Fc-independent phagocytosis: implications for IVIG and other therapies in immune-mediated thrombocytopenia.

Phagocytes were first described by Dr. Metchnikoff in 1873. The roles of phagocytes in innate and adaptive immunity have been well established to date, although the molecular mechanisms involved in initiating phagocytosis (through Fc or other receptors) remain to be further explored. Phagocytes in the reticuloendothelial system, particularly macrophages, have been implicated in the clearance of senescent blood cells. The destruction of these cells may be primarily mediated via an Fc-independent pathway. Fc-independent phagocytosis may also play an important role in platelet clearance, including in autoimmune thrombocytopenia (ITP), and in clearance of platelet-rich emboli detached from sites of vascular injury. In ITP, the two major platelet auto-antigens have been located on glycoprotein (GP)IIbIIIa and the GPIb complex. It has been demonstrated that anti-GPIb antibodies, in contrast to anti-GPIIbIIIa, can induce thrombocytopenia in an Fc-independent manner. We further demonstrated in an animal model that intravenous IgG (IVIG) is unable to ameliorate thrombocytopenia caused by most anti-GPIb antibodies, despite its efficacy in anti- GPIIbIIIa-mediated thrombocytopenia. Our data was supported by subsequent retrospective studies with ITP patients by several independent groups. Most recently, we found that anti-GPIb-mediated ITP was also resistant to steroid therapy and that platelet activation and apoptosis induced by anti-GPIb antibodies may be involved in the Fc-independent platelet clearance. Therefore, identification of antibody specificity in patients, e.g. anti-GPIIbIIIa (Fc-dependent) versus anti-GPIb (Fc-independent), may be important for therapies against ITP, as well as other immune-mediated thrombocytopenias.

Relative efficacy of steroid therapy in immune thrombocytopenia mediated by anti-platelet GPIIbIIIa versus GPIbα antibodies.

Immune thrombocytopenia (ITP) is characterized by platelet clearance mediated primarily by autoantibodies against the platelet GPIIbIIIa and/or GPIbα. Steroid therapy is a first-line treatment for ITP. However, some patients are refractory to this therapy and currently no method can predict which patients will respond. To evaluate whether steroids are equally efficacious in treating patients with ITP caused by anti-GPIIbIIIa versus anti-GPIbα antibodies, we performed a retrospective study on 176 newly diagnosed patients with acute ITP who had severe bleeding symptoms and were admitted as resident patients to the hospital. The patients were treated first with intravenous administration of high-dose dexamethasone (DXM), followed by oral administration of prednisone. Response to therapy was observed in a majority of patients with antibodies specific for GPIIbIIIa (31/43) or without detectable antibodies against either GPIIbIIIa or GPIbα (36/45). In contrast, the steroid response was significantly lower in patients with anti-GPIbα antibodies (9/34) or with antibodies against both GPIbα and GPIIbIIIa (16/54). The preliminary findings of this study suggest that in future prospective clinical trials including corticosteroids, the anti-GPIbα, and -GPIIbIIIa status should be assessed in order to test its potential relevance in deciding future treatments.

The maternal immune response to fetal platelet GPIbα causes frequent miscarriage in mice that can be prevented by intravenous IgG and anti-FcRn therapies.

Fetal and neonatal immune thrombocytopenia (FNIT) is a severe bleeding disorder caused by maternal antibody-mediated destruction of fetal/neonatal platelets. It is the most common cause of severe thrombocytopenia in neonates, but the frequency of FNIT-related miscarriage is unknown, and the mechanism(s) underlying fetal mortality have not been explored. Furthermore, although platelet αIIbß3 integrin and GPIbα are the major antibody targets in immune thrombocytopenia, the reported incidence of anti-GPIbα-mediated FNIT is rare. Here, we developed mouse models of FNIT mediated by antibodies specific for GPIbα and ß3 integrin and compared their pathogenesis. We found, unexpectedly, that miscarriage occurred in the majority of pregnancies in our model of anti-GPIbα-mediated FNIT, which was far more frequent than in anti-ß3-mediated FNIT. Dams with anti-GPIbα antibodies exhibited extensive fibrin deposition and apoptosis/necrosis in their placentas, which severely impaired placental function. Furthermore, anti-GPIbα (but not anti-ß3) antiserum activated platelets and enhanced fibrin formation in vitro and thrombus formation in vivo. Importantly, treatment with either intravenous IgG or a monoclonal antibody specific for the neonatal Fc receptor efficiently prevented anti-GPIbα-mediated FNIT. Thus, the maternal immune response to fetal GPIbα causes what we believe to be a previously unidentified, nonclassical FNIT (i.e., spontaneous miscarriage but not neonatal bleeding) in mice. These results suggest that a similar pathology may have masked the severity and frequency of human anti-GPIbα-mediated FNIT, but also point to possible therapeutic interventions.