What causes low platelet counts (thrombocytopenia)?

Causes of Low Platelet Counts (Thrombocytopenia)

Low platelet counts result from three primary mechanisms: decreased production in the bone marrow, increased destruction (immune or non-immune), or splenic sequestration, with the most common causes being immune thrombocytopenia (ITP), drug-induced thrombocytopenia, bone marrow disorders, and viral infections. 1, 2

Major Mechanisms and Causes

Decreased Platelet Production

• Bone marrow disorders including myelodysplastic syndromes, leukemias, and other malignancies impair megakaryocyte function and are critical causes requiring bone marrow examination in patients over 60 years 1, 2
• Bone marrow suppression occurs from chronic alcohol use, iron overload, certain medications, and viral infections (particularly hepatitis C and HIV) 2
• Inherited thrombocytopenias such as thrombocytopenia-absent radius syndrome, Wiskott-Aldrich syndrome, and MYH9-related disease affect platelet production from birth 1, 2
• 22q11.2 deletion syndrome causes characteristically lower platelet counts with large platelets and reduced platelet quality, though usually mild 3

Increased Platelet Destruction

Immune-Mediated Destruction

• Primary immune thrombocytopenia (ITP) is an autoimmune disorder with immunologic destruction of otherwise normal platelets, diagnosed by exclusion after ruling out secondary causes 1, 2
• Secondary immune thrombocytopenia occurs with autoimmune disorders (lupus, antiphospholipid syndrome), viral infections (HIV, HCV, H. pylori), lymphoproliferative disorders, drug-induced thrombocytopenia, and common variable immune deficiency 1, 2
• 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
• Drug-induced thrombocytopenia should always be considered and may be difficult to exclude 1, 4

Non-Immune Destruction

• Thrombotic microangiopathies including TTP-HUS, disseminated intravascular coagulation (DIC), and antiphospholipid syndrome cause platelet consumption 1, 4
• HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) and preeclampsia cause thrombocytopenia in pregnancy 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 2

Special Populations

• Gestational thrombocytopenia is the most common cause in pregnancy, typically mild (platelet count >70,000/μL) 1
• Cyanotic congenital heart disease causes thrombocytopenia due to polycythemia and hyperviscosity, with platelet counts inversely correlating with hematocrit levels 1

Diagnostic Algorithm

Step 1: Exclude Pseudothrombocytopenia

• Repeat platelet count in heparin or sodium citrate tubes, as EDTA-dependent platelet agglutination can falsely lower counts 1, 2, 5
• Review peripheral blood smear to identify platelet clumping 1, 4

Step 2: Distinguish Isolated vs. Multi-Lineage Cytopenias

• Complete blood count with differential distinguishes isolated thrombocytopenia from pancytopenia, which suggests bone marrow failure or infiltration 1, 2
• Peripheral blood smear examination assesses platelet morphology and identifies abnormal white cells or red cell fragments 1, 2

Step 3: Identify Red Flags Requiring Urgent Evaluation

• Splenomegaly, hepatomegaly, or lymphadenopathy suggests secondary causes rather than primary ITP 1, 4
• Abnormal hemoglobin, white blood cell count, or white cell morphology requires additional investigation 1, 2
• Constitutional symptoms (fever, weight loss, bone pain) suggest infection or malignancy 1, 4
• Non-petechial rash is not typical of ITP and warrants further workup 1

Step 4: Targeted Testing Based on Clinical Context

• Infectious disease screening should include HIV, hepatitis C, and H. pylori testing in adults with suspected ITP 1, 2, 4
• Coagulation studies (PT, aPTT, fibrinogen, D-dimers) should be obtained to evaluate for DIC in patients with severe thrombocytopenia 1
• Anti-PF4 antibodies should be tested when clinical probability of HIT is intermediate or high based on the 4T score 1
• Immunoglobulin measurement may identify common variable immune deficiency, as ITP can be its presenting feature 1, 2

Step 5: Determine Need for Bone Marrow Examination

Bone marrow examination is indicated when: 1, 2, 4

• Age ≥60 years (to exclude myelodysplastic syndromes, leukemias, or other malignancies)
• Systemic symptoms present (fever, weight loss, bone pain)
• Abnormal blood count parameters beyond thrombocytopenia
• Atypical peripheral smear findings (schistocytes, leukocyte inclusion bodies)
• Minimal or no response to first-line ITP therapies
• Splenectomy is being considered

Bone marrow examination is NOT necessary in: 1, 2

• Patients with typical ITP features (isolated thrombocytopenia, normal physical exam except bleeding manifestations, age <60 years)

Critical Clinical Pitfalls to Avoid

• Missing pseudothrombocytopenia by not reviewing the peripheral smear can lead to unnecessary interventions 1, 2
• Assuming elevated immature platelet fraction (IPF) definitively confirms ITP, as severe ITP can present with low IPF 1
• Relying solely on IPF in older patients, as age >60 years mandates bone marrow examination regardless of IPF 1
• Overlooking drug-induced thrombocytopenia by not obtaining a comprehensive medication history including over-the-counter drugs and supplements 1, 4
• Failing to recognize secondary causes of ITP (HIV, HCV, H. pylori, autoimmune disorders), which have different natural histories and responses to therapy 1
• Not considering inherited thrombocytopenias, with family history and platelet size on smear providing critical clues 1
• Delaying bone marrow examination in treatment-refractory cases, as failure to respond to IVIg, anti-D, or corticosteroids warrants bone marrow evaluation 1

Bleeding Risk Stratification

• Platelet count >50 × 10³/μL: Generally asymptomatic 5
• Platelet count 20-50 × 10³/μL: May have mild skin manifestations (petechiae, purpura, ecchymosis) 5
• Platelet count <10 × 10³/μL: High risk of serious bleeding 5

Important caveat: Some conditions present with both bleeding and thrombosis despite low platelets, including antiphospholipid syndrome, heparin-induced thrombocytopenia, and thrombotic microangiopathies 5. In these conditions, the mortality risk from thrombosis may exceed bleeding risk, fundamentally altering management priorities.