Severe Hemolysis Due to Passenger Lymphocyte Syndrome After Hematopoietic Stem Cell Transplantation From an HLA-Matched Related Donor Open Access

A 61-year-old white man was diagnosed with chronic lymphocytic leukemia 2½ years prior to his last admission to our hospital. The most recent bone marrow biopsy, which had been performed 7 months prior to admission, showed acute myelogenous leukemia with deletion of the short arm p11.2 on chromosome 18. The patient was started on chemotherapy, and red blood cell transfusions were done every 2 weeks as a result of the patient's persistently low hemoglobin levels.

The patient was admitted for hematopoietic stem cell transplantation, and conditioning therapy consisted of busulfan and cytoxan. He continued to receive multiple cytomegalovirus-negative and irradiated blood and blood component transfusions, including red blood cells (group O, Rh-positive), fresh frozen plasma (groups A and AB), HLA, and/or crossmatched platelet pheresis (group A, Rh-positive; group O, Rh-positive; and group O, Rh-negative), because of persistently low hemoglobin and platelet counts (Table 1). On day +5, the patient developed fever, pneumonia, upper and lower respiratory and upper gastrointestinal bleeding, and diffuse skin petechiae. On day +8, the patient (group A, Rh-positive) received the first graft infusion of HLA-matched related peripheral blood stem cells (Table 2) from his sister (group O, Rh-positive). Cyclosporine without methotrexate was given for graft versus host disease prophylaxis. This patient received a second graft infusion on day +13. Respiratory and gastrointestinal bleeding continued posttransplantation, with the new development of small hemorrhages in left frontal and right occipital areas of his brain (seen on computed tomographic scan); skin rashes consistent with acute graft versus host disease (on biopsy); and increasing levels of total and direct bilirubin, blood urea nitrogen, creatinine, and lactate dehydrogenase (Table 3). The patient's blood type prior to and immediately posttransplantation was group A, Rh-positive. Three days after the second graft infusion (day +16), the patient's blood type converted to group O, Rh-positive (Table 4), with a negative direct antiglobulin test (Table 5) and the presence of anti-A₁ (Table 6). The patient was started on granulocyte colony–stimulating factor and continuous venovenous hemodialysis on day +17. The patient expired on day +22.

Immune hemolysis may occur following bone marrow or peripheral blood stem cell transplant, when there is ABO incompatibility between donor and recipient. The immune hemolysis is caused by “Passenger Lymphocyte Syndrome.” The syndrome is attributed to the production of antibodies by the donor B lymphocytes (“passenger lymphocytes”) in a primary1 or secondary immune response against the recipient's red blood cell antigens.2 In HLA-identical donor-recipient pairs in peripheral blood progenitor cell transplantation, ABO incompatibility exists in about 30% to 40% of cases, half of which are due to minor mismatch.1 Delayed immune hemolysis due to alloantibodies produced by passenger B-lymphocytes most commonly occurs in group A or B recipients who are given group O peripheral blood stem cell graft.1 This syndrome can be regarded as a type of graft-versus-host disease.3 

Although commonly occurring within the ABO system, other blood group systems (ie, Rh, Kidd, Lewis) can be involved.3 This syndrome has also been reported to occur after solid organ transplantation (ie, kidney, liver, heart-lung, spleen, and pancreas). The frequency of antibody production and hemolysis was highest in heart-lung transplants, intermediate in liver transplants, and lowest in kidney transplants.2 

Viable passenger B lymphocytes are capable of producing adequate levels of antibodies, which could lead to hemolysis of the recipient's red blood cells between 5 and 15 days after transplantation.2,4 Although numerical and functional B-lymphocyte reconstitution normally takes 3 months or more, the passenger lymphocytes have the capacity for rapid and high antibody production, even within a week posttransplantation.5 

The incidence of hemolysis after ABO-incompatible transplants has not been established,4 and this may be related to the use of graft-versus-host disease posttransplant immunosuppressive agents like cyclosporine A and FK506 (tacrolimus) treatment3,5 without methotrexate.1–7 Cyclosporine permits rapid proliferation of B lymphocytes while suppressing the T lymphocytes.3 On the other hand, methotrexate is toxic to the B lymphocytes, preventing their proliferation and, thus, antibody production.

Not all patients who develop the antibody will undergo red blood cell hemolysis. Several factors affect the severity of hemolysis, and these factors include the amount of lymphoid tissue transplanted, the level of antibody in the donor before transplantation, the rapid rise in antibody titer in the recipient after transplantation, and possibly the recipient secretor status.3 

Hemolysis usually has an abrupt onset, varies in severity, and is self-limited but can lead to renal failure, multiorgan failure, and death. Hemolysis is manifested by rapidly decreasing levels of hemoglobin with increasing levels of bilirubin, lactate dehydrogenase, blood urea nitrogen, and creatinine, but decreasing haptoglobin levels and positive direct antiglobulin test. It is important to monitor patients at risk by performing serial measurements of such parameters.

In most instances, hemolysis can be managed by transfusion of compatible red blood cells, empirical use of corticosteroids, and maintenance of renal perfusion. Exchange transfusion, hemodialysis for acute renal failure, and splenectomy for solid organ transplants should also be considered.3,8 

Peripheral blood stem cell or bone marrow transplantation often leads to chimerism, wherein the patient possesses a mixed cell population. Our case demonstrates the development of severe immune hemolysis after receiving an ABO minor mismatch stem cell transplant, with graft versus host disease prophylaxis of cyclosporine without methotrexate. The cyclosporine suppressed T-cell function but not B-cell production. Normally, the drop in antibody titers follows an exponential curve and usually occurs 6 to 8 weeks after transplantation.6 However, the rapid rise and high antibody production within 10 days of transplantation led to the rapid clearance of group A red blood cells in the patient's circulation, with replacement by the group O donor's red blood cells 3 days after the second graft infusion. Therefore, our case confirms that there is a potential risk of hemolysis when using graft-versus-host disease prophylaxis cyclosporine alone without methotrexate in hematopoietic stem cell transplantation with an ABO mismatch.