What are the causes of thrombocytopenia?

Causes of Thrombocytopenia

Major Mechanistic Categories

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

Decreased Platelet Production

Bone marrow disorders represent a critical category requiring exclusion, particularly in older patients. 1

• Malignant conditions including myelodysplastic syndromes, acute leukemias, and bone marrow fibrosis impair megakaryocyte function and platelet production. 1, 2
• Aplastic anemia and megaloblastic anemia directly affect platelet production through bone marrow failure. 1
• Viral infections can suppress bone marrow platelet production, particularly HIV and hepatitis C, which may also infect megakaryocyte progenitor cells. 2, 3
• Inherited thrombocytopenias such as thrombocytopenia-absent radius syndrome, Wiskott-Aldrich syndrome, and MYH9-related disease cause congenital production defects. 1, 2
• 22q11.2 deletion syndrome characteristically presents with lower platelet counts and large platelets. 2

Increased Platelet Destruction

Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterized by immunologic destruction of otherwise normal platelets and represents the most common cause in patients with isolated thrombocytopenia and no systemic illness. 1, 2

Secondary immune thrombocytopenia occurs in multiple clinical contexts and differs in natural history and treatment response from primary ITP: 1, 2

• Autoimmune disorders including systemic lupus erythematosus, antiphospholipid antibody syndrome, immune thyroid disease, and Evans syndrome. 2, 3
• Lymphoproliferative disorders such as chronic lymphocytic leukemia and large granular T-lymphocyte leukemia. 2, 3
• Chronic infections including H. pylori (which generates cross-reacting antibodies), HIV (cross-reactive antibodies and impaired megakaryocyte production), and hepatitis C (immune complexes binding platelet Fc receptors plus decreased thrombopoietin production). 2, 3
• Common variable immune deficiency can present with ITP as an initial manifestation. 2
• Post-vaccination or viral infection in children, particularly after measles-mumps-rubella vaccination or infections with Epstein-Barr virus, cytomegalovirus, or varicella zoster virus, caused by cross-reacting antibodies. 2, 3
• Drug-induced thrombocytopenia from medications generating drug-dependent platelet antibodies. 2, 4

Thrombotic Conditions Causing Thrombocytopenia

Critical pitfall: Several life-threatening conditions present with both thrombocytopenia AND thrombosis, not bleeding. 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. 2
• Thrombotic microangiopathies including thrombotic thrombocytopenic purpura and atypical hemolytic uremic syndrome cause platelet consumption through microvascular thrombosis. 2, 5
• Antiphospholipid syndrome causes both thrombocytopenia and arterial/venous thrombosis. 2
• Disseminated intravascular coagulation (DIC) consumes platelets through widespread activation of coagulation. 2

Pregnancy-Related Causes

• Gestational thrombocytopenia is the most common cause in pregnancy, presenting with mild thrombocytopenia (platelet count >70 × 10⁹/L). 2
• Preeclampsia and HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) represent obstetric emergencies requiring immediate recognition. 2, 4

Splenic Sequestration

• Hepatic disease with portal hypertension causes splenomegaly and platelet sequestration, often combined with decreased thrombopoietin production. 2, 3
• Cyanotic congenital heart disease triggers platelet consumption through polycythemia and hyperviscosity, with platelet counts inversely correlating with hematocrit levels. 2

Pseudothrombocytopenia

Critical pitfall: EDTA-dependent platelet agglutination causes falsely low platelet counts and must be excluded before pursuing extensive workup. 2, 4

Algorithmic Diagnostic Approach

First, exclude pseudothrombocytopenia by repeating the platelet count in heparin or sodium citrate tubes and reviewing the peripheral blood smear. 2, 4

Second, determine if thrombocytopenia is isolated or part of pancytopenia through complete blood count with differential. 1, 2

Third, distinguish acute from chronic thrombocytopenia by reviewing previous platelet counts. 4

Fourth, identify red flags requiring immediate hospitalization: 2, 4

• Acute onset with platelet count <20 × 10⁹/L
• Active bleeding
• Suspected HIT, thrombotic microangiopathy, or HELLP syndrome
• Fever, weight loss, bone pain, or systemic symptoms
• Splenomegaly, hepatomegaly, or lymphadenopathy
• Abnormal hemoglobin, white blood cell count, or white cell morphology

Fifth, for patients >60 years or with atypical features, bone marrow examination is mandatory to exclude myelodysplastic syndromes, leukemias, or other malignancies. 1, 2

Sixth, test for secondary causes in adults with suspected ITP: 1, 2

• HIV and hepatitis C (mandatory testing)
• H. pylori (eradication therapy can resolve thrombocytopenia)
• Antiphospholipid antibodies if thrombosis present
• Immunoglobulin levels to exclude common variable immune deficiency