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Cold Agglutinin Disease

Cold Agglutinin Syndrome

Cold agglutinin disease is a subcategory of autoimmune hemolytic anemias and is caused by antibodies (mostly IgM type, sometimes IgG or IgA) directed towards the red blood cells. This disease is primary or secondary to an infection, malignancy or connective tissue disease.


Presentation

The disease usually affects women and may become apparent in the 5th- 7th decade of life [1] [2].

Patients may have symptoms and signs due to anemia such as chronic fatigue and pallor, especially since hemoglobin may drop as low as 4.5 g/dl [3].

Symptoms worsen in cases of trauma or a febrile disease because the hemolysis becomes acute [4].

Other symptoms are triggered by exposure to cold and consist of livedo reticularis and acrocyanosis (that does not go through the three phases of the Raynaud phenomenon) or Raynaud syndrome [5] [6] [7]. Obstruction of circulation by agglutinated red blood cells may occur, leading to cutaneous necrosis.

Hemoglobinuria is due to hemolysis but is less important than the one seen in paroxysmal nocturnal hemoglobinuria open link. Patients may also exhibit dizziness, tinnitus, vision abnormalities, amenorrhea and pain in the extremities after cold exposure.

The clinician might notice a low degree splenomegaly, lymphadenopathy, jaundice and signs of an underlying disease: pneumonia, mononucleosis, lymphoma or leukemia, lupus erythematous. Severe anemia might precipitate heart failure. Hepatomegaly may be present if the underlying disease is an immunoproliferative disease but it is not a consequence of cold agglutinin disease per se.

Fatigue
  • Cold agglutinin disease manifests as acute or chronic hemolytic anemia, with associated pallor and fatigue.[orpha.net]
  • Patients may have symptoms and signs due to anemia such as chronic fatigue and pallor, especially since hemoglobin may drop as low as 4.5 g/dl. Symptoms worsen in cases of trauma or a febrile disease because the hemolysis becomes acute.[symptoma.com]
  • If your anemia is severe and/or you are symptomatic from the anemia (rapid heart rate, fatigue, dizziness) you will likely need a red blood cell transfusion.[verywell.com]
Raynaud Phenomenon
  • A 60-year-old male who had been treated for polymyalgia rheumatica (PMR) with Raynaud's phenomenon was admitted to our hospital with acrocyanosis and rapid progressive anemia.[ncbi.nlm.nih.gov]
  • Other symptoms are triggered by exposure to cold and consist of livedo reticularis and acrocyanosis (that does not go through the three phases of the Raynaud phenomenon) or Raynaud syndrome.[symptoma.com]
Fever
  • We previously described a paradoxical form of chronic cold agglutinin disease (CAD) in which haemolysis occurred during episodes of fever but only marginally during exposure to colds.[ncbi.nlm.nih.gov]
  • Other complaints include a continuous, nonproductive cough with low grade fever. She believes that her symptoms are due to the winter temperature, as her symptoms improve when she is indoors.[medbullets.com]
  • Blood Investigations A 55 yr old male presented to the Emergency Department with fever, chills, rigor and yellowish discoloration of eyes and urine. He had a history of travel to Chennai.[keralamedicaljournal.com]
  • He had 102.7 fever, low blood, dehighdrated, etc... Drs felt he got infection due to low resistance from chemo. We are so overwhelmed.[healthunlocked.com]
  • Betty is a 28-year-old Caucasian female who presented to the Emergency Room with shortness of breath, cough, chills, and fever of 4 day duration. Her sputum was yellow and thick in consistency.[blog.medicalalgorithms.com]
Chills
  • Blood Investigations A 55 yr old male presented to the Emergency Department with fever, chills, rigor and yellowish discoloration of eyes and urine. He had a history of travel to Chennai.[keralamedicaljournal.com]
  • Betty is a 28-year-old Caucasian female who presented to the Emergency Room with shortness of breath, cough, chills, and fever of 4 day duration. Her sputum was yellow and thick in consistency.[blog.medicalalgorithms.com]
  • Case Report A 16-year-old male patient was admitted to our Emergency Medicine Department with complaints of continuous high grade fever associated with chills and rigors for 8 days, yellowish discoloration of urine and eyes for 2 days, vomiting for 1[jbclinpharm.org]
Aspiration
  • Bone marrow aspiration showed discrete hyperplasia of the erythropoietic system. She was diagnosed as low-titer cold agglutinin disease rousing secondarily to SSc. The anemia was alleviated with the oral administration of prednisolone.[ncbi.nlm.nih.gov]
  • If reticulocytes are found to be low, decreased bone marrow erythropoiesis should be suspected and demonstrated by needle aspiration. This can be due to infection or lymphoproliferative disease.[symptoma.com]
  • Furthermore, we observed a near complete elimination of CD20 cells from bone marrow aspirates after most courses of rituximab therapy in responders and nonresponders.[doi.org]
  • Bone marrow aspiration showed discrete hyperplasia but no signs of lymphoproliferative disorders. A peripheral blood smear showed clumping of adherent erythrocytes [Figure 1] d.[ijdvl.com]
Cutaneous Manifestation
  • We present the case of a woman where the diagnosis of cold agglutinin disease could be made after we had noticed slight cutaneous manifestations during a routine examination.[ncbi.nlm.nih.gov]
Long Arm
  • It was observed in all patients with abnormal karyotype, either as a complete trisomy or as a partial trisomy of the long arm. The importance of this particular karyotypic aberration in the monitoring of CAD is emphasized.[ncbi.nlm.nih.gov]
Headache
  • Symptoms during hemolytic crises'' may include severe pain in the back and legs, headache, vomiting, diarrhea, dark urine and hepatosplenomegaly.[orpha.net]
  • Signs and symptoms of hemolytic anemia may include: Tiredness (fatigue) Dizziness Headaches Cold hands and feet Pale skin Dark urine Jaundice Chest pain Pain in the back or legs Vomiting or diarrhea Heart problems such as an irregular heartbeat (arrhythmia[en.wikipedia.org]
  • Symptoms during hemolytic crises may include severe pain in the back and legs, headache, vomiting, diarrhea, dark urine, and hepatosplenomegaly.[askhematologist.com]
Dark Urine
  • Symptoms during hemolytic crises'' may include severe pain in the back and legs, headache, vomiting, diarrhea, dark urine and hepatosplenomegaly.[orpha.net]
  • Symptoms during hemolytic crises may include severe pain in the back and legs, headache, vomiting, diarrhea, dark urine, and hepatosplenomegaly.[askhematologist.com]
  • Some signs of anemia are fatigue, headache, lack of energy and stamina, a yellow pallor and perhaps a yellowing of the eyes, dark urine, irritability, mental confusion, and an enlarged spleen.[coldagglutinindisease.org]

Workup

Workup normally starts with a standard complete blood count, which reveals anemia and red blood cell agglutination. The mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC) are falsely elevated. This type of anemia is regenerative, therefore reticulocyte count is high. If reticulocytes are found to be low, decreased bone marrow erythropoiesis should be suspected and demonstrated by needle aspiration. This can be due to infection or lymphoproliferative disease. Hemolysis causes hyperbilirubinemia and elevated lactate dehydrogenase. As with other hemolytic anemias, spherocytes may be present.

The next step is to perform a Coombs reaction, that determines if the red blood cells are coated with immunoglobulin, complement or both in vivo. If positive, and in cold agglutinin disease this test is usually positive for IgM, it should be followed by the determination of the titer of antibodies and their thermal activity [8].

Titers higher than 1:512 are considered to be clinically significant, while titers greater than 1:64 are considered abnormal. If high titers are found, blood should also be tested after being warmed to 37 degrees Celsius. [9] [10]. When bovine serum albumin is added during cold agglutinin titer and thermal amplitude testing, the results provide a better correlation with the clinical condition. [11]

Another useful test is protein electrophoresis or immunoelectrophoresis to determine if dysproteinemia is present.

Given the fact that cold agglutinin disease is often secondary to other diseases, certain entities should be tested for: influenza, infectious mononucleosis, AIDS, hepatitis, malaria, cytomegalovirus infection, systemic lupus erythematosus [12], scleroderma, rheumatoid arthritis [13], sarcomas [14], carcinomas [15], melanomas, and immunoproliferative diseases. If the latter is suspected, bone marrow evaluation and lymph node biopsies should be performed.

Lactate Dehydrogenase Increased
  • dehydrogenase) Increased DAT (direct anti-globulin test) for anti-C3d (antibody to complement protein C3d) Present Haptoglobin Decreased Cold agglutinin titers Present C3, C4, CH50 Decreased What imaging studies (if any) will be helpful in making or[cancertherapyadvisor.com]
Complement Fixing Antibody
  • Complement-fixing antibody levels to Mycoplasma pneumoniae, influenza A, and adenoviruses were measured repeatedly throughout the clinical illness and were persistently nondiagnostic.[ncbi.nlm.nih.gov]

Treatment

  • Medical researchers have found the response to rituximab is seen on average within 1 to 2 months of treatment and the effect of the treatment lasts for about 1 to 2 years.[web.archive.org]
  • The role of bortezomib in the treatment of cryoglobulinemic vasculitis needs further investigation.[ncbi.nlm.nih.gov]
  • Management and treatment Patients with few clinical symptoms and mild anemia may not require treatment but only avoidance of cold. Keeping the patient warm may be sufficient treatment. The disease is usually refractory to corticosteroids.[orpha.net]
  • The most common reason for treatment initiation was progressive anemia (39 patients [53%]), treatment of other CAD symptoms (18 patients [25%]), and treatment of underlying disorder (9 patients [12%]).[doi.org]

Prognosis

  • Mild to moderate primary (unknown cause) cold agglutinin disease can also be associated with a good prognosis if excessive exposure to the cold is avoided.[web.archive.org]
  • Each has a different underlying cause, management, and prognosis, making classification important when treating a patient with AIHA.[en.wikipedia.org]
  • We reviewed the clinical and pathologic features, prognosis, and management in the literature and describe our institutional experience to improve strategies for accurate diagnosis and treatment.[ncbi.nlm.nih.gov]
  • Prognosis The disease has a chronic course and the outcome is usually benign, except in patients with recurrent episodes of severe anemia or in whom the underlying B-cell lymphoma has an aggressive course.[orpha.net]

Etiology

  • The current knowledge about the etiology, clinical presentation and treatment of the disease is briefly discussed.[ncbi.nlm.nih.gov]
  • Etiology Cold agglutinin disease can be primary (idiopathic) or secondary, caused by an underlying condition, such as infection ( Mycoplasma pneumoniae ), lymphoproliferative disorders, systemic autoimmunity or neoplasm.[orpha.net]

Epidemiology

  • The aim of this study was to collect comprehensive and precise data the on epidemiology, clinical and pathological features, course, and therapy of CAD.[ncbi.nlm.nih.gov]
  • Summary Epidemiology Cold agglutinin disease represents an estimated 16-32% of AIHA, whose annual incidence is estimated to be between 1/35,000-1/80,000 in North America and Western Europe.[orpha.net]
  • 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]
  • Epidemiology AIHA is a rare disease. Warm AIHA occurs in 1 in 75,000-80,000 patients yearly. It tends to occur in the elderly. The incidence increases after age 40 with a peak between age 60 and 70.[clinicaladvisor.com]
Sex distribution
Age distribution

Pathophysiology

  • Original papers and reviews of the recent years on studies of the biochemistry and specificity of CAs and the pathophysiology of AIHA. A crucial point for the severity of AIHA caused by CAs is the CA-binding capacity to red cells in vivo.[ncbi.nlm.nih.gov]
  • […] 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]
  • Selection Criteria : Original papers and reviews of the recent years on studies of the biochemistry and specificity of CAs and the pathophysiology of AIHA.[karger.com]

Prevention

  • To prevent her having an exacerbation of haemolysis, we chose to treat her prophylactically with eculizumab along with the usual perioperative precautions. Aortic valve replacement was undertaken with full cardiopulmonary bypass at normothermia.[ncbi.nlm.nih.gov]
  • TNT009 thereby prevents downstream disease processes involving phagocytosis, inflammation, and cell lysis.[businesswire.com]
  • Causes - Cold agglutinin disease Prevention - Cold agglutinin disease Not supplied. Diagnosis - Cold agglutinin disease Prognosis - Cold agglutinin disease Not supplied. Treatment - Cold agglutinin disease Not supplied.[checkorphan.org]

References

Article

  1. Petz LD. Cold antibody autoimmune hemolytic anemias. Blood Rev 2008;22(1):1-15.
  2. Berentsen S, Ulvestad E, Langholm R, et al. Primary chronic cold agglutinin disease: a population based clinical study of 86 patients. Haematologica 2006;91(4):460-466
  3. Berentsen S, Tjønnfjord GE. Diagnosis and treatment of cold agglutinin mediated autoimmune hemolytic anemia. Blood Rev 2012;26(3):107-115.
  4. Ulvestad E, Berentsen S, Mollnes TE. Acute phase haemolysis in chronic cold agglutinin disease. Scand J Immunol 2001;54(1-2):239-242.
  5. Läuchli S, Widmer L, Lautenschlager S. Cold agglutinin disease—the importance of cutaneous signs. Dermatology 2001;202(4):356-358.
  6. Mitchell AB, Pergrum GD, Gill AM. Cold agglutinin disease with Raynaud’s phenomenon. Proc R Soc Med 1974;67(2):113-115.
  7. McNicholl FP. Clinical syndromes associated with cold agglutinins. Transfus Sci. 2000 Feb-Apr; 22(1-2):125-33.
  8. Petz LD. Cold antibody autoimmune hemolytic anemias. Blood Rev 2008;22(1):1-15
  9. Lechner K, Jäger U. How I treat autoimmune hemolytic anemias in adults. Blood 2010;116(11):1831-1838.
  10. Gertz MA. Cold hemolytic syndrome. Hematology Am Soc Hematol Educ Program. 2006;19-23.
  11. Garratty G, Petz LD, Hoops JK. The correlation of cold agglutinin titrations in saline and albumin with haemolytic anaemia. Br J Haematol. 1977 Apr; 35(4):587-95.
  12. Srinivasan N, Oswal A, Garg S, et al. Cold agglutinin induced hemolysis in a newly diagnosed systemic lupus erythematosus. Am J Med Sci 2010;339(3):270-273.
  13. Cholongitas E, Ioannidou D. Acrocyanosis due to cold agglutinins in a patient with rheumatoid arthritis. J Clin Rheumatol 2009;15(7):375.
  14. Cao L, Kaiser P, Gustin D, Hoffman R, Feldman L. Cold agglutinin disease in a patient with uterine sarcoma. Am J Med Sci 2000;320(5):352-354.
  15. Al-Matham K, Alabed I, Zaidi SZ, Qushmaq KA. Cold agglutinin disease in fibrolamellar hepatocellular carcinoma: a rare association with a rare cancer variant. Ann Saudi Med 2011;31(2):197-200.

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Last updated: 2019-07-11 20:43