Causes of Thrombocytopenia
Thrombocytopenia results from four primary mechanisms: decreased platelet production, increased platelet destruction, splenic sequestration, or dilution/clumping, with the most critical distinction being between decreased production (requiring bone marrow evaluation in high-risk patients) and immune-mediated destruction (the most common cause in otherwise healthy individuals). 1, 2, 3
Major Mechanistic Categories
Decreased Platelet Production
Bone marrow disorders including myelodysplastic syndromes, leukemias, and other malignancies impair megakaryocyte function and represent the most dangerous causes requiring immediate exclusion in patients over 60 years or those with systemic symptoms. 1, 2, 4
Bone marrow suppression occurs from chronic alcohol use, iron overload, certain medications, and viral infections, particularly hepatitis C and HIV. 4
Inherited thrombocytopenias such as thrombocytopenia-absent radius syndrome, Wiskott-Aldrich syndrome, and MYH9-related disease affect platelet production from birth and may present with similar clinical features to acquired causes. 1, 2, 4
Increased Platelet Destruction
Primary immune thrombocytopenia (ITP) is an autoimmune disorder with immunologic destruction of otherwise normal platelets, diagnosed only after excluding all secondary causes. 1, 2, 4, 5
Secondary immune thrombocytopenia associates with multiple conditions: autoimmune disorders (particularly antiphospholipid syndrome), viral infections (HIV, hepatitis C), lymphoproliferative disorders, drug-induced thrombocytopenia, common variable immune deficiency, bone marrow transplantation, and vaccination. 1, 4
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, 4
Thrombotic microangiopathies including antiphospholipid syndrome and disseminated intravascular coagulation cause both thrombocytopenia and paradoxical thrombosis. 1
Drug-induced immune thrombocytopenia most commonly associates with cinchona alkaloid derivatives (quinine, quinidine), sulfonamides, NSAIDs, anticonvulsants, disease-modifying antirheumatic drugs, and diuretics. 6
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. 4
Pregnancy-Related Causes
Gestational thrombocytopenia is the most common cause in pregnancy, typically presenting with mild thrombocytopenia (platelet count >70,000/μL) and must be distinguished from immune thrombocytopenia. 1
Pregnancy-induced hypertension/preeclampsia and HELLP syndrome can cause severe thrombocytopenia requiring emergency hospitalization. 1, 3
Special Population Considerations
- Cyanotic congenital heart disease causes thrombocytopenia due to polycythemia and hyperviscosity triggering 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 mandate urgent evaluation for alternative diagnoses beyond primary ITP:
Splenomegaly, hepatomegaly, or lymphadenopathy suggests secondary causes including lymphoproliferative disorders, chronic liver disease, or infections. 1, 2, 4
Abnormal hemoglobin level, white blood cell count, or white cell morphology indicates bone marrow failure or infiltration rather than isolated immune destruction. 1, 4
Constitutional symptoms including fever, weight loss, or bone pain suggest underlying infection or malignancy. 1, 4
Non-petechial rash is not typical of ITP and should prompt additional testing. 1
Schistocytes on peripheral smear indicate thrombotic microangiopathy requiring emergency evaluation. 1
Common Pitfalls to Avoid
Pseudothrombocytopenia from EDTA-dependent platelet agglutination can falsely lower counts; always repeat in heparin or sodium citrate tubes before proceeding with extensive workup. 1, 2, 4, 3
Missing secondary causes of ITP (HIV, HCV, H. pylori, autoimmune disorders) leads to incorrect natural history assumptions and treatment failures. 1
Overlooking drug-induced thrombocytopenia may be difficult to exclude but must always be considered, as withdrawal of the causative agent is curative. 1, 6
Failing to recognize inherited thrombocytopenias in patients with lifelong mild thrombocytopenia or positive family history prevents unnecessary immunosuppressive therapy. 1
Delaying bone marrow examination in patients over 60 years risks missing myelodysplastic syndromes or leukemias, which have catastrophic mortality implications if untreated. 1, 4