Paroxysmal Cold Hemoglobinuria Clinical Presentation
- Author: Neetu Radhakrishnan, MD; Chief Editor: Emmanuel C Besa, MD more...
The initial inciting event to the predisposition of D-L antibody synthesis remains unknown. However, paroxysmal cold hemoglobinuria can occur soon after developing upper respiratory and gastrointestinal symptoms.
Once strongly linked with syphilis, paroxysmal cold hemoglobinuria is now associated with numerous infectious agents. Identified pathogens have included the following: measles, mumps, influenza, varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), adenovirus, parvovirus B19, Coxsackie A9, Haemophilus influenzae, Mycoplasma pneumoniae, and Klebsiella pneumoniae.[5, 7, 8, 19] The development of the D-L antibody has also been reported following measles immunization. Other associations include solid organ and hematopoietic neoplasms as previously noted.
Within minutes to a few hours of exposure to cold temperatures, the patient develops a combination of the following: sudden onset of back and abdominal pain, headache, leg cramps, fever, rigors, chills, nausea, vomiting, diarrhea, and esophageal spasms. The hemoglobinuria can be severe enough to alter the urine to a dark red-brown color, although hematuria is generally minimal or absent. Oliguria or anuria can develop upon renal dysfunction. Cold urticaria and jaundice may also occur. These generalized symptoms are likely attributed to the release of large quantities of hemoglobin from lysed RBCs, which then act as an irritant to various tissues.
Patients who present with paroxysmal cold hemoglobinuria are in acute distress, with obvious pain and elevation of body temperature.
Symptoms associated with respiratory infection are the most common initial presentation.
Physical signs of massive RBC hemolysis include pallor, icterus, and urticarial dermal eruption. Severe hemoglobinuria is commonly detected during the acute event, resulting in a red-brown discoloration to the urine.
Hepatosplenomegaly can be attributed to an underlying lymphoproliferative or other neoplastic process, but it has also been observed as a reactive process in 25% of paroxysmal cold hemoglobinuria cases. A clinical examination (to rule out lymphadenopathy and/or splenomegaly) is obligatory.
Another feature can be sequelae of microthrombosis, but generally it is rare.
Other constitutional symptoms are likely related to an underlying secondary pathologic process.
Known risk factors for paroxysmal cold hemoglobinuria are attributed to underlying pathogenic states, including infectious diseases and neoplasms (see History).In the adult population, infections and neoplasms have been associated with the development of D-L antibody.
Reported neoplasms include solid organ carcinomas as seen with pulmonary small cell carcinoma and hematopoietic disorders such as non-Hodgkin lymphoma (NHL), chronic lymphocytic lymphoma (CLL), primary myelofibrosis with myeloid metaplasia, myelodysplastic syndrome, and in the presence of a monoclonal protein with Bence Jones proteinuria.[6, 11, 23, 24, 25, 26, 27]
In most cases, the P antigen must be present on the RBCs for paroxysmal cold hemoglobinuria to develop. As most people express P antigen on their erythrocytes, nearly the entire population is susceptible to reactivity by the D-L antibody.
The degree and duration of hypothermia that is required to precipitate hemolysis depends on the temperature requirement of the antibody-RBC reaction and on the concentration availability of complement.
Male sex appears to be a risk factor in at least 1 study.
Donath J, Landsteiner K. Uber paroxysmale haemoglobinurie. Munchen Medicine Wochenschr. 1904. 51:1590-3.
Gottsche B, Salama A, Mueller-Eckhardt C. Donath-Landsteiner autoimmune hemolytic anemia in children. A study of 22 cases. Vox Sang. 1990. 58(4):281-6. [Medline].
Eder AF. Review: acute Donath-Landsteiner hemolytic anemia. Immunohematology. 2005. 21(2):56-62. [Medline].
Kypson AP, Warner JJ, Telen MJ, Milano CA. Paroxysmal cold hemoglobinuria and cardiopulmonary bypass. Ann Thorac Surg. 2003 Feb. 75(2):579-81. [Medline].
Taylor CJ, Neilson JR, Chandra D, Ibrahim Z. Recurrent paroxysmal cold haemoglobinuria in a 3-year-old child: a case report. Transfus Med. 2003 Oct. 13(5):319-21. [Medline].
Sokol RJ, Hewitt S, Stamps BK. Autoimmune haemolysis associated with Donath-Landsteiner antibodies. Acta Haematol. 1982. 68(4):268-77. [Medline].
Sokol RJ, Hewitt S, Stamps BK, Hitchen PA. Autoimmune haemolysis in childhood and adolescence. Acta Haematol. 1984. 72(4):245-57. [Medline].
Win N, Stamps R, Knight R. Paroxysmal cold haemoglobinuria/Donath-Landsteiner test. Transfus Med. 2005 Jun. 15(3):254. [Medline].
Vaglio S, Arista MC, Perrone MP, et al. Autoimmune hemolytic anemia in childhood: serologic features in 100 cases. Transfusion. 2007 Jan. 47(1):50-4. [Medline].
Breccia M, D'Elia GM, Girelli G, et al. Paroxysmal cold haemoglobinuria as a tardive complication of idiopathic myelofibrosis. Eur J Haematol. 2004 Oct. 73(4):304-6. [Medline].
Wynn RF, Stevens RF, Bolton-Maggs PH, Schwe K, Will AM. Paroxysmal cold haemoglobinuria of childhood: a review of the management and unusual presenting features of six cases. Clin Lab Haematol. 1998 Dec. 20(6):373-5. [Medline].
Bell CA, Zwicker H, Rosenbaum DL. Paroxysmal cold hemoglobinuria (P.C.H.) following mycoplasma infection: anti-I specificity of the biphasic hemolysin. Transfusion. 1973 May-Jun. 13(3):138-41. [Medline].
Rausen AR, LeVine R, Hsu TC, Rosenfield RE. Compatible transfusion therapy for paroxysmal cold hemoglobinuria. Pediatrics. 1975 Feb. 55(2):275-8. [Medline].
Petz LD, Garratty G. Acquired Immune Hemolytic Anemias. New York, NY: Churchill Livingstone; 1980. 37-50.
Dacie J. The Haemolytic Anaemias. 3rd ed. New York, NY: Churchill Livingstone; 1992. 210-362.
Ziman A, Hsi R, Goldfinger D. Transfusion Medicine Illustrated: Donath-Landsteiner antibody-associated hemolytic anemia after Haemophilus influenzae infection in a child. Transfusion. 2004 Aug. 44(8):1127-8. [Medline].
Vergara LH, Mota MC, Sarmento Ada G, Duarte CA, Barbot JM. [Acute renal failure secondary to paroxysmal cold hemoglobinuria] [Spanish]. An Pediatr (Barc). 2006 Mar. 64(3):267-9. [Medline]. [Full Text].
Kim GM, Kim CH, Kim BS. Multiple cerebral infarction and microbleeds associated with adult-onset paroxysmal cold hemoglobinuria. J Clin Neurosci. 2009 Feb. 16(2):348-9. [Medline].
Papalia MA, Schwarer AP. Paroxysmal cold haemoglobinuria in an adult with chicken pox. Br J Haematol. 2000 May. 109(2):328-9. [Medline].
Lippman SM, Winn L, Grumet FC, Levitt LJ. Evans' syndrome as a presenting manifestation of atypical paroxysmal cold hemoglobinuria. Am J Med. 1987 May. 82(5):1065-72. [Medline].
Sharara AI, Hillsley RE, Wax TD, Rosse WF. Paroxysmal cold hemoglobinuria associated with non-Hodgkin's lymphoma. South Med J. 1994 Mar. 87(3):397-9. [Medline].
Sivakumaran M, Murphy PT, Booker DJ, et al. Paroxysmal cold haemoglobinuria caused by non-Hodgkin's lymphoma. Br J Haematol. 1999 Apr. 105(1):278-9. [Medline].
Stefanizzi C, Breccia M, Santopietro M, et al. Unusual association of paroxysmal cold hemoglobinuria as the first sign of disease in myelodysplastic patient. Int J Hematol. 2009 Jun. 89(5):720-1. [Medline].
Sinha A, Richardson G, Patel RT. Cold agglutinin related acrocyanosis and paroxysmal haemolysis. Eur J Vasc Endovasc Surg. 2005 Nov. 30(5):563-5. [Medline].
Chrobak L. Paroxysmal nocturnal hemoglobinuria (membrane defect, pathogenesis, aplastic anemia, diagnosis). Acta Medica (Hradec Kralove). 2000. 43(1):3-8. [Medline].
Prasad AS, Berman L, Tranchida L, Poulok MD. Red cell hypoplasia, cold hemoglobinuria and M-type gamma G serum paraprotein and Bence Jones proteinuria in a patient with lymphoproliferative disorder. Blood. 1968 Feb. 31(2):151-65. [Medline]. [Full Text].
Subbarayan PR, Shichishima T, Yoshida H, Maruyama Y, Naiki M. Report on a patient with paroxysmal cold hemoglobinuria. Int J Hematol. 1997 Feb. 65(2):165-7. [Medline].
Chen R, Nagarajan S, Prince GM, et al. Impaired growth and elevated fas receptor expression in PIGA(+) stem cells in primary paroxysmal nocturnal hemoglobinuria. J Clin Invest. 2000 Sep. 106(5):689-96. [Medline]. [Full Text].
Brodsky RA, Mukhina GL, Li S, et al. Improved detection and characterization of paroxysmal nocturnal hemoglobinuria using fluorescent aerolysin. Am J Clin Pathol. 2000 Sep. 114(3):459-66. [Medline].
Garratty G. Erythrophagocytosis on the peripheral blood smear and paroxysmal cold hemoglobinuria. Transfusion. 2001 Aug. 41(8):1073-4. [Medline].
Lechner K, Jäger U. How I treat autoimmune hemolytic anemias in adults. Blood. 2010 Sep 16. 116(11):1831-8. [Medline].
Roy-Burman A, Glader BE. Resolution of severe Donath-Landsteiner autoimmune hemolytic anemia temporally associated with institution of plasmapheresis. Crit Care Med. 2002 Apr. 30(4):931-4. [Medline].
Nordhagen R, Stensvold K, Winsnes A, Skyberg D, Storen A. Paroxysmal cold haemoglobinuria. The most frequent acute autoimmune haemolytic anaemia in children?. Acta Paediatr Scand. 1984 Mar. 73(2):258-62. [Medline].
Lindgren S, Zimmerman S, Gibbs F, Garratty G. An unusual Donath-Landsteiner antibody detectable at 37 degrees C by the antiglobulin test. Transfusion. 1985 Mar-Apr. 25(2):142-4. [Medline].
Nordhagen R. Two cases of paroxysmal cold hemoglobinuria with a Donath-Landsteiner antibody reactive by the indirect antiglobulin test using anti-IgG. Transfusion. 1991 Feb. 31(2):190-1. [Medline].
Thomas AT. Autoimmune hemolytic anemias. Lee GR, Foerster J, Lukens J, et al, eds. Wintrobe's Clinical Hematology. 10th ed. Baltimore, Md: Williams & Wilkins; 1999. 1233-63.
Gertz MA. Management of cold haemolytic syndrome. Br J Haematol. 2007 Aug. 138(4):422-9. [Medline].
Hothi DK, Bass P, Morgan M, et al. Acute renal failure in a patient with paroxysmal cold hemoglobinuria. Pediatr Nephrol. 2007 Apr. 22(4):593-6. [Medline].
Koppel A, Lim S, Osby M, Garratty G, Goldfinger D. Rituximab as successful therapy in a patient with refractory paroxysmal cold hemoglobinuria. Transfusion. 2007 Oct. 47(10):1902-4. [Medline].
Gregory GP, Opat S, Quach H, Shortt J, Tran H. Failure of eculizumab to correct paroxysmal cold hemoglobinuria. Ann Hematol. 2011 Aug. 90(8):989-90. [Medline].