Optimizing Treatment for TTP and Platelet Refractoriness

描述(由申请人提供)： 研究一：血栓性血小板减少性紫癜(TTP)是一种罕见的病因不明的疾病，由于微血栓阻塞小血管而导致多器官功能障碍。在过去的三十年里，等离子体疗法将死亡率从近100%降低到了20%左右。虽然大多数患者从最初的发作中恢复，但复发率很高，TTP仍然是一种发病率和死亡率都很高的疾病。最近发现yon Willebrand因子裂解酶(VWCP)水平降低与疾病活动性之间的关系，以及在一些患者中针对这种蛋白的自身抗体的证明，增加了额外的免疫调节治疗可能是有益的可能性。我们提出了一项随机研究，将血浆置换与血浆置换加皮质类固醇进行比较，以检验皮质类固醇将增加持久完全应答率的假设。我们还建议确定脾切除是否会降低TTP复发患者的复发率。将vWCP水平与疾病活动性相关联的研究，以及其他可能与疾病相关的实验室研究正在计划之中。 研究二：血小板同种异体免疫和伴随的血小板输注无效的预防策略并不完全有效，特别是在以前通过输注非白细胞减少的血液产品或怀孕而暴露于人类白细胞抗原和血小板抗原的个人中。选择血小板产品以避免难治性患者的同种抗体反应是这些患者输血支持的主要方式，但对于哪种选择策略对这一临床问题最有效还没有达成共识。我们建议比较血小板交叉配型和人类白细胞抗原配型在为随机供者血小板输注无效的患者提供血小板输注支持方面的有效性。在此背景下，我们还将确定与人类白细胞抗原或血小板特异性同种免疫无关的因素(非免疫因素，ABO血型不合)对血小板输注反应的影响程度。这些信息将在为难治性患者设计有效和低成本的血小板输注方案方面非常有用。

DESCRIPTION (provided by applicant): Study I: Thrombotic thrombocytopenic purpura (TTP) is a rare disorder of uncertain etiology that causes multi-organ dysfunction due to occlusion of small blood vessels by microthrombi. Over the past three decades plasma therapy has reduced the mortality rate from nearly 100% to about 20%. Although most patients recover from the initial episode, the relapse rate is high, and TTP remains a disease with substantial morbidity and mortality. Recent discovery of an association between decreased yon Willebrand factorcleaving protease (vWCP) levels and disease activity together with the demonstration of an autoantibody directed at this protein in some patients, raise the possibility that additional immunomodulatory therapy may be of benefit. We propose a randomized study comparing plasma exchange to plasma exchange plus corticosteroids to test the hypothesis that corticosteroids will increase the rate of durable complete responses. We also propose to determine if splenectomy will decrease the subsequent relapse rate in patients who have experienced a relapse of TTP. Studies correlating vWCP levels to disease activity and additional laboratory studies characterizing other possible disease correlates are planned. Study II: Prevention strategies for platelet alloimmunization and accompanying platelet transfusion refractoriness are not completely effective, particularly in individuals previously exposed to HLA and platelet antigens through transfusion of non-leukocyte reduced blood products or pregnancy. Selecting platelet products to avoid a refractory patient's alloantibody response is a mainstay of transfusion support for these patients but there is no consensus on which selection strategy is most effective for this clinical problem. We propose to compare the effectiveness of platelet crossmatching with HLA matching in providing platelet transfusion support to patients who are refractory to random donor platelet transfusions. In this context we will also determine the extent to which factors unrelated to HLA or platelet-specific alloimmunization (non-immune factors, ABO incompatibility) influence platelet transfusion responses. This information will be extremely useful in designing effective and cost-efficient platelet transfusion protocols for refractory patients.