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

Causes of Chronic Thrombocytopenia

Chronic thrombocytopenia results from four primary mechanisms: decreased platelet production, increased destruction (immune or non-immune), splenic sequestration, and dilution, with the specific cause determined by systematic evaluation of the clinical context and laboratory findings. 1, 2

Decreased Platelet Production

Bone marrow disorders are a major category causing inadequate platelet production:

• 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 1
• Bone marrow suppression occurs from chronic alcohol use, iron overload, certain medications, and viral infections (particularly hepatitis C and HIV) 3, 1
• Inherited thrombocytopenias including thrombocytopenia-absent radius syndrome, Wiskott-Aldrich syndrome, and MYH9-related disease affect platelet production from birth 1, 2

Reduced thrombopoietin levels in chronic liver disease represent a central mechanism, as this hepatically-produced growth factor is essential for megakaryocyte stimulation and platelet production 3, 4

Increased Platelet 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 multiple associated conditions 1:

• Autoimmune disorders (antiphospholipid syndrome, systemic lupus erythematosus)
• 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

Non-immune destruction in liver cirrhosis increases from shear stress, fibrinolysis, and bacterial translocation 3

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, 5, 4

Chronic Liver Disease as a Multifactorial Cause

Chronic liver disease produces thrombocytopenia through combined mechanisms 3, 4:

• Decreased thrombopoietin synthesis (central mechanism)
• Splenic sequestration from portal hypertension
• Bone marrow suppression (alcohol, hepatitis C, iron overload)
• Increased platelet destruction

Moderate thrombocytopenia (50,000-75,000/μL) occurs in approximately 13% of cirrhotic patients 5

Diagnostic Approach to Identify the Cause

Initial evaluation must exclude pseudothrombocytopenia by repeating the platelet count in heparin or sodium citrate tubes, as EDTA-dependent platelet agglutination can falsely lower counts 1, 2, 6

Complete blood count with differential distinguishes isolated thrombocytopenia from pancytopenia, which suggests bone marrow failure or infiltration 1, 2

Peripheral blood smear examination is essential to assess platelet morphology and identify abnormal white cells or red cell fragments 1, 2

Red flags requiring additional investigation 1:

• Splenomegaly, hepatomegaly, or lymphadenopathy (suggests secondary causes, not primary ITP)
• Abnormal hemoglobin, white blood cell count, or white cell morphology
• Constitutional symptoms (fever, weight loss) suggesting infection or malignancy
• Non-petechial rash

Infectious disease screening should include HIV, hepatitis C, and H. pylori testing in adults with suspected ITP 1, 2

Bone marrow examination is indicated for patients over 60 years, those with atypical features, or when systemic symptoms suggest underlying malignancy or myelodysplasia, but is not necessary in typical ITP presentations 1, 2

Immunoglobulin measurement may identify common variable immune deficiency, as ITP can be its presenting feature 1

Common Pitfalls to Avoid

Failing to recognize secondary causes of immune thrombocytopenia leads to inappropriate treatment, as these conditions have different natural histories and therapeutic responses 1

Mistaking pseudothrombocytopenia for true thrombocytopenia results in unnecessary interventions and patient anxiety 1

Overlooking drug-induced thrombocytopenia is problematic, as medication review is essential but causality may be difficult to establish 1, 2

Not considering inherited thrombocytopenias in younger patients with chronic thrombocytopenia and family history can delay correct diagnosis 1