The anti-c antibody forms when the human immune system encounters a foreign red blood cell marker, a process known as alloimmunization. The anti-c antibody belongs to the Rhesus (Rh) blood group system, which is important in transfusion medicine and obstetrics. Its development is a direct immune response, almost always triggered by exposure to foreign red blood cells containing the ‘c’ antigen.
Understanding the ‘c’ Antigen and Anti-c Antibody
The ‘c’ antigen is a protein structure located on the surface of red blood cells, encoded by the RHCE gene on chromosome 1. It is one of the five primary antigens that make up the Rh blood group system (D, C, E, and e). Approximately 80% of the U.S. population possesses the ‘c’ antigen, meaning they are ‘c’ positive. Individuals who are ‘c’ negative naturally lack this specific protein marker.
The anti-c antibody is an immunoglobulin G (IgG) molecule produced by the immune system of a ‘c’ negative person exposed to ‘c’ positive red blood cells. These antibodies recognize and destroy red blood cells carrying the ‘c’ antigen. The IgG classification is significant because this type of antibody can cross the placenta during pregnancy, which has major implications for fetal health. The ‘c’ antigen is the most clinically significant Rh antigen after the D antigen.
Primary Cause: Alloimmunization via Blood Transfusion
The most common non-pregnancy-related mechanism for the formation of the anti-c antibody is through a blood transfusion. This occurs when a patient whose red blood cells are ‘c’ negative receives blood from a donor who is ‘c’ positive. The donor’s ‘c’ positive red cells introduce the foreign antigen into the recipient’s bloodstream, initiating an immune response.
The recipient’s immune system detects the unfamiliar ‘c’ protein as a threat. Specialized white blood cells, including B lymphocytes, are activated to produce antibodies against the antigen. This initial exposure, called sensitization, leads to the creation of short-lived IgM antibodies and long-lasting memory B cells and IgG anti-c antibodies.
The initial exposure may not cause an immediate problem, as antibody levels are often too low or delayed. However, the patient becomes “sensitized,” meaning their immune system is primed for a rapid response upon subsequent exposure. If the patient is later transfused with ‘c’ positive blood again, memory cells trigger an accelerated production of anti-c, leading to a potentially severe reaction. This rapid secondary response, known as the anamnestic response, requires that all future transfusions use ‘c’ negative blood. The risk of forming this antibody is elevated in patients who require frequent transfusions, such as those with sickle cell disease or thalassemia.
Secondary Cause: Fetal-Maternal Exposure during Pregnancy
The second major cause of anti-c antibody development is related to pregnancy, occurring when a ‘c’ negative mother carries a fetus who inherited the ‘c’ antigen from the father. This incompatibility exposes the maternal immune system to foreign fetal red blood cells. Sensitization is generally triggered by a fetomaternal hemorrhage, which is the mixing of fetal and maternal blood.
This mixing most frequently occurs during labor and delivery, as the placenta separates from the uterine wall. However, sensitization can also happen following events like miscarriage, ectopic pregnancy, trauma to the abdomen, or invasive obstetric procedures. Although the mother may initially produce IgM antibodies, which cannot cross the placenta, the immune system quickly switches to producing the smaller, placenta-crossing IgG anti-c antibodies.
Often, the first ‘c’ positive pregnancy results in sensitization but does not harm the fetus because the mother’s immune response is delayed until delivery. Once the mother is sensitized, any subsequent ‘c’ positive pregnancy is at risk because the pre-existing IgG anti-c antibodies can cross the placenta and enter the fetal circulation. This risk remains even after the widespread use of anti-D immune globulin, which only prevents sensitization to the D antigen, not the ‘c’ antigen. Anti-c alloimmunization is less common than anti-D, occurring in approximately 0.07% of all pregnancies, but its consequences can be severe.
Clinical Relevance of Anti-c Antibody Formation
The presence of the anti-c antibody is clinically significant because it dictates strict requirements for future blood transfusions and poses a serious risk during pregnancy. The primary concern in transfusion medicine is the potential for a Hemolytic Transfusion Reaction (HTR). If a sensitized patient receives ‘c’ positive blood, the pre-existing anti-c antibodies will quickly bind to the transfused red blood cells, leading to their destruction.
This rapid destruction of transfused cells can manifest as either an acute HTR, causing immediate symptoms like fever, chills, and kidney failure, or a Delayed HTR, which occurs days to weeks after the transfusion. To prevent this, blood banks must ensure that any patient with a detected anti-c antibody only receives red blood cell units that are confirmed to be ‘c’ negative.
In obstetrics, the clinical relevance centers on Hemolytic Disease of the Fetus and Newborn (HDFN). The maternal anti-c IgG antibodies cross the placenta and attack the ‘c’ positive fetal red blood cells, causing fetal anemia. This destruction can range from mild to severe, potentially leading to hydrops fetalis (severe fetal swelling) or even fetal death. Anti-c is recognized as a potent non-D Rh antibody capable of causing severe HDFN, necessitating careful monitoring and sometimes intrauterine blood transfusions.