Medicine:Cold sensitive antibodies

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Cold sensitive antibodies
Other namesCold reactive antibodies, cold reacting antibodies

Cold sensitive antibodies (CSA) are antibodies sensitive to cold temperature. Some cold sensitive antibodies are pathological and can lead to blood disorder. These pathological cold sensitive antibodies include cold agglutinins, Donath–Landsteiner antibodies, and cryoglobulins which are the culprits of cold agglutinin disease, paroxysmal cold hemoglobinuria in the process of Donath–Landsteiner hemolytic anemia, and vasculitis, respectively.

Cold agglutinin antibodies

Cold agglutinins are antibodies, typically immunoglobulin M (IgM), that are acquainted with and then binding the antigens on red blood cells, typically antigens "I" or "i" on the RBC surface,[1] in the environment in which the temperatures are lower than normal core body temperature and, thus, ends up leading to agglutinations of the red blood cells and hemolysis reaction occurring outside the vessels (extra-vessels), resulting in anemia without hemoglobinuria in ordinary cases.[2]

Cold agglutinins can cause two pathological conditions, that are, primary cold agglutinin disease (CAD)[3] and secondary cold agglutinin syndrome (CAS),[2] both of which are sole two subtypes of cold agglutinin disease.

Primary cold agglutinin disease is idiopathic, meaning the phenomenons of agglutinations of the red blood cells and hemolysis reaction occurring outside the vessels are absent from any underlying cause.[3] Nevertheless, what is known is, those with idiopathic cold agglutinin disease are susceptible to having or developing mild clonal bone marrow disorder.[3]

Secondary cold agglutinin syndrome refers to cold agglutinin disease that is identified to be caused by viral infection, autoimmune disorder, lymphoid malignancy, or any other underlying disease.[4]

Thermal amplitude

Cold agglutinins (CA) are autoantibodies that agglutinate RBCs with a temperature optimum of 3-4 °C but may also act in a warmer environment, depending on the thermal amplitude of the CA. If the thermal amplitude exceeds 28–30 °C, the CA will be pathogenic. Low-affinity CA also occurs in many healthy individuals; these nonpathogenic CA are polyclonal, have low thermal amplitude, and are present in low titers, not higher than 256 and usually lower than 64. More than 90% of pathogenic CA are of the IgM class and these IgM macromolecules can be pentameric or hexameric.[5]

Donath–Landsteiner antibodies

Donath–Landsteiner antibodies share similarities with cold agglutinin disease in recognition and connection of the antigens on the red blood cells' surface in the presence of relatively lower temperatures compared to core body temperature. Yet, the place where the hemolysis taking place differentiates between D-L antibodies and cold agglutinin.[6][7][8] D-L antibodies rather fix complement system which result in hemolysis in vessels (intra-vessels). Blood vessels are pathways carrying living-required elements to reach everywhere inside the body through circulation. This explains why the clinical manifestations of hemolysis caused by D-L antibodies are in line with representations of hemoglobinemia and hemoglobinuria. D-L antibodies, typically IgG, are characterized by targeting against red blood cells' on-surface antigens called "P".[9][10]

The pathophysiology of Donath–Landsteiner hemolytic anemia has been entitled as paroxysmal cold hemoglobinuria.

Cryoglobulins antibodies

Cryoglobulins are abnormal antibodies that only dissolve/disappear at temperature higher than 37 °C (99 °F) and form solid or gel-like immune complexes in presence of the environment under 37 °C (99 °F),[11][12] which can block blood vessels and cause a variety of health problems[12] including inflammation and organ damage.[13][14]

Many people affected by cryoglobulins will not experience any unusual signs or symptoms. When present, symptoms vary but may include breathing problems; fatigue; glomerulonephritis; joint pain or muscle pain; purpura; Raynaud's phenomenon; skin death; and/or skin ulcers. In some cases, the exact underlying cause is unknown; however, cryoglobulinemia can be associated with a variety of conditions including certain types of infection; chronic inflammatory diseases (such as autoimmune disease); and/or cancers of the blood or immune system. Treatment varies based on the severity of the condition, the symptoms present in each person and the underlying cause.[12]

At least 90% of cases having cryoglobulins in body, hepatitis C is to blame,[11][13] reflecting the importance of preclusion of hepatitis C.[11][13] The presence of cryoglubulins in body satisfies the criterion of the diagnosis of cryoglobulinemia, a disease that inflame the blood vessels and organs like kidney, nerves, joints, lungs and skin.[11] Normally, no cryoglobulins should be found in the body.[11]

Cryoglobulins more than often do not interact with red blood cells, unless it combines the features of cold agglutinin with cryoglobulins, although the chance is deemed rare. Therefore, cryoglobulins don't produce hemolysis effect, however its serious complications such as systemic inflammatory or neoplastic disorders can in turn lead to anemia.[13]

Comparisons between cryoglobulin, cold agglutinin and Donath–Landsteiner antibodies

Although there is some overlap of symptoms, cryoglobulinemia and cold agglutinin disease differ in the process by which blood vessels become blocked.[12] In cryoglobulinemia, antibodies accumulate and block blood vessels.[12][15] In cold agglutinin disease, antibodies (different from those in cryoglobulinemia) attack and kill red blood cells, which then accumulate and block blood vessels.[12][16]

Three types of pathological cold sensitive antibodies can all trigger Raynaud's phenomenon.[17][18][19][20][21][22]

Three types of pathological cold antibodies can all be acquired.[23][24][25][26]


Type Composition Percent of cases Association with other diseases
Type I Monoclonal IgG, IgM, IgA, or their κ or λ light chains 10–15% Hematological diseases, particularly MGUS, smoldering multiple myeloma, multiple myeloma, Waldenström's macroglobulinemia, and chronic lymphocytic leukemia[27]
Type II Monoclonal IgM plus polyclonal IgG or, rarely, IgA 50–60% Infectious diseases, particularly hepatitis C infection, HIV infection, and Hepatitis C and HIV coinfection; hematological diseases particularly B cell disorders; autoimmune diseases[27]
Type III Polyclonal IgM plus polyclonal IgG or IgA 25–30% Autoimmune diseases, particularly Sjögren syndrome and less commonly systemic lupus erythematosus and rheumatoid arthritis; infectious diseases particularly HCV infection[27]


Complement activation plays a definitive but limited role in warm-antibody AIHA (w-AIHA), whereas primary cold agglutinin disease (CAD), secondary cold agglutinin syndrome (CAS), and paroxysmal cold hemoglobinuria (PCH) are entirely complement-dependent disorders.[5]

Hemolysis site

Hemolysis induced by cold agglutinin disease taking place outside the vessels while which of Donath–Landsteiner antibodies is taking place inside the vessels.[10][9]


  1. Pascual, V; Victor, K; Spellerberg, M; Hamblin, TJ; Stevenson, FK; Capra, JD (1992-10-01). "VH restriction among human cold agglutinins. The VH4-21 gene segment is required to encode anti-I and anti-i specificities.". Journal of Immunology 149 (7): 2337–44. ISSN 0022-1767. PMID 1382098. 
  2. 2.0 2.1 Berentsen, Sigbjørn (2018-01-24). "How I manage patients with cold agglutinin disease". British Journal of Haematology (Wiley) 181 (3): 320–330. doi:10.1111/bjh.15109. ISSN 0007-1048. PMID 29363757. 
  3. 3.0 3.1 3.2 Małecka, Agnieszka; Trøen, Gunhild; Tierens, Anne; Østlie, Ingunn; Małecki, Jędrzej; Randen, Ulla; Wang, Junbai; Berentsen, Sigbjørn et al. (19 December 2017). "Frequent somatic mutations of KMT 2D ( MLL 2 ) and CARD 11 genes in primary cold agglutinin disease". British Journal of Haematology (Wiley) 183 (5): 838–842. doi:10.1111/bjh.15063. ISSN 0007-1048. PMID 29265349. 
  4. Randen, U.; Troen, G.; Tierens, A.; Steen, C.; Warsame, A.; Beiske, K.; Tjonnfjord, G. E.; Berentsen, S. et al. (18 October 2013). "Primary cold agglutinin-associated lymphoproliferative disease: a B-cell lymphoma of the bone marrow distinct from lymphoplasmacytic lymphoma". Haematologica (Ferrata Storti Foundation (Haematologica)) 99 (3): 497–504. doi:10.3324/haematol.2013.091702. ISSN 0390-6078. PMID 24143001. 
  5. 5.0 5.1 Berentsen, Sigbjørn; Sundic, Tatjana (2015-01-29). "Red Blood Cell Destruction in Autoimmune Hemolytic Anemia: Role of Complement and Potential New Targets for Therapy". BioMed Research International (Hindawi Limited) 2015: 363278. doi:10.1155/2015/363278. ISSN 2314-6133. PMID 25705656. 
  6. Silberstein, LE; Berkman, EM; Schreiber, AD (1987). "Cold hemagglutinin disease associated with IgG cold-reactive antibody.". Annals of Internal Medicine 106 (2): 238–42. doi:10.7326/0003-4819-106-2-238. ISSN 0003-4819. PMID 3800184. 
  7. Rosse, WF; Adams, JP (1980). "The variability of hemolysis in the cold agglutinin syndrome.". Blood 56 (3): 409–16. doi:10.1182/blood.v56.3.409.bloodjournal563409. ISSN 0006-4971. PMID 7407408. 
  8. Zilow, G; Kirschfink, M; Roelcke, D (1994). "Red cell destruction in cold agglutinin disease.". Infusionstherapie und Transfusionsmedizin 21 (6): 410–5. doi:10.1159/000223021. ISSN 1019-8466. PMID 7873920. 
  9. 9.0 9.1 Trisha Simone Tavares (2019-02-02). Donath-Landsteiner Hemolytic Anemia: Practice Essentials, Pathophysiology, Etiology. Retrieved 2019-02-11. 
  10. 10.0 10.1 Barcellini, W (2015), "Pitfalls in the diagnosis of autoimmune haemolytic anaemia.", Blood Transfusion = Trasfusione del Sangue 13 (1): 3–5, doi:10.2450/2014.0252-14, ISSN 1723-2007, PMID 25636128 
  11. 11.0 11.1 11.2 11.3 11.4 "Cryoglobulins: MedlinePlus Medical Encyclopedia". 2019-01-28. 
  12. 12.0 12.1 12.2 12.3 12.4 12.5 "Cold agglutinin disease". 2015-09-11. 
  13. 13.0 13.1 13.2 13.3 Ferri, C; Zignego, AL; Pileri, SA (2002). "Cryoglobulins". Journal of Clinical Pathology 55 (1): 4–13. doi:10.1136/jcp.55.1.4. PMID 11825916. 
  14. "Cryoglobulinemia". 
  15. "Cryoglobulinemia: MedlinePlus Medical Encyclopedia". 2019-01-28. 
  16. Cold Agglutinin Disease: Practice Essentials, Pathophysiology, Etiology. 2019-02-02. Retrieved 2019-02-13. 
  17. Gaddy, Clifford G. (1958-09-01). "Raynaud's Syndrome Associated with Idiopathic Cryoglobulinemia and Cold Agglutinins". Archives of Internal Medicine (American Medical Association (AMA)) 102 (3): 468–77. doi:10.1001/archinte.1958.00030010468020. ISSN 0003-9926. PMID 13570737. 
  18. Mitchell, AB; Pergrum, GD; Gill, AM (1974). "Cold agglutinin disease with Raynaud's phenomenon.". Proceedings of the Royal Society of Medicine 67 (2): 113–5. doi:10.1177/003591577406700212. ISSN 0035-9157. PMID 4544972. 
  19. C. G. M. KALLENBERG; G. W. PASTOOR; A. A. WOUDA; T. H. THE (1982). "Antinuclear antibodies in patients with Raynaud's phenomenon: clinical significance of anticentromere antibodies". Annals of the Rheumatic Diseases 41 (4): 382–387. doi:10.1136/ard.41.4.382. PMID 7051989. 
  20. Lodi, Gianluca; Resca, Daniela; Reverberi, Roberto (2010-08-06). "Fatal cold agglutinin-induced haemolytic anaemia: a case report". Journal of Medical Case Reports (Springer Nature) 4 (1): 252. doi:10.1186/1752-1947-4-252. ISSN 1752-1947. PMID 20691050. 
  21. Gertz, M. A. (2006-01-01). "Cold Hemolytic Syndrome". Hematology (American Society of Hematology) 2006 (1): 19–23. doi:10.1182/asheducation-2006.1.19. ISSN 1520-4391. PMID 17124034. 
  22. J. J. VAN LOGHEM, Jn.; E. MENDES DE LEON, M.D.; HERTA FRENKEL-TIETZ; IIA VAN DER HART (1952). "Two Different Serologic Mechanisms of Paroxysmal Cold Hemoglobinuria, Illustrated by Three Cases". Blood. 
  23. WIENER, AS; UNGER, LJ; COHEN, L; FELDMAN, J (1956). "Type-specific cold auto-antibodies as a cause of acquired hemolytic anemia and hemolytic transfusion reactions: biologic test with bovine red cells.". Annals of Internal Medicine 44 (2): 221–40. doi:10.7326/0003-4819-44-2-221. ISSN 0003-4819. PMID 13292836. 
  24. Mehrotra, TN (1960). "Immunological Identification of the Pathological Cold Auto-Antibodies of Acquired Haemolytic Anaemia as β2M-Globulin". Immunology 3 (3): 265–271. 
  25. Acquired Autoimmune Hemolytic Anemia
  26. Allgood, JW; Chaplin, H Jr (1967). "Idiopathic acquired autoimmune hemolytic anemia. A review of forty-seven cases treated from 1955 through 1965.". The American Journal of Medicine 43 (2): 254–73. doi:10.1016/0002-9343(67)90168-4. ISSN 0002-9343. PMID 6034957. 
  27. 27.0 27.1 27.2 "Cryoglobulinemia". Blood Reviews 21 (4): 183–200. 2007. doi:10.1016/j.blre.2006.12.002. PMID 17289231.