Etiopathology of Immune Thrombocytopenic Purpura (ITP)
ITP is an autoimmune disorder where the immune system produces antibodies and cytotoxic T cells against platelet surface proteins, causing both increased platelet destruction and impaired platelet production. 1, 2
Dual Pathophysiologic Mechanisms
The etiopathology of ITP involves two key mechanisms that work in tandem:
Increased platelet destruction occurs when autoantibodies (primarily against platelet glycoproteins GPIIb/IIIa and GPIb/IX) coat platelets, leading to their premature removal by the reticuloendothelial system, particularly in the spleen 3, 4
Impaired platelet production represents a paradigm shift from historical understanding—newer evidence demonstrates that platelet production is decreased in many patients, not just increased destruction 1, 5
Cytotoxic T cell involvement adds another layer to the pathophysiology, as platelets are also destroyed by cell-mediated immune responses, not solely by antibodies 4, 2
Classification by Etiology
Primary ITP
- Primary (idiopathic) ITP occurs in isolation without an identifiable trigger, representing an autoimmune response to an unknown stimulus 6, 2
- This remains a diagnosis of exclusion after ruling out secondary causes 6
Secondary ITP: Specific Triggers and Mechanisms
Autoimmune associations:
- Antiphospholipid antibody syndrome is one of the most common autoimmune associations with secondary ITP 6
- Common variable immune deficiency (CVID) can present with ITP as its initial manifestation 6
Viral infections with distinct mechanisms:
Hepatitis C virus (HCV) causes thrombocytopenia through multiple pathways: 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, and splenic sequestration from portal hypertension 6
Human immunodeficiency virus (HIV) triggers ITP via cross-reactive antibodies against platelet antigens, infection of megakaryocyte-dependent progenitor cells, and impaired platelet production 6
Helicobacter pylori generates antibodies that cross-react with platelet antigens 6
Drug-induced mechanisms:
- Medications trigger immune thrombocytopenia through drug-dependent antibodies that demonstrate drug-dependence, immunoglobulin binding to platelets, and platelet specificity 6
- Heparin-induced thrombocytopenia (HIT) presents with moderate thrombocytopenia (30-70 × 10⁹/L) occurring 5-10 days after heparin initiation 6
Cellular and Immune Dysregulation
- The pathophysiology involves abnormalities in both innate and adaptive immune systems, comprising humoral and cell-mediated immune responses 7
- The disease is heterogeneous with variable clinical manifestations, reflecting the complexity of immune dysregulation 8
Clinical Implications of Pathophysiology
Beyond hemorrhage—thrombotic risk:
- ITP paradoxically carries an increased thrombotic risk related to young hyperactive platelets, platelet microparticles, rebalanced hemostasis, complement activation, endothelial activation, antiphospholipid antibodies, and inhibition of natural anticoagulants 7
Mortality considerations:
- Adults with ITP have a 1.3- to 2.2-fold higher mortality than the general population due to cardiovascular disease, infection, and bleeding 8
Critical Diagnostic Red Flags for Secondary Causes
When evaluating etiology, specific findings suggest secondary rather than primary ITP:
- Splenomegaly, hepatomegaly, or lymphadenopathy 6
- Constitutional symptoms including fever, weight loss, or bone pain 6
- Abnormal hemoglobin, white blood cell count, or white cell morphology 6
- Non-petechial rash 6
Essential screening for secondary causes in adults includes HIV testing, hepatitis C testing, and immunoglobulin measurement to exclude CVID 6