What causes a low platelet count (thrombocytopenia)?

Causes of Low Platelet Count (Thrombocytopenia)

Thrombocytopenia results from three primary mechanisms: decreased platelet production in the bone marrow, increased platelet destruction (immune-mediated or consumptive), or splenic sequestration, with the most critical step being exclusion of pseudothrombocytopenia before pursuing further evaluation. 1, 2

Immediate Exclusion: Pseudothrombocytopenia

• Always verify true thrombocytopenia first by examining the peripheral blood smear for EDTA-dependent platelet clumping, which causes falsely low automated counts 1, 2, 3
• Collect a new blood sample in citrate or heparin anticoagulant and repeat the platelet count to confirm 2, 3

Major Mechanisms and Causes

Decreased Platelet Production

Bone marrow disorders that impair megakaryocyte function include:

• Myelodysplastic syndromes, leukemias, and malignancies that infiltrate the bone marrow 1, 2
• Bone marrow suppression from chronic alcohol use, certain medications, viral infections (hepatitis C, HIV), and iron overload 1, 2
• Inherited thrombocytopenias such as thrombocytopenia-absent radius syndrome, Wiskott-Aldrich syndrome, MYH9-related disease, and 22q11.2 deletion syndrome 1

Increased Platelet Destruction

Immune-mediated 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, 1, 2
• Secondary immune thrombocytopenia associated with HIV, hepatitis C, H. pylori infection, autoimmune diseases (lupus, antiphospholipid syndrome), lymphoproliferative disorders, common variable immune deficiency, and drug-induced causes 1, 2

Drug-induced thrombocytopenia:

• 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 1, 2, 5
• Other medications including quinine-containing beverages, herbal supplements, and numerous prescription drugs 1, 6

Consumptive thrombocytopenia:

• Disseminated intravascular coagulation (DIC) from sepsis, malignancy, or obstetric complications 1, 2
• Thrombotic microangiopathies including thrombotic thrombocytopenic purpura (TTP) and antiphospholipid syndrome 1
• HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) in pregnancy 1

Splenic Sequestration

• Splenomegaly from liver cirrhosis, portal hypertension, or hematologic disorders traps platelets in the enlarged spleen 2, 7

Dilutional and Multifactorial Causes

• Hemodilution in perioperative settings, massive transfusion, or extracorporeal circuits 2
• Pregnancy-related: Gestational thrombocytopenia (most common, typically platelet count >70 × 10⁹/L), preeclampsia, or HELLP syndrome 1
• Chronic liver disease with multifactorial mechanisms including decreased thrombopoietin production, splenic sequestration, and bone marrow suppression 1, 8

Essential Diagnostic Algorithm

Step 1: Confirm True Thrombocytopenia

• Peripheral blood smear review to exclude pseudothrombocytopenia and identify platelet clumping 1, 2, 3

Step 2: Determine Isolated vs. Multi-lineage Involvement

• Complete blood count with differential to distinguish isolated thrombocytopenia from pancytopenia 1, 2
• Pancytopenia suggests bone marrow failure, malignancy, or severe infection requiring urgent evaluation 2

Step 3: Identify Life-Threatening Causes Requiring Emergency Management

• TTP, DIC, HELLP syndrome, acute leukemia, and HIT require immediate recognition and treatment 2, 3
• Obtain PT, aPTT, fibrinogen, and D-dimer if severe thrombocytopenia to screen for DIC 1, 2

Step 4: Evaluate for Secondary Causes in Suspected ITP

• HIV and hepatitis C testing mandatory in all adults with suspected ITP, regardless of risk factors 1, 2, 6
• H. pylori testing as eradication therapy can resolve thrombocytopenia 1, 2, 6
• Comprehensive medication history including over-the-counter drugs, herbal supplements, and recent heparin exposure 1, 6

Step 5: Age-Specific Considerations

• Patients >60 years require bone marrow examination to exclude myelodysplastic syndromes, leukemias, or other malignancies, regardless of how typical the presentation appears 1, 6
• Children with typical ITP features (isolated thrombocytopenia, normal physical exam, no systemic symptoms) do not require bone marrow examination 1

Critical Red Flags Suggesting Alternative Diagnoses

Physical examination findings that exclude primary ITP:

• Splenomegaly, hepatomegaly, or lymphadenopathy mandate investigation for secondary causes 1, 2
• Fever, weight loss, bone pain, or systemic symptoms require bone marrow examination 1, 6

Laboratory abnormalities beyond isolated thrombocytopenia:

• Anemia (except microcytic from chronic blood loss), leukopenia, or abnormal white cell morphology 1, 6
• Schistocytes on peripheral smear suggest thrombotic microangiopathy 1

Common Pitfalls to Avoid

• Missing pseudothrombocytopenia by relying solely on automated counts without peripheral smear review 1, 2, 3
• Failing to test for HIV, HCV, and H. pylori in adults with suspected ITP, as these infections may be clinically indistinguishable from primary ITP and can precede other symptoms by years 1, 2
• Overlooking drug-induced thrombocytopenia by not obtaining detailed medication history including quinine-containing beverages and herbal supplements 1, 6
• Assuming elevated immature platelet fraction (IPF) definitively confirms ITP, as severe ITP can present with low IPF 1
• Not recognizing HIT in patients with recent heparin exposure, which requires immediate cessation of heparin and alternative anticoagulation 1, 2, 5