Continuing Education Activity

In the early 1900s, the four different blood types within the ABO blood group system were identified. Knowledge of these blood types and the implications associated with ABO incompatibility has improved patient care and decreased associated morbidity. This activity reviews the ABO blood group system, highlights complications of ABO incompatibility, and emphasizes the appropriate selection of blood products by the interprofessional team-based on ABO blood typing.

Objectives:

• Describe the ABO blood group system antigens and antibodies.
• Review the blood typing methods and reasons why discrepancies in blood typing can occur.
• Summarize typical scenarios of hemolysis due to ABO incompatibility.
• Identify appropriate blood products that should be ordered for patients in the context of their ABO blood type.

Introduction

The ABO blood group system was first discovered in the early 1900s, and since that time, our understanding of the ABO blood group system has increased significantly.  These discoveries have led to safer transfusion practices.[1][2] The ABO blood group system spans beyond transfusion medicine and has been used in the study of populations by anthropologists, police in forensic science, and lawyers in paternity claims.

Function

ABO Antigens and Antibodies

People can be divided into four main groups (A, B, O, and AB) based on the agglutination patterns of their red blood cells. The ABO blood group system consists of A and B antigens on red blood cells and their corresponding antibodies in the sera of people who do not express those antigens.[1][2] ABO antigens exist on the surface of red blood cells as well as the surfaces of the other tissues and secretions. Anti-A and anti-B antibodies are naturally-occurring and are made by immunocompetent people starting at approximately six months of age.[3][4]

The A and B blood group antigens are oligosaccharide antigens generated by reactions catalyzed by glycosyltransferases. The expression of these antigens determines the blood type of the patient. The human ABO gene is found on chromosome 9; it spans over 18 kilobases and is made up of 7 coding exons.  Functional A and B alleles encode the A and B glycosyltransferases, leading to the synthesis of A and B antigens. Due to nucleotide substitutions leading to amino acid substitutions, A and B genes encode the A and B transferases with different sugar specificities. The O genes are not active because they cannot produce functional enzymes.

Group O individuals have an H gene found on chromosome 19, forming the H-antigen. This antigen serves as a precursor oligosaccharide needed to form the A and B antigens. H antigens are abundantly noted in type O individuals. If the A and B genes are both present, then some of the H becomes A, and some become B, forming the AB group. If the H gene is defective or not present, then the H antigen cannot be formed, and therefore A or B cannot be formed. The consequence is a rare phenotype known as the Bombay phenotype. Patients with the Bombay phenotype have antibodies in the plasma similar to those present in the plasma of type O individuals, but they also have clinically significant anti-H antibodies.[3][5][4]

Based on the pattern and degree of agglutination using reference antibodies and red blood cells, subgroups of ABO have also been identified. Subgroups are distinguished by decreased amounts of A, B, or O (H) antigens on the red blood cells. Blood type A has the most variation with different subgroups; type A1 has the standard amount of antigen A, with decreasing amounts of this antigen noted in the subsequent subtypes.[5]

Issues of Concern

Discrepancies in Blood Typing

Before a transfusion, ABO typing is routinely performed to provide the safest transfusion possible. Forward typing (antigen typing for A and B on red cells) and reverse typing (testing for anti-A and anti-B in the patient’s plasma) are performed. The forward and reverse typing are performed to confirm the blood type. However, discrepancies between forward and reverse typing may occur. The discordance can be due to a lack or excess of antigens or antibodies.  If a discrepancy is found, the first step is to perform confirmatory assessments to evaluate for any errors in testing or technical problems.  Various clinical scenarios can also explain these discrepancies.

 In forward typing, the patient’s red blood cells are combined with commercial antisera.  Weaker RBC agglutination than expected (weak or missing reactivity) can occur in cases of A or B subgroups.  Additional RBC reactivity on forward typing can occur in cases of acquired B phenomenon. The acquired B phenotype occurs in cases where bacterial enzymatic changes lead to the conversion of N-acetylgalactosamine (A antigen) into galactose (B antigen); this phenomenon has been documented in cases of bacterial infections and colorectal malignancy.[6][7] 

Reverse ABO typing combines a patient’s plasma with commercial red blood cells. Possible causes of weaker than expected plasma reactivity include immunosuppression, very young or old age, hypogammaglobulinemia, and prior treatment with rituximab.  Unexpected or “extra” reactivity detected in reverse typing can be seen in patients who have received intravenous immune globulin (IVIG) or non-ABO-matched plasma products.[8]

Choosing the Safest Blood Products

In the simplest terms, individuals with type O blood are considered “universal donors” for red blood cells, and type AB patients are “universal recipients” for red cells from patients with any ABO blood type. Type AB plasma is compatible with all other ABO blood types.  There are, however, many caveats and clinical scenarios to consider when choosing the safest and most appropriate blood products for each patient.

The ABO antigen is fully developed at birth; however, newborns do not start making antibodies until 3 to 6 months of age. The antibodies present in the serum of newborns under four months of age are passively transferred from the mother. Therefore when a red cell transfusion is ordered for an infant under four months of age, the mother’s blood type must be considered.[9] Forward typing is performed to determine a newborn’s blood type, but reverse typing is not performed in infants in the first few months of life. 

Platelets have ABO antigens, but the expression is variable; these antigens are only strongly expressed in a minority of patients. Platelets are, however, suspended in plasma containing ABO antibodies.  The plasma accompanying the platelets may cause hemolysis if the plasma is not compatible with the recipient’s red blood cells.[10] In the emergency setting for the bleeding patient requiring blood products, group AB plasma, and group O-negative red blood cells have been traditionally transfused to avoid ABO incompatibility and avoid delays while blood typing is being performed.  Group AB plasma does not contain Anti-A or Anti-B antibodies and is therefore compatible with all ABO blood groups.  The supply of AB plasma is, however, limited. Newer approaches in the emergency treatment of patients without a known ABO blood type include transfusion of type A plasma and low-titer group O whole blood. While transfusion of even a small amount of ABO-incompatible red blood cells can lead to severe hemolysis and morbidity, clinically significant hemolysis has not been described in cases of type A plasma or low-titer group O whole blood transfusions into patients for whom these products are ABO-incompatible.[11]

Clinical Significance

While there is variability in the ABO phenotype frequencies among different ethnic and racial groups, blood type O is generally the most prevalent worldwide, followed by types A and B, respectively. Type B is more common in the Asian population. Blood type AB is the rarest of the ABO phenotypes.[12] ABO antigens are not only found on red blood cells but are also expressed on the surface of many different types of human cells. The importance of ABO blood type antigens stretches beyond transfusion medicine, as many reports suggest the involvement of the ABO system in several disease processes. ABO blood groups have been linked with the susceptibility to various diseases, including hematologic disorders, cancer, infections, and cardiovascular diseases.[13]

Clinically significant antibodies can lead to adverse events during transfusion and can also lead to hemolytic disease of the fetus and newborn after placental transmission from mother to fetus.  Hemolytic disease of the newborn (HDN) occurs due to incompatibility between the blood of the mother and the baby. Antibodies from the mother cross the placenta during pregnancy and attack the baby’s red blood cells. ABO incompatibility between mother and infant can cause hemolysis and hyperbilirubinemia in the infant.  HDN due to ABO incompatibility tends to be less severe than that caused by Rh compatibility because fetal red cells tend to express less of the ABO blood group antigens than adults. Also, the ABO blood group antigens are present on various tissues, which decreases the likelihood that ABO antibodies will bind to their targets on fetal red cells. The degree of severity of hemolysis varies greatly.  HDN can occur with the first pregnancy and has a high recurrence rate.[14][15][16] 

A hemolytic transfusion reaction is one type of reaction that can occur with the transfusion of blood products. Acute hemolytic transfusion reactions most commonly occur with transfusion of red blood cells, although they can develop with transfusions of other blood products. An acute hemolytic transfusion reaction occurs within 24 hours of the transfusion. Acute hemolytic reactions are most often caused by incompatibility between the donor product and recipient blood group system, most commonly the ABO blood group system. The classic presentation of acute hemolytic transfusion reaction includes fever, red/brown urine, and back/flank pain. However, not all patients will present in this way; other symptoms that may be noted include hypotension, chills, renal failure, and disseminated intravascular coagulation.[17] 

Once an acute hemolytic transfusion is suspected, the transfusion should be immediately stopped. The most common cause of death during a transfusion is a clerical error, where an incompatible unit of blood was transfused, and so clerical error should be ruled-out and ensure the correct blood product was given to the intended patient. The remaining blood product, along with a sample of blood from the patient, should be sent to the blood bank for repeat ABO testing on the patient after the reaction. Repeat cross-matching is then performed, and patient samples should be sent to evaluate for renal failure, hemoglobinemia, hemoglobinuria, disseminated intravascular coagulation, and hemolysis. Treatment for an acute hemolytic transfusion reaction is mainly supportive care, and specific treatments are determined by the specific complications noted.

Enhancing Healthcare Team Outcomes

The discovery of the ABO system has led to increased safety in the transfusion of blood products. Understanding the ABO blood group system is essential to ensure appropriate blood products are administered to patients. Practitioners should know the appropriate blood products to transfuse based on ABO typing and recognize typical presentations of ABO incompatibility. Knowledge of the ABO blood system, prevention of complications with appropriate blood product administration, and prompt identification of signs/symptoms of ABO incompatibility will improve patient care and decrease morbidity.

From the bedside to the blood bank, the medical team must collaborate to ensure that transfusions are administered safely to minimize complications. The blood bank team must determine the most appropriate blood product to release. Communication from the clinical team is necessary to provide clinical background and information regarding adverse transfusion-related events to the blood bank team. Administering a transfusion safely can only occur with the teamwork of physicians, advanced care practitioners, nurses, and technologists in the blood bank.