Paroxysmal Cold Hemoglobinuria

No Results

No Results

processing….

Paroxysmal cold hemoglobinuria (PCH) is a form of autoimmune hemolytic anemia (AIHA) that, while rare, is nevertheless one of the most common causes of acute AIHA in young children. In PCH, the red blood cells are targeted by an autoantibody, the Donath-Landsteiner antibody, whose formation is most often triggered by infectious disease or neoplasms. ^[1]

Episodes of PCH typically develop within minutes to a few hours after exposure to cold temperatures. Patients present with a combination of the following: sudden onset of back and abdominal pain, headache, leg cramps, fever, rigors, chills, nausea, vomiting, diarrhea, and esophageal spasms. Severe hemoglobinuria is commonly detected during the acute event, resulting in a red-brown discoloration to the urine. See Presentation.

The mainstay of treatment for PCH is supportive care and the avoidance of cold exposure. Warmed, packed RBC transfusions are used for life-threatening hemolysis and symptomatic anemia. See Treatment. Acute episodes of PCH are generally transitory and recurrence is rare.

Paroxysmal cold hemoglobinuria (PCH) has the distinction of being the first, albeit rarest, type of autoimmune hemolytic anemia (AIHA) to be identified. This condition was first described in 1854 as an abrupt onset of systemic manifestations, including severe anemia and hemoglobinuria, occurring upon exposure to cold temperatures and resulting from massive intravascular hemolysis.

At the beginning of the 20th century, Julius Donath and Karl Landsteiner advanced the understanding of the pathophysiology of this disorder when they discovered a unique “biphasic hemolysin” in blood that could be demonstrated in the laboratory. This antibody attached to red blood cells (RBCs) in the cold and induced hemolysis when the RBCs are warmed due to complement activity. Together these investigators devised and published in 1904 what was to be the first immunohematologic test, referred to as the Donath-Landsteiner test. ^{[2, 3, 4, 5]} (See Lab Studies.)

In the latter half of the 19th century, the most common cause of paroxysmal cold hemoglobinuria was congenital or adult tertiary-stage syphilis. The ability to treat syphilis through antibiotic use resulted in the near elimination of this secondary cause of the chronic form of the disorder. Currently, episodes of paroxysmal cold hemoglobinuria usually occur after a viral infection and are abrupt in onset and transitory. A study of children found that as many as 40% of immune hemolytic anemias were due to the Donath-Landsteiner (D-L) antibody. ^{[6, 7]}

Although most cases of paroxysmal cold hemoglobinuria occur as an acute event in children younger than 5 years, recurrent episodes have been reported. ^{[7, 8, 9, 10, 11]} Furthermore, because the D-L antibody does not necessarily occur with a specified cold exposure event, nor is it recurrent in nature, an alternative classification of Donath-Landsteiner hemolytic anemia was proposed. ^[12]

With an underlying disease that is controllable or self-limited, the process may resolve spontaneously and quickly. Unfortunately, due to the transitory nature of paroxysmal cold hemoglobinuria, lack of awareness may lead to a failure in recognizing and diagnosing this uncommon syndrome.

For patient education resources, see Anemia.

Paroxysmal cold hemoglobinuria shares similar antibody thermal activity range as cold hemagglutinin disease (CHD), the more common cold variant of autoimmune hemolytic anemia. However, the D-L antibody is not classified as a monophasic immunoglobulin M (IgM), but rather a biphasic, usually polyclonal, IgG. The D-L antibody is known to bind to various antigens such as I-, i-, p-, Pr-, on the RBC surface; yet, the glycosphingolipid P antigen is considered its primary target. ^[7]

This interaction sensitizes the erythrocytes to allow further interaction with the complement system. However, unlike cold hemagglutinin disease in which the IgM-complement interaction results in the cells’ removal (via extravascular phagocytosis), paroxysmal cold hemoglobinuria occurs upon completion of complement lysis within the vascular circulation. Intravascular hemolysis occurs preferentially at 37°C, at which temperature the antibody has dissociated yet maintains maximal complement activity, providing the biphasic nature of the disease.

The exact etiology of the D-L antibody is unknown. There is a close temporal relationship observed between viral or bacterial agents and the development of paroxysmal cold hemoglobinuria within 2-3 weeks of upper respiratory or gastrointestinal symptoms. Young children are the most susceptible within the general population, developing a single, brief, postviral hemolytic episode. ^{[3, 13]}

The stimulus for production of this antibody is likely a form of molecular mimicry in which a microorganism’s antigen shares structural similarity to the P antigen on human RBCs, resulting in immunogenic cross-reactivity. ^[4] Interestingly, the P antigen has been found on lymphocytes and skin fibroblasts; the latter is thought to be the reason for the development of urticaria in persons with paroxysmal cold hemoglobinuria.

Because complement-mediated injury to the RBC is an intravascular process, hemoglobinemia, hemoglobinuria, and, sometimes, renal failure may develop. ^{[11, 14, 15, 16, 17, 18]} Even after the acute event remits, the D-L antibody may persist for 1-8 months to several years. ^[19]

United States

Paroxysmal cold hemoglobinuria (PCH) is a rare disorder, with a prevalence rate that is largely unknown within the US population or worldwide.  PCH occurs almost exclusively in children and accounts for 1-5% of childhood autoimmune hemolytic anemia (AIHA). ^[20]

International

Sokol et al estimated the annual incidence of paroxysmal cold hemoglobinuria at 0.4 cases per 100,000 population. ^{[8, 9]} Unfortunately, due to the scarcity of subjects, European epidemiologic results have varied widely from as low as 1.6% to as high as 40% of autoimmune hemolytic anemia cases, with the latter value restricted to children. ^{[7, 11, 19]}

When paroxysmal cold hemoglobinuria is promptly diagnosed and appropriately treated with supportive care, most patients recover spontaneously within days to a few weeks. Thus, the prognosis for this disorder is excellent. Fatality is a rare event, more commonly attributed to severe anemia.

No racial predisposition is recognized for paroxysmal cold hemoglobinuria.

There is a mild male sex predilection with paroxysmal cold hemoglobinuria; the male-to-female ratio is approximately 2:1 to 5:1. ^{[11, 15]}

Acute paroxysmal cold hemoglobinuria is a disease that affects mostly young children, commonly following an acute viral or upper respiratory illness. Chronic paroxysmal cold hemoglobinuria is commonly seen in the elderly. Contributory secondary causes are generally neoplastic in origin, followed by infections.

Paroxysmal Cold Hemoglobinuria. National Organization for Rare Disorders. Available at https://rarediseases.org/rare-diseases/paroxysmal-cold-hemoglobinuria/. 2012; Accessed: January 4, 2018.

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].

Bunch C, Schwartz FC, Bird GW. Paroxysmal cold haemoglobinuria following measles immunization. Arch Dis Child. 1972 Apr. 47(252):299-300. [Medline]. [Full Text].

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].

Bird GW, Wingham J, Martin AJ, et al. Idiopathic non-syphilitic paroxysmal cold haemoglobinuria in children. J Clin Pathol. 1976 Mar. 29(3):215-8. [Medline]. [Full Text].

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.

Gertz MA. Cold hemolytic syndrome. Hematology Am Soc Hematol Educ Program. 2006. 19-23. [Medline]. [Full Text].

Berentsen S. Role of Complement in Autoimmune Hemolytic Anemia. Transfus Med Hemother. 2015 Sep. 42 (5):303-10. [Medline]. [Full Text].

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].

Rosse WF, Hillmen P, Schreiber AD. Immune-mediated hemolytic anemia. Hematology Am Soc Hematol Educ Program. 2004. 48-62. [Medline]. [Full Text].

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].

Chandrashekar V, Soni M. Florid erythrophagocytosis on the peripheral smear. J Lab Physicians. 2012 Jan. 4(1):59-61. [Medline]. [Full Text].

Mukhopadhyay S, Keating L, Souid AK. Erythrophagocytosis in paroxysmal cold hemoglobinuria. Am J Hematol. 2003 Nov. 74(3):196-7. [Medline]. [Full Text].

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].

Zeller MP, Arnold DM, Al Habsi K, Cserti-Gazdewich C, Delage G, Lebrun A, et al. Paroxysmal cold hemoglobinuria: a difficult diagnosis in adult patients. Transfusion. 2017 Jan. 57 (1):137-143. [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].

Neetu Radhakrishnan, MD Associate Professor (Adjunct) of Medicine, Division of Hematology/Oncology, University of Cincinnati Medical Center; Hematology/Oncology Medical Director, West Chester Outpatient Clinics

Neetu Radhakrishnan, MD is a member of the following medical societies: American College of Physicians, American Society of Clinical Oncology, American Society of Hematology

Disclosure: Nothing to disclose.

Ronald A Sacher, MBBCh, FRCPC, DTM&H Professor of Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

Ronald A Sacher, MBBCh, FRCPC, DTM&H is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Clinical and Climatological Association, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society of Blood Transfusion, International Society on Thrombosis and Haemostasis, Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Ronald A Sacher, MBBCh, FRCPC, DTM&H Professor of Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

Ronald A Sacher, MBBCh, FRCPC, DTM&H is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Clinical and Climatological Association, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society of Blood Transfusion, International Society on Thrombosis and Haemostasis, Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Paul Schick, MD Emeritus Professor, Department of Internal Medicine, Jefferson Medical College of Thomas Jefferson University; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Adjunct Professor of Medicine, Lankenau Hospital

Paul Schick, MD is a member of the following medical societies: American College of Physicians, American Society of Hematology

Disclosure: Nothing to disclose.

Corinne Goldberg, MD Fellow in Transfusion Medicine/Blood Banking, Transfusion Medicine Department, Hoxworth Blood Center, University of Cincinnati

Disclosure: Nothing to disclose.

Rajalaxmi McKenna, MD, FACP Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems

Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis

Disclosure: Nothing to disclose.

Harry L Messmore, Jr, MD Professor, Department of Medicine, Division of Hematology/Oncology, Loyola University Stritch School of Medicine

Harry L Messmore, Jr, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Angiology, American College of Physicians, American Heart Assocation, American Society of Hematology, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Paroxysmal Cold Hemoglobinuria

Research & References of Paroxysmal Cold Hemoglobinuria|A&C Accounting And Tax Services
Source

Share on Facebook

Tweet

Follow us