Massive Immune Hemolysis In Blood Stem Cell Transplants

由于轻微的ABO血型不合而导致的大量免疫溶血是异基因造血移植中一种未被充分认识的潜在的致命并发症。外周血干细胞(PBSC)移植中淋巴成分的增加和快速植入可能会增加这一事件的频率和严重性。此外，非清髓性调节方案有利于快速而有力的供体类型的免疫重建，依赖供体淋巴细胞来介导抗肿瘤效果和持久的髓系植入。为了进一步发挥移植物抗肿瘤作用，移植后抗移植物抗宿主病治疗方案中经常省略甲氨蝶呤等抗增殖剂。我们在第一例接受非清髓性PBSC移植的NIH患者中观察到了突然的灾难性溶血，其中包括轻微的ABO血型不合。我们建立了密切的临床和实验室监测方案，对在NHLBI和NCI服务上进行的连续9例ABO血型不合的非清髓PBSC移植进行密切的临床和实验室监测。所有9例患者均单独应用环孢素A预防移植物抗宿主病。另外发现了两例大量免疫溶血病例。干细胞输注后7至11天开始溶血。这两个病例对剧烈的水合和及时的供者相容的红细胞输注反应迅速，没有不良的临床后果。所有溶血患者的直接抗球蛋白试验(DAT)均呈阳性，与相关受体血型有洗脱反应(2例抗-A，1例抗-B)。然而，无论是DAT的强度还是献血者的同种血凝素滴度，都不能区分有溶血和无溶血的病例。这些结果表明，在ABO血型不合的小患者中，供者乘客B淋巴细胞产生的同种血凝素，单用环孢素预防GVHD的PBSC移植，可以在相当比例的高危受试者中介导大量免疫溶血。鉴于这种高风险，NHLBI方案中的抗GVHD方案被改变为包括抗增殖剂霉酚酸酯(MMF)。在接下来的10例小型ABO血型不合的非清髓干细胞移植中，没有一例伴有明显的免疫溶血，尽管出现了血清学异常。GVHD方案不断改进，以最大化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，并正在减少MMF剂量，以努力提高移植后的完全缓解率。我们继续监测高危时期(移植后第6至11天)的每日血细胞计数和红细胞血清学检查(DAT、IAT)，并在这些病例中及时进行供者相容的红细胞输注。提高认识可以避免干细胞移植后由于轻微ABO血型不合而导致的严重并发症，应该在所有此类病例中进行实践。

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.