Optimizing Treatment for TTP and Platelet Refractoriness

描述（由申请人提供）： 研究I：血栓性血小板减少性紫癜（TTP）是一种病因不明的罕见疾病，由于微血栓阻塞小血管而导致多器官功能障碍。 在过去的三十年中，等离子体疗法已经将死亡率从近100%降低到约20%。 虽然大多数患者从初始发作中恢复，但复发率很高，TTP仍然是一种具有显著发病率和死亡率的疾病。 最近发现的相关性降低yon Willebrand因子裂解蛋白酶（vWCP）水平和疾病的活动性，以及针对这种蛋白质的自身抗体在一些患者中的证明，提出了额外的免疫调节治疗可能是有益的。 我们建议进行一项比较血浆置换与血浆置换加皮质类固醇的随机研究，以检验皮质类固醇将增加持久完全缓解率的假设。 我们还建议确定脾切除术是否会降低TTP复发患者随后的复发率。 计划将vWCP水平与疾病活动性相关的研究和表征其他可能的疾病相关性的额外实验室研究。 研究II：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，特别是在先前通过输注非白细胞减少的血液制品或妊娠暴露于HLA和血小板抗原的个体中。 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的输血支持的支柱，但没有共识的选择策略是最有效的这个临床问题。 我们建议比较血小板交叉配型与HLA配型在为随机供体血小板输注难治性患者提供血小板输注支持方面的有效性。 在这种情况下，我们也将确定在何种程度上无关的因素HLA或血小板特异性同种异体免疫（非免疫因素，ABO血型不合）影响血小板输注反应。 这一信息将是非常有用的设计有效和成本效益的血小板输注方案难治性患者。

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.