What is the disease mechanism of Immune Thrombocytopenia Purpura (ITP)?

Disease Mechanism of Immune Thrombocytopenia Purpura (ITP)

ITP is an autoimmune disorder characterized by both increased immune-mediated destruction of platelets and impaired platelet production, resulting in isolated thrombocytopenia with a platelet count less than 100 × 10^9/L in the absence of other identifiable causes. 1

Primary Pathophysiological Mechanisms

Autoimmune-Mediated Platelet Destruction

• Autoantibodies (primarily IgG) target platelet membrane glycoproteins, most commonly GPIIb-IIIa and GPIb-IX, leading to accelerated platelet clearance 2
• Antibody-coated platelets are primarily destroyed by macrophages in the reticuloendothelial system, particularly in the spleen 3, 4
• Complement activation may contribute to platelet destruction in some patients 2
• The initial antigenic response likely occurs in the spleen, followed by stimulation of other antibody-producing tissues, particularly the bone marrow 2

Impaired Platelet Production

• Contrary to traditional understanding that focused solely on destruction, current evidence shows that autoantibodies also target megakaryocytes in the bone marrow 1, 2
• These autoantibodies cause megakaryocyte damage and inhibit megakaryocyte maturation and platelet production 2
• Normal or decreased (rather than increased) platelet turnover is observed in the majority of patients, supporting impaired production as a key mechanism 2
• The effectiveness of thrombopoietin receptor agonists in many ITP patients further confirms the role of impaired production 2

Cell-Mediated Immune Mechanisms

• Cytotoxic T cells contribute to platelet destruction through direct lysis of autologous platelets 2
• Both innate and adaptive immune systems are involved in the autoimmune response 5
• T-cell dysregulation, particularly with abnormal T helper cell subsets, contributes to loss of immune tolerance 1
• Multiple antibodies may be produced due to epitope spreading, where the immune response extends from the initial target epitope to other epitopes 2

Clinical Implications of Pathophysiology

Bleeding Risk

• The primary clinical concern has traditionally been bleeding due to thrombocytopenia 1, 3
• Severe bleeding is reported in 9.5% of adults and 20.2% of children with ITP 1
• Intracranial hemorrhage, though rare (1.4% of adults and 0.1-0.4% of children), represents the most serious complication 1

Paradoxical Thrombotic Risk

• Recent evidence suggests ITP patients also have an increased risk of thrombosis 5
• Thrombotic risk is related to several factors:
  • Presence of young hyperactive platelets
  • Increased platelet microparticles
  • Rebalanced hemostasis
  • Complement activation
  • Endothelial activation
  • Presence of antiphospholipid antibodies
  • Inhibition of natural anticoagulants 5

Disease Classification and Progression

• ITP is classified as primary (occurring in isolation) or secondary (associated with other disorders such as autoimmune diseases, viral infections, or certain drugs) 6, 1
• Based on duration, ITP is categorized as:
  • Newly diagnosed
  • Persistent (3-12 months)
  • Chronic (≥12 months) 1
• Children have higher rates of spontaneous remission compared to adults, with 62-74% experiencing remission depending on age 1
• Adult ITP more commonly follows a chronic course with lower remission rates 1

Diagnostic Implications

• ITP remains a diagnosis of exclusion requiring isolated thrombocytopenia, normal peripheral blood smear except for reduced platelets, and absence of other obvious causes 1
• Bone marrow examination is generally unnecessary in patients with typical features of ITP 6, 1
• Testing for platelet autoantibodies can be useful but is not routinely required for diagnosis 6, 1

Understanding the dual mechanisms of increased destruction and impaired production is essential for appropriate therapeutic targeting in ITP management.