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Everything You Didn’t Know About Rh Factor

December 14, 2021
Elizabeth Brem, MD

Dr. Elizabeth Brem (@DrLizBrem) is an assistant professor in the Division of Hematology/Oncology, Department of Medicine, at University of California, Irvine School of Medicine. She specializes in lymphomas (B- and T-cell, Hodgkin lymphoma), chronic lymphocytic leukemia, and multiple myeloma. She attended medical school at SUNY Buffalo in her hometown of Buffalo, New York, and did her residency and fellowship at Beth Israel Deaconess Medical Center/Harvard Medical School in Boston. She currently lives in Huntington Beach, California. Dr. Brem is a prolific ASH volunteer. Prior to joining ASH News Daily, she served as an associate editor for ASH Clinical News and has also been a member of the ASH Trainee Council and Committee on Communications. She looks forward to her next adventure in 2022 as a member of the ASH Publications Committee. In addition to a wealth of knowledge about ASH, Dr. Brem contributes some deep-rooted journalistic chops. “In high school, I wrote for the kid’s section of the local paper, The Buffalo News,” she shared. “I still have a ‘Reporters Notebook’ that they gave me!” 


The moment I read the description of the E. Donnall Thomas Lecture presented by Dr. Connie Westhoff titled “Rh and Transfusion in the Era of Genomics,” was the moment I realized how little I knew about Rh factor. I suspect those of us who are not trained in transfusion medicine had a lot to learn from Dr. Westhoff. Did you know that Rh antigens play a role in ammonia/ammonium transport? Did you know that one can genotype Rh antigens to reduce the risk of alloimmunization with transfusions?  

Dr. Westhoff is the 2021 recipient of the E. Donnall Thomas Lecture and Prize named after Dr. Thomas, a past ASH President who was awarded the Nobel Prize in Medicine (along with his colleague Dr. Joseph E. Murray) in 1990 for his pioneering work on bone marrow transplantation as a treatment for leukemia. This award was created in 1992 and “recognizes pioneering research achievements in hematology that have represented a paradigm shift or significant discovery in the field.” Dr. Westhoff earned this honor for her internationally known work in transfusion medicine. She uncovered the genetic diversity of Rh factor using high-throughput methods of genotyping and has studied how mutations in Rh contribute to Rh incompatibility after transfusion. She has dedicated her career to improving safety and care for patients with sickle cell disease using these genomic techniques. Dr. Westhoff is strongly respected by her peers and has served as a board member for the Association for the Advancement of Blood and Biotherapies (AABB), Chair of the ASH Scientific Committee on Transfusion Medicine, and a board member for the National Blood Foundation. She is currently the Executive Scientific Director for the National Center of Blood Group Genomics and head of the Laboratory for Blood Group Genomics at the New York Blood Center. She also serves as an adjunct assistant professor at the University of Pennsylvania. Dr. Westhoff accepted the award “on behalf of all transfusion medicine professionals.” 

Dr. Westhoff grew up in a farming community in South Dakota and started her career as a laboratory technologist; it was her practical experience in the lab investigating the cases of blood transfusion incompatibilities that inspired her research career. Dr. Westhoff noted that her career start was “non-traditional” as she returned to school after several years of both working in hospital laboratories and being a parent. She completed her PhD in molecular genetics at the University of Nebraska where she also completed a postdoctoral fellowship. She developed the hypothesis that Rh antigens were responsible for some of the unexplained reactions that she had observed in the lab. This motivated her career focus of better defining the genetics and function of the Rh system. In 1998, Dr. Westhoff received a National Institutes of Health Fellowship in Transfusion Medicine at the University of Pennsylvania. During this fellowship, she demonstrated that the biological function of Rh factor was to transport ammonia. She subsequently established the first laboratory for blood genotyping for the American Red Cross and served as the scientific director for the Molecular Blood Group and Platelet Antigen Testing Laboratory from 2004 to 2010. 

Dr. Westhoff taught us that an Rh blood type is not as simple as positive or negative, that Rh typing is “much more complex at the genetic level.” The Rh locus has two genes. One encodes for RhD, the one that makes a person “Rh positive.” The other encodes for Rh C and E antigens. She tackled Rh “mysteries,” noting that some people typed serologically as RhD positive can make anti-D antibodies. She notes this can occur due to “the extreme genetic diversity” at the Rh loci; serologic typing cannot detect altered RhD protein or low levels of RhD protein. Heterozygosity for the altered or weak alleles occurs in about 2 to 5 percent of people and varies by ethnicity.  

In terms of practical advice for the practicing clinician routinely ordering blood, Dr. Westhoff recommended that we all “consider ordering blood that is antigen matched for more than ABO and RhD for patients needing recurring blood transfusion therapy” to reduce the risk of alloimmunization that could impact future transfusions throughout the patient’s lifetime. When asked for a key takeaway from her presentation, Dr. Westhoff noted, “Blood transfusion remains the number one, most prescribed lifesaving drug therapy in use today but relies on approaches that have not materially changed in more than 50 years. We can now perform more precise blood typing by DNA-based testing, and we can match patients and donors more accurately for ‘personalized’ blood transfusion, improving outcomes by avoiding alloimmunization, which represents a paradigm shift in therapy.” In her presentation, Dr. Westhoff referenced ASH clinical practice guidelines for transfusion support in sickle cell disease, published in Blood Advances, which recommend red cell antigen profiling “at the earliest opportunity” (ideally before first transfusion). Genotyping is preferred over serologic phenotyping. Matching for other Rh antigens, especially RhC, is also important as it can help reduce transfusion complications for patients with sickle cell disease. In keeping with the strong theme of diversity and equity at this year’s annual meeting, Dr. Westhoff called for more diversity in our blood donor pool to allow us to do better matching for blood.  

Dr. Westhoff’s work is not finished. When asked where the field of transfusion medicine is going, she noted that for use of genetic blood typing to have more widespread adoption, cost must be minimized. She is currently involved in efforts to develop a low-cost testing platform targeting all red cell, platelet, and human leukocyte-antigen types that “promises to change the way transfusion therapy is delivered.” She explained that the financial barriers result “from the lack of a direct link between transfusion therapy and reimbursement in the U.S. health care system.” She also identified numerous unanswered questions in the field of transfusion medicine. She noted that blood transfusions are a “massive challenge of foreign cellular antigens” and that very little is known about the response to transfusions at a basic immunologic level. “An expected increase in hemoglobin value is insufficient as a measure of efficacy. It may be that both donor and patient factors impact outcomes,” she stated. In terms of advice for budding young scientists eager to tackle these questions, Dr. Westhoff offered, “Find a topic that interests you and pursue it with a passion. Search out and approach appropriate mentors. Dont wait to be approached. Your interest in them will motivate their investment in you.”  

Dr. Brem indicated no relevant conflicts of interest.  

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