Skip to main content

Advertisement

SpringerLink
Log in

Demographic characteristics, thromboembolism risk, and treatment patterns for patients with cold agglutinin disease in Japan

  • Original Article
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

Cold agglutinin disease (CAD) is a rare, complement-mediated autoimmune hemolytic anemia. Patients with CAD in the United States and Europe have an increased incidence of thromboembolism (TE), but comparable information for patients in other regions is lacking. Thus, we examined TE risk for patients with CAD in Japan. Patients with CAD (at least three claims with a CAD diagnosis; Japanese Disease Code 2830009) and non-CAD controls were retrospectively identified (2008–2017) from a large hospital-based administrative claims dataset in Japan. Cohorts were compared using conditional logistic regression. We identified 344 patients with CAD (53.2% female; mean age: 66.8 years) and 3440 matched controls. Patients with CAD had higher TE rates than controls (34.9% vs. 17.9%; P < 0.0001). Both arterial and venous TEs were increased in the CAD group when compared with the control group (25.0% vs. 4.6% and 8.4% vs. 4.0%, respectively; both P < 0.0001). Most arterial TEs in the CAD cohort (87.2%) were myocardial infarctions. The overall odds ratio for TE development in CAD was 2.81 (95% confidence interval 2.18–3.61). CAD in Japan is characterized by an increased risk of TE. The rate of arterial TEs was particularly high in this patient population.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Berentsen S. Complement activation and inhibition in autoimmune hemolytic anemia: focus on cold agglutinin disease. Semin Hematol. 2018;55(3):141–9.

    PubMed  Google Scholar 

  2. Berentsen S, Ulvestad E, Langholm R, Beiske K, Hjorth-Hansen H, Ghanima W, et al. Primary chronic cold agglutinin disease: a population based clinical study of 86 patients. Haematologica. 2006;91(4):460–6.

    PubMed  Google Scholar 

  3. Shi J, Rose EL, Singh A, Hussain S, Stagliano NE, Parry GC, et al. TNT003, an inhibitor of the serine protease C1s, prevents complement activation induced by cold agglutinins. Blood. 2014;123(26):4015–22.

    CAS  PubMed  Google Scholar 

  4. Berentsen S. Cold agglutinin disease. Hematol Am Soc Hematol Educ Program. 2016;2016(1):226–31.

    Google Scholar 

  5. Jäger U, D'Sa S, Schörgenhofer C, Bartko J, Derhaschnig U, Sillaber C, et al. Inhibition of complement C1s improves severe hemolytic anemia in cold agglutinin disease: a first-in-human trial. Blood. 2019;133(9):893–901.

    PubMed  PubMed Central  Google Scholar 

  6. Randen U, Trøen G, Tierens A, Steen C, Warsame A, Beiske K, et al. Primary cold agglutinin-associated lymphoproliferative disease: a B-cell lymphoma of the bone marrow distinct from lymphoplasmacytic lymphoma. Haematologica. 2014;99(3):497–504.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Mullins M, Jiang X, Bylsma LC, Fryzek JP, Reichert H, Chen EC, et al. Cold agglutinin disease burden: a longitudinal analysis of anemia, medications, transfusions, and health care utilization. Blood Adv. 2017;1(13):839–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Broome C, Cunningham JM, Mullins M, Jiang X, Bylsma LC, Fryzek J, et al. Increased risk of thrombotic events in cold agglutinin disease: a 10-year retrospective analysis. Res Pract Thromb Haemost. 2020;4(4):628–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Bylsma LC, Gulbech Ording A, Rosenthal A, Ozturk B, Fryzek JP, Arias JM, et al. Occurrence, thromboembolic risk, and mortality in Danish patients with cold agglutinin disease. Blood Adv. 2019;3(20):2980–5.

    PubMed  PubMed Central  Google Scholar 

  10. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Berentsen S, Ulvestad E, Gjertsen BT, Hjorth-Hansen H, Langholm R, Knutsen H, et al. Rituximab for primary chronic cold agglutinin disease: a prospective study of 37 courses of therapy in 27 patients. Blood. 2004;103(8):2925–8.

    CAS  PubMed  Google Scholar 

  12. Berentsen S, Randen U, Oksman M, Birgens H, Tvedt THA, Dalgaard J, et al. Bendamustine plus rituximab for chronic cold agglutinin disease: results of a Nordic prospective multicenter trial. Blood. 2017;130(4):537–41.

    CAS  PubMed  Google Scholar 

  13. Yamauchi H, Iwamasa K, Yanagisawa K, Tamai T, Yasukawa M, Fujita S. Low titer cold agglutinin disease due to anti-HI antibody and a review of this disease in Japan. Rinsho Ketsueki. 1995;36(4):334–8.

    CAS  PubMed  Google Scholar 

  14. Iwasaki H. Acronecrosis with cold agglutinin disease mimics diabetic gangrene. Intern Med. 2013;52(7):837–8.

    PubMed  Google Scholar 

  15. Imashuku S, Kudo N, Takagishi K, Saigo K. Two cases of primary cold agglutinin disease associated with megaloblastic anemia. Case Rep Hematol. 2015;2015:913795.

    PubMed  PubMed Central  Google Scholar 

  16. Shiiya C, Ota M. Cold agglutinin disease presenting as livedo racemosa. CMAJ. 2017;189(22):E781.

    PubMed  PubMed Central  Google Scholar 

  17. Onishi S, Ichiba T, Miyoshi N, Nagata T, Naito H. Unusual underlying disorder for pulmonary embolism: cold agglutinin disease. J Cardiol Cases. 2017;15(2):43–5.

    PubMed  Google Scholar 

  18. Swiecicki PL, Hegerova LT, Gertz MA. Cold agglutinin disease. Blood. 2013;122(7):1114–21.

    CAS  PubMed  Google Scholar 

  19. Hill QA, Stamps R, Massey E, Grainger JD, Provan D, Hill A; on behalf of the British Society for Haematology. The diagnosis and management of primary autoimmune haemolytic anaemia. Br J Haematol. 2017;176:395–411.

    PubMed  Google Scholar 

  20. Schubothe H. The cold hemagglutinin disease. Semin Hematol. 1966;3(1):27–47.

    CAS  PubMed  Google Scholar 

  21. Berentsen S, Randen U, Tjønnfjord GE. Cold agglutinin-mediated autoimmune hemolytic anemia. Hematol Oncol Clin North Am. 2015;29(3):455–71.

    PubMed  Google Scholar 

  22. Majoor CJ, Sneeboer MM, de Kievit A, Meijers JC, van der Poll T, Lutter R, et al. The influence of corticosteroids on hemostasis in healthy subjects. J Thromb Haemost. 2016;14(4):716–23.

    CAS  PubMed  Google Scholar 

  23. Toyoda K. Epidemiology and registry studies of stroke in Japan. J Stroke. 2013;15(1):21–6.

    PubMed  PubMed Central  Google Scholar 

  24. Ungprasert P, Tanratana P, Srivali N. Autoimmune hemolytic anemia and venous thromboembolism: a systematic review and meta-analysis. Thromb Res. 2015;136(5):1013–7.

    CAS  PubMed  Google Scholar 

  25. Habib A, Kunzelmann C, Shamseddeen W, Zobairi F, Freyssinet JM, Taher A. Elevated levels of circulating procoagulant microparticles in patients with beta-thalassemia intermedia. Haematologica. 2008;93(6):941–2.

    CAS  PubMed  Google Scholar 

  26. Zhou Z, Behymer M, Guchhait P. Role of extracellular hemoglobin in thrombosis and vascular occlusion in patients with sickle cell anemia. Anemia. 2011;2011:918916.

    PubMed  Google Scholar 

  27. Rother RP, Bell L, Hillmen P, Gladwin MT. The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. JAMA. 2005;293(13):1653–62.

    CAS  PubMed  Google Scholar 

  28. Boyce S, Eren E, Lwaleed BA, Kazmi RS. The activation of complement and its role in the pathogenesis of thromboembolism. Semin Thromb Hemost. 2015;41(6):665–72.

    CAS  PubMed  Google Scholar 

  29. Markiewski MM, Nilsson B, Ekdahl KN, Mollnes TE, Lambris JD. Complement and coagulation: strangers or partners in crime? Trends Immunol. 2007;28(4):184–92.

    CAS  PubMed  Google Scholar 

  30. Conway EM. Reincarnation of ancient links between coagulation and complement. J Thromb Haemost. 2015;13(Suppl 1):S121–32.

    CAS  PubMed  Google Scholar 

  31. Verschoor A, Langer HF. Crosstalk between platelets and the complement system in immune protection and disease. Thromb Haemost. 2013;110(5):910–9.

    CAS  PubMed  Google Scholar 

  32. Lee JW, Jang JH, Kim JS, Yoon SS, Lee JH, Kim YK, et al. Clinical signs and symptoms associated with increased risk for thrombosis in patients with paroxysmal nocturnal hemoglobinuria from a Korean registry. Int J Hematol. 2013;97(6):749–57.

    PubMed  Google Scholar 

  33. Sakurai M, Jang JH, Chou WC, Kim JS, Wilson A, Nishimura JI, et al. Comparative study on baseline clinical characteristics of Asian versus non-Asian patients with paroxysmal nocturnal hemoglobinuria. Int J Hematol. 2019;110(4):411–8.

    CAS  PubMed  Google Scholar 

  34. Kanakura Y, Ohyashiki K, Shichishima T, Okamoto S, Ando K, Ninomiya H, et al. Safety and efficacy of the terminal complement inhibitor eculizumab in Japanese patients with paroxysmal nocturnal hemoglobinuria: the AEGIS clinical trial. Int J Hematol. 2011;931:36–46.

    Google Scholar 

  35. Patzelt J, Verschoor A, Langer HF. Platelets and the complement cascade in atherosclerosis. Front Physiol. 2015;6:49.

    PubMed  PubMed Central  Google Scholar 

  36. Carter AM. Complement activation: an emerging player in the pathogenesis of cardiovascular disease. Scientifica (Cairo). 2012;2012:402783.

    Google Scholar 

  37. Speidl WS, Kastl SP, Huber K, Wojta J. Complement in atherosclerosis: friend or foe? J Thromb Haemost. 2011;9(3):428–40.

    CAS  PubMed  Google Scholar 

  38. Haskard DO, Boyle JJ, Mason JC. The role of complement in atherosclerosis. Curr Opin Lipidol. 2008;19(5):478–82.

    CAS  PubMed  Google Scholar 

  39. Fumagalli S, Perego C, Zangari R, De Blasio D, Oggioni M, De Nigris F, et al. Lectin pathway of complement activation is associated with vulnerability of atherosclerotic plaques. Front Immunol. 2017;8:288.

    PubMed  PubMed Central  Google Scholar 

  40. Speidl WS, Exner M, Amighi J, Kastl SP, Zorn G, Maurer G, et al. Complement component C5a predicts future cardiovascular events in patients with advanced atherosclerosis. Eur Heart J. 2005;26(21):2294–9.

    CAS  PubMed  Google Scholar 

  41. Distelmaier K, Adlbrecht C, Jakowitsch J, Winkler S, Dunkler D, Gerner C, et al. Local complement activation triggers neutrophil recruitment to the site of thrombus formation in acute myocardial infarction. Thromb Haemost. 2009;102(3):564–72.

    CAS  PubMed  Google Scholar 

  42. Sauter RJ, Sauter M, Reis ES, Emschermann FN, Nording H, Ebenhöch S, et al. Functional relevance of the anaphylatoxin receptor C3aR for platelet function and arterial thrombus formation marks an intersection point between innate immunity and thrombosis. Circulation. 2018;138(16):1720–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Høiland II, Liang RA, Hindberg K, Latysheva N, Brekke OL, Mollnes TE, et al. Associations between complement pathways activity, mannose-binding lectin, and odds of unprovoked venous thromboembolism. Thromb Res. 2018;169:50–6.

    PubMed  Google Scholar 

Download references

Acknowledgements

This study was funded by Sanofi. Editorial assistance for the development of this paper was provided by Tonya Goodman, CMPP, and Francis John Golder, BVSc, PhD, DACVAA, of JK Associates Inc., a member of the Fishawack Group of Companies, and was funded by Sanofi.

Author information

Authors and Affiliations

  1. Division of Support in Community Medicine, Center for Community Medicine, Regional Medical Center, Center for Regional Medical Care, Jichi Medical University, 3311 – 1 Yakushiji Shimotsuke-shi, Tochigi, Japan

    Toyomi Kamesaki

  2. Osaka University, Osaka, Japan

    Jun-ichi Nishimura & Yuzuru Kanakura

  3. Kawasaki Medical School, Kurashiki, Japan

    Hideho Wada

  4. IQVIA Solutions K.K., Tokyo, Japan

    Eric Yu

  5. Sanofi, Waltham, MA, USA

    Elisa Tsao & Jaime Morales

  6. Sumitomo Hospital, Osaka, Japan

    Yuzuru Kanakura

Authors
  1. Toyomi Kamesaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jun-ichi Nishimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hideho Wada
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eric Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Elisa Tsao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jaime Morales
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yuzuru Kanakura
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the data collection, interpretation of data, and drafting and revising of the manuscript. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Toyomi Kamesaki.

Ethics declarations

Conflict of interest

T. Kamesaki and J. Nishimura have received honoraria from Sanofi Japan. E. Yu is an employee of IQVIA Solutions K.K., Japan, which received consulting fees from Sanofi during the conduct of the study. E. Tsao and J. Morales are employees of Sanofi. H. Wada and Y. Kanakura have no competing interests to declare.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

12185_2020_2899_MOESM1_ESM.docx

Supplementary file1 (DOCX 21 kb) Supplementary Table 1A. ICD-10 diagnostic codes excluded for primary analysis. Hb, hemoglobin; ICD-10, International Classification of Diseases, Tenth Revision. Supplementary Table 1B. Japanese Disease Codes excluded for primary analysis. Supplementary Table 2. ICD-10 codes used for analysis of thromboembolism. ICD-10, International Classification of Diseases, Tenth Revision. Supplementary Table 3. Diagnoses excluded for sensitivity analysis of cold agglutinin disease. HIV, human immunodeficiency virus; ICD-10, International Classification of Diseases, Tenth Revision; MALT, mucosa-associated lymphoid tissue; NK, natural killer.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kamesaki, T., Nishimura, Ji., Wada, H. et al. Demographic characteristics, thromboembolism risk, and treatment patterns for patients with cold agglutinin disease in Japan. Int J Hematol 112, 307–315 (2020). https://doi.org/10.1007/s12185-020-02899-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-020-02899-6

Keywords

Search

Navigation