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

Causes of Low Platelets (Thrombocytopenia)

Major Mechanistic Categories

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

Decreased Platelet Production

• Bone marrow infiltration or failure from myelodysplastic syndromes, acute leukemias, lymphomas, or metastatic solid tumors impairs megakaryocyte function and represents the most critical cause requiring urgent evaluation in patients over 60 years. 2, 3
• Bone marrow suppression occurs from chronic alcohol use, certain medications (chemotherapy, valproic acid, linezolid), viral infections (hepatitis C, HIV, parvovirus, cytomegalovirus), and iron overload. 4, 2
• Inherited thrombocytopenias including thrombocytopenia-absent radius syndrome, Wiskott-Aldrich syndrome, MYH9-related disease, and 22q11.2 deletion syndrome affect platelet production from birth and typically present with large platelets on peripheral smear. 5, 2, 3

Increased Platelet Destruction

• Primary immune thrombocytopenia (ITP) is an autoimmune disorder with antibody-mediated destruction of otherwise normal platelets, diagnosed only after excluding all secondary causes. 4, 2
• Secondary immune thrombocytopenia occurs with multiple associated conditions:
  • Autoimmune disorders (systemic lupus erythematosus, antiphospholipid syndrome) 5, 2
  • Viral infections (HIV, hepatitis C, which may precede other symptoms by years) 4, 5
  • Lymphoproliferative disorders 5, 2
  • Drug-induced thrombocytopenia (quinine, sulfonamides, vancomycin, heparin) 5, 3
  • Common variable immune deficiency 5, 2
  • H. pylori infection 5
• 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. 5, 2
• Thrombotic microangiopathies including thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), disseminated intravascular coagulation (DIC), and antiphospholipid syndrome cause platelet consumption with concurrent thrombosis risk. 5, 3, 1
• Pregnancy-related causes include gestational thrombocytopenia (most common, typically platelet count >70 × 10⁹/L), preeclampsia/HELLP syndrome (hemolysis, elevated liver enzymes, low platelets), and pregnancy-associated ITP. 5

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. 2

Other Mechanisms

• Acute viral infections and live attenuated virus vaccinations produce transient thrombocytopenia that typically resolves spontaneously. 4
• Chronic infections including parvovirus and cytomegalovirus can produce persistent thrombocytopenia. 4
• Thyroid disease (both hyperthyroidism with reduced platelet survival and hypothyroidism with decreased platelet production) causes mild thrombocytopenia that often resolves with restoration of euthyroid state. 4
• Cyanotic congenital heart disease triggers platelet consumption due to polycythemia and hyperviscosity, with platelet counts inversely correlating with hematocrit levels. 5

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 and is the most common laboratory artifact. 5, 2, 3, 1

Step 2: Distinguish Isolated vs. Multi-lineage Cytopenias

• Obtain complete blood count with differential to determine if thrombocytopenia is isolated or accompanied by anemia/leukopenia, as pancytopenia suggests bone marrow failure or infiltration. 4, 5, 2

Step 3: Examine Peripheral Blood Smear

• Mandatory peripheral smear review confirms true thrombocytopenia, assesses platelet size (large platelets suggest inherited thrombocytopenias or ITP), identifies schistocytes (suggesting thrombotic microangiopathy), and detects abnormal white cells or blasts (suggesting leukemia). 5, 2, 3

Step 4: Identify Red Flags Requiring Urgent Evaluation

• Splenomegaly, hepatomegaly, or lymphadenopathy excludes primary ITP and mandates investigation for lymphoproliferative disorders, liver disease, or infections. 5, 3
• Constitutional symptoms (fever, weight loss, bone pain) suggest underlying malignancy, infection, or systemic autoimmune disease. 5, 3
• Abnormal hemoglobin, white blood cell count, or white cell morphology beyond isolated thrombocytopenia requires bone marrow examination. 5, 2

Step 5: Mandatory Infectious Disease Screening

• Test all adults with suspected ITP for HIV and hepatitis C virus regardless of risk factors, as these infections may be clinically indistinguishable from primary ITP and can occur years before other symptoms develop. 4, 5, 2
• Consider H. pylori testing, as eradication therapy can resolve thrombocytopenia in infected patients. 5, 2

Step 6: Determine Need for Bone Marrow Examination

• Bone marrow examination is NOT necessary in patients with typical ITP features: isolated thrombocytopenia, normal physical exam except bleeding manifestations, and no systemic symptoms. 4, 5, 3
• Bone marrow examination IS mandatory for:
  • Patients over 60 years (to exclude myelodysplastic syndromes, leukemias, or other malignancies) 5, 2
  • Presence of systemic symptoms (fever, weight loss, bone pain) 5, 2
  • Abnormal blood count parameters beyond isolated thrombocytopenia 5, 2
  • Atypical peripheral smear findings (schistocytes, leukocyte inclusion bodies) 5
  • Minimal or no response to first-line ITP therapies 5

Step 7: Additional Testing Based on Clinical Context

• Coagulation studies (PT, aPTT, fibrinogen, D-dimer) should be obtained in patients with severe thrombocytopenia to evaluate for disseminated intravascular coagulation. 5
• Anti-PF4 antibodies should be tested immediately when clinical probability of HIT is intermediate or high based on the 4T score. 5
• Immunoglobulin measurement may identify common variable immune deficiency, as ITP can be its presenting feature. 5, 2
• Antithyroid antibody and thyroid function testing may be useful, as 8-14% of ITP patients develop clinical hyperthyroidism or hypothyroidism. 4

Common Pitfalls to Avoid

• Failing to recognize 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. 5
• Mistaking pseudothrombocytopenia for true thrombocytopenia occurs when EDTA-dependent platelet agglutination is not excluded by repeating the count in alternative anticoagulants. 5, 1
• Not considering inherited thrombocytopenias in younger patients with lifelong mild thrombocytopenia and family history, as these may present with similar clinical features to ITP. 5
• Overlooking drug-induced thrombocytopenia, which may be difficult to exclude but should always be considered by reviewing all medications including over-the-counter drugs and supplements. 5, 3
• Missing constitutional symptoms (fever, weight loss, night sweats) that suggest underlying disorders such as lymphoma, leukemia, or chronic infection rather than primary ITP. 5
• Assuming elevated immature platelet fraction (IPF) definitively confirms ITP, as severe ITP can present with low IPF, and age over 60 years mandates bone marrow examination regardless of IPF. 5