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, and dilution or clumping. 1, 2

Decreased Platelet Production

Bone marrow disorders are a critical category that must be excluded, particularly in older patients. 1, 2

• Malignant conditions include myelodysplastic syndromes, acute and chronic leukemias, lymphomas, and metastatic solid tumors that infiltrate the marrow. 1, 2, 3
• Aplastic anemia causes pancytopenia with hypocellular marrow and requires bone marrow examination for diagnosis. 2
• Megaloblastic anemia from vitamin B12 or folate deficiency impairs megakaryocyte maturation. 2
• Bone marrow suppression occurs with chronic alcohol use, certain medications (chemotherapy, valproic acid, linezolid), viral infections (HIV, hepatitis C, EBV, CMV), and iron overload. 1

Inherited thrombocytopenias include thrombocytopenia-absent radius syndrome, Wiskott-Aldrich syndrome, MYH9-related disease, and 22q11.2 deletion syndrome (which presents with characteristically large platelets). 1, 2, 3

Increased Platelet Destruction

Immune-Mediated Destruction

Primary immune thrombocytopenia (ITP) is a diagnosis of exclusion after ruling out all secondary causes, characterized by antibody-mediated destruction of otherwise normal platelets. 1, 2, 3, 4

Secondary immune thrombocytopenia has multiple associated conditions that must be systematically excluded: 1, 2, 3

• Viral infections: HIV and hepatitis C can be clinically indistinguishable from primary ITP and may precede other symptoms by years—testing for HIV and HCV is mandatory in all adults with suspected ITP, regardless of risk factors. 1, 3
• H. pylori infection: Eradication therapy should be administered when present, as it can resolve thrombocytopenia. 1
• Autoimmune disorders: Systemic lupus erythematosus, antiphospholipid syndrome, rheumatoid arthritis, and common variable immune deficiency. 1, 2
• Lymphoproliferative disorders: Chronic lymphocytic leukemia, lymphomas, and other hematologic malignancies. 1, 2, 3
• Bone marrow transplantation and vaccination can trigger secondary immune thrombocytopenia. 1, 2

Drug-induced immune thrombocytopenia typically presents 5-14 days after drug exposure and can be caused by antibiotics (vancomycin, cefazolin, oxacillin, clindamycin, doxycycline, SMX-TMP), GPIIb-IIIa inhibitors, quinine, sulfonamides, and certain chemotherapies. 1

Heparin-induced thrombocytopenia (HIT) 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 and test anti-PF4 antibodies immediately when clinical probability is intermediate or high. 1

Non-Immune Destruction

Thrombotic microangiopathies cause platelet consumption through microvascular thrombosis: 1, 3

• Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) require prompt diagnosis and treatment to prevent catastrophic outcomes. 1
• Disseminated intravascular coagulation (DIC) causes consumption of platelets and coagulation factors through widespread fibrin and platelet deposition—diagnose with PT, aPTT, fibrinogen, and D-dimers. 1
• Antiphospholipid syndrome causes thrombocytopenia with thrombosis, not bleeding. 1

Consumption thrombocytopenia occurs with extracorporeal circuits, intra-aortic balloon pumps, and cardiac surgery with cardiopulmonary bypass. 1

Splenic Sequestration

Hypersplenism from cirrhosis, portal hypertension, or infiltrative diseases causes pooling of up to 90% of platelets in an enlarged spleen. 5, 6

Dilution

Massive transfusion or fluid resuscitation can dilute platelet counts without true platelet loss. 5, 7

Pregnancy-Related Causes

Gestational thrombocytopenia is the most common cause in pregnancy, presenting with mild thrombocytopenia (platelet count >70 × 10⁹/L) and must be distinguished from ITP. 1

Pregnancy-induced hypertension/preeclampsia and HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) are obstetric emergencies requiring immediate recognition. 1, 5

Special Populations

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

Critical Diagnostic Pitfalls to Avoid

Pseudothrombocytopenia from EDTA-dependent platelet clumping can falsely lower automated counts—always exclude this first by examining a peripheral blood smear and repeating the count in a citrate or heparin tube. 1, 2, 3, 5

Missing secondary causes of ITP (HIV, HCV, H. pylori, autoimmune disorders, lymphoproliferative disorders) leads to incorrect diagnosis and inappropriate treatment—these conditions have different natural histories and responses to therapy. 1, 3

Overlooking drug-induced thrombocytopenia requires a detailed medication history including over-the-counter medications, herbal supplements, and any heparin exposure within the past 3 months. 1, 3

Failing to recognize red flags that exclude primary ITP: splenomegaly, hepatomegaly, lymphadenopathy, constitutional symptoms (fever, weight loss, bone pain), or abnormalities beyond isolated thrombocytopenia on CBC or peripheral smear. 1, 3