eee eee The pathophysiology of ITP has undergone much investigation in recent decades and is @ disease of both increased platelet dastruction as well asa disease of inappropriately low platelet production. The historical studies of Herrington (27) and others (28-21) showed that the infusion of plasma or blood products from patients with ITP caused a dectine in platelet count heathy recipients with eventual Identfication that antiplatelet antibodies played a major role in this disorder (28 32,33). Indead, modem methods detected antiplatelat antibody on the surface of 280 (89%) of 360 ITP patent platelet samples. Multiple antibodies ageinat multiple antigens were commen: of these 280, 145 (62%) had antibodies against all 3 major platelet antigens, GPlibilla, GPIb/IX, and GPlallla: faw had antibodies only against GPILIIX (3.9%) or GPlailla (0%) (Figure 1). Figure 1 Antipiatelet antibody ‘esting in ITP patients. In 250 ITP patients, 360 assays were performed. In 80 patients Ty (63 in arial remission: 27 with active disease) all antibody tests were negative (18) (Other studies have shown thet platelet production is inhibited to various degrees in patients with ITP. Platelet kinetic studies have shown a normal or reduced rate of platelet production from megakaryocytes (24,35). Indeed, the plasma from 12 of 18 ITP patients megakaryocyte growth by 26-95% (36). T cells may play a role directly in attacking platelets or megakaryocytes and alterations in T regulatory lymphocytes may also open a window for loss of immune tolerance (37). Megekaryocytes in the bone marrow have been shown ibited in vitro to undergo apoptosis (38). Figure 2 cummarizes these offects on megakaryocytes. Figure 2 Pethophysiology of megakaryocytes i ITP. In ITP the normal platelet shedding megakaryccy'e (A) is attacked by arti-platelet megakaryocyte antbody (B) and ante-platelev megakaryocyte lymphocytes (C) and stops shedding platelets 2s it undergoes apoptosis (D). When TPO (or a TPO-RA) binds to the TPO receptor (E), apoptosis, is stopped end platelet shedding continues (F).