Bühler L, Goepfert C, Kitamura H, Basker M, Gojo S, Alwayn I P, Chang Q, Down J D, Tsai H, Wise R, Sachs D H, Cooper D K, Robson S C, Sackstein R
Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston, USA.
Bone Marrow Transplant. 2001 Jun;27(12):1227-36. doi: 10.1038/sj.bmt.1703067.
Thrombotic microangiopathy (TM) is a serious complication of bone marrow transplantation (BMT) that resembles thrombotic thrombocytopenic purpura (TTP). In attempting to achieve hematopoietic cell chimerism in the pig-to-baboon model, we have observed TM following infusion of high doses (>10(10) cells/kg) of porcine peripheral blood mobilized progenitor cells (PBPC) into baboons. We performed investigations to analyze the pathobiology of this TM and to test therapeutic interventions to ameliorate it. PBPC were obtained by leukapheresis of cytokine-stimulated swine. The initial observations were made in two baboons that underwent a non-myeloablative regimen (NMR) prior to PBPC transplantation (TX) (group 1). We then studied three experimental groups. Group 2 (n = 2) received NMR without PBPC TX. Group 3 (n = 2) received PBPC TX alone. Group 4 (n = 6) received NMR + PBPC TX combined with prostacyclin, low-dose heparin, methylprednisolone, and cyclosporine was replaced by anti-CD40L mAb in five cases. Baboons in groups 1 and 3 developed severe thrombocytopenia (<10,000/mm3), intravascular hemolysis with schistocytosis (>10/high powered field (hpf)), increase in plasma lactate dehydrogenase (LDH) (2500-9000 U/l), transient neurologic changes, renal insufficiency, and purpura. Autopsy on two baboons confirmed extensive platelet thrombi in the microcirculation, and, similar to clinical BMT-associated TM/TTP, no unusually large vWF multimers or changes in vWF protease activity were observed in the plasma of baboons with TM. In group 2, self-limited thrombocytopenia occurred for 10-15 days following NMR. Group 4 baboons developed thrombocytopenia (<20,000/mm3) rarely requiring platelet transfusion, minimal schistocytosis (<3/hpf), minor increase in LDH (<1000 U/l), with no clinical sequelae. We conclude that high-dose porcine PBPC infusion into baboons induces a microangiopathic state with vWF biochemical parameters resembling clinical BMT-associated TM/TTP and that administration of antithrombotic and anti-inflammatory agents can ameliorate this complication.
血栓性微血管病（TM）是骨髓移植（BMT）的一种严重并发症，类似于血栓性血小板减少性紫癜（TTP）。在猪到狒狒模型中试图实现造血细胞嵌合体时，我们观察到在将高剂量（>10¹⁰个细胞/千克）猪外周血动员祖细胞（PBPC）输注到狒狒体内后出现了TM。我们进行了研究以分析这种TM的病理生物学并测试改善它的治疗干预措施。PBPC通过对细胞因子刺激的猪进行白细胞分离术获得。最初的观察是在两只狒狒身上进行的，它们在PBPC移植（TX）之前接受了非清髓性方案（NMR）（第1组）。然后我们研究了三个实验组。第2组（n = 2）接受NMR但未进行PBPC TX。第3组（n = 2）仅接受PBPC TX。第4组（n = 6）接受NMR + PBPC TX，并联合前列环素、低剂量肝素，在5例中用抗CD40L单克隆抗体替代环孢素。第1组和第3组的狒狒出现了严重的血小板减少症（<10,000/mm³）、伴有裂体细胞症的血管内溶血（>10/高倍视野（hpf））、血浆乳酸脱氢酶（LDH）升高（2500 - 9000 U/l）、短暂的神经学变化、肾功能不全和紫癜。对两只狒狒进行尸检证实微循环中有广泛的血小板血栓，并且与临床BMT相关的TM/TTP相似，在患有TM的狒狒血浆中未观察到异常大的vWF多聚体或vWF蛋白酶活性的变化。在第2组中，NMR后出现了持续10 - 15天的自限性血小板减少症。第4组的狒狒出现了血小板减少症（<20,000/mm³），很少需要输注血小板，裂体细胞症极少（<3/hpf），LDH略有升高（<1000 U/l），没有临床后遗症。我们得出结论，向狒狒体内输注高剂量猪PBPC会诱导一种微血管病状态，其vWF生化参数类似于临床BMT相关的TM/TTP，并且给予抗血栓和抗炎药物可以改善这种并发症。
