A blood transfusion is often a life-saving medical procedure, replacing lost or damaged blood components in a patient. However, receiving blood can become acutely dangerous if the donor’s blood type does not match the recipient’s. When incompatible blood is introduced, it triggers an immediate and severe immune response known as an acute hemolytic transfusion reaction (AHTR). This reaction rapidly destroys the transfused red blood cells, initiating a cascade of internal events that can quickly overwhelm the body’s systems.
The Biological Basis of Incompatibility
The danger of an incompatible transfusion stems from specific markers, called antigens, found on the surface of red blood cells (RBCs). Compatibility is determined primarily by the ABO system and the Rh system. The ABO system categorizes blood into four main types—A, B, AB, and O—based on the presence of A and B antigens. Type A carries the A antigen, Type B carries the B antigen, Type AB carries both, and Type O carries neither.
A person’s plasma naturally contains antibodies against the antigens their own red cells lack. For instance, a person with Type A blood has pre-formed anti-B antibodies circulating in their bloodstream. These antibodies, particularly those in the ABO system, are powerful immunoglobulin M (IgM) molecules ready to attack foreign antigens immediately upon exposure. This is why a Type A recipient receiving Type B blood suffers a violent reaction, as their anti-B antibodies instantly recognize the donor’s B antigens as hostile.
The Rh system, primarily focused on the D antigen, also plays a significant role in incompatibility. Rh antibodies are usually only created after a sensitizing event like a previous transfusion or pregnancy, unlike ABO antibodies which are present from early childhood. The recipient’s immune system, alerted by these pre-existing or pre-sensitized antibodies, treats the transfused blood cells as foreign invaders, setting the stage for destruction.
The Immediate Reaction: Agglutination and Hemolysis
When incompatible red blood cells enter the recipient’s circulation, the pre-formed antibodies rapidly bind to the foreign antigens on the donor cell surfaces. This binding causes the transfused red cells to stick together, a process called agglutination, resulting in visible clumping. This initial clumping is merely the prelude to the more damaging event: the activation of the complement system.
The complement system is a powerful cascade of plasma proteins that forms part of the innate immune defense. Once activated by the antibody-antigen complex, this system culminates in the formation of the membrane attack complex (MAC) on the surface of the clumped red cells. The MAC creates pores in the red cell membrane, causing the cells to rapidly rupture and spill their contents into the bloodstream. This catastrophic destruction of red cells within the blood vessels is known as intravascular hemolysis.
The massive rupture releases cellular debris and large amounts of free hemoglobin, which cause subsequent systemic damage. Hemoglobin carries oxygen inside the red cell, but when freely circulating in the plasma, it becomes highly toxic. The body’s natural scavenging proteins, such as haptoglobin, are quickly overwhelmed by the volume of released hemoglobin, allowing the toxic protein to cause widespread harm. This event can occur with the transfusion of as little as a few milliliters of incompatible blood.
Systemic Fallout: Organ Damage and Fatal Shock
The overwhelming release of free hemoglobin and the systemic immune response lead to fatal consequences across multiple organ systems. A primary target is the kidney, resulting in acute kidney injury (AKI). Free hemoglobin is directly toxic to the delicate renal tubules, the structures responsible for filtering waste. As the hemoglobin is filtered, it can obstruct these tubules, forming casts that physically block urine flow.
Free hemoglobin scavenges nitric oxide, a molecule that helps keep blood vessels dilated, causing severe vasoconstriction in the renal arteries. This combination of direct toxicity, physical blockage, and reduced blood flow rapidly leads to acute kidney failure.
The antigen-antibody reaction also triggers a widespread inflammatory response, which is a major contributor to circulatory collapse. The complement cascade releases inflammatory mediators, known as anaphylatoxins, which promote the release of cytokines from white blood cells. These signaling molecules cause systemic vasodilation, meaning the blood vessels throughout the body widen dramatically.
The resulting drop in systemic vascular resistance, combined with increased fluid leakage from the vessels, leads to a sudden, dangerous fall in blood pressure. This state is known as hypovolemic or septic shock, which starves the body’s tissues of oxygen and causes multi-organ failure.
The reaction can trigger disseminated intravascular coagulation (DIC). Cellular debris and immune complexes activate the clotting cascade throughout the circulatory system. This leads to the formation of countless tiny blood clots that consume the body’s available clotting factors and platelets. The result is a paradox: widespread clotting in the microvasculature alongside severe, life-threatening bleeding due to the exhaustion of clotting resources. DIC interrupts microcirculation, compounding damage to organs like the kidney and liver, and is frequently the final fatal event in an incompatible transfusion reaction.