Ierino F L, Kozlowski T, Siegel J B, Shimizu A, Colvin R B, Banerjee P T, Cooper D K, Cosimi A B, Bach F H, Sachs D H, Robson S C
Transplantation Biology Research Center, Massachusetts General Hospital, Boston 12129, USA.
Transplantation. 1998 Dec 15;66(11):1439-50. doi: 10.1097/00007890-199812150-00006.
Intravascular fibrin deposition and platelet sequestration occur with porcine xenograft rejection by baboons. Disseminated intravascular coagulopathy may arise either as a direct consequence of the failure to fully deplete xenoreactive natural antibodies and block complement, or because of putative cross-species molecular incompatibilities in this discordant species combination.
Three baboons were conditioned with retrovirally transduced autologous bone marrow to induce tolerance to swine antigens. Xenoreactive natural antibodies and complement were depleted by plasmapheresis and the use of Gal alpha1-3Gal column adsorptions; baboons were then splenectomized and underwent renal xenografting from inbred, miniature pigs. Soluble complement receptor type-1 with protocol immunosuppression (mycophenolate mofetil, 15-deoxyspergualin, steroids, and cyclosporine) was administered.
A bleeding diathesis was clinically evident from days 5 to 12 after transplantation in two baboons. Low levels of circulating C3a, C3d, and iC3b were measured despite the absence of functional circulating complement components. Profound thrombocytopenia with abnormalities in keeping with disseminated intravascular coagulopathy were observed. Prolongation of prothrombin and partial thromboplastin times was accompanied by evidence for tissue factor-mediated coagulation pathways, high levels of thrombin generation (prothrombin fragment F(1+2) production and thrombin-antithrombin complex formation), fibrinogen depletion, and production of high levels of the fibrin degradation product D-dimer. Importantly, these disturbances resolved rapidly after the excision of the rejected xenografts in two surviving animals. Histopathological examination of the rejected xenografts confirmed vascular injury, fibrin deposition, platelet deposition, and localized complement activation.
Systemic coagulation disturbances are associated with delayed xenograft rejection.
狒狒对猪异种移植物的排斥反应会发生血管内纤维蛋白沉积和血小板扣押。弥散性血管内凝血可能是由于未能完全清除异种反应性天然抗体和阻断补体直接导致的，也可能是由于这种不匹配物种组合中假定的跨物种分子不相容性所致。
对三只狒狒用逆转录病毒转导的自体骨髓进行预处理，以诱导对猪抗原的耐受性。通过血浆置换和使用Galα1-3Gal柱吸附来清除异种反应性天然抗体和补体；然后对狒狒进行脾切除，并接受来自近交系小型猪的肾异种移植。给予可溶性补体受体1型并采用方案免疫抑制（霉酚酸酯、15-脱氧精胍菌素、类固醇和环孢素）。
两只狒狒在移植后第5天至第12天临床上出现明显的出血素质。尽管循环中缺乏功能性补体成分，但仍检测到低水平的循环C3a、C3d和iC3b。观察到严重的血小板减少症，伴有与弥散性血管内凝血相符的异常。凝血酶原时间和部分凝血活酶时间延长，同时有组织因子介导的凝血途径的证据、高水平的凝血酶生成（凝血酶原片段F(1+2)产生和凝血酶-抗凝血酶复合物形成）、纤维蛋白原消耗以及高水平的纤维蛋白降解产物D-二聚体产生。重要的是，在两只存活动物中切除被排斥的异种移植物后，这些紊乱迅速得到缓解。对被排斥的异种移植物的组织病理学检查证实了血管损伤、纤维蛋白沉积、血小板沉积和局部补体激活。
全身性凝血紊乱与异种移植物延迟排斥有关。
