A ‘Dangerous’ Group O Donor: Severe Hemolysis in All Recipients of Organs from a Donor with Multiple Red Cell Alloantibodies

Introduction

The passenger lymphocyte syndrome (PLS) refers to the clinical phenomenon of alloimmune hemolysis resulting from the adoptive transfer of viable lymphocytes from the donor during solid organ or hematopoietic stem cell (HSC) transplant (1,2). It has been most commonly reported following nonmyeloablative HSC transplant, particularly in the context of minor ABO mismatch (2,3). Rarely, the severity of hemolysis results in death despite transfusion support and supportive care (4). Hemolysis due to PLS appears to be less common following solid organ transplant (1,2), and the relative frequency of PLS appears to be related to the volume of transplanted lymphoid tissue. PLS usually results from antibodies active within the ABO and Rh systems (5–9). Rarely, it may occur due to non-ABO/Rh antibodies, particularly if the organ donor has been previously sensitized to other red cell (RC) antigens by transfusion or pregnancy (5,9,10). Where multiple organs are transplanted from a single donor, the development of PLS in two of four recipients has been reported (9). We describe series of cases where PLS developed in all three recipients of organs from a donor with multiple RC alloantibodies, including anti-k. The implications for management, including transfusion support, are discussed.

Case Series and Results

Recipient 1

A 61-year-old male with advanced emphysema and pulmonary fibrosis underwent right single lung transplant. He belonged to blood group O, Rh (D) positive [R2r], K–k+. His baseline full blood examination (FBE) was normal (hemoglobin [Hb] 150 g/L) and he had a negative RC antibody screen and direct antiglobulin test (DAT). No blood products were administered intraoperatively. Posttransplant immunosuppression included cyclosporine, mycophenolate and prednisolone.

From posttransplant day (PTD) 0 to 10, Hb fell from 126 to 69 g/L without bleeding (see Figure 1). Investigations revealed elevated hemolytic markers, a positive DAT due to IgG, and marked spherocytosis. The initial antibody screen was negative; however, anti-D (but not anti-C or −k) was detected in the RC eluate. There was no associated renal impairment or hemoglobinuria. Management included increasing the prednisolone dose to 100 mg daily, folate supplementation and transfusion of three RC units (O, Rh (D) negative [rr], k+), with a posttransfusion Hb increment to 113 g/L.

Ongoing immune hemolysis required a second transfusion episode at PTD 37. To facilitate tapering of corticosteroids, intravenous immunoglobulin (IVIG; 1.5 g/kg in divided doses) was administered. The patient subsequently stabilized from a hematological perspective, but required a protracted inpatient stay due to infective complications. Three months posttransplant, he is receiving 15 mg prednisolone, and has mild compensated hemolysis with a negative antibody screen, but persisting DAT positivity due to anti-D.

Discussion

PLS is a rare but recognized complication of solid organ transplantation which may result in significant hemolysis. Hemolysis can have a brisk onset and protracted natural history, despite escalation of immune suppression. In our case series, serological evidence of immune hemolysis was detectable as early as day 4 (in the liver transplant recipient) and persisted in all three organ recipients for at least 3 months. Fortunately, the period of transfusion support was short-lived, as all recipients mounted an adequate compensatory reticulocytosis.

Management strategies for PLS are anecdotal, as described in case reports and small series (1,2). Therapeutic interventions include escalation of immunosuppression, immune-modulation (e.g. by IVIG) and specifically targeting B-lymphocytes using monoclonal antibodies such as rituximab (8). Decompensated anemia usually requires provision of antigen negative RC units for transfusion. Antigen negative RC units are usually readily available when PLS is due to ABO or Rh antibodies. However, where multiple RC alloantibodies are implicated in hemolysis, antigen negative units are potentially more difficult to source, further confounded, as in this series, by the presence of antibodies to high-incidence RC antigens (e.g. Cellano [k] is expressed by 99.6% of the Australian blood donor population) (11). The possibility of multiple organ recipients requiring transfusion support with such a rare RC phenotype places considerable demand on blood services in these cases (although only one of our three organ recipients ultimately needed k-negative units).

Our series confirms the capacity for PLS to arise due to antibodies within the Rh system in the context of single lung transplantation. It is also the first known report implicating anti-k in PLS. Anti-k is a potentially clinically significant antibody which is known to cause delayed hemolytic transfusion reactions and hemolytic disease of the newborn. The contribution of anti-k antibody to hemolysis in this case series is uncertain, particularly as it was only detected in the liver recipient in the context of multiple other antibody specificities.

Although PLS occurring in half of the recipients of organs from the same donor has been described (9), in our series every organ recipient developed significant hemolysis. However, the severity of hemolysis and RC alloantibody status varied substantially between our individual patients. This clinical and laboratory heterogeneity underscores a complex biological situation. Engraftment of viable lymphocytes is facilitated by the dose of lymphoid tissue within the graft and degree of recipient immunosuppression (1,2). The importance of donor-derived memory B-lymphocytes within the transplanted organ is highlighted by this case series, as we observed hemolysis due to a variety of antibody specificities in all solid organ recipients from a single donor. Although HLA-sharing promotes lymphocyte engraftment in transfusion-associated graft versus host disease (12) and transfusion-associated microchimerism (13), it was not necessary to facilitate PLS in our transplant recipients (Table 1). Thus, PLS occurs despite the presence of HLA-disparity between donor and recipients.

We conclude that the detection of a positive RC antibody screen in a donor should prompt careful monitoring of organ recipients for the development of hemolysis. Preemptive adjuncts to immunosuppression (such as IVIG or rituximab) could be considered where an organ recipient has the potential to develop PLS against a high incidence RC antigen. In such cases, early notification of blood services may facilitate call-up of phenotyped rare RC donors and provision of compatible units.