The interplay between GPIb/IX antibodies, platelet hepatic sequestration, and TPO levels in patients with chronic ITP.

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 examined 53 patients with chronic and nonsplenectomized ITP for whom we conducted indium-labeled autologous platelet scintigraphy and measured platelet antibodies and TPO levels. Upon stratification toward 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, but not 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 increased platelet hepatic sequestration and elevated TPO levels in patients with severe thrombocytopenic ITP; however, further research is warranted to elucidate the pathophysiologic mechanisms.

Anti-glycoprotein antibodies and sequestration pattern of indium-labeled platelets in immune thrombocytopenia.

Antiglycoprotein (anti-GP) antibodies play an important role in the pathophysiology of immune thrombocytopenia (ITP). The sequestration pattern of platelets in the spleen and liver can be studied with 111In-labeled autologous platelet scans. No studies have investigated the role of anti-GP antibodies in sequestration patterns in ITP patients. In this study, we examined the association between antibodies and (1) platelet sequestration site and (2) clearance rate of platelets. All ITP patients receiving an 111In-labeled autologous platelet study between 2014 and 2018 were included. Antibodies were measured using the direct MAIPA method to determine the presence and titer of anti-GPIIb/IIIa, anti-GPIb/IX, and anti-GPV antibodies. Multivariate regression models were used to study the association between anti-GP antibodies, sequestration site, and clearance rate. Seventy-four patients were included, with a mean age of 36 years. Forty-seven percent of the patients showed a predominantly splenic sequestration pattern, 29% mixed, and 25% a hepatic pattern. In 53% of the patients, anti-GP antibodies were detected. Regression models showed a significant association between splenic sequestration and GPV autoantibodies. Furthermore, in patients where antibodies were present, the clearance rate was higher in patients with a splenic sequestration. Anti-GPV antibodies are associated with a splenic sequestration pattern in ITP patients. These associations provide insight into the possible pathophysiological mechanisms of ITP, which may lead to better detection and treatment of this partly idiopathic and prevalent disease.

Platelets in ITP: Victims in Charge of Their Own Fate?

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.

Potential Diagnostic Approaches for Prediction of Therapeutic Responses in Immune Thrombocytopenia.

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.