CAD is a rare, chronic, autoimmune haemolytic anaemia with potentially serious acute and chronic consequences that are driven by C1 activation of the classical complement pathway1
The diagnosed prevalence for CAD is estimated to be up to 20 per 1,000,000 people2-4
Median age of onset is approximately 60 years, but CAD has been diagnosed in patients as young as 30 years2,5-7
C1-activated haemolysis in CAD is caused by chronic activation of the classical complement pathway8,9
Activated C1 triggers the classical complement pathway leading to further downstream consequences and chronic haemolysis
Complement activation results in a proinflammatory state10-14
Persistent activation of the classical complement pathway leads to the production of anaphylatoxins C3a and C5a, promoting inflammation
A complex interplay exists between complement, inflammation and coagulation8,10,15-19
Cross talk occurs between the coagulation cascade and inflammatory processes
Additional studies are needed to better understand the clinical consequences of CAD
“Cold” can be a misunderstood trigger of CAD7,20-22
“Cold” in CAD does not represent weather or season
CAD=Cold Agglutinin Disease; Hb=haemoglobin; IgM=immunoglobulin M; LDH=lactate dehydrogenase; RBC=red blood cell.
*Complement activation can also result in a proinflammatory state.
†C1 amplification leads to activation of C3, resulting predominantly in extravascular haemolysis and intravascular haemolysis through C5 activation.
‡Cold agglutinins that are reactive at temperatures >30 °C have the potential to be clinically significant regardless of the antibody titer. If thermal amplitude exceeds 28 °C to 30 °C, RBCs will agglutinate in acral parts of the circulation even at mild ambient temperatures; often, complement fixation and complement-mediated haemolysis will ensue.
References: 1. Berentsen S, Beiske K, Tjønnfjord GE. Primary chronic cold agglutinin disease: an update on pathogenesis, clinical features and therapy. Hematology. 2007;12(5):361-370. doi:10.1080/10245330701445392 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, Barcellini W, D’Sa S, et al. Cold agglutinin disease revisited: a multinational, observational study of 232 patients. Blood. 2020;136(4):480-488. doi:10.1182/blood.2020005674 4. Bylsma LC, Gulbech Ording A, Rosenthal A, et al. Occurrence, thromboembolic risk, and mortality in Danish patients with cold agglutinin disease. Blood Adv. 2019;3(20):2980-2985. doi:10.1182/bloodadvances.2019000476 5. Mullins M, Jiang X, Bylsma LC, et al. Cold agglutinin disease burden: a longitudinal analysis of anemia, medications, transfusions, and health care utilization. Blood Adv. 2017;1(13):839-848. doi:10.1182/bloodadvances.2017004390 6. Berentsen S, Tjønnfjord GE. Diagnosis and treatment of cold agglutinin mediated autoimmune hemolytic anemia. Blood Rev. 2012;26(3):107-115. doi:10.1016/j.blre.2012.01.002 7. Berentsen S, Röth A, Randen U, Jilma B, Tjønnfjord GE. Cold agglutinin disease: current challenges and future prospects. J Blood Med. 2019;10:93-103. doi:10.2147/JBM.S177621 8. Noris M, Remuzzi G. Overview of complement activation and regulation. Semin Nephrol. 2013;33(6):479-492. doi:10.1016/j.semnephrol.2013.08.001 9. Berentsen S. Complement activation and inhibition in autoimmune hemolytic anemia: focus on cold agglutinin disease. Semin Hematol. 2018;55(3):141-149. doi:10.1053/j.seminhematol.2018.04.002 10. Berentsen S. New insights in the pathogenesis and therapy of cold agglutinin-mediated autoimmune hemolytic anemia. Front Immunol. 2020;11:590. doi:10.3389/fimmu.2020.00590 11. Landsem A, Nielsen E, Fure H, et al. C1-inhibitor efficiently inhibits Escherichia coli-induced tissue factor mRNA up-regulation, monocyte tissue factor expression and coagulation activation in human whole blood. Clin Exp Immunol. 2013;273(2):217-229. doi:10.1111/cei.12098 12. Cofiell R, Kukreja A, Bedard K, et al. Eculizumab reduces complement activation, inflammation, endothelial damage, thrombosis, and renal injury markers in aHUS. Blood. 2015;125(21):3253-3262. doi:10.1182/blood-2014-09-600411 13. Weitz IC, Razavi P, Rochanda L, et al. Eculizumab therapy results in rapid and sustained decreases in markers of thrombin generation and inflammation in patients with PNH independent of its effects on hemolysis and microparticle formation. Thromb Res. 2012;130(3):361-368. doi:10.1016/j.thromres.2012.04.001 14. Montoya JG, Holmes TH, Anderson JN, et al. Cytokine signature associated with disease severity in chronic fatigue syndrome patients. Proc Natl Acad Sci USA. 2017;114(34):E7150-E7158. doi:10.1073/pnas.1710519114 15. Markiewski MM, Nilsson B, Ekdahl KN, Mollnes TE, Lambris JD. Complement and coagulation: strangers or partners in crime? Trends Immunol. 2007;28(4):184-192. doi:10.1016/j.it.2007.02.006 16. Foley JH, Conway EM. Cross talk pathways between coagulation and inflammation. Circ Res. 2016;118(9):1392-1408. doi:10.1161/CIRCRESAHA.116.306853 17. Gelbenegger G, Schoergenhofer C, Derhaschnig U, et al. Inhibition of complement C1s in patients with cold agglutinin disease: lessons learned from a named patient program. Blood Adv. 2020;4(6):997-1005. doi:10.1182/bloodadvances.2019001321 18. Oikonomopoulou K, Ricklin D, Ward P, et al. Interactions between coagulation and complement—their role in inflammation. Semin Immunopathol. 2012;34(1):151-165. doi:10.1007/s00281-011-0280-x 19. de Bont C, Boelens W, Pruijn G. NETosis, complement, and coagulation: a triangular relationship. Cell Mol Immunol. 2019;16(1):19-27. doi.org/10.1038/s41423-018-0024-0 20. Röth A. Do temperature and time matter in cold agglutinin disease? Blood. 2020;136(4)380-381. doi:10.1182/blood.2020006566 21. Thermal amplitude test. Cold Agglutinin Disease News. Updated August 19, 2019. Accessed March 30, 2022. coldagglutininnews.com/thermal-amplitude-test/ 22. Hopkins C, Walters TK. Thermal amplitude test. Immunohematology. 2013;29(2):49-50. 23. Thermal amplitude test. Cold Agglutinin Disease News website. Updated August 19, 2019. Accessed January 4, 2021. coldagglutininnews.com/thermal-amplitude-test/ 24. Hopkins C, Walters TK. Thermal amplitude test. ResearchGate website. Updated July 29, 2020. Accessed January 4, 2021.