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

Causes of Low Platelets (Thrombocytopenia)

Thrombocytopenia results from three primary mechanisms: decreased platelet production, increased platelet destruction, or splenic sequestration, with the specific cause determined through systematic evaluation of blood counts, peripheral smear, and targeted testing based on clinical presentation. 1, 2, 3

Decreased Platelet Production

Bone marrow disorders are critical causes requiring immediate consideration, particularly in patients over 60 years or those with systemic symptoms:

• Myelodysplastic syndromes, leukemias, and other malignancies impair megakaryocyte function and represent the most concerning causes 1, 2, 3
• Bone marrow suppression occurs from chronic alcohol use, certain medications, and viral infections (particularly hepatitis C and HIV) 3
• Inherited thrombocytopenias including thrombocytopenia-absent radius syndrome, Wiskott-Aldrich syndrome, and MYH9-related disease affect platelet production from birth 1, 2, 3

Increased Platelet Destruction

Primary immune thrombocytopenia (ITP) is an autoimmune disorder with immunologic destruction of otherwise normal platelets, diagnosed only after excluding secondary causes 1, 2, 3, 4

Secondary immune thrombocytopenia occurs with multiple associated conditions 1, 2, 3:

• Autoimmune disorders (lupus, antiphospholipid syndrome)
• Viral infections (HIV, hepatitis C, H. pylori)
• Lymphoproliferative disorders
• Drug-induced thrombocytopenia
• Common variable immune deficiency

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, 3

Thrombotic microangiopathies including TTP-HUS, disseminated intravascular coagulation (DIC), antiphospholipid syndrome, and HELLP syndrome cause platelet consumption 1, 2, 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 3

Diagnostic Algorithm

Step 1: Exclude Pseudothrombocytopenia

First, repeat the platelet count in heparin or sodium citrate tubes to exclude EDTA-dependent platelet agglutination, which can falsely lower counts 1, 2, 3, 5

Step 2: Examine Peripheral Blood Smear

The peripheral blood smear is essential to assess platelet morphology and identify abnormalities 6, 1, 2:

• Normal or large platelets with normal RBC/WBC morphology suggests ITP
• Schistocytes suggest thrombotic microangiopathy
• Giant platelets suggest inherited thrombocytopenia
• Abnormal white cells suggest leukemia or lymphoproliferative disorder

Step 3: Distinguish Isolated vs. Pancytopenia

Complete blood count with differential distinguishes isolated thrombocytopenia (suggests ITP or drug-induced) from pancytopenia (suggests bone marrow failure or infiltration) 1, 2, 3

Step 4: Identify Red Flags Requiring Additional Testing

Physical examination findings that suggest secondary causes 1, 2, 3:

• Splenomegaly, hepatomegaly, or lymphadenopathy
• Constitutional symptoms (fever, weight loss)
• Non-petechial rash
• Abnormal hemoglobin or white blood cell morphology

Step 5: Targeted Infectious Disease Screening

Test for HIV, hepatitis C, and H. pylori in adults with suspected ITP 1, 2, 3

Step 6: Consider Bone Marrow Examination

Bone marrow examination is indicated for patients over 60 years, those with atypical features (abnormal CBC, splenomegaly, systemic symptoms), or when malignancy or myelodysplasia is suspected 1, 2, 3

Bone marrow examination is NOT necessary in patients with typical ITP features: isolated thrombocytopenia, normal peripheral smear except for low platelets, no organomegaly, no constitutional symptoms 3

Common Pitfalls to Avoid

Missing pseudothrombocytopenia by not repeating the count in non-EDTA tubes leads to unnecessary workup 1, 2, 3

Failing to recognize drug-induced thrombocytopenia requires careful medication review, as this may be difficult to exclude 1, 2

Overlooking inherited thrombocytopenias in younger patients with lifelong mild thrombocytopenia can lead to unnecessary treatment 1

Not considering pregnancy-related causes in women of childbearing age, including gestational thrombocytopenia (most common, platelet count >70,000), preeclampsia, or HELLP syndrome 1

Missing HIT in hospitalized patients on heparin requires high clinical suspicion when thrombocytopenia develops 5-10 days after heparin exposure 1, 3