Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder in which, via unresolved mechanisms, platelets and megakaryocytes (MKs) are targeted by autoantibodies and/or T cells resulting in increased platelet destruction and impairment of MK function. Over the years, several therapeutic modalities have become available for ITP, however, therapeutic management has proven to be very challenging in several cases. Patients refractory to treatment can develop a clinically worsening disease course, treatment-induced toxicities and are predisposed to development of potentially life-endangering bleedings. It is therefore of critical importance to timely identify potential refractory patients, for which novel diagnostic approaches are urgently needed in order to monitor and predict specific therapeutic responses. In this paper, we propose promising diagnostic investigations into immune functions and characteristics in ITP, which may potentially be exploited to help predict platelet count responses and thereby distinguish therapeutic responders from non-responders. This importantly includes analysis of T cell homeostasis, which generally appears to be disturbed in ITP due to decreased and/or dysfunctional T regulatory cells (Tregs) leading to loss of immune tolerance and initiation/perpetuation of ITP, and this may be normalized by several therapeutic modalities. Additional avenues to explore in possible prediction of therapeutic responses include examination of platelet surface sialic acids, platelet apoptosis, monocyte surface markers, B regulatory cells and platelet microparticles. Initial studies have started evaluating these markers in relation to response to various treatments including glucocorticosteroids (GCs), intravenous immunoglobulins (IVIg) and/or thrombopoietin receptor agonists (TPO-RA), however, further studies are highly warranted. The systematic molecular analysis of a broad panel of immune functions may ultimately help guide and improve personalized therapeutic management in ITP.

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Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder. The pathophysiological mechanisms leading to low platelet levels in ITP have not been resolved, but at least involve autoantibody-dependent and/or cytotoxic T cell mediated platelet clearance and impaired megakaryopoiesis. In addition, T cell imbalances involving T regulatory cells (Tregs) also appear to play an important role. Intriguingly, over the past years it has become evident that platelets not only mediate hemostasis, but are able to modulate inflammatory and immunological processes upon activation. Platelets, therefore, might play an immuno-modulatory role in the pathogenesis and pathophysiology of ITP. In this respect, we propose several possible pathways in which platelets themselves may participate in the immune response in ITP. First, we will elaborate on how platelets might directly promote inflammation or stimulate immune responses in ITP. Second, we will discuss two ways in which platelet microparticles (PMPs) might contribute to the disrupted immune balance and impaired thrombopoiesis by megakaryocytes in ITP. Importantly, from these insights, new starting points for further research and for the design of potential future therapies for ITP can be envisioned.

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder with an incompletely understood pathophysiology, but includes platelet-clearance in the spleen and liver via T-cells and/or platelet-autoantibodies. Strikingly, thrombopoietin (TPO) levels remain low in ITP. Platelet-glycoprotein (GP)Ibα has been described to be required for hepatic TPO generation, however, the role of GPIb-antibodies in relation to platelet hepatic sequestration and TPO-levels, with consideration of platelet counts, remains to be elucidated. Therefore, we performed a study in which we included 53 chronic and non-splenectomized ITP patients for which we conducted indium labeled autologous platelet scintigraphy, measured platelet-antibody profiles and TPO-levels. Upon stratification towards the severity of thrombocytopenia, no negative association was observed between GPIb/IX-antibodies and TPO levels, suggesting that GPIb/IX-antibodies do not inhibit or block TPO levels. Surprisingly, we observed a positive association between GPIb/IX-antibody levels and TPO levels, and GPIb/IX-antibodies and platelet hepatic sequestration, in patients with severe thrombocytopenia, but not in patients with mild or moderate thrombocytopenia. In addition, platelet hepatic sequestration and TPO levels were positively associated. This collectively indicates that GPIb/IX-antibodies may be associated with an increased platelet hepatic sequestration and elevated TPO levels in severe thrombocytopenic ITP patients, however, further research is warranted to elucidate the pathophysiological mechanisms.