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Blood, 6 August 2009, Vol. 114, No. 6, pp. 1135-1136.
Double jeopardyBLOODCENTER OF WISCONSIN
Patients treated with the widely used "RGD-mimetic" platelet inhibitors sometimes experience severe but self-limited thrombocytopenia after exposure to one of these agents. Since thrombocytopenia occurs within a few hours, it is generally thought that the responsible drug-dependent antibodies affect only circulating platelets.
The issue of whether platelet-specific antibodies can damage megakaryocytes and impair platelet production has a long and interesting history. Almost a century ago, Frank observed that, although normal or increased numbers megakarocytes were present in the bone marrow of patients with "essential (idiopathic, autoimmune) thrombocytopenic purpura" (ITP), many of the cells were small, agranular, and devoid of free platelets clustered about their periphery.2 From these findings, he concluded that low platelet counts in this condition were the result of insufficient platelet production by defective megakaryocytes. However, a contemporary, George Minot, concluded from his examinations of bone marrow that, in such cases, platelets were destroyed "as fast as they were formed."3 Thereafter followed a lively and long controversy over which of these mechanisms was the main cause of thrombocytopenia in ITP. In the very first issue of Blood, published in 1946, William Dameshek summarized his extensive study of marrow morphology in patients with ITP and agreed with Frank that "... the fundamental defect leading to thrombocytopenia is a dysfunction of the megakaryocytes ... "4 In the subsequent 20 years, it was shown that ITP is associated with platelet-specific autoantibodies.5,6 Moreover, technical advances made it possible to measure the lifespan of transfused and autologous platelets, and studies using the new tools showed that platelet survival is markedly shortened in almost all cases of ITP.7 Accordingly, Baldini concluded in an authoritative review published in 1966 that "... the old hypothesis ... of a toxic depression of megakaryocytes and their activity resulting in thrombocytopenia (in ITP) has (now) been disproved ... "8 The idea that platelet-reactive antibodies might be cytotoxic for megakaryocytes would not die, however. In the subsequent 4 decades, in vivo and in vitro studies provided evidence that antibodies, and perhaps cellular immune mechanisms as well, can in fact act on megakaryocytes to suppress platelet production.9,10 Patients with immune thrombocytopenia appear to be heterogeneous in respect to which of the 2 mechanisms predominates, making it likely that platelet antibodies differ from patient to patient in their ability to adversely affect megakaryocyte viability and maturation. The antibody studied by Greinacher et al provides a particularly striking example of an immunoglobulin that not only caused acute destruction of peripheral platelets, but also depleted the bone marrow of mature megakaryocytes expressing GPIIb/IIIa. This causes more severe and prolonged thrombocytopenia than is usually the case in patients sensitive to the platelet inhibitors eptifibatide or tirofiban.11 Antibodies associated with this condition appear to recognize a restricted domain in the vicinity of the RGD recognition site of GPIIb/IIIa. Studies to determine whether other immunoglobulins of this type are selectively cytotoxic to megakaryocytes could be rewarding.
Footnotes
Conflict-of-interest disclosure: The author declares no competing financial interests.
REFERENCES
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