy-specific causes 1:

• Gestational thrombocytopenia (most common, typically mild with platelet count >70,000/μL)
• Preeclampsia/pregnancy-induced hypertension
• HELLP syndrome (hemolysis, elevated liver enzymes, low platelets)

Splenic Sequestration

Hypersplenism from portal hypertension in advanced liver fibrosis causes platelet trapping, contributing to thrombocytopenia in up to 76% of patients with chronic liver disease 3.

Pseudothrombocytopenia

EDTA-dependent platelet agglutination falsely lowers platelet counts and must be excluded first by repeating the count in heparin or sodium citrate tubes 1, 2, 3.

Special Populations

• Cyanotic congenital heart disease: Polycythemia and hyperviscosity trigger platelet consumption, with platelet counts inversely correlating with hematocrit levels, resulting in mild thrombocytopenia (100,000-150,000/μL) more commonly than severe (<50,000/μL) 1

Critical Red Flags Requiring Immediate Investigation

The following findings indicate alternative diagnoses beyond primary ITP and mandate additional testing 1, 2, 3:

• Splenomegaly, hepatomegaly, or lymphadenopathy
• Abnormal hemoglobin level, white blood cell count, or white cell morphology
• Non-petechial rash
• Constitutional symptoms (fever, weight loss, bone pain)
• Abnormal peripheral smear findings (schistocytes, leukocyte inclusion bodies)
• Age >60 years (mandates bone marrow examination to exclude myelodysplasia or malignancy)

Common Pitfalls to Avoid

• Failing to exclude pseudothrombocytopenia first can lead to unnecessary workup and treatment 1, 3
• Missing secondary causes (HIV, HCV, H. pylori) that have specific treatments altering natural history 1, 2, 3
• Overlooking inherited thrombocytopenias in patients with lifelong mild thrombocytopenia and family history 1, 3
• Not recognizing conditions with both bleeding and thrombosis risk (HIT, antiphospholipid syndrome, TTP) where anticoagulation may be required despite low platelets 1, 4
• Delaying bone marrow examination in patients >60 years where myelodysplasia and leukemia are critical diagnoses affecting mortality 1, 3