Donor-derived red blood cell antibodies and immune hemolysis after allogeneic bone marrow transplantation

Abstract

Six cases of immune hemolytic anemia attributed to donor-derived red cell antibodies after allogeneic bone marrow transplantation (BMT) are reported. In 2/6 cases, severe intravascular hemolysis was seen, 6/6 required increased red cell transfusion, and 1/6 was treated by plasma exchange. All recipients were receiving cyclosporine to prevent graft-v- host disease. Investigations showed that in each case, the donor lacked ABO or Rho(D) red cell antigens present in the recipient. The direct antiglobulin test was positive in 6/6. Relevant serum antibody (anti-A, four cases; anti-B, one case; anti-D, one case) was first detected one to three weeks after BMT. Eluates made from recipient red cells showed the same specificity as serum antibody. Maximum hemolysis occurred nine to 16 days after BMT, suggesting that active production of antibody by “passenger” donor lymphocytes was the likely mechanism of hemolysis, rather than passive transfer of antibody in the marrow infusion. Retrospective analysis of 21 consecutive cyclosporine-treated BMT patients receiving marrow lacking ABO or D antigens present in the recipient showed that (1) 15/18 patients tested had red cell antibody production against recipient red cell antigens; (2) despite the frequent presence of antibody specific for recipient red cell antigens, only 3/21 patients developed clinically significant hemolysis; (3) clinical hemolysis could not be predicted by donor or recipient red cell antibody titers. We conclude that although red cell antibody against recipient antigens is frequently produced after minor ABO and D mismatched BMT in cyclosporine-treated recipients, only 10% to 15% of cases develop clinically significant immune hemolysis. The data presented show that the most likely source of antibody is “passenger” donor lymphoid cells.

Autoimmune Hemolytic Anemias: Classifications, Pathophysiology, Diagnoses and Management

“…AIHA comprises seven distinct types that have been categorized mainly based on serological findings [3,12]. The seven types of AIHA are as follows: warm-antibody autoimmune hemolytic anemia (wAIHA); cold-antibody AIHA (includes cold agglutinin syndrome (CAS) and cold agglutinin disease (CAD)); mixed AIHA (also called combined cold and warm AIHA); paroxysmal cold hemoglobinuria (PCH), also called Donath-Landsteiner antibody test-positive AIHA; direct antiglobulin test-negative AIHA (DATnegative AIHA); drug-induced autoimmune hemolytic anemia (DIAIHA); and passenger lymphocyte syndrome (PLS) (related to transplantation, and presenting as AIHA with a specificity) [2,3,5,[15][16][17][18][19][20][21][22][23][24][25] (see Table 1). AIHA should be suspected if the patient shows signs and symptoms of anemia and other causes of the anemia, such as bleeding, underproduction, paroxysmal nocturnal hemoglobinuria (PNH), and other potential causes of anemia have been ruled out [3], see Section 1.1 above.…”

“…Passenger lymphocyte syndrome is diagnosed when following a solid organ or bone marrow transplant, the patient develops an antibody to the recipient's RBCs. While presenting serologically as a wAIHA, with or without specificity, it is owing to the donor's B-cells producing an antibody to the recipient's residual RBCs [17,25].…”

“…DAT-negative AIHA is rare [3,22] and difficult to diagnose [24]. Passenger lymphocyte syndrome (PLS) occurs after transplantation and is related to the immune cells from the donor, transferred via the graft, subsequently producing host-specific anti-RBC antibodies, thereby mimicking AIHA [17,25]. In the future, the incidence of AIHA may increase due to the use of stem cell transplantation and checkpoint inhibitors in the treatment of cancers [27,28].…”

“…Allogeneic transplantation includes bone marrow transplantation (BMT) and solid organ transplantation. In BMT, host lymphocytes are transferred into the recipient from the bone marrow or stem cell material obtained from the donor [17,25,112,113]. In solid organ transplantation, donor lymphocytes can be "passengers" in the solid organ obtained from the donor, and these can be transferred into the recipient [114][115][116][117][118].…”

“…In solid organ transplantation, donor lymphocytes can be "passengers" in the solid organ obtained from the donor, and these can be transferred into the recipient [114][115][116][117][118]. It is feasible for donor lymphocytes that have been transferred to produce antibodies that are specific to RBC antigens in the recipient's body but not present on the donor's own red cells [17,25,[112][113][114][115][116][117][118]. Indeed, sometimes these passenger lymphocytes in either BMT or solid organ transplants are obtained from donors who have been sensitized to produce alloantibodies to antigens for which they lack.…”