Paroxysmal Cold Haemoglobinuria: A Clinico-Pathological Study of Patients with a Positive Donath-Landsteiner Test

Abstract

52 patients (30 male, 22 female) with paroxysmal cold haemoglobinuria (PCH) were identified by critically examining the records of all cases with Donath-Landsteiner antibodies seen over a 37 year period. Although ages ranged from 1–82 years, PCH was much commoner in young children; the median age at presentation was 5 and the peak incidence, 0.4 per year per 100,000 of the population at risk, was in the 4 years and under group. 44 patients had acute transient PCH, 3 chronic non-syphilitic PCH and 1 chronic syphilitic PCH; 4, in whom the positive Donath-Landsteiner tests were incidental findings, could not be classified.Acute PCH typically presented in young children as sudden onset of malaise, haemoglobinuria and pallor, often associated with mild jaundice—all 30 patients who were 13 or younger had this type. There was usually a history of a recent viral type infection, most commonly of the upper respiratory tract. The occurrence of acute PCH had no obvious relation to exposure to cold. Dramatic and rapid falls in haemoglobin level were common, often accompanied initially by relative or absolute reticulocytopenia. The illness was severe, but the prognosis was generally good and the majority of patients had completely recovered within one month, some requiring no treatment. In approximately 68% of patients, blood transfusion was needed; the P blood group was not taken into account, but the patients were kept warm throughout. Steroids (usually prednisolone) were given in many cases; but since there was no evidence to support their benefit, it was recommended that they were stopped as soon as the diagnosis was confirmed.Chronic non-syphilitic PCH was much rarer; the patients had a characteristic presentation of severe systemic symptoms (paroxysms) and haemoglobinuria brought on by exposure to cold. The clinical manifestations varied in intensity between individuals; at the extreme, severe debility was experienced over many years. Warmth and avoidance of cold were an effective treatment, though in a severely afflicted patient, an attack could be precipitated by relatively little exposure to cold. With chronic syphilitic PCH there was the added need to treat the specific infection.The direct antiglobulin test was almost always positive (50 out of 51 cases tested), with C3d coating the red cells. The Donath-Landsteiner antibodies were of IgG class, but this was rarely demonstrated unless direct antiglobulin tests were carried out at 4°C. The antibodies showed the classical anti-P specificity in 27 of the 30 patients tested; other specificities were unusual. Although acting much better as haemolysins, Donath-Landsteiner antibodies could also cause weak agglutination at room temperature. This was paralleled in vivo by predominantly intravascular haemolysis with an extravascular component. Diagnosis was usually easy when PCH was suspected, though in some patients Donath-Landsteiner tests did not become positive until more sensitive techniques involving papainised red cells or two-stage procedures were employed.Of particular interest was the association in some cases with lymphoproliferative disorders, collagen disease, myelodysplastic syndrome, delayed haemolytic transfusion reaction and other types of autoimmune haemolytic anaemia. In one patient, an aetiological relationship was confirmed by a saline extract of lymphoma tissue behaving as a strong Donath-Landsteiner antibody with the same anti-P specificity as the serum. 4 patients had other types of autoimmune haemolysis concomitant with, but distinct from, the PCH; in 3 cases this was cold haemagglutinin disease and in one it was warm type autoimmune haemolytic anaemia.