LAUSR

P aroxysmal cold hemoglobinuria (PCH) is a relatively rare autoimmune hemolytic anemia (AIHA). It is characterized by a weak-affinity, “biphasic” autoantibody that only binds red blood cells (RBCs) at low temperatures with recruitment and binding of early complement components. Although the antibody dissociates at higher temperatures, complement remains bound with complement activation and hemolysis. It has been proposed that the repetitive association and dissociation of antibody during normal circulation is a key element in the pathophysiology of the disease. Historically, PCH was a chronic condition associated with advanced syphilis. The first published case of PCH is generally attributed to Dr Dressler in 1854, who described intermittent hemoglobinuria in a 10-year-old child with congenital syphilis. Over the next 50 years, several more cases of intermittent hemoglobinuria in syphilitic patients were documented, with episodes often precipitated by cold exposure. This observation led to two clinical tests—the Rosenbach test and the Ehrlich test. In the Rosenbach test, an attack was precipitated by submerging the patient’s feet in cold water for 10 minutes and close observation for the development of hemoglobinuria. In the Ehrlich test, a ligature was placed around one finger and the patient’s hand was immersed in ice water. The presence of hemoglobinemia in the ligated finger was considered a positive test. These two clinical tests informed the development of the Donath-Landsteiner (DL) test (1904), which remains the definitive test for PCH even today. In their assay, Donath and Landsteiner attempted to recapitulate the disease in vitro, by first incubating patient plasma and RBCs at 48C, followed by warming at 378C. Their findings clarified that PCH was caused by “a circulating hemolysin present in plasma, that the hemolysin was only able to bind red cells at low temperatures and that complement (alexin) was necessary for hemolysis or the ‘second phase’ of the disease.” Using the DL test, and the newly developed Wasserman assay for syphilis (1906), Landsteiner and others were able to confirm the strong correlation between PCH and syphilis during the early 20th century. It is interesting to note that multiple authors observed that children appeared to be particularly susceptible and often presented with more severe hemolysis than their adult counterparts. Another clinical observation made by an early investigator was a paroxysmal enlargement of the spleen and sometimes the liver after a PCH attack, consistent with an element of extravascular hemolysis. As public health measures and antibiotics eliminated advanced syphilis, it became clear that PCH could occur in other conditions. By the 1950s, PCH was categorized as 1) chronic syphilitic; 2) chronic nonsyphilitic; and 3) acute, transient nonsyphilitic. In 1963, Phillip Levine provided the first evidence that the antibody in PCH was directed against an antigen of the P-blood group system after testing six PCH samples against P1, P2, and p RBCs. 5 This specificity was refined by Worlledge and Rousso in 1965, who identified an anti-P immunoglobulin (Ig)G after testing against P1 and P RBCs. After the identification of the glycosphingolipid (GSL) globoside as the P-antigen, Schwarting and colleagues used purified globoside and Forssmann antigen to inhibit antibody-mediated hemolysis. A more recent article demonstrated direct binding of PCH serum to purified globoside and RBC neutral GSLs by thin-layer chromatography. Although anti-P IgG is the most common antibody encountered in PCH, there are PCH cases with biphasic IgM and IgA antibodies, and other carbohydrate specificities (I, i, HI, Pr). Today, PCH is predominantly a pediatric disease, accounting for 6% to 30% of all pediatric AIHAs. It is almost always a postinfectious complication after an upper respiratory tract infection (URI; >70% cases) or gastrointestinal illness: other causes include vaccination, autoimmune disorders, and hematopoietic malignancies. Pediatric PCH patients tend to be quite young (median age, 5 years) and male with a history of infection 1 to 3 weeks before presentation. Hemolysis is often sudden and severe, with hemoglobin (Hb) values often decreasing to less than 6 g/dL. Diagnostic findings are a C31 direct antiglobulin test (DAT), the absence of warm autoantibodies, and a detectable biphasic DL hemolysin early in the disease. On occasion, PCH can present with a negative DAT and positive DL test. Despite recent infection, PCH is not associated with an increase in cold agglutinin titers. Peripheral blood findings include spherocytosis and autoagglutination or rouleaux in 50% and 17% to 25% of cases, respectively. RBC-neutrophil rosettes and erythrophagocytosis by neutrophils, which are usually cited as pathognomonic findings for PCH, are encountered infrequently (9%). In this issue of TRANSFUSION, Prince and colleagues describe a textbook-perfect case of PCH, and doi:10.1111/trf.14128