What causes Immune Thrombocytopenic Purpura (ITP)?

What Causes ITP?

ITP is an autoimmune disorder where the immune system produces antibodies and cytotoxic T cells against platelet surface proteins (primarily GPIIb/IIIa and GPIb/IX), leading to both increased platelet destruction and impaired platelet production. 1, 2

Primary Pathophysiologic Mechanisms

The disease involves a dual mechanism of thrombocytopenia:

Immune-Mediated Platelet Destruction

• Autoantibodies bind to platelet membrane glycoproteins (GPIIb/IIIa and/or GPIb/IX are targeted in approximately 75% of patients), marking them for destruction 3, 4
• Destruction occurs primarily in the spleen through antibody-dependent cellular phagocytosis, where antibody-coated platelets are removed by splenic macrophages 5, 4
• Complement-dependent cytotoxicity may also contribute to platelet lysis 6
• Cytotoxic T lymphocytes can directly induce lysis of autologous platelets 3, 6

Impaired Platelet Production

• Autoantibodies also bind to megakaryocytes in the bone marrow, inhibiting platelet production and maturation 3, 4
• This challenges the historical belief that ITP was solely a destructive process—newer evidence demonstrates that platelet production is decreased in many patients 1, 2
• Morphologic studies show megakaryocyte damage in most ITP patients, and platelet turnover is normal or decreased in the majority 3

Classification by Etiology

Primary ITP

• Occurs in isolation without an identifiable trigger, representing an autoimmune response to an unknown stimulus 1, 2
• The platelet membrane proteins become antigenic for unclear reasons, initiating the autoimmune cascade 3

Secondary ITP

Secondary forms are associated with identifiable triggers 1:

• Autoimmune diseases, particularly antiphospholipid antibody syndrome 1
• Viral infections, including hepatitis C (HCV) and human immunodeficiency virus (HIV) 1, 2
• Certain drugs (quinidine, heparin, sulfonamides, sulfonylureas, dipyridamole, and salicylates) 1
• Alcohol causes thrombocytopenia through multiple mechanisms 1
• Cancers and immunotherapy/cellular therapies may trigger immune-mediated thrombocytopenia sharing common pathophysiology with ITP 6
• Vaccines have been reported as potential triggers 6

Site of Autoantibody Production

• The initial antigenic response likely occurs in the spleen, where local autoantibody production leads to high concentrations 3, 4
• Subsequently, other antibody-producing tissues are stimulated, particularly the bone marrow 3, 4
• The spleen's unique environment—with one-third of the platelet mass present at all times and rich in phagocytic cells—makes it the major site of platelet destruction 4

Epitope Spreading

• Many patients produce multiple antibodies against different platelet antigens, a phenomenon attributed to epitope spreading where the immune response broadens over time 3

Important Clinical Caveat

Drug-induced thrombocytopenia must always be considered and may be difficult to exclude 1. A thorough medication history is essential, as discontinuation of the offending agent may resolve the thrombocytopenia without need for immunosuppressive therapy.