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Pathology > Basic Hematology > Red Cell Disorders > Anitbody Mediated Hemolysis

Antibody Mediated Hemolysis

In autoimmune hemolytic anemia (AIHA) RBCs are destroyed by antibodies made by a person against their own RBCs.

AIHA is divided into two types: an IgG or "warm" type (optimally active at 37oC) and an IgM or "cold" type (optimally active at 4oC).

In AIHA the antibody coated RBC membrane is removed bit by bit, usually in the spleen. As this happens the cell becomes increasingly spherical maintaining essentially the same volume.

AIHA varies in severity and often waxes and wanes. Splenomegaly is usually present.

Before going further, be sure you understand the direct antiglobulin test (DAT).

The DAT detects antibodies attached to the patient's RBCs. This is important for classifing and understanding the immune hemolytic anemias.

The DAT is also known as the direct Coombs test.

The detection of free antibodies against RBCs in the patient serum requires the use of the indirect Coombs test. You should review this as well!

Warm AIHA, the most common type of immune hemolytic anemia is mediated by IgG autoantibodies against RBC surface antigens (active at 37° C).

Non-Hodgkin's Iymphomas, Hodgkin's disease, and autoimmune disorders (rheumatoid arthritis; SLE), and drugs (methyl dopa) are common causes of warm AIHA; however, most cases are idiopathic.

In addition to the usual findings associated with hemolytic anemia (RBC polychromasia, increased unconjugated bilirubin,

Decreased haptoglobin, and hemoglobinuria) there is prominent spherocytosis on the PBS and a positive DAT (direct Coombs' test).

Cold AIHA or cold agglutinin disease, caused by IgM antibodies most active at <30oC, is a hemolytic anemia characterized by RBC agglutination and hemolysis in acral cold exposed areas of the body. An IgM complement fixing antibody binds to RBCs at 28-31oC.

The fixed complement causes intravascular hemolysis. As RBCs are warmed in the central organs the bound IgM is lost leaving only bound C3 (DAT positive only for C3).

Cold agglutinin disease is associated with Iymphoma (antibodies against anti-i), Mycoplasma pneumonia (antibodies against anti-I), and rarely infectious mononucleosis (antibodies against anti-i).

People with cold agglutinin disease have a chronic hemolytic anemia with periods of jaundice, and hemoglobinuria.

Cold agglutinin disease with RBC agglutination may be associated with Raynaud's phenomenon.


Laboratory findings in cold agglutinin disease are similar to warm AIHA (RBC polychromasia, increased unconjugated bilirubin, decreased haptoglobin, and hemoglobinuria), but usually with less spherocytosis.

In many cases agglutination of RBCs is seen on peripheral blood smears (room temperature). C3 is found only on the RBC surface by the DAT.

AIHA in association with idiopathic thrombocytopenic purpura (ITP) is known as Evans syndrome.

Treatment of AIHA, warm or cold, includes: 1) treatment of the underlying disease, 2) discontinue offending drugs, and 3) corticosteroids (Prednisone).

Agglutination of erythrocytes is seen on this peripheral blood smear.


Transfusion of ABO incompatible blood and Rh (rhesus) -disease of the newborn are the two most common examples of antibody produced by one person reacting with RBCs of another.

Allogeneic transplantation (renal, hepatic, cardiac and bone marrow) can cause a hemolytic anemia due to donor-derived RBC antibodies produced in the recipient by donor lymphocytes.


Immune hemolytic anemias are commonly drug related.

Two well defined mechanisms by which a drug can cause a hemolytic anemia are: 1) antibody against a drug-RBC membrane complex (penicillin), and 2) complement activation following a drug-protein complex on the RBC (quinidine). In each, the hemolytic anemia gradually disappears when the drug is discontinued.

A third mechanism is that in which a drug induces a warm AIHA, possibly by drug (Methyldopa) induced inhibition of T-suppressor allowing uninhibited autoantibody production by B cells. Despite drug withdrawal, antibodies may remain for months.


Of the drug related immune hemolytic anemias which result in an intravascular hemolysis?

A. the hapten formation mechanism
B. the immune complex mechanism
C. the autoimmune mechanism
D. both the immune complex and autoimmune mechanisms
E. both the hapten and immune complex mechanisms


Infections may initiate a hemolytic crisis in G-6-PD deficiency or in cases of meningcoccal or pneumococcal septicemia cause a microangiopathic hemolytic anemia. Intravascular and extravascular hemolysis of infected RBCs may occur in malaria.

Drugs and toxins may cause intravascular hemolysis through the formation of Heinz bodies resulting in damaged membranes thus destroying RBCs. Lead and arsenic poisoning often cause hemolysis.

Severe thermal burns damage RBCs forming acanthocytes, schistocytes, and spherocytes.

RBC survival may be shortened in renal failure (burr cells) and in liver disease (acanthocytes and target cells).

Numerous spherocytes and a few schistocytes in the PBS from a patient suffering from severe burns.

Hemolytic disease of the newborn (erythroblastosis fetalis) is secondary to maternal alloimmunization to fetal RBC antigens (maternal antibodies cross the placenta; react with fetal RBCs and cause a fetal hemolytic anemia).

Most commonly, the mother is Rh-type d and the fetus Rh-type D.

Hemolytic disease of the newborn may be due to ABO incompatibility, where the mother is blood group O and the infant is blood group A or B.

Hemolytic disease of the newborn may cause stillbirth, fetal heart failure, and

kernicterus (bilirubin staining of basal ganglia and other CNS structures) leading to neurologic damage.

Hemolytic disease of the newborn is relatively uncommon because of routine administration of anti-D IgG antiserum (removes fetal RBCs from the maternal circulation; prevents maternal alloimmunization) of D-negative mothers at the time of delivery of a D-positive infant.

Photo courtesy Thomas C Bithell, M.D.

In the rare paroxysmal cold hemoglobinuria, the antibodies (Donath-

Landsteiner) are IgG and are against the P blood group antigens.

Such antibodies are usually associated with viral infections (measles and mumps) and usually found in children without lasting sequale.

Acute hemolysis results when warming follows exposure to the cold. The lysis is complement induced and takes place in warm conditions following antibody - RBC binding in the cold.

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