Paroxysmal cold hemoglobinuria
|Paroxysmal cold hemoglobinuria|
Paroxysmal cold hemoglobinuria (PCH) is an autoimmune hemolytic anemia featured by complement-mediated intravascular hemolysis after cold exposure. It can present as an acute non-recurrent postinfectious event in children, or chronic relapsing episodes in adults with hematological malignancies or tertiary syphilis. Described by Julius Donath (1870-1950) and Karl Landsteiner (1868-1943) in 1904, PCH is one of the first clinical entities recognized as an autoimmune disorder.
Signs and symptoms
Pediatric patients usually present with acute onset of hemolytic anemia with fatigue, exercise intolerance, pallor, jaundice, and hemoglobinuria, preceded by exposure to cold temperature and preceding viral-like illness. This may be complicated by acute renal failure due to nephrotoxic free hemoglobin and tubular obstruction. Although the disease may be fulminant during onset, the acute form generally follows a transient, self-limiting course.
Chronic relapsing PCH manifests as episodic hemoglobinuria and anemic symptoms, usually milder than the acute form. While the classical syphilitic PCH becomes infrequent, paraneoplastic cause with underlying hematological malignancies especially in the elderly should be considered. Hepatosplenomegaly and adenomegaly are not pertinent to PCH, unless associated with underlying lymphoproliferative disorders. This form remains refractory if the underlying condition is not treated.
Cause and pathophysiology
The exact pathogenesis is not fully elucidated. The hallmark feature is the formation of polyclonal IgG autoantibody against the P antigen, which is a polysaccharide surface antigen on red cells in most humans. As a weak, biphasic antibody, it absorbs to the P antigen in the cold temperature as in the periphery in the primary phase, and fixes complement on recirculation to the core temperature in the secondary phase, resulting in intravascular hemolysis.
Infectious agents are implicated in the acute form of PCH. Viral agents include measles, mumps, Epstein-Barr virus, cytomegalovirus, varicella-zoster virus, influenza virus, and adenovirus. Non-viral agents include Mycoplasma pneumoniae and Haemophilus influenzae. Chronic relapsing PCH is classically associated with syphilis, as well as hematological malignancies including non-Hodgkin lymphoma and myeloproliferative neoplasms.
The purposes of laboratory investigations are to:
- Confirm the presence of intravascular hemolysis in terms of metabolic products of red cells and hematopoietic response.
- Establish the diagnosis of autoimmune hemolytic anemia and differentiate from other AIHA.
- Identify other supporting features as in hematopathological findings.
For intravascular hemolysis, the laboratory parameters include increased serum free hemoglobin, lactate dehydrogenase, unconjugated bilirubin, and reduced haptoglobin. Urine tests may show elevated hemoglobinuria and hemosiderinuria in chronic cases. Reticulocytosis may not be apparent in the acute phase or when there is viral-induced myelosuppression.
Once the clinical suspicion of autoimmune hemolytic anemia is made, direct antiglobulin test (DAT) or direct Coombs' test is the first line of investigation to confirm the presence of warm autoantibodies. Testing with polyspecific and IgG-specific antiglobulin agents is usually negative, and that with C3-specific agent may be positive. On excluding warm autoimmune hemolytic anemia (WAIHA), the cold agglutinin titer should be examined for cold agglutinin disease (CAD). The diagnosis of PCH is suspected when both WAIHA and CAD are excluded. The complement level is usually low.
Donath-Landsteiner test is the confirmatory test for PCH. It involves the cooling of the patient's serum to 4°C to allow the absorption of anti-P autoantibodies to the red cells, followed by warming to 37°C to activate complement fixation and hemolysis. Indirect DL test with addition of ABO-compatible P antigen-positive blood can be performed in case the direct DL test is negative, since the complement in the original serum may be consumed and result in false negative.
The hematopathological findings can reflect both the presence of intravascular hemolysis and the underlying immunological process. The complete blood count usually shows normocytic anemia. Reticulocytosis may be subtle in the acute phase. Peripheral blood smear may show corresponding polychromasia. Neutrophil erythrophagocytosis is suggestive of PCH, while the absence of red cell agglutination as in CAD or microshperocytosis in WAIHA should also be noted.
Management and Prognosis
Acute PCH is usually transient and self-limiting. Supportive treatment includes rest, normothermia and transfusion when indicated. Intensive care for the development of acute kidney injury should be offered. Plasmapheresis is proposed to be an adjunctive measure to facilitate recovery. Steroids and other immunosuppressants are sometimes administered and the beneficial effect is uncertain. Immunotherapy is considered in refractory to corticosteroids and immunosuppression. Monoclonal antibodies e.g. rituximab (anti-CD20) and eculizumab (anti-C5) have been used but the therapeutic benefits are controversial. Antibiotic therapy should be given if syphilitic cause is confirmed, while investigations and management for hematological malignancies should be pursued in adult patients with unexplained PCH.
Estimated incidence of PCH is 0.4 per 100000 population, and the prevalence ranges from 1.6% to 40% in patients with autoimmune hemolytic anemia. The prevalence depends on the sensitivity of the immunologic methods applied. The age of onset is often <5 years in the pediatric population, with male predominance ranging from 2.5:1 to 5:1 in male-to-female ratio.
The majority of PCH were accounted by congenital or tertiary syphilis in the early 1900s. Since the application of antibiotic therapy and prenatal screening, syphilitic PCH has become a rare entity. It is now increasingly recognized in pediatric patients with preceding viral-like illness.
- Shanbhag, Satish; Spivak, Jerry (June 2015). "Paroxysmal Cold Hemoglobinuria". Hematology/Oncology Clinics of North America. 29 (3): 473–478. doi:10.1016/j.hoc.2015.01.004. ISSN 0889-8588. PMID 26043386.
- Moticka, Edward J. (2013). Historical perspective on evidence-based immunology. Elsevier Science Publishing. p. 300. ISBN 9780123983817.
- Deuel, J W; Schaer, C A; Boretti, F S; Opitz, L; Garcia-Rubio, I; Baek, J H; Spahn, D R; Buehler, P W; Schaer, D J (2016-01-21). "Hemoglobinuria-related acute kidney injury is driven by intrarenal oxidative reactions triggering a heme toxicity response". Cell Death and Disease. 7 (1): e2064. doi:10.1038/cddis.2015.392. ISSN 2041-4889. PMC 4816175. PMID 26794659.
- Sokol, R.J.; Hewitt, S.; Stamps, Barbara K.; Hitchen, Patricia A. (1984). "Autoimmune Haemolysis in Childhood and Adolescence". Acta Haematologica. 72 (4): 245–257. doi:10.1159/000206397. ISSN 0001-5792. PMID 6438992.
- Vaglio, Stefania; Arista, Maria Cristina; Perrone, Maria Paola; Tomei, Gabriella; Testi, Anna Maria; Coluzzi, Serelina; Girelli, Gabriella (January 2007). "Autoimmune hemolytic anemia in childhood: serologic features in 100 cases". Transfusion. 47 (1): 50–54. doi:10.1111/j.1537-2995.2007.01062.x. ISSN 0041-1132. PMID 17207229.
- Jordan, WS Jr; Prouty, RL (April 1952). "The mechanism of hemolysis in paroxysmal cold hemoglobinuria. III. Erythrophagocytosis and leukopenia". Blood. 7:4 (4): 387–403. PMID 14915984.
- Sokol, R.J.; Hewitt, S.; Stamps, Barbara K. (1982). "Autoimmune Haemolysis Associated with Donath-Landsteiner Antibodies". Acta Haematologica. 68 (4): 268–277. doi:10.1159/000206992. ISSN 0001-5792. PMID 6817570.
- Sanford, Kimberly W.; Roseff, Susan D. (April 2010). "Detection and Significance of Donath-Landsteiner Antibodies in a 5-year-old Female Presenting With Hemolytic Anemia". Laboratory Medicine. 41 (4): 209–212. doi:10.1309/lm1e9z2qzerepai. ISSN 0007-5027.
- Ziman, Alyssa; Cohn, Claudia; Carey, Patricia M.; Dunbar, Nancy M.; Fung, Mark K.; Greinacher, Andreas; Stanworth, Simon; Heddle, Nancy M.; Delaney, Meghan (2016-12-04). "Warm-reactive (immunoglobulin G) autoantibodies and laboratory testing best practices: review of the literature and survey of current practice". Transfusion. 57 (2): 463–477. doi:10.1111/trf.13903. ISSN 0041-1132. PMID 27917465.
- Ogose T, Wakata Y, Kaneko M, Shinahara K, Takechi T, Kotani H (October 2007). "A case of recurrent paroxysmal cold hemoglobinuria with the different temperature thresholds of Donath-Landsteiner antibodies". J. Pediatr. Hematol. Oncol. 29 (10): 716–9. doi:10.1097/MPH.0b013e31814d6845. PMID 17921855.
- Zanella, Alberto; Barcellini, Wilma (2014-10-01). "Treatment of autoimmune hemolytic anemias". Haematologica. 99 (10): 1547–1554. doi:10.3324/haematol.2014.114561. ISSN 0390-6078. PMC 4181250. PMID 25271314.
- Koppel, Ahrin; Lim, Stephen; Osby, Melanie; Garratty, George; Goldfinger, Dennis (October 2007). "Rituximab as successful therapy in a patient with refractory paroxysmal cold hemoglobinuria". Transfusion. 47 (10): 1902–1904. doi:10.1111/j.1537-2995.2007.01414.x. ISSN 0041-1132. PMID 17880618.
- Rodrigo, Chaturaka; Rajapakse, Senaka; Gooneratne, Lallindra (2015-04-22). "Rituximab in the treatment of autoimmune haemolytic anaemia". British Journal of Clinical Pharmacology. 79 (5): 709–719. doi:10.1111/bcp.12498. ISSN 0306-5251. PMC 4415708. PMID 25139610.
- Gregory, Gareth Peter; Opat, Stephen; Quach, Hang; Shortt, Jake; Tran, Huyen (2010-11-26). "Failure of eculizumab to correct paroxysmal cold hemoglobinuria". Annals of Hematology. 90 (8): 989–990. doi:10.1007/s00277-010-1123-x. ISSN 0939-5555. PMID 21110191.
- Gertz, Morie A. (2006-01-01). "Cold Hemolytic Syndrome". ASH Education Program Book. 2006 (1): 19–23. doi:10.1182/asheducation-2006.1.19. ISSN 1520-4391. PMID 17124034.