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

Causes of Thrombocytopenia

Thrombocytopenia results from four primary mechanisms: decreased platelet production, increased platelet destruction (immune or non-immune), splenic sequestration, or hemodilution, with the specific cause determined through systematic evaluation of clinical context, complete blood count, and peripheral blood smear. 1, 2

Decreased Platelet Production

Bone Marrow Disorders

• Myelodysplastic syndromes, leukemias, and other malignancies impair megakaryocyte function and represent critical causes requiring bone marrow examination in patients over 60 years or those with systemic symptoms (fever, weight loss, bone pain). 1, 2
• Bone marrow infiltration from metastatic solid tumors or lymphoproliferative disorders directly suppresses platelet production. 3, 4
• Aplastic anemia causes pancytopenia with thrombocytopenia as one component. 4

Toxic and Infectious Suppression

• Chronic alcohol use directly suppresses bone marrow platelet production and is a common multifactorial cause. 1, 5
• Viral infections (particularly hepatitis C, HIV, parvovirus, and CMV) suppress bone marrow production through direct megakaryocyte infection or immune-mediated mechanisms. 1, 6
• Medications causing bone marrow suppression include chemotherapy agents, valproic acid, and certain antibiotics. 1, 7

Inherited Thrombocytopenias

• Thrombocytopenia-absent radius syndrome, Wiskott-Aldrich syndrome, and MYH9-related disease affect platelet production from birth and should be considered when family history or large platelets are present. 1, 2
• 22q11.2 deletion syndrome causes characteristically lower platelet counts with large platelets and reduced platelet quality. 6, 2

Increased Platelet 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 systematic evaluation. 1, 6
• ITP in adults typically has insidious onset without preceding illness and follows a chronic course, whereas childhood ITP is usually acute and self-limited with two-thirds recovering spontaneously within 6 months. 8, 2

Secondary Immune Thrombocytopenia

• Autoimmune disorders, particularly antiphospholipid antibody syndrome (one of the most common associations), systemic lupus erythematosus, and rheumatoid arthritis. 6, 2
• Common variable immune deficiency (CVID) can present with ITP as its initial manifestation, making immunoglobulin measurement essential. 1, 6
• Hepatitis C virus causes thrombocytopenia through multiple mechanisms: antibodies cross-reacting with platelet antigens, immune complexes binding to platelet Fcγ receptors, direct megakaryocyte infection, decreased thrombopoietin production, and splenic sequestration. 6
• HIV infection triggers ITP via cross-reactive antibodies against platelet antigens and infection of megakaryocyte progenitor cells. 6, 2
• Helicobacter pylori generates antibodies that cross-react with platelet antigens; eradication therapy should be administered when detected. 6, 2
• Lymphoproliferative disorders including chronic lymphocytic leukemia and lymphomas. 6, 2

Drug-Induced Thrombocytopenia

• Immune-mediated drug-induced thrombocytopenia occurs with antibiotics (vancomycin, cefazolin, oxacillin, clindamycin, doxycycline, SMX-TMP), GPIIb-IIIa inhibitors, quinine, and sulfonamides, typically presenting 5-14 days after drug exposure. 2, 7
• 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. 1, 6, 2
• Drug-dependent antibodies demonstrate drug-dependence, immunoglobulin binding to platelets, and platelet specificity. 6, 2

Non-Immune Destruction

• Disseminated intravascular coagulation (DIC) causes consumption of platelets and coagulation factors through widespread fibrin and platelet deposition, requiring coagulation studies (PT, aPTT, fibrinogen, D-dimers). 2, 9
• Thrombotic microangiopathies (thrombotic thrombocytopenic purpura and hemolytic uremic syndrome) cause platelet consumption through microvascular thrombosis with schistocytes on peripheral smear. 2, 9
• Consumption thrombocytopenia occurs with extracorporeal circuits, intra-aortic balloon pumps, and cardiac surgery with cardiopulmonary bypass. 2

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. 1
• Splenomegaly from any cause (lymphoma, storage diseases, portal vein thrombosis) sequesters platelets. 3, 5

Hemodilution and Other Mechanisms

• Massive transfusion dilutes existing platelets without adequate replacement. 9, 4
• Pregnancy-related causes include gestational thrombocytopenia (most common, typically mild with platelet count >70,000), preeclampsia/HELLP syndrome, and acute fatty liver of pregnancy. 2, 9
• 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. 2

Critical Diagnostic Algorithm

Step 1: Exclude Pseudothrombocytopenia

• Repeat platelet count in heparin or sodium citrate tubes to exclude EDTA-dependent platelet agglutination, which falsely lowers counts. 1, 2, 9
• Manual peripheral blood smear review by a qualified hematologist confirms true thrombocytopenia and identifies platelet clumping. 2

Step 2: Assess Complete Blood Count Pattern

• Isolated thrombocytopenia suggests ITP, drug-induced thrombocytopenia, or splenic sequestration. 1, 2
• Pancytopenia suggests bone marrow failure, infiltration, or aplastic anemia requiring bone marrow examination. 1, 2

Step 3: Peripheral Blood Smear Examination

• Normal-sized or slightly enlarged platelets with normal red and white cell morphology support ITP. 2
• Schistocytes indicate thrombotic microangiopathy requiring urgent evaluation. 2, 9
• Giant platelets approaching red blood cell size suggest inherited thrombocytopenias. 2
• Immature or abnormal white cells mandate bone marrow examination for malignancy. 2

Step 4: Identify Red Flags Requiring Urgent Evaluation

• Splenomegaly, hepatomegaly, or lymphadenopathy excludes primary ITP and mandates investigation for secondary causes. 1, 2
• Constitutional symptoms (fever, weight loss, bone pain) suggest underlying malignancy or infection. 1, 6
• Abnormal hemoglobin, white blood cell count, or white cell morphology requires bone marrow examination. 1, 6
• Non-petechial rash suggests alternative diagnoses. 6

Step 5: Mandatory Infectious Disease Screening

• HIV testing is mandatory in all adults with suspected ITP regardless of risk factors, as HIV may be clinically indistinguishable from primary ITP and can precede other symptoms by years. 6, 2
• Hepatitis C testing is mandatory in all adults with suspected ITP. 6, 2
• H. pylori testing should be performed, as eradication therapy can resolve thrombocytopenia. 6, 2

Step 6: Determine Need for Bone Marrow Examination

• Mandatory indications: Age >60 years, systemic symptoms, abnormal blood count parameters beyond isolated thrombocytopenia, atypical peripheral smear findings, or failure to respond to first-line ITP therapies. 1, 2
• Not necessary: Typical ITP features in patients <60 years with isolated thrombocytopenia, normal physical exam except bleeding manifestations, and normal peripheral smear. 8, 2

Common Pitfalls to Avoid

• Missing pseudothrombocytopenia by relying solely on automated counts without peripheral smear review leads to unnecessary workup and treatment. 2, 9
• Failing to test for HIV and hepatitis C in all adults with suspected ITP, as these infections require different management and may precede other symptoms by years. 6, 2
• Overlooking drug-induced thrombocytopenia by not obtaining detailed medication history including over-the-counter medications and herbal supplements. 2, 7
• Assuming elevated immature platelet fraction definitively confirms ITP, as severe ITP can present with low immature platelet fraction. 2
• Delaying bone marrow examination in patients >60 years regardless of typical ITP presentation, as this age mandates exclusion of myelodysplastic syndromes and malignancies. 1, 2