Various hematologic conditions can be caused by alloantibodies and autoantibodies (Table 1).

Table1. Immunohematologic Diseases

Autoimmune Hemolytic Anemia

Autoimmune hemolytic anemia can be classified into the following four groups:

 • Warm-reactive autoantibodies (most common)

• Cold-reactive autoantibodies ( <20% of cases)

 • Paroxysmal cold hemoglobinuria (rare)

• Drug-induced hemolysis ( <20 % of cases)

Warm Autoimmune Hemolytic Anemia. This anemia is associated with antibodies reactive at warm temperatures (i.e., 37° C [98.6° F]). In more than 75% of cases, the erythrocytes are coated with both IgG and complement, although some may demonstrate coating with IgG alone or, less often, with complement coating. In warm autoimmune hemolytic anemia, negligible serum autoantibody exists because the antibody reacts optimally at 37° C (98.6° F ) and is being continuously adsorbed by red blood cells (RBCs) in vivo. Elution of the antibody from the RBCs (mechanical removal of antibodies) can demonstrate an autoantibody, but testing for specificity is not routinely necessary.

Cold Autoimmune Hemolytic Anemia. Cold hemagglutinin disease (CHAD), acute or chronic, is the most common type of hemolytic anemia associated with cold-reactive autoantibodies. The acute form is often secondary to Mycoplasma pneumoniae infection or lymphoproliferative disorders such as lymphoma. The chronic form is seen in older patients and produces mild to moderate hemolysis. In addition, Raynaud’s phenomenon and hemoglobinuria occur in cold weather.

In CHAD, a cold-reactive IgM autoantibody reacts with RBCs in the peripheral circulation when the body temperature falls to 32° C (89.6° F) or lower and binds complement to the cells. Therefore, complement is the only globulin detected on the erythrocytes. Elutions prepared from RBCs collected at 37° C (98.6° F ) will not demonstrate antibody reactivity in the eluate. Paroxysmal Cold Hemoglobinuria. Previously associated with syphilis, paroxysmal cold hemoglobinuria is now seen more often as an acute transient condition secondary to viral infections, particularly in young children. It may also occur as an idiopathic chronic disease in older people.

The autoantibody is an IgG protein that reacts with RBCs in colder parts of the body; this produces complement components C3 and C4 to bind irreversibly to the erythrocytes. At warmer temperatures, RBCs are hemolyzed and the antibody elutes from the cells. Eluates are also nonreactive. This IgG autoantibody, a biphasic hemolysin, can be demonstrated by performing the classic Donath-Landsteiner test. The auto antibody has anti-p specificity and reacts with all except the rare p or pk phenotypes. Exceptions that include examples with anti-IH specificity have been described.

Drug-Induced Hemolysis. Coating of RBCs demonstrated by a positive direct anti–human globulin test (DAT) result may be drug induced and accompanied by hemolysis (Table 2). The reactivity has been described as being caused by four basic mechanisms: (1) drug adsorption; (2) immune complexing; (3) membrane modification; and (4) autoantibody formation. Drug Adsorption. Penicillin is a representative example of an agent that displays drug adsorption. In this type of mechanism, the drug strongly binds to any protein, including RBC mem brane proteins. This binding produces a drug-RBC-hapten complex that can stimulate antibody formation. The antibody is specific for this complex and no reactions will take place unless the drug is adsorbed on erythrocytes. Massive doses of IV penicillin are needed to coat the erythrocytes sufficiently for antibody attachment to occur.

Table2. Drug-Induced Positive Direct Antiglobulin Test

Approximately 3% of affected patients will demonstrate a positive DAT result and less than 5% will develop hemolytic anemia because of the drug. The hemolysis of RBCs is usually extravascular and occurs slowly. It is not life-threatening and will abate when penicillin is discontinued. There appears to be no connection between this type of antibody production and allergic penicillin sensitivity caused by IgE production.

Other drugs that display drug adsorption are cephalothin derivatives (e.g., cephalothin [Keflin], quinidine).

Immune Complexing. Immune complexing is associated with a variety of drugs, including phenacetin, quinine, rifampin, and stibophen. In this interaction, the drug and antibody form a complex in the serum and attach nonspecifically to the RBCs. Once attached, this complex initiates the complement cascade, which culminates in intravascular hemolysis. The immune complex may dissociate from the RBC membrane after complement activation and attach to another erythrocyte. This allows a small amount of drug to produce a severe anemia. When the offending drug is discontinued, the hemolytic process disappears quickly.

Membrane Modification. Drugs of the cephalosporin type (e.g., cephalothin) occasionally cause a positive DAT result with polyspecific and monospecific anti–human globulin antisera by membrane modification. In this type of mechanism, the drug alters the membrane so that there is nonspecific absorption of globulins, including IgG, IgM, IgA, and complement. Hemolysis is not a common complication in this type of membrane augmentation.

Autoantibody Formation. Drugs such as methyldopa (Aldomet), levodopa, and mefenamic acid (Ponstel) have been implicated in positive DAT results caused by autoantibody formation. The autoantibody formed recognizes a part of the RBC and therefore reacts with most normal RBCs. Some drug-induced autoantibodies have been shown to have specificities that appear to be of the Rh type, but most have no apparent specificity. Antibody production ceases with withdrawal of the drug.

Idiopathic Thrombocytopenic Purpura

 Idiopathic thrombocytopenic purpura is now also known as immunologic thrombocytopenic purpura (ITP). Patients with ITP usually demonstrate petechiae, bruising, menorrhagia, and bleeding after minor trauma. ITP may be acute or chronic. Children are most often affected with the acute type, whereas adults predominantly experience the chronic type. This common disorder may complicate other antibody-associated disorders such as SLE.

Thrombocytopenia, a condition of absent or severely decreased platelets ( <10 -20 × 10⁹/L), may result from a wide variety of conditions, such as after extracorporeal circulation in cardiac bypass surgery or from alcoholic liver disease. However, most thrombocytopenic conditions can be classified into the following three major categories:

• Decreased production of platelets

 • Disorders of platelet distribution

• Increased destruction or use of platelets

Decreased platelet production may result from invasion of the bone marrow by neoplastic cells and is usually not associated with an immunologic cause. Disorders of platelet distribution are associated with a sequestering of platelets in the spleen for various nonimmunologic reasons. Increased destruction or use of platelets, however, is associated with immunologic mechanisms. These mechanisms of destruction are caused by antigens, antibodies, or complement.

Drugs or foreign substances that can cause platelet destruction include quinidine, sulfonamide derivatives, heroin, morphine, and snake venom. Sulfonamide derivative reactions involve the interaction of platelet antigens with drug antibodies. Morphine reactions involve the activation of complement.

Bacterial sepsis causes increased destruction of platelets resulting from the attachment of platelets to bacterial antigen antibody immune complexes. Certain microbial antigens may initially attach to platelets, followed by specific antibodies to the microorganism. This mechanism has been reported to cause the thrombocytopenia that frequently complicates Plasmodium falciparum malaria.

Antibodies of autoimmune or isoimmune origin may cause increased destruction of platelets. Examples of thrombocytopenias of isoimmune origin include posttransfusion purpura and isoimmune neonatal thrombocytopenia. Neonatal autoimmune thrombocytopenia is a condition caused by immunization of a pregnant female by a fetal platelet antigen and by transplacental passage of maternal IgG platelet antibodies. The antigen is inherited by the fetus from the father and is absent on maternal platelets. Posttransfusion purpura is a rare form of isoimmune thrombocytopenia.

Pernicious Anemia

 Pernicious anemia is a megaloblastic anemia characterized by a variety of hematologic and chemical manifestations (Table 3). PA is caused by a deficiency of vitamin B12 that results from the patient’s inability to secrete intrinsic factor. In autoimmune cases of PA, anti-IF or antiparietal antibodies have been reported. Demonstration of these antibodies supports the theory that PA is an autoimmune disorder. Nutritional disorders (e.g., vegan diet, gastric bypass surgery, AIDS, small bowel disorders, and competition for vitamin B12) can be nonimmunological causes of PA.

Table3. Hematologic and Chemical Findings in Pernicious Anemia

Assays for anti-IF measure antibodies to IF. The presence of IF–blocking antibodies is diagnostic of PA. Antibodies can be demonstrated in about 60% of cases. Antiparietal cell assays measure antibodies to parietal cells (large cells on the margins of the peptic glands of the stomach). Most patients with PA (80%) have parietal cell antibodies. In the presence of these antibodies, gastric biopsy almost always demonstrates gastritis. Low antibody titers to parietal cells are often found with no clinical evidence of PA or atrophic gastritis and are sometimes seen in older patients.

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