The pathogenesis of immune thrombocytopaenic purpura Nichola Cooper and James Bussel Department of Pediatrics, Weill Medical College of Cornell University, New York, NY, USA British Journal of Haematology, 133, 364–374

The role of the spleen Kaznelson 1916  splenectomy normalizes platelet count  established crucial role of the spleen in ITP Doan et al 1960  sea blue (lipid laden) histiocytes in the spleen - the platelet ‘destroyer’

The antiplatelet factor Harrington et al 1951  infusion of plasma from patients with ITP induced thrombocytopenia in normal recipients Dixon and Rosse 1975  quantified platelet-associated IgG

The antiplatelet factor Leeuwen et al  Glanzman’s thrombasthenia : lack platelet GPIIb/IIIa Cines & Blanchette 2002  Epitope spreading : antibody to multiple glycoproteins  anti GPIIb/IIIa, anti GPIb/IX, anti GPIa/IIa

The antiplatelet factor Roark et al 2002  the extraordinarily high usage of the V H 3-30 heavy-chain gene in ITP patients Antiplatelet autoantibodies  clonally restricted  from a limited number of B cell clones T cell dependent antibody production

Immune tolerance Central thymic tolerance Peripheral tolerance  sequester from the circulation : lens, testes  co-stimulatory signals : deletion or anergy  T-regulatory cells check self-reactive T cells  B cell deletion in the bone marrow

Autoimmunity Co-stimulatory signals  CD40-CD40Ligand or CD28-CD28/86 Cross-reaction of antigens via molecular mimicry  H. pylori Platelets increase their expression of CD40L and other immune molecules  contribute to their immunological recognition

Th1 and Th2 responses Th1  IFN-γ, TNF-β, IL-2  cell-mediated inflammatory reactions  delayed hypersensitivity reactions Th2  IL-4, 5, 6, 9, 10, 13  regulation of strong antibody and allergic reactions

T-cell abnormalities

Th1 bias compared with Th2 in adults with chronic ITP Release of cytokines that interfere with megakaryocyte maturation and/or platelet release Direct toxic effect of T cells

T-cell abnormalities

Megakaryocytes and platelet production GPIIb–IIIa and GPIb–IX ITP plasma on control of megakaryocytopoiesis  suppression of in vitro production of megakaryocytes from cord blood cells by plasma from ITP patients with detectable antiplatelet antibodies. (Chang et al 2003)  ITP plasma also inhibited megakaryocyte maturation resulting in fewer 4N, 8N and 16N cells. (McMillan et al 2004)

Megakaryocytes and platelet production Electron microscopic studies  50–75% of ITP megakaryocytes had extensive damage with abnormalities of the membrane system (Stahl et al, 1986) Ultrastructural abnormalities  apoptosis have been described in around 78% of ITP megakaryocytes (Houwerzijl et al, 2004)

Fc receptors Destruction by MPS is primarily mediated by the Fc receptors Balance between activating and inhibitory receptors  FcγRIIA and FcγRIIIA  FcγRIIB Important for response to treatments  IV anti-D : FcRIIA  Rituximab : FcRIIIA

Genetic susceptibility increased incidence in patients with immunodeficiency diseases  common variable immunodeficiency (CVID)  secondary hypogammaglobulinaemia  selective IgA deficiency  autoimmune lymphoproliferative syndrome (ALPS)  CD40 ligand deficiency (hyper-IgM syndrome)

Genetic susceptibility SNP : TNF-β (+252) G/G  frequent in patients with ITP when compared with control (21% vs. 7%)  the frequency of circulating anti-GPIIb/IIIa antibody-producing B cells was significantly higher (Satoh et al, 2004)

Virus-associated ITP HIV  possibly via loss of T-cell regulation, and a wide variety of autoantibodies are reported in HIV patients HCV  this virus appears to generally increase the production of a number of autoantibodies (Pivetti et al, 1996) EBV  inducing lymphoproliferation and increased antibody formation

Bacteria-associated ITP H. pylori eradication and platelet increase  Gasbarrini et al 1998  Michel et al 2003, Franchi & Veneri 2004 Molecular mimicry  H.pylori CagA protein Change cytokine milieu