Causes of Thrombocytopenia
Primary Mechanistic Classification
Thrombocytopenia results from four fundamental mechanisms: decreased platelet production, increased platelet destruction, splenic sequestration, or dilution/clumping—and these mechanisms frequently overlap in clinical practice. 1, 2, 3
Decreased Platelet Production
Bone Marrow Disorders
- Myelodysplastic syndromes, leukemias, and other malignancies impair megakaryocyte function and represent the most critical causes requiring bone marrow examination, particularly in patients over 60 years or those with systemic symptoms such as fever, weight loss, or bone pain. 1, 2, 4
- Aplastic anemia causes pancytopenia with failure of all hematopoietic cell lines. 2
- Megaloblastic anemia from vitamin B12 or folate deficiency affects platelet production alongside red cell and white cell production. 2
- Bone marrow infiltration from metastatic solid tumors or lymphoma physically replaces megakaryocytes. 2
Toxic and Infectious Suppression
- Chronic alcohol use directly suppresses megakaryocyte production and is a common multifactorial cause of thrombocytopenia. 1, 4, 5
- Viral infections, particularly hepatitis C and HIV, suppress bone marrow platelet production and may precede other clinical manifestations by years. 1, 4
- Iron overload impairs megakaryocyte function. 4
- Medications including chemotherapy agents, valproic acid, and certain antibiotics directly suppress platelet production. 4
Inherited Thrombocytopenias
- Thrombocytopenia-absent radius (TAR) syndrome, Wiskott-Aldrich syndrome, and MYH9-related disease affect platelet production from birth and should be suspected when family history is positive or when giant platelets approaching red blood cell size are seen on peripheral smear. 1, 2, 4
- 22q11.2 deletion syndrome is associated with characteristically lower platelet counts, large platelets, and reduced platelet quality, though usually mild. 1
Increased Platelet Destruction
Immune-Mediated Destruction
Primary Immune Thrombocytopenia (ITP)
- Primary ITP is an autoimmune disorder with antibody-mediated destruction of otherwise normal platelets, diagnosed only after excluding all secondary causes through comprehensive testing. 1, 2, 4
- In adults, ITP typically has insidious onset with no preceding illness and follows a chronic course. 1
- In children, ITP usually follows viral infection and two-thirds recover spontaneously within 6 months. 1
Secondary Immune Thrombocytopenia
- Autoimmune disorders including systemic lupus erythematosus and antiphospholipid syndrome cause secondary immune thrombocytopenia. 1, 2
- Viral infections including HIV, hepatitis C, and Epstein-Barr virus cause secondary immune thrombocytopenia that may be clinically indistinguishable from primary ITP. 1, 4
- Lymphoproliferative disorders including chronic lymphocytic leukemia and lymphoma are associated with immune-mediated platelet destruction. 1, 2
- Common variable immune deficiency (CVID) can present with ITP as its initial manifestation. 1, 4
- H. pylori infection causes immune thrombocytopenia in some patients, and eradication therapy can lead to complete hematologic remission. 1
Drug-Induced Immune Thrombocytopenia
- Antibiotics including vancomycin, cefazolin, oxacillin, clindamycin, doxycycline, and trimethoprim-sulfamethoxazole cause drug-dependent antibodies. 1
- Quinine, sulfonamides, and GPIIb-IIIa inhibitors are well-documented causes, with typical onset 5-14 days after drug exposure. 1
- Heparin-induced thrombocytopenia (HIT) typically presents with moderate thrombocytopenia (30-70 × 10⁹/L) occurring 5-10 days after heparin initiation and is paradoxically associated with thrombosis rather than bleeding; evaluate using the 4T score. 1, 4, 3
Non-Immune Destruction
Thrombotic Microangiopathies
- Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) cause platelet consumption through microvascular thrombosis and require prompt diagnosis to prevent catastrophic outcomes. 1, 3
- Disseminated intravascular coagulation (DIC) causes consumption of platelets and coagulation factors through widespread fibrin and platelet deposition, typically in the setting of sepsis or malignancy. 1, 5
- Antiphospholipid syndrome causes thrombocytopenia with thrombosis, not bleeding. 1, 3
Mechanical Destruction
- Extracorporeal circuits, intra-aortic balloon pumps, and cardiac surgery with cardiopulmonary bypass cause consumption thrombocytopenia. 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
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, 5
- Splenomegaly from any cause (lymphoma, myeloproliferative disorders, storage diseases) sequesters platelets. 5
Dilution and Pseudothrombocytopenia
- Massive transfusion dilutes circulating platelets. 3
- EDTA-dependent platelet agglutination (pseudothrombocytopenia) is a laboratory artifact that must always be excluded by repeating the platelet count in heparin or sodium citrate tubes. 1, 4, 3
Pregnancy-Specific Causes
- 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
- Preeclampsia and HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) cause thrombocytopenia in pregnant patients and require emergency hospitalization. 1, 3
Critical Diagnostic Pitfalls to Avoid
- Never diagnose ITP without personal review of the peripheral blood smear, as automated counters can miss pseudothrombocytopenia, giant platelets, or schistocytes. 1
- Never skip HIV and hepatitis C testing in adults with suspected ITP, regardless of risk factors, as these infections can be clinically indistinguishable from primary ITP and may precede other symptoms by years. 1, 4
- Missing secondary causes of ITP (HIV, HCV, H. pylori, autoimmune disorders, lymphoproliferative disorders) leads to misdiagnosis, as these conditions have different natural histories and responses to therapy. 1
- Presence of splenomegaly, hepatomegaly, or lymphadenopathy excludes primary ITP and mandates investigation for secondary causes. 1, 4
- Constitutional symptoms (fever, weight loss, bone pain) suggest underlying disorders rather than primary ITP and require bone marrow examination. 1, 4