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]

  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]

  We ask about general symptoms (anxious mood, depressed mood, fatigue, pain, and stress) regardless of condition. Last updated: January 30, 2019 [patientslikeme.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]

  Álvaro Giráldez Gallego, María Elisa Cordero Matía, José Manuel Sousa Martín, Abstract Epstein-Barr virus, a member of the Herpesviridae family, is responsible for the infectious mononucleosis clinical syndrome, which mainly includes the pharyngitis, fever [reed.es]

  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]

• Raynaud Syndrome

  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]

  In its classic presentation with haemolytic anaemia and Raynaud's syndrome, cold agglutinin disease is usually idiopathic. [jmedicalcasereports.biomedcentral.com]

  syndrome, cold agglutinin disease is usually idiopathic. [emedicine.medscape.com]

• Asymptomatic

  All hemolytic anemias feature varying degrees of fatigue, pallor, and weakness (from asymptomatic disease to life-threatening hemolytic crisis ), although some diseases have more specific findings (e.g., venous thrombosis in paroxysmal nocturnal hemoglobinuria [amboss.com]

  It is thought that many people who develop 'pathological' cold agglutinins remain asymptomatic or become only subclinically unwell. [patient.info]

  It is frequently well tolerated and asymptomatic without need for a specific treatment. [ejca.eg.net]

  This test is highly sensitive and specific; it is positive in over 99% of patients with the syndrome and less than 1% of the asymptomatic general population. 4. [clinicaladvisor.com]

  In fact, non-severe asymptomatic forms of CAD may require only protection against exposure to cold temperatures and occasional transfusion support in winter. 1, 83, 84 Erythrocyte transfusions can safely be given in CAD, provided appropriate precautions [doi.org]

• Chills

  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]

  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]

  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]

• Nausea

  […] symptoms Abnormal urinary color Abnormal urinary colour Abnormal urine color [ more ] 0012086 Back pain 0003418 Diarrhea Watery stool 0002014 Headache Headaches 0002315 Hepatomegaly Enlarged liver 0002240 Lymphadenopathy Swollen lymph nodes 0002716 Nausea [web.archive.org]

  […] enlarged or swollen lymph nodes. 80–99% of people have these symptoms Arthralgia Autoimmunity Fatigue Hemolytic anemia Muscular weakness Pallor5–29% of people have these symptoms Abnormal urine color Back pain Diarrhea Headache Hepatomegaly Lymphadenopathy Nausea [en.wikipedia.org]

• Vascular Disease

  Cold agglutinin disease is a form of autoimmune hemolytic anemia caused by cold-reacting antibodies and classified as either primary (idiopathic) or secondary (due to an underlying disease). [arupconsult.com]

  Drug-Lab Interactions Results increased in blood dyscrasias, liver disease, or collagen vascular diseases Some antibiotics (penicillin and cephalosporins) can interfere with the development of cold agglutinins. [ebmconsult.com]

  HIV infection Hepatitis Cytomegalovirus (CMV) infection Malaria (review of thick and thin blood smears) If collagen vascular disease is a possibility, blood tests for the following disorders should be performed: Systemic lupus erythematosus (SLE) Rheumatoid [web.archive.org]

  If collagen-vascular disease is possible, perform autoantibody tests according to the suspected underlying syndrome. CXR if mycoplasma is suspected. Abdominal ultrasound or CT scan if suspected hepato/splenomegaly or lymphadenopathy is detected. [patient.info]

• Hypertension

  […] with aplastic anemia Clinical symptoms Pallor, excessive fatigue ;, weakness Intermittent jaundice and episodes of red/ dark urine Venous thrombosis in unusual locations (e.g., hepatic, cerebral, abdominal veins) Vasoconstriction : headache, pulmonary hypertension [amboss.com]

  His coronary risk factors were hypertension and hyperlipidemia. Routine cold antibody screening is not performed in our center. The operative plan was three grafts (one arterial and two saphenous vein grafts) on moderate (30-32°C) CPB. [ejca.eg.net]

  The role and efficacy of antibiotic prophylaxis in this setting remains unclear, and not all investigators recommend this approach. 1, 28 Finally, small, but not insignificant additional risks include thromboembolism and pulmonary hypertension. 29, 30 [doi.org]

  Syndrome of hemolysis, elevated liver enzymes, and low platelet count: a severe consequence of hypertension in pregnancy. Am J Obstet Gynecol. 1982; 142 (2):159–167. [ PubMed ] [ Google Scholar ] 87. [ncbi.nlm.nih.gov]

• 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]

• Headache

  Symptoms during hemolytic ``crises'' may include severe pain in the back and legs, headache, vomiting, diarrhea, dark urine and hepatosplenomegaly. [orpha.net]

  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 ), a heart murmur, an enlarged heart, or heart failure. [rarediseases.info.nih.gov]

• Stroke

  The patient died in February 2000 from a stroke. [nature.com]

  Haiqiang Jin, Wei Sun, Yongan Sun, Yining Huang and Yunchuang Sun, Report of cold agglutinins in a patient with acute ischemic stroke, BMC Neurology, 15, 1, (2015) ., Red Cell Antibodies Against Self‐Antigens, Bound Antigens and Induced Antigens, Mollison's [doi.org]

  But about a month ago, mark had an optic nerve stroke in left eye. Dr strongly recommeded chemo rituxan/ bensamustine twice a month for 4-6 months. In order to put CAD to rest. [healthunlocked.com]

  It is hypothesized that a part of unexplained postoperative strokes, low cardiac output, and renal failure may be related to unrecognized CA. [ejca.eg.net]

• Excitement

  Sir John Dacie, The immune haemolytic anaemias: a century of exciting progress in understanding, British Journal of Haematology, 114, 4, (770-785), (2001) ., Bibliography Articles Cited in Commentaries, Hematology, 10.1016/B978-012448510-5.50184-9, (1023 [doi.org]

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

  LDH (lactate 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 [cancertherapyadvisor.com]

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]

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]

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]

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]

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]

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]

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]

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]

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]

Find articles by Jaffe, C. in: JCI | PubMed | Google Scholar Find articles by Atkinson, J. in: JCI | PubMed | Google Scholar Find articles by Frank, M. in: JCI | PubMed | Google Scholar Abstract To define the pathophysiologic mechanisms of cold agglutinin [doi.org]

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]

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10. Gertz MA. Cold hemolytic syndrome. Hematology Am Soc Hematol Educ Program. 2006;19-23.
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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.