COAGULATION AND THROMBOTIC DISORDERS ASSOCIATED WITH PIG ORGAN AND HEMATOPOIETIC CELL TRANSPLANTATION IN NONHUMAN PRIMATES
COAGULATION AND THROMBOTIC DISORDERS ASSOCIATED WITH PIG ORGAN AND HEMATOPOIETIC CELL TRANSPLANTATION IN NONHUMAN PRIMATES
复制标题
与非人灵长类动物的猪器官和造血细胞移植相关的凝血和血栓性疾病
作者：
L. Bühler;M. Basker;I. Alwayn;C. Goepfert;H. Kitamura;T. Kawai;S. Gojo;T. Kozłowski;F. Ierino;M. Awwad;D. Sachs;R. Sackstein;S. Robson;D. Cooper
背景资料。在非人类灵长类动物中，通过诱导混合造血型嵌合体状态来实现对猪移植器官的耐受性的努力与凝血和血栓形成的障碍有关。猪造血细胞对受体血管内皮细胞和血小板的激活和/或供体器官血管内皮细胞的激活和/或物种间的分子差异可能起作用。放射治疗或药物治疗可能会增强内皮细胞的激活和/或损伤。方法：研究方法。我们研究了非人类灵长类动物在(1)旨在诱导混合造血嵌合和耐受(TIR)的方案(包括全身照射、T细胞去除和脾切除)、(2)猪骨髓或猪外周血动员的祖细胞移植(PCTx)和/或(3)猪器官移植(POTx)后的凝血和血小板激活参数。对五个试验组进行了研究。GP 1猕猴(n=6)接受TIR+异基因造血细胞和肾脏、心脏或TIR+细胞和肾脏的异种移植，GP 2恒河猴(n=4)接受TIR+(±)自体造血细胞输注或不加(±)自体造血细胞输注，GP 3(n=12)PCTx±TIR，GP 4(n=5)POTx±TIR，GP 5(n=4)TIR+PCTx+POTx。测定血小板计数、凝血酶原时间、部分凝血活酶时间、纤维蛋白原水平、纤维蛋白裂解产物和/或D-二聚体。结果。在没有不协调的(猪)细胞或器官移植的情况下(组1和组2)，TIR仅导致一过性血小板减少，与辐射引起的骨髓抑制一致。单独使用PCTx(第3组)与血栓性血小板减少(TTP)样微血管病变状态的快速发展有关，当PCTx与TIR联合使用时，这种状态持续更长时间。POTx(±TIR)(第4组)与弥散性血管内凝血(DIC)的血小板计数和纤维蛋白原逐渐下降有关；在移植物切除后，DIC基本消失。当TIR、PCTx和POTx联合使用时(第5组)，最初的TTP样状态在第一周内被DIC的消耗性图像所取代，需要取出移植物。结论。PCTx和POTx都会导致止血和凝血参数的深刻变化，如果不协调的异种造血细胞和器官移植要完全成功，就必须克服这些变化。在暴露于异种细胞或血管化异种移植物后，无序的血栓调节可能会加剧血管损伤，并增强凝血通路的激活。
Background. Efforts to achieve tolerance to transplanted pig organs in nonhuman primates by the induction of a state of mixed hematopoietic chimerism have been associated with disorders of coagulation and thrombosis. Activation of recipient vascular endothelium and platelets by porcine hematopoietic cells and/or activation of donor organ vascular endothelium and/or molecular differences between the species may play roles. Irradiation or drug therapy could possibly potentiate endothelial cell activation and/or injury. Methods. We have investigated parameters of coagulation and platelet activation in nonhuman primates after (1) a regimen aimed at inducing mixed hematopoietic chimerism and tolerance (TIR that included total body irradiation, T cell depletion, and splenectomy; (2) pig bone marrow or pig peripheral blood mobilized progenitor cell transplantation (PCTx); and/or (3) pig organ transplantation (POTx). Five experimental groups were studied. Baboons were the recipient subjects in all groups except Group 1. Gp 1 Cynomolgus monkeys (n=6) underwent TIR + allotransplantation of hematopoietic cells and a kidney or heart or TIR + concordant xenotransplantation (using baboons as donors) of cells and a kidney; Gp 2 Baboons (n=4) underwent TIR with or without (±) autologous hematopoietic cell infusion; Gp 3 (n=12) PCTx±TIR; Gp 4 (n=5) POTx±TIR; Gp 5 (n=4) TIR + PCTx + POTx. Platelet counts, with plasma prothrombin time, partial thromboplastin time, fibrinogen levels, fibrin split products and/or D-dimer were measured. Results. In the absence of a discordant (porcine) cellular or organ transplant (Groups 1 and 2), TIR resulted in transient thrombocytopenia only, in keeping with bone marrow depression from irradiation. PCTx alone (Group 3) was associated with the rapid development of a thrombotic thrombocytopenic (TTP)-like microangiopathic state, that persisted longer when PCTx was combined with TIR. POTx (±TIR) (Group 4) was associated with a gradual fall (over several days) in platelet counts and fibrinogen with disseminated intravascular coagulation (DIC); after graft excision, the DIC generally resolved. When TIR, PCTx and POTx were combined (Group 5), an initial TTP-like state was superseded by a consumptive picture of DIC within the first week, necessitating graft removal. Conclusions. Both PCTx and POTx lead to profound alterations in hemostasis and coagulation parameters that must be overcome if discordant xenotransplantation of hematopoietic cells and organs is to be fully successful. Disordered thromboregulation could exacerbate vascular damage and potentiate activation of coagulation pathways after exposure to xenogeneic cells or a vascularized xenograft.
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猪与人异种移植中血栓调节蛋白活性的评价。
影响因子：
0.9
作者：
Lawson,JH;Daniels,LJ;Platt,JL
通讯作者：
Platt,JL
影响因子：
6.2
作者：
LEVENTHAL, JR;DALMASSO, AP;BAUMGARTNER
通讯作者：
BAUMGARTNER
联合抗体和补体耗竭对非人灵长类动物心脏异种移植物存活率不一致的协同作用。
影响因子：
6.2
作者：
Leventhal,JR;Sakiyalak,P;Witson,J;Simone,P;Matas,AJ;Bolman,RM;Dalmasso,AP
通讯作者：
Dalmasso,AP
影响因子：
6.2
作者：
Kozlowski, T;Shimizu, A;Sachs, DH
通讯作者：
Sachs, DH