The Rh factor is a specific protein, known as the D antigen, found on the surface of red blood cells. When an Rh-negative individual receives Rh-positive blood, the body recognizes the foreign D antigen. This exposure establishes a permanent state of immunological memory with severe consequences for any future exposure to Rh-positive blood. This poses a significant threat to future transfusions and to pregnancies for women of childbearing age.
How the Body Identifies Incompatible Blood
When Rh-negative blood is exposed to Rh-positive blood for the first time, the immune system begins a process called sensitization. This initial exposure triggers B-lymphocytes to produce anti-D antibodies, including immunoglobulin M (IgM) and then immunoglobulin G (IgG). Because this antibody production is delayed and takes time, the first incompatible transfusion often results in a reaction that is mild or entirely asymptomatic. The significance of this initial exposure is not the immediate reaction but the establishment of immunological memory for any subsequent exposure to the D antigen.
The Acute Reaction: Hemolysis and Symptoms
A severe reaction occurs when a sensitized Rh-negative person receives Rh-positive blood a second time. Pre-existing anti-D antibodies rapidly bind to the transfused Rh-positive red blood cells, initiating an Acute Hemolytic Transfusion Reaction (AHTR). This binding activates the complement cascade, leading to the rapid destruction, or hemolysis, of the donor red blood cells inside the blood vessels. The destruction of red blood cells releases free hemoglobin directly into the bloodstream, a state known as hemoglobinemia. The free hemoglobin molecules are filtered by the kidneys, which can cause significant damage to the renal tubules, leading to acute kidney injury and potentially complete renal failure.
Patients experiencing an AHTR often exhibit severe physical symptoms. Early signs include a sudden onset of fever and chills. As the reaction progresses, patients may report pain in the back, flank, or chest, along with nausea and vomiting, progressing to hypotension (low blood pressure) and shock.
Long-Term Consequences: Future Transfusions and Pregnancy Risk
Once an Rh-negative person is sensitized by an incompatible transfusion, the production of anti-D antibodies is a permanent state. The presence of these circulating antibodies means that the individual must exclusively receive Rh-negative blood for all future transfusions. Any subsequent transfusion of Rh-positive blood will immediately trigger the rapid and severe AHTR previously described, which carries a risk of death.
Pregnancy Risk
The long-term consequences are particularly serious for Rh-negative women of childbearing potential. The anti-D antibodies produced after sensitization are primarily of the IgG class, which is unique because these antibodies are small enough to readily cross the placenta into the fetal bloodstream. If an Rh-sensitized woman becomes pregnant with an Rh-positive fetus, the maternal antibodies will attack the red blood cells of the developing baby.
This immune attack on the fetal red blood cells causes Hemolytic Disease of the Fetus and Newborn (HDFN), also known as Rh disease. The destruction of the fetal red cells leads to anemia, which can range from mild to severe, and the baby’s liver and spleen may enlarge as they try to compensate for the rapid cell loss. With each subsequent Rh-positive pregnancy, the risk and severity of HDFN generally increase because the maternal antibody response may become more robust. Severe HDFN can result in hydrops fetalis, a life-threatening condition where the fetus develops massive fluid accumulation and organ failure.