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Paroxysmal Cold Hemoglobinuria

Paroxysmal cold hemoglobinuria constitutes a disorder that causes sudden-onset anemia, hemoglobinuria, and a variety of other systemic manifestations, following exposure to cold temperature. It is classified under the wider category of autoimmune hemolytic anemias.


Presentation

Paroxysmal cold hemoglobinuria (PCH) has been a recognized medical entity for more than 150 years. It more commonly affects pediatric patients and is nowadays associated with prior infections, mainly pertaining to the respiratory tract. Cold temperatures act as a stimulus for a cascade of symptoms and signs to appear; the condition may lapse into chronicity with multiple episodes occurring in an individual's life, even though this is a rare phenomenon [1] [2].

Clinically significant symptoms and signs typically appear minutes after the patient has been exposed to cold, but the reaction may be delayed even to after a few hours following exposure. Hemolysis is severe to the extent that urine may appear brown-colored, with no or, rarely, minimal presence of blood. Fever with rigor is common, alongside abdominal cramping, pallor, nausea, vomiting, diarrhea, cephalalgia, and muscle spasms in the lower extremities. Should the kidneys be affected as well, the condition may progress to the renal dysfunction that presents with oliguria or even anuria in extreme circumstances; jaundice and urticarial rash may also develop [3].

Patients may report a history of prior infection localized in the respiratory tract during the past 1 to 2 weeks, although other types of infections have been linked to paroxysmal cold hemoglobinuria as well [4]. Hepatosplenomegaly may complete the clinical picture, as can microthrombosis which is an uncommon manifestation [5]. PCH is usually a self-limited, spontaneously resolving disorder that subsides over a period of a few days to some weeks after an episode [6].

Chills
  • Usually, hemoglobin was present in the first specimen of urine passed after the onset of symptoms, and the interval between chilling and the development of symptoms ranged from a few minutes to eight hours.[rarediseases.org]
  • The syphilitic form is caused by a specific hemolysin which becomes fixed to erythrocytes when the patient is chilled and causes hemolysis when the patient is subsequently warmed.[annals.org]
  • Common clinical symptoms Sudden onset of fever Chills Abdominal cramps Back pain Intermittent episodes of hemoglobinuria Typical laboratory findings Elevated bilirubin level Decreased hemoglobin Polychromatophilia, nucleated RBCs, and poikilocytosis may[labce.com]
  • PCH usually appears in young children as recurrent high fevers, chills, and passage of red-brown urine. The diagnostic test for PCH is the Donath-Landsteiner test, an in vitro assay for biphasic hemolysis.[ncbi.nlm.nih.gov]
  • Symptoms Exposure to cold classically precedes symptoms Headache Back pain and Leg Pain Abdominal cramps Vomiting and Diarrhea Fever and chills V. Signs Splenomegaly Hepatomegaly Transient Jaundice Pale fingers, toes, and tip of nose VI.[fpnotebook.com]
Rigor
  • Fever with rigor is common, alongside abdominal cramping, pallor, nausea, vomiting, diarrhea, cephalalgia, and muscle spasms in the lower extremities.[symptoma.com]
  • Features such as fever, rigors, back/leg/ abdominal pain, headache, nausea, oesophageal pain and spasm, vomiting and diarrhoea are relatively common.[patient.info]
  • Symptoms of anemia Pallor Fatigue Dyspnea Poor feeding Symptoms of hemolysis Jaundice Dark urine caused by hemoglobinuria Systemic symptoms Fever, rigors Pain or cramps in the back, legs, or abdomen Headache Nausea, vomiting, diarrhea Vasomotor symptoms[forums.prohealth.com]
  • […] blood cells (RBCs) in the cold and inducing hemolysis due to complement activation when the RBCs are warmed. [1] [2] [4] [14] Episodes are heralded by a combination of the following: sudden onset of back and abdominal pain, headache, leg cramps, fever, rigors[ijcasereportsandimages.com]
  • On exposure to cold, patients with PCH present with symptoms like fever, rigor, leg pain, back pain and abdominal pain followed by hemoglobinuria, anemia and eventually renal failure 7.[ispub.com]
Precocious Puberty
  • Puberty 148 XLMRHypotonic Facies Syndrome 27 Pseudohypoparathyroidism 149[books.google.com]
Splenomegaly
  • Signs Splenomegaly Hepatomegaly Transient Jaundice Pale fingers, toes, and tip of nose VI.[fpnotebook.com]
  • Typically there was a sudden onset of pallor and malaise; jaundice, splenomegaly and hepatomegaly were found in about half the subjects. Haemoglobinuria was characteristic of Donath-Landsteiner haemolysis.[doi.org]
  • Signs of hemolysis include jaundice and splenomegaly. Vasomotor signs include cyanosis, Raynaud phenomenon, and gangrene.[forums.prohealth.com]
Abdominal Cramps
  • Fever with rigor is common, alongside abdominal cramping, pallor, nausea, vomiting, diarrhea, cephalalgia, and muscle spasms in the lower extremities.[symptoma.com]
  • Common clinical symptoms Sudden onset of fever Chills Abdominal cramps Back pain Intermittent episodes of hemoglobinuria Typical laboratory findings Elevated bilirubin level Decreased hemoglobin Polychromatophilia, nucleated RBCs, and poikilocytosis may[labce.com]
  • Symptoms Exposure to cold classically precedes symptoms Headache Back pain and Leg Pain Abdominal cramps Vomiting and Diarrhea Fever and chills V. Signs Splenomegaly Hepatomegaly Transient Jaundice Pale fingers, toes, and tip of nose VI.[fpnotebook.com]
  • cramping, headaches, hemoglobinuria, Raynaud phenomenon, cold urticaria, jaundice Lab Positive direct Coombs test–using anti-C3 antiserum, anemia, hemoglobinuria, haptoglobin, LD, BR; the antibody is a non-agglutinating IgG that binds to RBCs at cold[medical-dictionary.thefreedictionary.com]
Hepatomegaly
  • Signs Splenomegaly Hepatomegaly Transient Jaundice Pale fingers, toes, and tip of nose VI.[fpnotebook.com]
  • Typically there was a sudden onset of pallor and malaise; jaundice, splenomegaly and hepatomegaly were found in about half the subjects. Haemoglobinuria was characteristic of Donath-Landsteiner haemolysis.[doi.org]
  • […] thrombocytopenia: mucosal bleeding, petechiae, and ecchymoses leukemia: infections thrombosis abdominal pain, fever, and rectal bleeding (mesenteric vein thrombosis) headache, vomiting, and seizures (cerebral venous sinous thrombosis) fever, jaundice, hepatomegaly[medbullets.com]
Hepatosplenomegaly
  • Hepatosplenomegaly may complete the clinical picture, as can microthrombosis which is an uncommon manifestation.[symptoma.com]
  • Temporary hepatosplenomegaly and mild hyperbilirubinemia may follow the onset of an attack. paroxysmal cold hemoglobinuria Hematology A disorder that is: (1) Rarely 'paroxysmal' clinically; (2) Not always precipitated by the cold; and (3) Not always associated[medical-dictionary.thefreedictionary.com]
  • 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. The exact pathogenesis is not fully elucidated.[en.wikipedia.org]
  • Pallor and tachycardia are likely to be present and the abdomen should be examined for evidence of hepatosplenomegaly (possible underlying neoplasm). Lymph node areas should be examined and the chest checked for evidence of current infection.[patient.info]
  • Symptoms of PCH may include severe pain in the back and legs, headache, vomiting, diarrhea, and passage of dark brown urine; hepatosplenomegaly may be present.[msdmanuals.com]
Back Pain
  • Common clinical symptoms Sudden onset of fever Chills Abdominal cramps Back pain Intermittent episodes of hemoglobinuria Typical laboratory findings Elevated bilirubin level Decreased hemoglobin Polychromatophilia, nucleated RBCs, and poikilocytosis may[labce.com]
  • Symptoms Exposure to cold classically precedes symptoms Headache Back pain and Leg Pain Abdominal cramps Vomiting and Diarrhea Fever and chills V. Signs Splenomegaly Hepatomegaly Transient Jaundice Pale fingers, toes, and tip of nose VI.[fpnotebook.com]
  • Symptoms Symptoms may include: Chills Fever Back pain Leg pain Abdominal pain Headache General discomfort, uneasiness, or ill feeling ( malaise ) Blood in the urine (red urine) Exams and Tests Laboratory tests can help diagnose this condition.[mountsinai.org]
Painful Muscle Cramps
  • A thorough medical history should reveal symptoms compatible with this type of hemolytic anemia such as pallor, abdominal pain, muscle cramps, diarrhea, vomiting, and other manifestations, following exposure to a cold temperature.[symptoma.com]
Myalgia
  • […] is caused by IgG–Donath-Landsteiner antibodies that react at 15ºC and are directed against the ubiquitous P antigen on red cells; PCH may be transient, and 2º to viral exanthemas of childhood Clinical After exposure to the cold, the Pt may experience myalgia[medical-dictionary.thefreedictionary.com]
Dark Urine
  • He was admitted because of dark urine after exposure to cold air. Laboratory tests indicated anemia, increased serum indirect bilirubin and lactate dehydrogenase, and decreased serum haptoglobin. Donath-Landsteiner (D-L) test was positive.[ncbi.nlm.nih.gov]
  • Systemic symptoms include the passage of dark urine, severe pain in the back and legs, headache, vomiting, diarrhea, and moderate reticulocytosis.[medical-dictionary.thefreedictionary.com]
  • Patient education Teach patients to observe for signs and symptoms of anemia (eg, dyspnea, palpitations, fatigue, pallor) and to observe for signs of hemolysis (eg, jaundice, dark urine, pain).[emedicine.com]
  • Presentation Symptoms/physical exam episodic dark urine with first urine of the day caused by hemoglobin chronic intravascular hemolytic anemia: pallor, fatigue, tachycardia, jaundice, and gross hematuria acute hemolytic episodes from activators of complement[medbullets.com]
Red Urine
  • Symptoms Symptoms may include: Chills Fever Back pain Leg pain Abdominal pain Headache General discomfort, uneasiness, or ill feeling ( malaise ) Blood in the urine (red urine) Exams and Tests Laboratory tests can help diagnose this condition.[mountsinai.org]
  • Case presentation An 18 year old female patient presented with acute symptoms of abdominal and flank pain, nausea, dark red urine, fevers and chills.[bmchematol.biomedcentral.com]
  • Upon further enquiry, daughter recounted were present a remote history of similar passage of red urine that resolved spontaneously. Medical history was significant for hypertension and dementia.[ijcasereportsandimages.com]
Headache
  • Systemic symptoms include the passage of dark urine, severe pain in the back and legs, headache, vomiting, diarrhea, and moderate reticulocytosis.[medical-dictionary.thefreedictionary.com]
  • Symptoms Exposure to cold classically precedes symptoms Headache Back pain and Leg Pain Abdominal cramps Vomiting and Diarrhea Fever and chills V. Signs Splenomegaly Hepatomegaly Transient Jaundice Pale fingers, toes, and tip of nose VI.[fpnotebook.com]
  • Less common findings associated with PCH include headaches, vomiting and diarrhea. Following an episode, affected individuals usually develop the signs of hemolysis including yellowing of the skin, whites of the eyes and mucous membranes (jaundice).[rarediseases.org]
  • Symptoms Symptoms may include: Chills Fever Back pain Leg pain Abdominal pain Headache General discomfort, uneasiness, or ill feeling ( malaise ) Blood in the urine (red urine) Exams and Tests Laboratory tests can help diagnose this condition.[mountsinai.org]

Workup

PCH requires an extensive workup for an accurate diagnosis to be achieved. A thorough medical history should reveal symptoms compatible with this type of hemolytic anemia such as pallor, abdominal pain, muscle cramps, diarrhea, vomiting, and other manifestations, following exposure to a cold temperature. Patients often report a preceding respiratory tract or other infection.

Following the medical history, blood cell studies, biochemical blood studies, urinalysis, direct antiglobulin testing, and the Donath-Landsteiner test should all be performed. Blood analysis will reveal anemia of varying severity that is expected to be normocytic and normochromic or even macrocytic. Reticulocytopenia is a common finding, especially in cases where profound symptomatology is involved. Other morphological abnormalities may be observed in the red blood cells such as poikilocytosis, polychromasia, spherocytosis, and nucleated erythrocytes. Erythrophagocytosis by neutrophils may also be present and strongly indicates the presence of paroxysmal cold hemoglobinuria [7] [8] [9].

Free hemoglobin or methemoglobin and hemosiderin are usually detected via urinalysis, especially early in the course of a PCH episode. Erythrocytes are not a frequent finding but may also be observed. A complete serum biochemical profile is useful, as it will illustrate pathologically increased values of lactate dehydrogenase (LDH) and unconjugated bilirubin, decreased haptoglobin levels, and the existence of free plasma hemoglobin. During the acute phase of paroxysmal cold hemoglobinuria, complement concentration, namely, C2, C3, and C4, are found to be low.

A direct antiglobulin test with monoclonal C3 antisera is usually positive in the acute phase [10]. Lastly, the Donath-Landsteiner antibody test is considered diagnostic of PCH and is also expected to be positive in such a case.

Treatment

  • Treatment is mainly supportive and with red cell transfusion, but immunosuppressive therapy may be effective in severe cases.[ncbi.nlm.nih.gov]
  • The clinical course and treatment of this condition, which has not been reported previously, are described. 2015 Wiley Periodicals, Inc. KEYWORDS: Donath-Landsteiner antibody; IgA; autoimmune hemolytic anemia; paroxysmal cold hemoglobinuria[ncbi.nlm.nih.gov]
  • Treatment Treating the underlying condition can help. For example, if PCH is caused by syphilis, symptoms may get better when the syphilis is treated. In some cases, medicines that suppress the immune system are used.[mountsinai.org]

Prognosis

  • Conclusion The prognosis of PCH associated with syphilis is usually considered excellent and benign.[edoriumjournals.com]
  • Outlook (Prognosis) People with this disease often get better quickly and do not have symptoms between episodes. In most cases, the attacks end as soon as the damaged cells stop moving through the body.[mountsinai.org]
  • Each has a different underlying cause, management, and prognosis, making classification important when treating a patient with AIHA.[en.wikipedia.org]

Etiology

  • HEENT, chest, cardiovascular and abdominal (no organomegaly) with rectal exam was normal, neurological exam was consistent with mild-moderate dementia, initially suggestive to Alzheimer' or vascular etiology.[ijcasereportsandimages.com]
  • Over the ensuing decades, the etiology of the condition was elucidated and a diagnostic test was developed. [5] In 1904, Donath and Landsteiner reported their characterization of the causative antibody. [6] The discovery of the D-L antibody has permitted[emedicine.com]
  • Applicable To Hemoglobinuria from exertion March hemoglobinuria Paroxysmal cold hemoglobinuria Use Additional Use Additional Help Certain conditions have both an underlying etiology and multiple body system manifestations due to the underlying etiology[icd10data.com]
  • Embolic etiology was also ruled out. Due to worsening of peripheral cyanosis and severe peripheral infarction, patient had transmetatarsal amputation of toes.[edoriumjournals.com]

Epidemiology

  • Quantification of IgG, IgA, IgM Other testing based on clinical presentation Differential Diagnosis Hemoglobinopathies Paroxysmal cold hemoglobinuria Paroxysmal nocturnal hemoglobinuria Thalassemias Connective tissue disease Antiphospholipid syndrome Background Epidemiology[arupconsult.com]
  • The antibodies detectable in the blood of those who suffer from PCH are known as 'Donath-Landsteiner antibodies'. [ 1 ] Epidemiology It is a very rare illness; there are no reliable population-incidence figures, but it is believed to be responsible for[patient.info]
Sex distribution
Age distribution

Pathophysiology

  • Pathophysiology Rare Immune Hemolytic Anemia Caused by complement fixing IgG autoantibody Activates classic complement pathway III. Causes Idiopathic Tertiary Syphilis Acute Viral Infection Mumps Measles IV.[fpnotebook.com]
  • […] pneumoniae Legionella pneumophila Viral Influenza A and B viruses Adenovirus Epstein-Barr virus Genetic – trisomy 3 and 12 Autoimmune disorders Systemic lupus erythematosus Systemic sclerosis (scleroderma) Antiphospholipid syndrome Ulcerative colitis Pathophysiology[arupconsult.com]
  • Figure 1 TABLE-1: TYPES OF COLD AGGLUTININ DISEASE (PCH - paroxysmal cold hemoglobinuria, DAT- direct antiglobulin test, C3 - complement third component, RBC -Red blood cell) Figure 2 TABLE – 2: CAUSES OF COLD AGGLUTININ DISEASE (CAD) In pathophysiology[ispub.com]
  • Pathophysiology of Hemolytic Anemia Normal bone marrow is capable of increasing its production rate by about 6 to 8 times.[medcaretips.com]

Prevention

  • Avoidance of cold in the recovery period is imperative to prevent recurrences, whereas a short course of corticosteroids may be of benefit in suppressing the antibody production.[ncbi.nlm.nih.gov]
  • Rapidly find the answers you need with separate sections on diseases and disorders, differential diagnosis, clinical algorithms, laboratory results, and clinical preventive services, plus an at-a-glance format that uses cross-references, outlines, bullets[books.google.com]
  • Prevention People who have been diagnosed with this disease can prevent future attacks by staying out of the cold. References Michel M. Autoimmune and intravascular hemolytic anemias. In: Goldman L, Schafer AI, eds. Goldman-Cecil Medicine. 25th ed.[mountsinai.org]
  • Prevention People who have been diagnosed with this disease can prevent future attacks by staying out of the cold. Images References Jager U, Lechner K. Autoimmune hemolytic anemia.[ufhealth.org]
  • Prevention People who have been diagnosed with this disease can prevent future attacks by staying out of the cold. visHeader References Michel M. Autoimmune and intravascular hemolytic anemias. In: Goldman L, Schafer AI, eds.[mclarenhealthplan.org]

References

Article

  1. Petz LD. Cold antibody autoimmune hemolytic anemias. Blood Rev. 2008;22(1):1–15.
  2. Taylor CJ, Neilson JR, Chandra D, Ibrahim Z. Recurrent paroxysmal cold haemoglobinuria in a 3-year-old child: a case report. Transfus Med. 2003;13(5):319–321.
  3. Vergara LH, Mota MC, Sarmento Ada G, Duarte CA, Barbot JM. [Acute renal failure secondary to paroxysmal cold hemoglobinuria] [Spanish]. An Pediatr (Barc). 2006;64(3):267-269.
  4. Koppel A, Lim S, Osby M, Garratty G, Goldfinger D. Rituximab as successful therapy in a patient with refractory paroxysmal cold hemoglobinuria. Transfusion. 2007;47(10):1902–1904.
  5. Kim GM, Kim CH, Kim BS. Multiple cerebral infarction and microbleeds associated with adult-onset paroxysmal cold hemoglobinuria. J Clin Neurosci. 2009;16(2):348-349.
  6. Akpoguma AO, Carlisle TL, Lentz SR. Case report: paroxysmal cold hemoglobinuria presenting during pregnancy. BMC Hematol. 2015; 15:3.
  7. Garratty G. Erythrophagocytosis on the peripheral blood smear and paroxysmal cold hemoglobinuria. Transfusion. 2001;41(8):1073-1074.
  8. Lechner K, Jäger U. How I treat autoimmune hemolytic anemias in adults. Blood. 2010 Sep;116(11):1831-1838.
  9. Roy-Burman A, Glader BE. Resolution of severe Donath-Landsteiner autoimmune hemolytic anemia temporally associated with institution of plasmapheresis. Crit Care Med. 2002;30(4):931-934.
  10. Mukhopadhyay S, Keating L, Souid AK. Erythrophagocytosis in paroxysmal cold hemoglobinuria. Am J Hematol. 2003;74(3):196-197.

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Last updated: 2018-06-21 19:04