Partnership between transfusion services and hematology is vital to the specialty
Transfusion medicine is an essential part of hematology practice, with blood transfusion playing an important role in treatment of many malignant and nonmalignant hematologic disorders. Transfusion medicine specialists are involved in many aspects of blood component therapy, including donor testing, pre-transfusion testing, blood component selection, transfusion indications, investigation of transfusion reactions, and product selection for the treatment of massive hemorrhage.
However, despite the close partnership between hematology and transfusion services, much of what these specialists do to ensure a safe transfusion may be a mystery. Shedding more light on these processes can only help build a successful partnership. ASH Clinical News spoke with transfusion medicine specialists to learn more about what happens to blood products behind the blood bank doors.
Screening, Antigens, and Incompatibility
Transfusion service testing is based on the principle of antigen-antibody binding causing hemolysis or decreased red cell survival, according to Connie M. Westhoff, SBB, PhD, executive scientific director of immunohematology and genomics at the New York Blood Center. “All pre-transfusion testing, manual or automated, relies on detection of red cell agglutination by an antibody as an incompatibility,” Dr. Westhoff explained.
If a patient were given the wrong ABO blood type, for example, natural antibodies in the patient’s plasma would react with the incorrect blood group antigen on the red blood cells and cause hemolysis or destruction.
ABO transfusion compatibilities can be life-threatening. For that reason, all hospital transfusion service laboratories have strict sample labeling requirements.
“If, for whatever reason, a sample was drawn from a different patient then it is labeled for – which can happen – we would end up transfusing the wrong blood. So, right off the bat, if we see any errors in labeling, we reject the specimen,” said Magali Fontaine, MD, PhD, director of transfusion services at the University of Maryland School of Medicine. Dr. Fontaine added that labeling requirements vary from institution to institution depending on safety checks.
Dr. Westhoff said that standards for labeling the patient pre-transfusion blood sample mandate that it be labeled from the wristband and contain the patient’s full name and hospital number. The patient’s blood group antigen (ABO) and Rh antigen (positive/negative) are typed twice. The donor unit is also typed at least twice – at the donor center and at the hospital. This all occurs before the product is entered into the hospital inventory.
Transfusion services must also maintain the past transfusion history of the patient for whom a type and screen are performed, including any previous testing results. For example, Dr. Fontaine said, “if the patient was transfused elsewhere, we would call that hospital or blood center to find out previous testing results, especially red blood cell antibody screen results.”
The red blood cell antibody screen looks for antibodies to red cell antigens other than ABO that were stimulated from previous exposure to foreign (non-self) red cells, such as through pregnancy or previous blood transfusion. This involves testing the patient plasma against standardized FDA-licensed commercial red cells that have been typed for all common antigens.
“If the antibody screen is negative, we are done testing the sample,” said Melissa Cushing, MD, division director of transfusion medicine and cellular therapy at Weill Cornell Medicine. “If the antibody screen is positive, we perform an antibody identification, which is a more complex version of the antibody screen.”
This screen includes testing the blood against a panel of 10 to 12 antigen-typed red cells to determine red cell antibody specificity. For patients with complex antibodies, many more cells may need to be tested; in these cases, the sample can be referred out to a regional reference laboratory within a blood center that has a larger inventory than the hospital.
“The donor units selected for crossmatch must also be ABO/Rh-typed and shown to be negative for the antigen corresponding to the antibody identified,” Dr. Westhoff said. “Crossmatching is the final step, which consists of incubation at 37°C between a sample of the selected red cell unit and the patient’s plasma, followed by the addition of a secondary anti-human globulin reagent to confirm the absence of agglutination.”
Today, most hospitals use an electronic crossmatch for patients with a negative antibody screen and no history of red cell antibodies. A blood bank’s laboratory information system will perform a virtual check for compatibility instead of a physical test between the patient’s sample and the donor red blood cells.
Determination of red cell compatibility may require hours of testing for patients who have multiple antibody specificities. These patient samples will often be sent to the blood center referral laboratory for complex antibody identification and to locate compatible red cell units, Dr. Westhoff said.
To illustrate the compatibility testing process in a complex patient, Dr. Cushing described a case of a woman who developed an antibody to the Kell red cell antigen during her pregnancy.
If she were to return years later in need of a transfusion, her antibody screen could be negative, but the transfusion service would always “honor the antibody” in her transfusion history. Red cell antibodies often become undetectable in the antibody screen over time, Dr. Cushing explained, but if the patient is exposed to the antigen again, an anamnestic immune response could occur, and the patient would be at risk of a delayed hemolytic transfusion reaction. “Kell-negative red blood cells would always be provided to that woman,” she said.
Avoiding Adverse Reactions
Hematologists and transfusion medicine specialists frequently interact, including in the diagnosis of hemolytic transfusion reactions or the management of hemolytic disease of the fetus and newborn (HDFN).
“We help hematologists determine if there are clinical or laboratory signs of hemolysis,” Dr. Fontaine said. “If there is laboratory evidence of hemolysis, we can look for antibodies on the red cell surface that could be responsible for the hemolysis.”
However, Dr. Fontaine noted that hemolysis is not always caused by red cell antibodies. “You have to go through both the clinical history and the lab evaluation to look for other possible reasons for hemolysis,” she said.
For example, a patient with mitral valve prolapse could experience mechanical hemolysis. This patient may need to be evaluated with an echocardiogram instead of undergoing antibody testing, Dr. Fontaine noted. “There is a whole list of possibilities in the differential diagnosis.”
If immune hemolytic anemia is suspected, a direct antiglobulin test can confirm the diagnosis. The test detects immunoglobulin G and complement components bound to the patient’s own red cells.
“Autoantibodies are also present in the plasma and agglutinate all red cells used for testing,” Dr. Westhoff explained. “Compatibility cannot be demonstrated without complex adsorptions, which can take several hours or more to perform.” These delays can threaten a safe transfusion. Many transfusion physicians will recommend transfusion of “antigen-matched” red cells when compatibility cannot be demonstrated by routine methods, Dr. Westhoff said.
“This involves testing the patient’s blood to determine which common antigens are lacking, which makes the blood more likely to be recognized as foreign if encountered on transfused red cells, and triggers an immune response,” she said. Donor units lacking antigen (typed as negative) are then selected for transfusion.
In Dr. Westhoff’s experience, patients with multiple antibodies who require intermittent or chronic transfusion often become well-known to the hospital transfusion and blood center referral laboratory staff. Between transfusion encounters, the staff attempt to identify and sequester potentially compatible units, based on donor units with complete antigen profiles (i.e., more than ABO and Rh typing).
HDFN, which occurs when a pregnant woman’s immune system attacks the blood cells of the fetus, is diagnosed in the transfusion service laboratory by testing maternal plasma for the presence of an antibody that will cross the placenta and bind to the red cells of the fetus. After birth, HDFN may be detected by a positive direct antiglobulin test on the baby. In mothers, these antibodies may result from having had a previous blood transfusion or, more commonly, from a previous pregnancy and delivery of a child who inherited a paternal red cell antigen that was lacking in the mother.
HDFN can occur from incompatibility of the Rh antigen system or other blood group antigens, but also from ABO blood group incompatibilities between mother and fetus. Women commonly are found to have antibodies that target Kell antigens, which can cross the placenta and lead to destruction of the fetal red blood cells.
“When an antibody to a red cell antigen is detected at prenatal screening, the paternal red cells are typed to determine the possibility that the fetus will inherit the corresponding antigen and potentially suffer complications of anemia,” Dr. Westhoff said. “DNA testing can now be used to determine paternal zygosity for the antigen in question and the fetal blood type from amniocytes.”
HDFN due to Rh is relatively uncommon in the U.S. because of prevention with injection of Rh immunoglobulin in Rh-negative mothers, but it can still occur. Dr. Cushing recently had a case of HDFN due to an antibody formed by the mother to an uncommon antigen expressed by the father. Since the antigen was uncommon, it was not picked up in the antibody screen on the mother’s plasma, but the baby’s direct antiglobulin test was positive and the baby had evidence of anemia and hemolysis.
“The American College of Obstetricians and Gynecologists has specific guidelines for when red cell antibody screening should happen,” Dr. Cushing said. “Depending on which antibody is found, there are different thresholds of concern for HDFN.”
When incompatibilities are found, the fetus will be monitored for anemia throughout the pregnancy. If serious anemia occurs, an intrauterine transfusion can be performed. If it is not detected early, HDFN can be extremely dangerous, even fatal.
Managing the Blood Supply
Another important area where hematologists and transfusion services collaborate is the management of the blood supply. Dr. Cushing, who has been in practice for about 15 years, said the blood supply issues since the start of the pandemic have been some of the most challenging she has ever seen. This was true even for plasma and cryoprecipitate, products that are typically unaffected by acute blood shortages because of their longer shelf life in the frozen state.
The goal of every transfusion service is to avoid the under- or overuse of blood and blood products, Dr. Cushing said.
“Most programs have guidelines for when transfusion is indicated and provide information that all practitioners should follow when deciding to order blood,” Dr. Cushing said. “During times of shortage, transfusion services will send messages alerting that the blood supply is low and that guidelines will be strictly enforced with prospective auditing.”
“Competition among nonprofit blood providers for hospital contracts leaves little for investment or exploration of new technologies.”
—Connie M. Westhoff, SBB, PhD
According to David F. Friedman, MD, associate medical director of the Transfusion Service and Apheresis Program at Children’s Hospital of Philadelphia, strategies for managing limited blood supply vary by the circumstance.
For example, when platelet needs cannot immediately be filled, the blood product supplier may be able to provide a more exact estimate of when the products will be available – whether in a few hours or a few days. Transfusion services may also call clinicians to discuss the clinical situations of the patients for whom platelets were ordered.
“Then the whole situation becomes a barrage of brokering and communication that we call ‘platelet triage.’ In these settings, the dilemma is mostly about determining which patients can wait,” Dr. Friedman said. “For example, an outpatient with a platelet count of 18×109/L who is not bleeding may be able to wait. On the other hand, a patient bleeding after cardiopulmonary bypass probably cannot wait.”
Dr. Friedman explained that the communications with the blood product suppliers and clinicians are psychologically complicated. They involve a lot of negotiation and should be assigned to more experienced personnel.
Communication is also key for long-term shortages, starting with letting clinical services know that there may be problems with supply. Dr. Friedman noted, though, that there is a delicate balance between alerting clinicians about potential issues: One does not want to be an alarmist and cancel scheduled elective surgeries, but it is also necessary to save units for emergencies.
Dr. Friedman’s institution is trying to develop objective criteria for transfusion of red cells in intensive care units (ICUs). These efforts include defining trigger hemoglobin levels and developing computerized decision support for patients in all sorts of clinical scenarios. The process is complicated and requires buy-in from ICU specialists.
Blood shortages are almost always present in one form or another, Dr. Fontaine noted. In many centers, particularly in tertiary centers like hers, they “live and breathe inventory.”
Dr. Westhoff added that maintaining adequate inventory is likely one of the biggest ongoing challenges in the field. “The last few years have seen significant reduction in number of red cell transfusions, due to patient blood management programs and the realization that a treatment hemoglobin goal of 7 g/dL rather than 10 g/dL is safe,” she said. “But, at the same time, there has been a continued increase in platelet product usage as cancer immunotherapies expand.”
Dr. Westhoff said that investing in research and development around transfusion services is also a major challenge. “Health-care reimbursement in the United States with its diagnosis-related group system unlinks blood product usage from direct compensation, resulting in pressure on the hospital transfusion service laboratory to manage and reduce costs,” Dr. Westhoff said. “Competition among nonprofit blood providers for hospital contracts leaves little for investment or exploration of new technologies without guaranteed return or direct cost savings.”
Together, these hamper innovation in transfusion medicine therapy, she said.
Finally, one of the biggest challenges that remain for blood centers is obtaining and retaining qualified staff.
“Staffing is a challenge across both collection centers and hospital-based transfusion services,” Dr. Fontaine said. “Especially after two years of a pandemic, staff are getting burned out and turnover is high.”
Technologies within these centers are improving and more automation is being incorporated into processes, Dr. Fontaine said, but there will always be a need for technical staff at the bench. —By Leah Lawrence