Advances in the pathophysiology of primary immune thrombocytopenia

Classically, immune thrombocytopenia (ITP) was thought to be caused by the destruction and insufficient production of platelets, as mediated by autoantibodies. More recently other immune mechanisms that contribute to the disease have been discovered. This review attempts to address the main unresolved questions in ITP.

We review the most current knowledge of the pathophysiology of ITP. Immunological effects of available therapies are also described.

The trigger may be a loss of tolerance due to molecular mimicry with cross-reaction of antibodies arising from infectious agents or drugs, genetic factors, and/or platelet Toll receptors. This loss of tolerance activates autoreactive effector B and T lymphocytes, which in turn initiates platelet destruction, mediated by cytotoxic T lymphocytes and the release of pro-inflammatory cytokines (IL-2/IL-17) by T helper (Th) cells (Th1/Th17). Th2 (anti-inflammatory) and regulatory B (Breg) and Treg cells are also inhibited (with decrease in IL-10/TGF-β), which leads to the disease becoming chronic. Some isotypes of autoantibodies may increase the bleeding risk. Corticosteroids, rituximab, and thrombopoietin receptor agonists (A-TPOs) all increase levels of Tregs and TGF-β. The A-TPOs also increase Breg levels, which could explain why complete remission has been seen in some cases.

A better understanding of the immunomodulatory effects of each ITP therapy is needed to best manage the disease.