Rh-Positive Fresh Frozen Plasma (FFP) Therapy Can Induce Cross-Reactive Immune Response to Red Blood Cell (RBC) Self-Antigen in Rh-Negative Patients Having Existing Alloimmunization to Rh-Antigen D
Authors: Szymanski Irma O. 
Published: October 2019

Abstract
Development of RBC autoantibodies in three Rh-negative patients following treatment with Rh-positive FFP is reported. Patients’ alloimmunization to Rh D antigen dates back several years.
Patient I, a 49-year old man, experienced an acute cardiac event due to ascending aortic dissection, aortic insufficiency and probable cardiac tamponade. His blood type was O, Rh negative and his serum contained no alloantibodies. He underwent cardiac surgery on emergency basis and experienced bleeding complications during the procedure. He received 53 units of RBC, 49 of them Rh- positive and many other blood products. On the 8th post-operative day the patient experienced cardiac tamponade, which was relieved surgically. Then his blood type was O, Rh positive and anti-D was detected in his serum due to primary immunization to the Rh D antigen.
The patient was re-admitted three months later for sharp epigastric pain. During that hospitalization no blood products were transfused; hematocrit varied between 33 to 29%. Blood typed as O, Rh negative, and manual direct antiglobulin test (DAT) was microscopically positive for IgG. Automated DAT was strongly positive for IgG1. Anti-D, anti-E and a panagglutinin (autoantibody) were present in his serum. The panagglutinin reacted strongly (2+) with Rh-positive RBC and less strongly (1+) with Rh-negative RBC, but both reactivities could be removed by absorption onto Rh-negative RBC. This “mimicking” antibody represented an autoantibody that was induced by alloimmunization to Rh antigen D.
Eleven years later the patient was readmitted for bleeding duodenal ulcers. His serum contained anti-D, anti-C, anti-E and anti-K. DAT was negative for the first three days. During the first 19 days of hospitalization he received seven units of compatible RBC and 16 units of Rh-positive FFP. Anti-D was present in the eluate from patient’s Rh-negative RBC during days 18 to 28. The patient had again developed an autoantibody after receiving Rh-positive FFP, which apparently contained RBC fragments.
Patient II was a 58-year old woman who underwent coronary artery bypass surgery. Her blood type was B, Rh negative and her serum contained anti-D and anti-K. During surgery and postoperative period she received ten compatible units of RBC and two units of B, Rh-positive FFP. The immediate post-operative course was unremarkable, but when discharged 8 days after surgery she had slight fever of unknown origin and Hct was 32.2%.
Nine days later she was admitted to another hospital with fever of 101oF, jaundice, melena, chest pain, leg pain and anemia (Hb 7.2gm/dL). Reticulocytes were 14.8% and haptoglobin was 0. No new alloantibodies were detected. She had a weakly positive manual DAT. The automated DAT showed severe coating of RBC with IgM. Autoimmune hemolytic anemia was diagnosed. Following prednisone therapy her hemoglobin and hematocrit levels normalized. We believe that the autoantibody was induced by RBC fragments in the Rh-positive FFP.
Patient III was a 72-year-old woman with admission diagnosis of possible HUS. The patients’ true blood type was A, Rh negative and her serum contained anti-C and anti-D. However, the initial blood sample was collected from a wrong patient whose blood type was O, Rh positive. Therefore she received four units of O, Rh-positive FFP before plasma exchange therapy was initiated. Her group A RBC were destroyed by anti-A in the transfused FFP. Surprisingly anti-D was also detected in the eluate of patients’ Rh-negative RBC. At that time the titer of anti-D had increased significantly over the original. Following destruction of anti-A coated RBC she still remained anemic, probably due to the autoantibody. After prednisone therapy Hct normalized steadily.
In summary, three Rh-negative patients with existing alloimmunization to the Rh antigen D developed anti-D mimicking autoantibodies after receiving Rh-positive FFP. The autoantibodies caused autoimmune hemolytic anemia in two of the patients. Further studies on RBC autoimmunization in alloimmunized patients are encouraged.

Disclosures
No relevant conflicts of interest to declare.