UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Paroxysmal cold hemoglobinuria

Author
Carlo Brugnara, MD
Section Editor
Stanley L Schrier, MD
Deputy Editor
Jennifer S Tirnauer, MD

INTRODUCTION

Paroxysmal cold hemoglobinuria (PCH) was one of the first hematologic syndromes to be recognized clinically. The association between red to brown urine (quickly recognized as hemoglobinuria) being passed following exposure to cold was established by 1872. The recognition that this syndrome was often seen in patients with syphilis soon followed and the demonstration of an antibody as the cause came in 1904, from the studies of Donath and Landsteiner [1].

This topic review will discuss the major features of PCH. The more common cold agglutinin syndromes are discussed separately. (See "Pathogenesis of autoimmune hemolytic anemia: Cold agglutinin disease" and "Cold agglutinin disease".)

PATHOPHYSIOLOGY

The antibody in PCH is a cold-reacting IgG. It is always polyclonal. Unlike cold-reacting IgM, it does not cause red cell agglutination but, similar to cold-reacting IgM, it is able to fix complement readily. The maximum temperature at which these antibodies are able to interact (ie, their thermal amplitude) varies greatly from patient to patient, as is also the case with the IgM cold agglutinins.

The mechanism of hemolysis in PCH is similar to that in cold agglutinin disease (CAD). As the blood circulates to the periphery, it cools, and the antibody and the first two components of complement are fixed to the RBC surface. The complement cascade is completed only when the RBC are subsequently warmed to 37°C. For reasons that are not clearly understood, perhaps because the antigen is located on the RBC membrane surface, these antibodies are quite efficient in bringing about direct lysis by complement; this results in intravascular hemolysis, hemoglobinuria, and hemosiderinuria. (See 'Antibody specificity' below and "Diagnosis of hemolytic anemia in the adult", section on 'Intravascular hemolysis'.)

Antibody specificity — The antigen with which the antibody in PCH interacts is the P antigen, a polysaccharide that is usually affixed to a ceramide moiety on the surface of the red cell [2]. This antibody will cause hemolysis in almost all subjects, since only rare individuals have red cells lacking the P antigen (the pp or Tj(a) - phenotype). Of interest, the P antigen structure is also a binding site for parvovirus, one strain of which (B19) causes transient pure red aplasia [3]. (See "Clinical manifestations and diagnosis of parvovirus B19 infection" and "Red blood cell antigens and antibodies", section on 'Lewis, P1P(K), GLOB, and I blood group systems'.)

               
To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Sep 2017. | This topic last updated: Jun 28, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
References
Top
  1. Donath J, Landsteiner K. Uber paroxysmale hämoglobinurie. Münch Med Wochenschr 1904; 51:1590.
  2. Levine P, Celano MJ, Falkowski F. The specificity of the antibody in paroxysmal cold hemoglobinuria (P.C.H.). Ann N Y Acad Sci 1965; 124:456.
  3. Brown KE, Anderson SM, Young NS. Erythrocyte P antigen: cellular receptor for B19 parvovirus. Science 1993; 262:114.
  4. Shirey RS, Park K, Ness PM, et al. An anti-i biphasic hemolysin in chronic paroxysmal cold hemoglobinuria. Transfusion 1986; 26:62.
  5. Santos Malavé C, Shardy DL, Hartman SK, Sampayo EM. Paroxysmal cold hemoglobinuria in a child with RSV: an underrecognized cause of hemolytic anemia. Am J Emerg Med 2016; 34:2252.e5.
  6. Göttsche B, Salama A, Mueller-Eckhardt C. Donath-Landsteiner autoimmune hemolytic anemia in children. A study of 22 cases. Vox Sang 1990; 58:281.
  7. Sokol RJ, Booker DJ, Stamps R. Erythropoiesis: Paroxysmal Cold Haemoglobinuria: A Clinico-Pathological Study of Patients with a Positive Donath-Landsteiner Test. Hematology 1999; 4:137.
  8. D'Angiò M, Ceglie T, Giovannetti G, et al. Visceral leishmaniasis presenting with paroxysmal cold haemoglobinuria. Blood Transfus 2014; 12 Suppl 1:s141.
  9. Sharara AI, Hillsley RE, Wax TD, Rosse WF. Paroxysmal cold hemoglobinuria associated with non-Hodgkin's lymphoma. South Med J 1994; 87:397.
  10. Sivakumaran M, Murphy PT, Booker DJ, et al. Paroxysmal cold haemoglobinuria caused by non-Hodgkin's lymphoma. Br J Haematol 1999; 105:278.
  11. Heddle NM. Acute paroxysmal cold hemoglobinuria. Transfus Med Rev 1989; 3:219.
  12. Bird GW, Wingham J, Martin AJ, et al. Idiopathic non-syphilitic paroxysmal cold haemoglobinuria in children. J Clin Pathol 1976; 29:215.
  13. Gertz MA. Management of cold haemolytic syndrome. Br J Haematol 2007; 138:422.
  14. Hernandez JA, Steane SM. Erythrophagocytosis by segmented neutrophils in paroxysmal cold hemoglobinuria. Am J Clin Pathol 1984; 81:787.
  15. Mukhopadhyay S, Keating L, Souid AK. Erythrophagocytosis in paroxysmal cold hemoglobinuria. Am J Hematol 2003; 74:196.
  16. Li W, Reddivalla N. Florid erythrophagocytosis by neutrophils in peripheral blood. Blood 2016; 128:739.
  17. SIRCHIA G, FERRONE S, MERCURIALI F. THE ACTION OF TWO SULFHYDRYL COMPOUNDS ON NORMAL HUMAN RED CELLS. RELATIONSHIP TO RED CELLS OF PAROXYSMAL NOCTURNAL HEMOGLOBINURIA. Blood 1965; 25:502.
  18. Zeller MP, Arnold DM, Al Habsi K, et al. Paroxysmal cold hemoglobinuria: a difficult diagnosis in adult patients. Transfusion 2017; 57:137.
  19. Ries CA, Garratty G, Petz LD, Fudenberg HH. Paroxysmal cold hemoglobinuria: report of a case with an exceptionally high thermal range Donath-Landsteiner antibody. Blood 1971; 38:491.
  20. Rausen AR, LeVine R, Hsu TC, Rosenfield RE. Compatible transfusion therapy for paroxysmal cold hemoglobinuria. Pediatrics 1975; 55:275.
  21. Koppel A, Lim S, Osby M, et al. Rituximab as successful therapy in a patient with refractory paroxysmal cold hemoglobinuria. Transfusion 2007; 47:1902.
  22. Gregory GP, Opat S, Quach H, et al. Failure of eculizumab to correct paroxysmal cold hemoglobinuria. Ann Hematol 2011; 90:989.
  23. Djaldetti M. Paroxysmal cold hemoglobinuria. CRC Crit Rev Clin Lab Sci 1978; 9:49.
  24. Mantadakis E, Bezirgiannidou Z, Martinis G, Chatzimichael A. Recurrence of paroxysmal cold hemoglobinuria in a boy after physical cooling for fever. J Pediatr Hematol Oncol 2011; 33:40.