Alloimmunization From Transfusions

What Is Meant by Transfusions and Transfusion Reactions?

Transfusion is a vital medical care procedure where whole blood or its components (plasma, red blood cells, white blood cells, platelets, and clotting factors) is transferred intravenously from one person (donor) to another (recipient). It is the most critical treatment intervention to compensate for blood loss or reduced blood components during medical emergencies (trauma, surgery, postpartum hemorrhage) as well as clinical conditions like anemia, thalassemia, hematological disorders, leukemia, and other chronic illnesses.

Blood present in all human beings is not homogenous (same). Human blood varies immunologically, where administration of mismatched blood or blood products leads to adverse effects known as transfusion reactions. Blood compatibility tests are carried out routinely before transfusions to prevent these unwanted complications. Standard compatibility tests include ABO blood group and Rh factor (RhD) typing. However, the risk of immunological incompatibility extends beyond ABO and Rh typing in certain cases due to the involvement of other antigenic complexes as alloimmunization phenomena.

What Is Alloimmunization?

Alloimmunization is the induction of an immune response when encountering exposure to alloantigens (antigens not from the same person but from a different individual of the same species). The recipient’s immune system produces antibodies against donor antigens (alloantigens) as they are considered foreign material and not compatible with the recipient's body. This led to clinical consequences such as

• Hemolysis of transfused blood (in blood transfusions).

• Graft or organ rejection (in case of allotransplanted tissue or organ transplantation).

• Fetal hemolysis or miscarriage during pregnancy.

Apart from major antigens of the ABO blood group and Rh factor antigens present in the red blood cells, immunological complexes involved in alloimmunization are,

• Major histocompatibility complex (present in leukocytes and T-lymphocytes) is also called HLA (human leukocyte antigens) system.

• Granulocyte-mediated antigens.

• Human platelet antigens (HPAs).

What Are the Causes of Alloimmunization?

The predisposing factors that trigger alloimmunization are

• Repeated or chronic transfusions.

• Prophylactic administration of blood components such as plasma, precipitates of platelets, and clotting factors.

• Multiple pregnancies.

• Tissue grafting.

• Organ transplantation.

• Bone marrow transplantation.

What Are the Consequences of Alloimmunization From Transfusions?

Alloimmunization is a major complication in recurrent transfusions as the recipient’s immune system gets sensitized to develop antibodies that would induce an immunogenic response on red blood cells, platelets, and other cellular components in subsequent transfusions. The consequences are manifested clinically as,

• Acute hemolytic transfusion reactions (due to ABO antibodies).

• Delayed hemolytic transfusion reactions (DHTRs) usually occur after seven to fourteen days of transfusion.

• Refractoriness to platelet transfusions due to HLA alloimmunization leads to the development of platelet antibodies.

• Alloimmunization of the mother’s antibodies against fetal red blood cell antigens results in hemolytic disease in the fetus or newborn.

• Post-transfusion destruction of platelets due to platelet alloantibodies leading to post-transfusion purpura.

• Thrombocytopenia in neonates.

• Febrile (nonhemolytic) transfusion reactions due to granulocyte-mediated alloimmunization.

• Lung injury (acute) due to the reaction between donor’s HLA antibodies with recipient leukocyte (white blood cells) antigens.

• Rejection of transplanted graft tissue or organ due to HLA antigens.

• Alloantibodies are produced against red blood cells after bone marrow transplantation.

What Are the Clinical Signs and Symptoms of Alloimmunization?

Clinical manifestations range from acute reactions to delayed responses. The severity of the immune response depends on the proportion and type of antigen involved.

• Acute hemolytic alloimmunizations are rare except ABO incompatibility.

• The onset of delayed hemolytic reactions occurs over a wide range of time periods; from 24 hours to three months after transfusions.

• Fever with chills.

• Jaundice.

• Pain and difficulty in breathing.

• Acute renal failure.

• Disseminated intravascular coagulation.

• Thrombocytopenia.

• Spontaneous bleeding.

• Nonimmune hemolysis causing sepsis.

• Splenomegaly due to increased destruction of red blood cells and platelets.

• Hemoglobinuria.

What Is the Diagnosis for Alloimmunization From Transfusions?

Laboratory screening tests often coincide with other hemolytic disorders. Therefore complete screening with past transfusional history and clinical evaluation is done to detect alloimmunization reactions.

• Hemoglobin level normally rises after transfusion. Failure to increase blood hemoglobin level is indicative of hemolytic reactions.

• Elevated levels of lactate dehydrogenase, reticulocytes, and bilirubin.

• Reduction in hematocrit values and haptoglobin.

• Presence of hemoglobin in urine.

• Positive Coombs’ test (direct and indirect antiglobulin).

• Elution assay to detect alloantibodies.

• Decreased platelet count.

• Flow cytometry to detect platelet antibodies.

• Enzyme-linked assay and solid-phase assay to detect HLA antigens.

• Monoclonal antibody immobilization assay to assess platelet antigens.

• HLA typing is recommended before further transfusions.

What Are the Treatment Interventions for Alloimmunization?

Delayed hemolytic transfusion reactions are mostly tolerable and require only continuous monitoring and supportive management.

• Intravenous injection of human immunoglobulin G (IVIG) blocks further hemolysis.

• IVIG (400 mg/kg) is administered within 24 hours of transfusion and infused slowly.

• Transfusion of antigen-negative RBCs is preferred.

• Administration of immune-compatible platelets.

• Use of antifibrinolytic agents to control intravascular bleeding.

• The administration of immunosuppressive drugs (Vincristine and Cyclosporin A ) is beneficial.

• If alloimmunization initiates during the transfusion procedure, the transfusion is stopped immediately.

• Continuous hydration is done and drugs like Mannitol are infused to increase urine output and inhibit the retention of water in the lungs.

What Are the Precautions to Be Followed to Prevent Alloimmunization?

• Counseling and consultation are to be done with a transfusion medicine specialist or hematologist for further transfusions.

• HLA typing is recommended.

• Proper identification of ABO alloantibodies before transfusion, and use of antigen-negative red blood cells for transfusion.

• Documentation of the previous episode of alloimmunization reactions is mandatory.

• Complete cross-matching of alloantibodies with antihuman globulin phase donor units.

• Filtration of leukocytes, removal of buffy coat, and deactivation of antigen-presenting cells by ultraviolet-B radiation reduce the occurrence of alloimmunization.

What Are the Medications Prescribed for Alloimmunization Reactions?

Clinicians should recommend a complete investigation and be familiar with the patient's status before prescribing medications such as immunosuppressive drugs and cytotoxic agents. These drugs are only supportive measures and do not cure alloimmunization reactions completely.

Conclusion

Alloimmunization is an immune response from an individual’s immune system to foreign antigens that most frequently occurs during transfusions, transplantations, and pregnancy. The occurrence of alloimmunization reactions has become challenging for transfusion therapy. Phenotype compatibility is to be completely assessed before transfusions to avoid alloimmunization reactions. Wider cross-matching and HLA typing are recommended to predict and prevent its complications. Alloimmunization has to be reduced to ensure better, safe, and more compatible transfusion.