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

Abstract

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.

Markers of refractory primary immune thrombocytopenia

“…The association between antiplatelet antibody and response to splenectomy is debated, impaired by heterogeneity in antibody testing and definition of response as well as by the low number of patients included in these retrospective series 6 . Recently, a retrospective study of 30 patients with ITP, positive antiplatelet antibody and indium‐labelled autologous platelet study (see below), demonstrated a slightly higher rate of splenic sequestration in case of the presence of anti‐GPIIb/IIIa (52.6%, n = 19) or anti‐GPV (52.6%, n = 19) antibodies than in case of the presence of anti‐GPIb/IX antibodies (37.5%, n = 16), 11 in line with the role of anti‐GPIIb/IIIa in splenic clearance of platelets and of anti‐GPIb/IX in hepatic clearance of platelets in ITP 12 …”

Current Understanding of Immune Thrombocytopenia: A Review of Pathogenesis and Treatment Options

“…An FCγR-independent pathway of platelet destruction is platelet desialylation. Studies have shown that GPIb/IX antibodies trigger platelet desialylation by recruiting neuramidase-1 to the plasma membrane [29]. Desialylated platelets are recognized by the Ashwell-Morell receptor expressed on hepatocytes, leading to their removal from circulation and to the production of TPO, a major growth factor of megakaryocytes [29].…”

Pathophysiologie und Diagnostik der Immunthrombozytopenie

“…Danach werden sie präferenziell über Ashwell-Morell-Rezeptoren (AMR) in der Leber phagozytiert, ein Fc-Rezeptor-unabhängiger Abbauweg [22]. Während die Fc-Rezeptor-abhängige Phagozytose von Thrombozyten in der Milz vor allem bei anti-GP-IIb/IIIa-Antikörpern stattfindet (70-80 % der Fälle), ist die Leber-prädominante Sequestrierung von Thrombozyten insbesondere bei Antikörpern gegen das Glykoprotein Ibα (20-40 % der Fälle) beschrieben [23] und spricht schlecht auf Therapien an, die gegen die Fc-Rezeptoren der Makrophagen in der Milz gerichtet sind, wie z. B. Immunglobuline [24].…”