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Published in: Thrombosis Journal 1/2021

Open Access 01-12-2021 | Disseminated Intravascular Coagulation | Research

Hypofibrinogenemia is associated with a high degree of risk in infectious diseases: a post-hoc analysis of post-marketing surveillance of patients with disseminated intravascular coagulation treated with thrombomodulin alfa

Authors: Kazuo Kawasugi, Hideo Wada, Goichi Honda, Noriaki Kawano, Toshimasa Uchiyama, Seiji Madoiwa, Naoki Takezako, Kei Suzuki, Yoshinobu Seki, Takayuki Ikezoe, Toshiaki Iba, Kohji Okamoto

Published in: Thrombosis Journal | Issue 1/2021

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Abstract

Background

In patients with infectious diseases, disseminated intravascular coagulation (DIC) is often diagnosed without the fibrinogen value. The relationship between hypofibrinogenemia and outcomes of DIC in infectious diseases has thus remained unclear.

Methods

We analyzed 3204 patients who received with thrombomodulin alfa (TM-α) for DIC and suspected DIC. Hypofibrinogenemia was defined by a fibrinogen level < 1.5 g/L.

Results

Hypofibrinogenemia was observed in 10.3% of patients with infectious diseases. The frequencies of both bleeding and organ failure symptoms, and the scores for organ failure or the DIC diagnostic criteria were significantly higher in infectious disease patients with hypofibrinogenemia, suggesting that in patients with infectious diseases, hypofibrinogenemia is associated with more progressive and severe DIC. Although the 28-day survival rate and the DIC resolution rate were both significantly lower for infectious disease patients with DIC with hypofibrinogenemia than for those without hypofibrinogenemia, this difference was not observed in DIC patients with hematological diseases.

Conclusions

Hypofibrinogenemia among infectious disease patients with DIC may reflect increased consumption of fibrinogen due to accelerated coagulation reactions, while hypofibrinogenemia among hematological disease patients with DIC may be caused by fibrinogenolysis due to hyperfibrinolysis, and frequently results in bleeding and multiple-organ failure.
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Literature
1.
go back to reference Levi M, Ten Cate H. Disseminated intravascular coagulation. N Engl J Med. 1999;341:586–92.CrossRef Levi M, Ten Cate H. Disseminated intravascular coagulation. N Engl J Med. 1999;341:586–92.CrossRef
2.
go back to reference Gando S, Levi M, Toh CH. Disseminated intravascular coagulation. Nat Rev Dis Primers. 2016;2:16037.CrossRef Gando S, Levi M, Toh CH. Disseminated intravascular coagulation. Nat Rev Dis Primers. 2016;2:16037.CrossRef
3.
go back to reference Wada H, Matsumoto T, Yamashita Y, Hatada T. Disseminated intravascular coagulation: testing and diagnosis. Clin Chim Acta. 2014;436C:130–4.CrossRef Wada H, Matsumoto T, Yamashita Y, Hatada T. Disseminated intravascular coagulation: testing and diagnosis. Clin Chim Acta. 2014;436C:130–4.CrossRef
4.
go back to reference Taylor FB Jr, Toh CH, Hoots K, Wada H, Levi M. Towards a definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost. 2001;86(5):1327–30.CrossRef Taylor FB Jr, Toh CH, Hoots K, Wada H, Levi M. Towards a definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost. 2001;86(5):1327–30.CrossRef
5.
go back to reference Wada H, Matsumoto T, Yamashita Y. Diagnosis and treatment of disseminated intravascular coagulation (DIC) according to four DIC guidelines. J Intensive Care. 2014;2:15.CrossRef Wada H, Matsumoto T, Yamashita Y. Diagnosis and treatment of disseminated intravascular coagulation (DIC) according to four DIC guidelines. J Intensive Care. 2014;2:15.CrossRef
6.
go back to reference Kobayashi N, Maegawa T, Takada M, Tanaka H, Gonmori H. Criteria for diagnosis of DIC based on the analysis of clinical and laboratory findings in 345 DIC patients collected by the research committee on DIC in Japan. Bibl Haemotol. 1983;49:265–75. Kobayashi N, Maegawa T, Takada M, Tanaka H, Gonmori H. Criteria for diagnosis of DIC based on the analysis of clinical and laboratory findings in 345 DIC patients collected by the research committee on DIC in Japan. Bibl Haemotol. 1983;49:265–75.
7.
go back to reference Gando S, Iba T, Eguchi Y, Ohtomo Y, Okamoto K, Koseki K, et al. Japanese Association for Acute Medicine Disseminated Intravascular Coagulation (JAAM DIC) Study Group. A multicenter, prospective validation of disseminated intravascular coagulation diagnostic criteria for critically ill patients: comparing current criteria. Crit Care Med. 2006;34:625–31.CrossRef Gando S, Iba T, Eguchi Y, Ohtomo Y, Okamoto K, Koseki K, et al. Japanese Association for Acute Medicine Disseminated Intravascular Coagulation (JAAM DIC) Study Group. A multicenter, prospective validation of disseminated intravascular coagulation diagnostic criteria for critically ill patients: comparing current criteria. Crit Care Med. 2006;34:625–31.CrossRef
8.
go back to reference Asakura H, Takahashi H, Uchiyama T, Eguchi Y, Okamoto K, Kawasugi K, et al. DIC subcommittee of the Japanese society on thrombosis and hemostasis. Proposal for new diagnostic criteria for DIC from the Japanese Society on Thrombosis and Hemostasis. Thromb J. 2016;14:42.CrossRef Asakura H, Takahashi H, Uchiyama T, Eguchi Y, Okamoto K, Kawasugi K, et al. DIC subcommittee of the Japanese society on thrombosis and hemostasis. Proposal for new diagnostic criteria for DIC from the Japanese Society on Thrombosis and Hemostasis. Thromb J. 2016;14:42.CrossRef
9.
go back to reference Wada H, Takahashi H, Uchiyama T, Eguchi Y, Okamoto K, Kawasugi K, et al. DIC subcommittee of the Japanese society on thrombosis and hemostasis. The approval of revised diagnostic criteria for DIC from the Japanese Society on Thrombosis and Hemostasis. Thromb J. 2017;15:17.CrossRef Wada H, Takahashi H, Uchiyama T, Eguchi Y, Okamoto K, Kawasugi K, et al. DIC subcommittee of the Japanese society on thrombosis and hemostasis. The approval of revised diagnostic criteria for DIC from the Japanese Society on Thrombosis and Hemostasis. Thromb J. 2017;15:17.CrossRef
10.
go back to reference Levi M, Toh CH, Thachil J, Watson HG. Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology. Br J Haematol. 2009;145:24–33.CrossRef Levi M, Toh CH, Thachil J, Watson HG. Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology. Br J Haematol. 2009;145:24–33.CrossRef
11.
go back to reference Wada H, Asakura H, Okamoto K, Iba T, Uchiyama T, Kawasugi K, et al. Japanese Society of Thrombosis Hemostasis/DIC subcommittee. Japanese Society of Thrombosis Hemostasis/DIC subcommittee. Expert consensus for the treatment of disseminated intravascular coagulation in Japan. Thromb Res. 2010;125:6–11.CrossRef Wada H, Asakura H, Okamoto K, Iba T, Uchiyama T, Kawasugi K, et al. Japanese Society of Thrombosis Hemostasis/DIC subcommittee. Japanese Society of Thrombosis Hemostasis/DIC subcommittee. Expert consensus for the treatment of disseminated intravascular coagulation in Japan. Thromb Res. 2010;125:6–11.CrossRef
12.
go back to reference Di Nisio M, Baudo F, Cosmi B, D'Angelo A, De Gasperi A, Malato A, et al. on behalf of the Italian Society for Thrombosis and Haemostasis. Diagnosis and treatment of disseminated intravascular coagulation: guidelines of the Italian Society for Haemostasis and Thrombosis (SISET). Thromb Res. 2012;129:e177–84.CrossRef Di Nisio M, Baudo F, Cosmi B, D'Angelo A, De Gasperi A, Malato A, et al. on behalf of the Italian Society for Thrombosis and Haemostasis. Diagnosis and treatment of disseminated intravascular coagulation: guidelines of the Italian Society for Haemostasis and Thrombosis (SISET). Thromb Res. 2012;129:e177–84.CrossRef
13.
go back to reference Wada H, Thachil J, Di Nisio M, Mathew P, Kurosawa S, Gando S, et al. The scientific standardization committee on DIC of the international society on thrombosis Haemostasis. Guidance for diagnosis and treatment of DIC from harmonization of the recommendations from three guidelines. J Thromb Haemost. 2013;11:761–7.CrossRef Wada H, Thachil J, Di Nisio M, Mathew P, Kurosawa S, Gando S, et al. The scientific standardization committee on DIC of the international society on thrombosis Haemostasis. Guidance for diagnosis and treatment of DIC from harmonization of the recommendations from three guidelines. J Thromb Haemost. 2013;11:761–7.CrossRef
14.
go back to reference Wada H, Okamoto K, Iba T, Kushimoto S, Kawasugi K, Gando S, et al. Japanese Society of Thrombosis Hemostasis/DIC subcommittee. Addition of recommendations for the use of recombinant human thrombomodulin to the “Expert consensus for the treatment of disseminated intravascular coagulation in Japan”. Thromb Res. 2014;134:924–5.CrossRef Wada H, Okamoto K, Iba T, Kushimoto S, Kawasugi K, Gando S, et al. Japanese Society of Thrombosis Hemostasis/DIC subcommittee. Addition of recommendations for the use of recombinant human thrombomodulin to the “Expert consensus for the treatment of disseminated intravascular coagulation in Japan”. Thromb Res. 2014;134:924–5.CrossRef
15.
go back to reference Saito H, Maruyama I, Shimazaki S, Yamamoto Y, Aikawa N, Ohno R, et al. Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: results of a phase III, randomized, double-blind clinical trial. J Thromb Haemost. 2007;5:31–41.CrossRef Saito H, Maruyama I, Shimazaki S, Yamamoto Y, Aikawa N, Ohno R, et al. Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: results of a phase III, randomized, double-blind clinical trial. J Thromb Haemost. 2007;5:31–41.CrossRef
16.
go back to reference Mimuro J, Takahashi H, Kitajima I, Tsuji H, Eguchi Y, Matsushita T, et al. Impact of recombinant soluble thrombomodulin (thrombomodulin alfa) on disseminated intravascular coagulation. Thromb Res. 2013;131:436–43.CrossRef Mimuro J, Takahashi H, Kitajima I, Tsuji H, Eguchi Y, Matsushita T, et al. Impact of recombinant soluble thrombomodulin (thrombomodulin alfa) on disseminated intravascular coagulation. Thromb Res. 2013;131:436–43.CrossRef
17.
go back to reference Asakura H, Takahashi H, Tsuji H, Matsushita T, Ninomiya H, Honda G, et al. Post-marketing surveillance of thrombomodulin alfa, a novel treatment of disseminated intravascular coagulation - safety and efficacy in 1,032 patients with hematologic malignancy. Thromb Res. 2014;133:364–70.CrossRef Asakura H, Takahashi H, Tsuji H, Matsushita T, Ninomiya H, Honda G, et al. Post-marketing surveillance of thrombomodulin alfa, a novel treatment of disseminated intravascular coagulation - safety and efficacy in 1,032 patients with hematologic malignancy. Thromb Res. 2014;133:364–70.CrossRef
18.
go back to reference Eguchi Y, Gando S, Ishikura H, Saitoh D, Mimuro J, Takahashi H, et al. Post-marketing surveillance data of thrombomodulin alfa: sub-analysis in patients with sepsis-induced disseminated intravascular coagulation. J Intensive Care. 2014;2:30.CrossRef Eguchi Y, Gando S, Ishikura H, Saitoh D, Mimuro J, Takahashi H, et al. Post-marketing surveillance data of thrombomodulin alfa: sub-analysis in patients with sepsis-induced disseminated intravascular coagulation. J Intensive Care. 2014;2:30.CrossRef
19.
go back to reference Warren BL, Eid A, Singer P, Pillay SS, Carl P, Novak I, et al. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA. 2001;286:1869–78.CrossRef Warren BL, Eid A, Singer P, Pillay SS, Carl P, Novak I, et al. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA. 2001;286:1869–78.CrossRef
20.
go back to reference Ranieri VM, Thompson BT, Barie PS, Dhainaut JF, Douglas IS, Finfer S, et al. PROWESS-SHOCK study group. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med. 2012;366:2055–64.CrossRef Ranieri VM, Thompson BT, Barie PS, Dhainaut JF, Douglas IS, Finfer S, et al. PROWESS-SHOCK study group. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med. 2012;366:2055–64.CrossRef
21.
go back to reference Vincent JL, Francois B, Zabolotskikh I, Daga MK, Lascarrou JB, Kirov MY, et al. SCARLET Trial Group. Effect of a recombinant human soluble thrombomodulin on mortality in patients with sepsis-associated coagulopathy: the SCARLET randomized clinical trial. JAMA. 2019;321:1993–2002.CrossRef Vincent JL, Francois B, Zabolotskikh I, Daga MK, Lascarrou JB, Kirov MY, et al. SCARLET Trial Group. Effect of a recombinant human soluble thrombomodulin on mortality in patients with sepsis-associated coagulopathy: the SCARLET randomized clinical trial. JAMA. 2019;321:1993–2002.CrossRef
22.
go back to reference Vincent JL, Moreno R, Takala J, Willatts S, De Mendonça A, Bruining H, et al. The SOFA (Sepsis-related organ failure assessment) score to describe organ dysfunction/failure. On behalf of the working group on Sepsis-related problems of the European Society of Intensive Care Medicine. Intensive Care Med. 1996;22:707–10.CrossRef Vincent JL, Moreno R, Takala J, Willatts S, De Mendonça A, Bruining H, et al. The SOFA (Sepsis-related organ failure assessment) score to describe organ dysfunction/failure. On behalf of the working group on Sepsis-related problems of the European Society of Intensive Care Medicine. Intensive Care Med. 1996;22:707–10.CrossRef
23.
go back to reference Okuzono S, Ishimura M, Kanno S, Sonoda M, Kaku N, Motomura Y, et al. Streptococcus pyogenes-purpura fulminans as an invasive form of group a streptococcal infection. Ann Clin Microbiol Antimicrob. 2018;17:31.CrossRef Okuzono S, Ishimura M, Kanno S, Sonoda M, Kaku N, Motomura Y, et al. Streptococcus pyogenes-purpura fulminans as an invasive form of group a streptococcal infection. Ann Clin Microbiol Antimicrob. 2018;17:31.CrossRef
24.
go back to reference Iba T, Gando S, Saitoh D, Ikeda T, Anan H, Oda S, et al. Efficacy and bleeding risk of antithrombin supplementation in patients with septic disseminated intravascular coagulation: a third survey. Clin Appl Thromb Hemost. 2017;23:422–8.CrossRef Iba T, Gando S, Saitoh D, Ikeda T, Anan H, Oda S, et al. Efficacy and bleeding risk of antithrombin supplementation in patients with septic disseminated intravascular coagulation: a third survey. Clin Appl Thromb Hemost. 2017;23:422–8.CrossRef
25.
go back to reference Wada H, Nagano T, Tomeoku M, Kuto M, Karitani Y, Deguchi K, et al. Coagulant and fibrinolytic activities in the leukemic cell lysates. Thromb Res. 1982;30:315–22.CrossRef Wada H, Nagano T, Tomeoku M, Kuto M, Karitani Y, Deguchi K, et al. Coagulant and fibrinolytic activities in the leukemic cell lysates. Thromb Res. 1982;30:315–22.CrossRef
26.
go back to reference Wada H, Kumeda Y, Ogasawara Z, Ohiwa M, Kaneko T, Tamaki S, et al. Plasminogen activators and their inhibitors in leukemic cell homogenates. Am J Hematol. 1993;42:166–70.CrossRef Wada H, Kumeda Y, Ogasawara Z, Ohiwa M, Kaneko T, Tamaki S, et al. Plasminogen activators and their inhibitors in leukemic cell homogenates. Am J Hematol. 1993;42:166–70.CrossRef
27.
go back to reference Wada H. Disseminated intravascular coagulation. Clin Chim Acta. 2004;344:13–21.CrossRef Wada H. Disseminated intravascular coagulation. Clin Chim Acta. 2004;344:13–21.CrossRef
28.
go back to reference Ito T, Thachil J, Asakura H, Levy JH, Iba T. Thrombomodulin in disseminated intravascular coagulation and other critical conditions-a multi-faceted anticoagulant protein with therapeutic potential. Crit Care. 2019;23:280.CrossRef Ito T, Thachil J, Asakura H, Levy JH, Iba T. Thrombomodulin in disseminated intravascular coagulation and other critical conditions-a multi-faceted anticoagulant protein with therapeutic potential. Crit Care. 2019;23:280.CrossRef
29.
go back to reference Wada H, Mori Y, Sakakura M, Gabazza EC, Kushiya F, Watanabe M, et al. High plasma levels of fibrinogen are associated with poor outcome. Am J Hematol. 2003;72:1–7.CrossRef Wada H, Mori Y, Sakakura M, Gabazza EC, Kushiya F, Watanabe M, et al. High plasma levels of fibrinogen are associated with poor outcome. Am J Hematol. 2003;72:1–7.CrossRef
30.
go back to reference Watanabe R, Wada H, Miura Y, Murata Y, Watanabe Y, Sakakura M, et al. Plasma levels of total plasminogen activator inhibitor-I and tissue plasminogen activator/inhibitor complex in patients with disseminated intravascular coagulation and thrombotic thrombocytopenic purpura. Clin Appl Thromb Haemost. 2001;7:229–33.CrossRef Watanabe R, Wada H, Miura Y, Murata Y, Watanabe Y, Sakakura M, et al. Plasma levels of total plasminogen activator inhibitor-I and tissue plasminogen activator/inhibitor complex in patients with disseminated intravascular coagulation and thrombotic thrombocytopenic purpura. Clin Appl Thromb Haemost. 2001;7:229–33.CrossRef
Metadata
Title
Hypofibrinogenemia is associated with a high degree of risk in infectious diseases: a post-hoc analysis of post-marketing surveillance of patients with disseminated intravascular coagulation treated with thrombomodulin alfa
Authors
Kazuo Kawasugi
Hideo Wada
Goichi Honda
Noriaki Kawano
Toshimasa Uchiyama
Seiji Madoiwa
Naoki Takezako
Kei Suzuki
Yoshinobu Seki
Takayuki Ikezoe
Toshiaki Iba
Kohji Okamoto
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Thrombosis Journal / Issue 1/2021
Electronic ISSN: 1477-9560
DOI
https://doi.org/10.1186/s12959-021-00264-z

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