Chapter 23: Cryopathic Hemolytic Anemia

• This type of anemia is caused by autoantibodies that bind red cells best at temperatures below 37°C, usually below 31°C.

• It is mediated through two major types of “cold antibody”: cold agglutinins and Donath-Landsteiner antibodies.

• Clinical features vary considerably, but in both types, the complement system plays a major role in red cell destruction.

• Cold agglutinins are immunoglobulin M (IgM) autoantibodies that agglutinate red cells, optimally between 0°C and 5°C. Complement fixation occurs at higher temperatures.

• This hemolytic anemia is classified as either primary (chronic cold agglutinin disease) or secondary (generally as a result of Mycoplasma pneumoniae infection or Epstein-Barr virus [EBV]–related infectious mononucleosis) (Table 23–1).

• Peak incidence for the primary (chronic) syndrome is in persons older than 50 years.

• This disorder characteristically has monoclonal IgM cold agglutinins and may be considered a symptomatic monoclonal gammopathy.

• Some patients develop a B-cell lymphoproliferative disorder (eg, Waldenström macroglobulinemia).

Pathogenesis

• The specificity of cold agglutinins is usually against I/i antigens. I is expressed heavily in adult red cells, weakly on neonatal red cells. The reverse is true of the i antigen, which also may still be expressed on reticulocytes.

• High proportions of IgM cold agglutinins with either anti-I or anti-i specificity have heavy-chain variable regions encoded by V_H4–34, a conserved immunoglobulin variable region gene.

• Naturally occurring cold agglutinins are present in low titer (less than 1:32) in normal persons. Transient hyperproduction of less clonally restricted antibodies occurs in the recovery phase of infections, such as EBV, mycoplasma, or cytomegalovirus.

• I/i antigens serve as mycoplasma receptors, which may lead to altered antigen presentation and to subsequent autoantibody production.

• In B-cell lymphomas, cold agglutinins may be produced by the malignant lymphocytes.

• The highest temperature at which antibodies can cause red cell agglutination is termed the thermal amplitude. The higher the thermal amplitude, the greater the risk of clinically significant hemolysis, depending on the ambient temperature.

• Cold agglutinins bind to red cells in the superficial dermal vessels, where temperatures may be less than 37°C, impeding capillary flow, producing acrocyanosis.

• Hemolysis is dependent on the antibody’s ability to bind complement to the red cell membrane (complement fixation); concurrent agglutination is not required for this process.

• Red cell injury then occurs either by direct lysis or enhanced phagocytosis by macrophages.

• Direct lysis results from propagation of the full complement sequence, but severe intravascular hemolysis from this cause is rare.

• Commonly, fragments C3b and C4b are deposited on the red cell surface, providing a stimulus for phagocytosis. The affected red cell may be engulfed and destroyed or released back into circulation as a spherocyte because of loss of some plasma membrane (partial phagocytosis).

• Red cells are released with a coating of C3dg, an inactive fragment that protects the red cells from further complement fixation and agglutination but results in a positive direct antiglobulin test.

Clinical Features

• Cold-agglutinin–mediated hemolysis accounts for 10% to 20% of all cases of autoimmune hemolytic anemia.

• Women are affected more commonly than men.

• Hemolysis is generally chronic, although episodes of acute hemolysis can occur on chilling.

• Acrocyanosis is frequently observed, but skin ulceration and necrosis are uncommon.

• Splenomegaly may occasionally be seen in the idiopathic form.

• The hemolysis caused by mycoplasma infection develops as the patient recovers from the infection and is self-limited, lasting 1 to 3 weeks.

• In patients with mycoplasma infections, clinically significant hemolysis is uncommon.

Laboratory Features

• Anemia is usually mild to moderate. On the blood film the red cells show autoagglutination (Figure 23–1), polychromasia, and spherocytosis.

• In the chronic syndrome, serum titers of cold agglutinins (generally IgM) can be greater than 1:100,000. The direct antiglobulin test is positive with anticomplement reagents. The cold agglutinin itself (IgM) is not detectable because it readily dissociates from the red cell at 37°C.

• As a rule, the higher the cold agglutinin titer, the higher the thermal amplitude. However, there are exceptions to this rule (lower titer and high thermal amplitude).

• Testing for cold agglutinin titer and thermal amplitude requires blood collection and serum separation at 37°C.

• Anti-I specificity is seen with idiopathic disease, M. pneumoniae, and some cases associated with lymphoma. Anti-i occurs with infectious mononucleosis and lymphomas. Rarely, the antibodies have other specificities, including Pr, M, or P antigens.

Differential Diagnosis

• When peripheral vaso-occlusive symptoms occur, especially if related to cold temperatures (Raynaud phenomenon), cryoglobulinemia should also be considered.

• In drug-induced immune hemolytic anemia, the direct antiglobulin test also may be positive only for complement.

• Mixed type autoimmune hemolysis can occur with a direct antiglobulin test positive for both IgG and complement, along with elevated cold agglutinin titers.

• Episodic hemolysis can result from paroxysmal cold hemoglobinuria (see below), paroxysmal nocturnal hemoglobinuria (see Chap. 43), march hemoglobinuria (see Chap. 19), and some red cell enzyme disorders (see Chap. 14).

Therapy, Course, and Prognosis

• Keeping the patient warm is important and may be the only treatment needed for mild conditions.

• Rituximab can be useful in symptomatic cases. Patients have responded to doses ranging from 100 to 375 mg/m² weekly for up to 4 weeks.

• The combination of rituximab and fludarabine has also been used successfully.

• Chlorambucil or cyclophosphamide have been used for more severe chronic cases.

• Splenectomy and glucocorticoids generally are not helpful (the latter may have some efficacy in low titer, high thermal amplitude cases), although very high dose glucocorticoids may be useful in severely ill patients.

• In critically ill patients, plasmapheresis may provide temporary relief.

• Generally, patients with the chronic syndrome have a stable condition and long-term survival.

• Postinfectious syndromes are self-limited, resolving in a few weeks.

• In patients with an associated lymphoma, treatment is usually directed at that disease.

• This very rare form of hemolytic anemia is characterized by recurrent massive hemolysis following exposure to cold. Formerly, this condition was more common, because of its association with syphilis. A self-limited form occurs in children following several types of viral infections.

Pathogenesis

• In the extremities, the cold reactive autoantibody (Donath-Landsteiner antibody), which is an IgG antibody, and early complement proteins bind to the red cells at low temperatures. On return to the 37°C environment, lysis occurs as a consequence of propagation of the classic complement sequence.

Clinical Features

• Two percent to 5% of all patients have autoimmune hemolytic anemia; the incidence of hemolytic anemia may exceed 30% in the pediatric population.

• Paroxysms of hemolysis occur with associated systemic symptoms—rigors, fever, diffuse myalgias, and headache. These symptoms and hemoglobinuria usually last several hours. Cold-induced urticaria may also occur.

Laboratory Features

• Hemoglobinuria with a rapid fall in hemoglobin level is usual and is associated with depressed complement levels. Spherocytes and erythrophagocytosis may be seen on the blood film.

• The direct antiglobulin test is positive for complement red blood cell coating during and immediately after an attack; the Donath-Landsteiner antibody itself is not detected by the test because it readily dissociates from the red cells.

• Antibody is detected by the biphasic Donath-Landsteiner test. Red cells are incubated with the patient’s serum at 4°C, then warmed to 37°C, at which point intense hemolysis occurs.

• Classically, the antibody (IgG type) has specificity for P blood group antigens, although other specificities have been noted.

• The Donath-Landsteiner antibody is a far more potent hemolysin than most cold agglutinins.

Differential Diagnosis

• Patients with paroxysmal cold hemoglobinuria lack elevated titers of cold agglutinins, distinguishing it from cold agglutinin disease.

Therapy, Course, and Prognosis

• Attacks can be prevented by avoiding cold exposure.

• Splenectomy and glucocorticoids are not of value.

• Urticaria may be treated with antihistamines.

• If related to syphilis, the hemolysis will resolve with antibiotic treatment of the infection.

• Postinfectious paroxysmal cold hemoglobinuria may resolve spontaneously in days to weeks, although the antibody may be detectable for years.

• In the idiopathic chronic form, long-term survival is common.

• Children may have a high mortality rate.