Massive Immune Hemolysis In Blood Stem Cell Transplants

由于轻微ABO血型不合引起的大量免疫溶血是一种未被充分认识的、潜在致命的异基因造血移植并发症。外周血干细胞（PBSC）移植中淋巴细胞含量增加和快速植入可能会增加该事件的频率和严重程度。此外，非清髓性预处理方案有利于快速和有力的供体型免疫重建，依赖于供体淋巴细胞介导抗肿瘤作用和持久的骨髓移植。为了促进移植物抗肿瘤效应，抗增殖剂如甲氨蝶呤经常从移植后抗GVHD方案中省略。我们在第一例接受非清髓性外周血干细胞移植的NIH患者中观察到了突发的、灾难性的溶血，该移植涉及轻微的ABO血型不合。我们建立了一个协议，密切的临床和实验室监测下九个连续的小ABO血型不合，非清髓性PBSC移植NHLBI和NCI服务。在所有9例病例中，仅使用环孢霉素预防GVHD。检测到另外两例大规模免疫溶血。溶血在干细胞输注后7至11天开始。这两个病例对剧烈水合反应迅速，并迅速进行供体相容性红细胞输注，无不良临床后果。所有溶血患者的直接抗球蛋白试验（DAT）均为阳性，对相关受体血型（2例抗A，1例抗B）呈阳性反应。然而，无论是DAT的强度，也没有供体同种血凝素滴度区分与那些没有溶血的情况下。这些结果表明，供体乘客B淋巴细胞产生的同种血凝素在轻微的ABO不相容，PBSC移植使用环孢素单独用于GVHD预防可以介导大量的免疫溶血在相当大的比例的受试者的风险。鉴于这种高风险，NHLBI方案中的抗GVHD方案改变为包括霉酚酸酯（MMF），一种抗增殖剂。尽管观察到血清学异常，但接下来的10例ABO血型不合的非清髓性干细胞移植均未出现明显的免疫溶血。GVHD治疗方案不断改进，以最大限度地提高移植物抗肿瘤免疫效果，同时最大限度地减少移植的其他免疫并发症，并减少MMF剂量，以提高移植后的完全缓解率。我们继续监测每日血细胞计数和红细胞血清学研究（DAT，IAT）在风险期间（移植后第6天至第11天），并在这些情况下及时给予供体相容的红细胞输注。提高认识可以避免由于干细胞移植后轻微ABO不相容而导致的严重并发症，并应在所有此类情况下进行实践。

Massive immune hemolysis due to minor ABO incompatibility is an underappreciated, potentially fatal complication of allogeneic hematopoietic transplantation. The increased lymphoid content and rapid engraftment seen with peripheral blood stem cell (PBSC) transplants may increase the frequency and severity of this event. In addition, nonmyeloablative conditioning regimens favor rapid and vigorous donor-type immune reconstitution, relying on donor lymphocytes to mediate both an anti-tumor effect and durable myeloid engraftment. To further the graft versus tumor effect, antiproliferative agents such as methotrexate are frequently omitted from posttransplant anti-GVHD regimens. We observed abrupt, catastrophic hemolysis in the first NIH patient to receive a nonmyeloablative PBSC transplant involving minor ABO incompatibility. We established a protocol for close clinical and laboratory monitoring of the next nine consecutive minor ABO-incompatible, nonmyeloablative PBSC transplants performed on NHLBI and NCI services. Cyclosporine alone was employed to prevent GVHD in all nine cases. Two additional cases of massive immune hemolysis were detected. Hemolysis began 7 to 11 days following stem cell infusion. Both cases responded rapidly to vigorous hydration and prompt donor-compatible red cell transfusions, without adverse clinical consequences. All patients with hemolysis demonstrated a positive direct antiglobulin test (DAT), with eluate reactivity against the relevant recipient blood group (anti-A in two cases, anti-B in one). However, neither the intensity of the DAT nor the donor isohemagglutinin titer distinguished cases with from those without hemolysis. These results demonstrate that isohemagglutinins produced by donor passenger B lymphocytes in minor ABO incompatible, PBSC transplants utilizing cyclosporine alone for GVHD prophylaxis can mediate massive immune hemolysis in a considerable proportion of subjects at risk. In view of this high risk, anti-GVHD regimens in NHLBI protocols were changed to include mycophenolate mofetil (MMF), an antiproliferative agent. None of the next 10 consecutive minor ABO incompatible nonmyeloablative stem cell transplants was accompanied by significant immune hemolysis, although serologic abnormalities were seen. GVHD regimens continue to be modified to maximize graft anti-tumor immune effects while minimizing other immune complications of transplant, and MMF doses are being reduced in an effort to increase complete remission rates posttransplant. We continue to monitor daily blood counts and red cell serologic studies (DAT, IAT) during the period at risk (day 6 to 11 posttransplant) and to promptly administer donor-compatible red cell transfusions in these cases. Improved awareness can avert serious complications due to minor ABO incompatibility following stem cell transplant and should be practiced in all such cases.