Chapter 101. Hemolytic Anemias and Anemia Due to Acute Blood Loss (Part 15) Severe acute AIHA can be a medical emergency. The immediate treatment almost invariably includes transfusion of red cells. This may pose a special problem because if the antibody involved is "unspecific," all the blood units cross- matched will be incompatible. In these cases it is often correct, paradoxically, to transfuse incompatible blood, the rationale being that the transfused red cells will be destroyed no less but no more than the patient's own red cells, and in the meantime the patient stays alive. Clearly this rather unique situation requires good liaison and understanding between the clinical unit treating the patient and the blood transfusion/serology lab. Paroxysmal Cold Hemoglobinuria (PCH) PCH is a rather rare form of AIHA occurring mostly in children, usually triggered by a viral infection, usually self-limited, and characterized by involvement of the so-called Donath-Landsteiner antibody. In vitro this antibody has unique serologic features: it has anti-P specificity and binds to red cells only at a low temperature (optimally at 4°C), but when the temperature is shifted to 37°C, lysis of red cells takes place in the presence of complement. Consequently, in vivo there is intravascular hemolysis, resulting in hemoglobinuria. Clinically, the differential diagnosis must include other causes of hemoglobinuria (Table 101-2), but the presence of the Donath-Landsteiner antibody will prove PCH. Active supportive treatment, including blood transfusion, is needed to control the anemia; subsequently, recovery is the rule. Cold Agglutinin Disease (CAD) This designation is used for a form of chronic AIHA that usually affects the elderly and has special clinical and pathologic features. First, the term cold refers to the fact that the autoantibody involved reacts with red cells poorly or not at all at 37°C, whereas it reacts strongly at lower temperatures. 1 As a result, hemolysis is more prominent the more the body is exposed to cold. The antibody is usually an IgM, usually has an anti-I specificity (the I antigen is present on the red cells of almost everyone), and may have a very high titer (1:100,000 or more has been observed). Second, the antibody is produced by an expanded clone of B lymphocytes, and sometimes its concentration in the plasma is high enough to show up as a spike in plasma protein electrophoresis—i.e., as a monoclonal gammopathy. Third, since the antibody is IgM, CAD is related to Waldenström macroglobulinemia (WM; Chap. 106), although in most cases the other clinical features of this disease are not present. Thus, CAD must be regarded as a form of WM, i.e., as a low-grade mature B-cell lymphoma that manifests at an earlier stage because the unique biologic properties of the IgM that it produces give the clinical picture of chronic HA. 1 In the past, this type of antibody was called a cold antibody, whereas the antibodies causing the more common form of AIHA were called warm antibodies. In mild forms of CAD, avoidance of exposure to cold may be all that is needed to enable the patient to live with a reasonably comfortable quality of life, but in more severe forms the management of CAD is not easy. Blood transfusion is not very effective because donor red cells are I-positive and will be removed rapidly. Immunosuppressive/cytotoxic treatment with prednisone, azathioprine, or cyclophosphamide can reduce the antibody titer, but clinical efficacy is limited, and in view of the chronic nature of the disease, the side effects may prove unacceptable. Plasma exchange is a rational approach, but it is laborious and must be carried out, in some patients, at very frequent intervals. The picture may be changing, as in a recent study rituximab gave a response rate of 60%. Given the long clinical course of CAD, it remains to be seen with what periodicity this agent will need to be administered. Paroxysmal Nocturnal Hemoglobinuria (PNH) PNH is an acquired chronic HA characterized by persistent intravascular hemolysis subject to recurrent exacerbations (Table 101-6; Fig. 101-8). In addition to hemolysis, there is often pancytopenia and a risk of venous thrombosis. This triad makes PNH a truly unique clinical condition; however, when not all of these three features are manifest on presentation, the diagnosis is often delayed, although it can be always made by appropriate laboratory investigations (see below). Figure 101-8 Consecutive urine samples from a patient with paroxysmal nocturnal hemoglobinuria (PNH). The variation in the severity of hemoglobinuria within hours is probably unique to this condition. . Chapter 101. Hemolytic Anemias and Anemia Due to Acute Blood Loss (Part 15) Severe acute AIHA can be a medical emergency. The immediate. persistent intravascular hemolysis subject to recurrent exacerbations (Table 101- 6; Fig. 101- 8). In addition to hemolysis, there is often pancytopenia and a risk of venous thrombosis. This triad. hemoglobinuria (Table 101- 2), but the presence of the Donath-Landsteiner antibody will prove PCH. Active supportive treatment, including blood transfusion, is needed to control the anemia; subsequently,