What are the causes of Immune Thrombocytopenic Purpura (ITP)?

Causes of Immune Thrombocytopenic Purpura (ITP)

ITP is an autoimmune disorder characterized by immunologic destruction of otherwise normal platelets, occurring either as a primary (idiopathic) condition or secondary to identifiable triggers including autoimmune diseases, viral infections, drugs, and lymphoproliferative disorders. 1

Primary ITP

Primary ITP occurs in response to an unknown stimulus and represents a diagnosis of exclusion after ruling out secondary causes and other forms of thrombocytopenia 1. The pathophysiology involves:

• Antibody-mediated platelet destruction through antibody-dependent cellular phagocytosis, complement-dependent cytotoxicity, and cytotoxic T lymphocyte-mediated mechanisms 2
• Impaired platelet production due to megakaryopoiesis alteration, challenging the historical model that ITP was purely a destructive process 1, 2
• Reticuloendothelial system clearance of antibody-coated or immune complex-coated platelets 3

Secondary ITP: Specific Causes and Mechanisms

Autoimmune Disorders

• Antiphospholipid antibody syndrome is one of the most common autoimmune associations with secondary ITP 1, 4
• Systemic lupus erythematosus (SLE) can trigger immune thrombocytopenia through cross-reactive antibodies 5
• Immune thyroid disease and Evans syndrome are recognized autoimmune triggers 5
• Common variable immune deficiency (CVID) can present with ITP as its initial manifestation 4, 6

Viral Infections

Hepatitis C virus (HCV) causes thrombocytopenia through multiple mechanisms 1, 5:

• Antibodies that cross-react with platelet antigens
• Immune complexes binding to platelet Fcγ receptors
• Direct infection of megakaryocyte bone marrow progenitor cells
• Decreased thrombopoietin production
• Splenic sequestration from portal hypertension

Human immunodeficiency virus (HIV) triggers ITP via 1, 5:

• Cross-reactive antibodies against platelet antigens
• Infection of megakaryocyte-dependent progenitor cells
• Impaired platelet production

Helicobacter pylori generates antibodies that cross-react with platelet antigens 1, 5

Acute viral infections in children (Epstein-Barr virus, cytomegalovirus, varicella zoster virus) cause sudden-onset thrombocytopenia through cross-reacting antibodies that closely mimic acute ITP 5

Lymphoproliferative Disorders

• Chronic lymphocytic leukemia (CLL) is the most common lymphoproliferative disorder associated with secondary ITP 5, 7
• Large granular T-lymphocyte leukemia can trigger immune-mediated platelet destruction 5
• Hodgkin's disease and non-Hodgkin's lymphomas share the same platelet destruction mechanism as primary ITP 7
• Responses to ITP treatment in these patients are frequently linked to remission of the primary malignancy 7

Drug-Induced ITP

• Medications can trigger immune thrombocytopenia, though specific causative agents may be difficult to identify 1, 8
• Drug-dependent antibodies demonstrate drug-dependence, immunoglobulin binding to platelets, and platelet specificity 4

Heparin-Induced Thrombocytopenia (HIT)

• HIT presents with moderate thrombocytopenia (30-70 × 10⁹/L) occurring 5-10 days after heparin initiation 4, 6
• Evaluated using the 4T score based on degree of thrombocytopenia, timing, thrombosis presence, and absence of other causes 4

Post-Vaccination and Immunotherapy

• Measles, mumps, and rubella vaccination in children can trigger sudden severe thrombocytopenia through cross-reacting antibodies 5
• Post-immunotherapy and cellular therapy immune-mediated thrombocytopenia may share common pathophysiology with classical ITP 2

Bone Marrow Transplantation

• Bone marrow transplantation is recognized as a potential trigger for secondary immune thrombocytopenia 4

Decreased Platelet Production Causes

While not strictly ITP, these must be excluded during diagnosis:

• Myelodysplastic syndromes, leukemias, and malignancies impair megakaryocyte function and require bone marrow examination in patients over 60 years 4, 6
• Inherited thrombocytopenias (thrombocytopenia-absent radius syndrome, Wiskott-Aldrich syndrome, MYH9-related disease) affect platelet production from birth 4, 6
• 22q11.2 deletion syndrome causes characteristically lower platelet counts with large platelets and reduced platelet quality 4

Critical Diagnostic Considerations

Red flags suggesting secondary causes rather than primary ITP include 4, 8:

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

Essential screening for secondary causes in adults with suspected ITP 1, 4:

• HIV testing
• Hepatitis C testing
• H. pylori screening (eradication therapy can resolve thrombocytopenia)
• Immunoglobulin measurement to exclude CVID