Chronic Cold Hemagglutinin Disease Research Articles

Cold haemagglutinin disease: clinical significance of serum haemolysins.

Two hundred and twenty-one patients with cold haemagglutinins of thermal amplitude > or = 30 degrees C (considered to be a reasonable indicator of clinical significance) were classified by in vitro haemolysin activity into three groups. Group 1 contained 116 individuals in whom haemolysins were never detected; the 74 patients in Group 2 had monophasic haemolysins alone; whereas both monophasic and biphasic haemolysins were detected in the 31 Group 3 patients. There was a significantly higher proportion of patients in Groups 2 and 3 with haptoglobin levels < 0.1 g/l compared with Groups 1 and 2, respectively (P < 0.005 and P < 0.001). Direct antiglobulin test results showed that the autoimmune response became more complex and IgM predominant through Groups 1-3, resulting in an increasing ability to activate complement which was reflected in increasing haemolysin activity and number of patients with active haemolysis. The 31 patients in Group 3 were mostly elderly (median age 71 years at presentation) and the majority had chronic cold haemagglutinin disease (CHAD), several in association with lymphoid neoplasms or carcinomas; only four had acute CHAD. The natural history of idiopathic chronic CHAD was of mild, well compensated haemolysis, punctuated by severe acute episodes necessitating intensive therapy. The condition often remained active for long periods and did not appear to affect natural lifespan. In some cases, no treatment (or just warmth) was needed; in others continuous or intermittent prednisolone and/or chlorambucil were effective; yet others required a greater variety and more intense therapy, or treatment of associated conditions. Blood transfusion support was frequently required when haemolysis was severe.

40] Human monoclonal antibodies directed against carbohydrates

Studies using human monoclonal antibodies have been instrumental in elucidating basic concepts in immunology and basic disease mechanisms in a variety of human disorders. Many human monoclonal antibodies that recognize known antigens specifically bind to carbohydrates. In particular, many of these antibodies recognize blood-group antigens. The serum of a patient presenting with chronic cold hemagglutinin disease contains an antibody recognizing an oligosaccharide antigen on red blood cells. In patients with plasma cell dyscrasia and peripheral neuropathy, the monoclonal antibody often binds to antigenic determinants on peripheral nerve myelin. This chapter lists some carbohydrate-specific human monoclonal antibodies in a tabular form.

Lymphoma in Primary Chronic Cold Hemagglutinin Disease Treated With Chlorambucil

Two patients with primary chronic cold hemagglutinin disease (CHAD) were treated with chlorambucil for ten and 7 1/2 years, with cumulative doses of 14 and 6.6 g, respectively. Both responded favorably, and malignant lymphoma eventually developed in both of them. An attempt to assess the incidence of lymphoma as part of the natural course of untreated CHAD failed for want of proof. Literature since 1970 reported no chlorambucil-associated lymphoma. Of 77 responses to a questionnaire mailed to 135 US hematology-oncology programs, 76 reported no examples of chlorambucil-associated lymphoma. One response, however, did relate that diffuse histiocytic lymphoma developed in three of 141 patients receiving prolonged chlorambucil therapy for polycythemia vera. Alkylating-agent therapy for CHAD might be associated with development of lymphoma.

Lymphoma in primary chronic cold hemagglutinin disease treated with chlorambucil

Lymphoma in primary chronic cold hemagglutinin disease treated with chlorambucil

Evidence for two anomalous I blood group determinants.

One normal donor has been found whose red blood cells type as I positive with all anti‐I sera except those obtained from patients with chronic cold hemagglutinin disease (CCHD). In addition, these cells had more H than other random O cells and may be devoid of i antigen. Complete absorption of non‐CCHD anti‐I with the unusual cells left an anti‐I reactive with other I positive cells. These unique cells have allowed definition of at least two separate I determinants present on adult cells.

Immunoglobulins in chronic cold haemagglutinin disease.

Summary.Total serum IgM levels in 32 patients with chronic cold haemagglutinin disease ranged from 100 to 2400 mg/100 ml; follow‐up in nine patients showed slowly progressive increases.The excess IgM was mostly cold agglutinin and although there was considerable variation in serologic activity on a molecular basis, specific lytic activity against enzyme‐treated red cells was very similar. The cold agglutinin IgM seemed well produced and closely parallel to normal IgM; few 7S units and little Bence‐Jones proteinuria were detected. Non cold‐agglutinin IgM levels were mostly normal, but 31% of patients showed subnormal levels of IgA or IgG especially when the IgM level was greater than 1000 mg/100 ml.

Inv Allotypes of Cold Agglutinin Kappa Chains

Abstract The normal globulins and the cold agglutinin kappa chains from 16 patients with the chronic cold hemagglutinin disease were tested for the Inv (1), Inv (2) and Inv (3) antigens. Ten of the patients had normal globulins with the Inv (-1, -2, 3) phenotype and this same phenotype was present on the cold agglutinin kappa chains tested. The remaining six patients had Inv (1, 2, 3) normal globulins, and of the cold agglutinin kappa chains from these patients, two had the Inv (-1, -2, 3) phenotype and four had the Inv (1, 2, -3) phenotype. Thus, the cold agglutinins of these six patients showed Inv allotypic exclusion compared with the normal immunoglobulins.

The in vivo metabolism of radioiodinated cold agglutinins of anti-I specificity.

1. The metabolism of six purified and radioiodinated cold agglutinins has been studied in five patients with chronic cold haemagglutinin disease and in six normal controls. Two of the patients showed overt haemolysis at the time of this study and all had complement components adsorbed to the surface of their red cells. 2. The mean fractional catabolic rate (FCR) of the cold agglutinins, studied in the patients from whom they were isolated (14·5%/day), was similar to the mean FCR of the same cold agglutinins in normal controls (15·6%/day) and there was no correlation between the FCR and the presence of haemolysis. Exposure to cold with a concomitant increase in haemolysis during the course of one of these studies had no effect on the catabolic rate of the cold agglutinin. 3. Individual values for the FCR ranged from 10·8 to 19·4%/day (corresponding to half-lives of 4·9–7·8 days) and appeared to be characteristic for each recipient. When two different cold agglutinins were studied simultaneously in the same subject their catabolism was virtually identical. 4. Untreated patients with chronic cold haemagglutinin disease were calculated to be synthesizing IgM at approximately ten times the normal rate. The fall in serum IgM concentration and agglutinin and haemolysin titres, following treatment with alkylating agents, appeared to be due to a diminution in the rate of synthesis and not due to increased catabolism. 5. ‘7S’ subunits of one of the cold agglutinins, which retained cold haemagglutinating activity, were rapidly catabolized in a normal subject.

Chronic autoimmune hemolytic anemia in childhood with cold antibodies, aplastic crises, and familial occurrence.

SummaryA report is given of two sisters who developed chronic autoimmune hemolytic anemia in their fourth and twelfth years of age, respectively. The serological findings were different in the two cases. In patient 1, a typical cold agglutinin with a titer of 256 at 4oC was found in the serum, and only complement on the red cells by the direct Coombs' test. The serum hemolysed trypsinized red cells at 37oC. Her sister had warm type hemolytic anemia with a γG antibody on her red cells. In case 1, the clinical course has been severe, with several exacerbations of the hemolytic process accompanied by erythroid aplasia in the bone marrow.Whereas acute autoimmune hemolytic anemia with cold antibodies is not rare in children, and may be elicited by mycoplasma or viral infections, chronic autoimmune hemolytic anemia is rarely seen before adulthood. The typical, chronic cold hemagglutinin disease with hemoglobinuria and Raynaud's phenomena has not been described in childhood, and was not present in our case. It is suggested that the disease in the case presented may have started as the result of an acute infection, and that for one reason or another (genetic predisposition?) the process has not shown the usual self‐limited course.Although a familial–probably genetic– predisposition exists for several autoimmune diseases, familial occurrence of autoimmune hemolytic anemia has rarely been observed. The authors have found nine convincing reports in the literature, and in only one of the reported families did the hemolytic anemia develop in childhood. In families predisposed to autoimmune diseases, a variety of γ‐globulin disturbances and autoimmune disorders are often found. The presence of a more fundamental, genetic aberration of the immune apparatus, preventing a normal immune homeostasis, may therefore be postulated.A brief comment is made on the possible mechanism of the repeated periods of erythroid aplasia in the patient with cold antibodies. It is suggested that a second antibody, causing hemolysis of trypsinized red cells at 37oC may be of importance by damaging the red cell precursors. The presence of this antibody may also possibly explain why the severity of the clinical picture of the patient did not seem to be related to exposure to cold.

Light chains in chronic cold haemagglutinin disease.

THE chronic cold haemagglutinin disease (CHAD) is a rare illness of unknown aetiology characterized by the presence in the serum of an autoantibody which causes marked agglutination of both patient's and normal red cells at temperatures below 37° C. The antibody is known to be a macroglobulin of the IgM sub-group of immunoglobulins1. There is often a spike in the β to γ1 globulin area on serum-protein electrophoresis owing to the presence of a large amount of electrophoretically homogeneous antibody2.