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Thromb Haemost 2022; 122(09): 1461-1468
DOI: 10.1055/a-1745-0420
Coagulation and Fibrinolysis

Impact of Fibrinogen Infusion on Thrombin Generation and Fibrin Clot Structure in Patients with Inherited Afibrinogenemia

Claudia Khayat‡   *
1   Department of Pediatrics, Hôtel-Dieu de France Hospital, Beirut, Lebanon
,
Rita Marchi‡   *
2   Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland
,
Stéphane Durual
3   Biomaterials Laboratory, University Clinics of Dental Medicine, University of Geneva, Geneva, Switzerland
,
Thomas Lecompte
4   Faculty of Medicine, University of Geneva, Geneva, Switzerland
5   Division of Angiology and Hemostasis, University Hospitals of Geneva, Geneva, Switzerland
,
Marguerite Neerman-Arbez
2   Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland
,
Alessandro Casini 
4   Faculty of Medicine, University of Geneva, Geneva, Switzerland
5   Division of Angiology and Hemostasis, University Hospitals of Geneva, Geneva, Switzerland
› Institutsangaben Funding This study was funded by Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (grant # 31003A_172864) to Marguerite Neerman-Arbez.
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Abstract

Introduction Inherited afibrinogenemia is a very rare disease characterized by complete absence of fibrinogen in the circulation and an increased risk in both thrombosis and bleeding. Infusion of fibrinogen concentrate (FC) is the main approach for prevention and management of bleeding; however, it has been reported to carry a thrombotic risk.

Methods We investigated the impact of a standard dose (40–100 mg/kg) of FC infusion on the thrombin generation (TG) parameters and the fibrin clot structure formed in plasma samples of patients with afibrinogenemia. Blood samples were collected from 20 patients before (T0) and 1 hour after infusion of FC (T1). TG was studied with calibrated automated thrombography. Fibrin clot structure was assessed with turbidimetry and scanning electron microscopy.

Results FC infusions (mean Clauss fibrinogen plasma level: 1.21 g/L at T1) led to a statistically significant increase in endogenous thrombin potential (ETP) (p < 0.0001) and thrombin peaks (p = 0.02). Nevertheless, when compared with healthy controls, patients' T1 lag times were longer (p = 0.002), ETP values were lower (p = 0.0003), and thrombin peaks were lower (p < 00001). All fibrin polymerization parameters (turbidimetry) obtained at T1 were comparable to those of patients with inherited hypofibrinogenemia matched for fibrinogen plasma levels.

Conclusion In summary, fibrinogen infusion with a standard dose of FC increased but did not correct TG and led to formation of fibrin clots similar to those of patients with hypofibrinogenemia. All in all, our results do not support the biological evidence of hypercoagulability induced by FC in patients with afibrinogenemia.

Keywords

afibrinogenemia - thrombosis - bleeding - fibrin - thrombin generation

Author Contributions

C.K., T.L., M.N.-A., and A.C. designed the study, analyzed the data, and wrote the paper; R.M. designed and performed experiments, analyzed the data, and wrote the paper; S.D. designed and performed experiments.


* These authors contributed equally to this work.


Supplementary Material



Publikationsverlauf

Eingereicht: 10. November 2021

Angenommen: 18. Januar 2022

Accepted Manuscript online:
19. Januar 2022

Artikel online veröffentlicht:
14. März 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Casini A, Neerman-Arbez M, de Moerloose P. Heterogeneity of congenital afibrinogenemia, from epidemiology to clinical consequences and management. Blood Rev 2021; 48: 100793
    CrossrefPubMedSuche in Google Scholar
  • 2 Palla R, Peyvandi F, Shapiro AD. Rare bleeding disorders: diagnosis and treatment. Blood 2015; 125 (13) 2052-2061
    CrossrefPubMedSuche in Google Scholar
  • 3 Menegatti M, Peyvandi F. Treatment of rare factor deficiencies other than hemophilia. Blood 2019; 133 (05) 415-424
    CrossrefPubMedSuche in Google Scholar
  • 4 Casini A, de Moerloose P. Fibrinogen concentrates in hereditary fibrinogen disorders: past, present and future. Haemophilia 2020; 26 (01) 25-32
    CrossrefPubMedSuche in Google Scholar
  • 5 Lasky J, Teitel J, Wang M, Dalton D, Schmidt DS, Brainsky A. Fibrinogen concentrate for bleeding in patients with congenital fibrinogen deficiency: observational study of efficacy and safety for prophylaxis and treatment. Res Pract Thromb Haemost 2020; 4 (08) 1313-1323
    CrossrefPubMedSuche in Google Scholar
  • 6 Bornikova L, Peyvandi F, Allen G, Bernstein J, Manco-Johnson MJ. Fibrinogen replacement therapy for congenital fibrinogen deficiency. J Thromb Haemost 2011; 9 (09) 1687-1704
    CrossrefPubMedSuche in Google Scholar
  • 7 Shapiro A. The use of prophylaxis in the treatment of rare bleeding disorders. Thromb Res 2020; 196: 590-602
    CrossrefPubMedSuche in Google Scholar
  • 8 Korte W, Poon MC, Iorio A, Makris M. Thrombosis in inherited fibrinogen disorders. Transfus Med Hemother 2017; 44 (02) 70-76
    CrossrefPubMedSuche in Google Scholar
  • 9 Nagler M, Kremer Hovinga JA, Alberio L. et al. Thromboembolism in patients with congenital afibrinogenaemia. Long-term observational data and systematic review. Thromb Haemost 2016; 116 (04) 722-732
    Thieme ConnectPubMedSuche in Google Scholar
  • 10 van Hylckama Vlieg A, Christiansen SC, Luddington R, Cannegieter SC, Rosendaal FR, Baglin TP. Elevated endogenous thrombin potential is associated with an increased risk of a first deep venous thrombosis but not with the risk of recurrence. Br J Haematol 2007; 138 (06) 769-774
    CrossrefPubMedSuche in Google Scholar
  • 11 Dargaud Y, Lienhart A, Negrier C. Prospective assessment of thrombin generation test for dose monitoring of bypassing therapy in hemophilia patients with inhibitors undergoing elective surgery. Blood 2010; 116 (25) 5734-5737
    CrossrefPubMedSuche in Google Scholar
  • 12 Young GA, Carmona R, Cano Garcia V. Thromboelastography and thrombin generation assay in inherited afibrinogenemia. Haemophilia 2018; 24 (06) e410 –e416
    CrossrefPubMedSuche in Google Scholar
  • 13 Undas A, Ariëns RA. Fibrin clot structure and function: a role in the pathophysiology of arterial and venous thromboembolic diseases. Arterioscler Thromb Vasc Biol 2011; 31 (12) e88 –e99
    CrossrefPubMedSuche in Google Scholar
  • 14 Leong L, Chernysh IN, Xu Y. et al. Clot stability as a determinant of effective factor VIII replacement in hemophilia A. Res Pract Thromb Haemost 2017; 1 (02) 231-241
    CrossrefPubMedSuche in Google Scholar
  • 15 Hofer S, Ay C, Rejtö J. et al. Thrombin-generating potential, plasma clot formation, and clot lysis are impaired in patients with bleeding of unknown cause. J Thromb Haemost 2019; 17 (09) 1478-1488
    CrossrefPubMedSuche in Google Scholar
  • 16 Ross C, Rangarajan S, Karimi M. et al. Pharmacokinetics, clot strength and safety of a new fibrinogen concentrate: randomized comparison with active control in congenital fibrinogen deficiency. J Thromb Haemost 2018; 16 (02) 253-261
    CrossrefPubMedSuche in Google Scholar
  • 17 Rodeghiero F, Tosetto A, Abshire T. et al; ISTH/SSC joint VWF and Perinatal/Pediatric Hemostasis Subcommittees Working Group. ISTH/SSC bleeding assessment tool: a standardized questionnaire and a proposal for a new bleeding score for inherited bleeding disorders. J Thromb Haemost 2010; 8 (09) 2063-2065
    Suche in Google Scholar
  • 18 Dargaud Y, Wolberg AS, Luddington R. et al. Evaluation of a standardized protocol for thrombin generation measurement using the calibrated automated thrombogram: an international multicentre study. Thromb Res 2012; 130 (06) 929-934
    CrossrefPubMedSuche in Google Scholar
  • 19 Pieters M, Philippou H, Undas A, de Lange Z, Rijken DC, Mutch NJ. Subcommittee on Factor XIII and Fibrinogen, and the Subcommittee on Fibrinolysis. An international study on the feasibility of a standardized combined plasma clot turbidity and lysis assay: communication from the SSC of the ISTH. J Thromb Haemost 2018; 16 (05) 1007-1012
    CrossrefPubMedSuche in Google Scholar
  • 20 Marchi R, Neerman-Arbez M, Gay V. et al. Comparison of different activators of coagulation by turbidity analysis of hereditary dysfibrinogenemia and controls. Blood Coagul Fibrinolysis 2021; 32 (02) 108-114
    CrossrefPubMedSuche in Google Scholar
  • 21 Neerman-Arbez M, de Moerloose P. Mutations in the fibrinogen gene cluster accounting for congenital afibrinogenemia: an update and report of 10 novel mutations. Hum Mutat 2007; 28 (06) 540-553
    CrossrefPubMedSuche in Google Scholar
  • 22 Hemker HC, Giesen P, Al Dieri R. et al. Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb 2003; 33 (01) 4-15
    CrossrefPubMedSuche in Google Scholar
  • 23 Duchemin J, Pan-Petesch B, Arnaud B, Blouch MT, Abgrall JF. Influence of coagulation factors and tissue factor concentration on the thrombin generation test in plasma. Thromb Haemost 2008; 99 (04) 767-773
    Thieme ConnectPubMedSuche in Google Scholar
  • 24 Kremers RM, Wagenvoord RJ, Hemker HC. The effect of fibrin(ogen) on thrombin generation and decay. Thromb Haemost 2014; 112 (03) 486-494
    PubMedSuche in Google Scholar
  • 25 Dupuy E, Soria C, Molho P. et al. Embolized ischemic lesions of toes in an afibrinogenemic patient: possible relevance to in vivo circulating thrombin. Thromb Res 2001; 102 (03) 211-219
    CrossrefPubMedSuche in Google Scholar
  • 26 Korte W, Feldges A. Increased prothrombin activation in a patient with congenital afibrinogenemia is reversible by fibrinogen substitution. Clin Investig 1994; 72 (05) 396-398
    CrossrefPubMedSuche in Google Scholar
  • 27 Djambas Khayat C, Lohade S, D'Souza F. et al. Efficacy and safety of fibrinogen concentrate for on-demand treatment of bleeding and surgical prophylaxis in paediatric patients with congenital fibrinogen deficiency. Haemophilia 2021; 27 (02) 283-292
    CrossrefPubMedSuche in Google Scholar
  • 28 Le Quellec S, Desjonqueres A, Rugeri L. et al. Combined life-threatening thromboses and hemorrhages in a patient with afibrinogenemia and antithrombin deficiency. Thromb J 2018; 16: 6
    CrossrefPubMedSuche in Google Scholar
  • 29 Chevalier Y, Dargaud Y, Argaud L, Ninet J, Jouanneau E, Négrier C. Successive bleeding and thrombotic complications in a patient with afibrinogenemia: a case report. Thromb Res 2011; 128 (03) 296-298
    CrossrefPubMedSuche in Google Scholar
  • 30 Djambas Khayat C, El Khorassani M, Lambert T. et al. Clinical pharmacology, efficacy and safety study of a triple-secured fibrinogen concentrate in adults and adolescent patients with congenital fibrinogen deficiency. J Thromb Haemost 2019; 17 (04) 635-644
    CrossrefPubMedSuche in Google Scholar
  • 31 Ross CR, Subramanian S, Navarro-Puerto J. et al. Pharmacokinetics, surrogate efficacy and safety evaluations of a new human plasma-derived fibrinogen concentrate (FIB Grifols) in adult patients with congenital afibrinogenemia. Thromb Res 2021; 199: 110-118
    CrossrefPubMedSuche in Google Scholar
  • 32 Lissitchkov T, Madan B, Djambas Khayat C. et al. Efficacy and safety of a new human fibrinogen concentrate in patients with congenital fibrinogen deficiency: an interim analysis of a phase III trial. Transfusion 2018; 58 (02) 413-422
    CrossrefPubMedSuche in Google Scholar
  • 33 Morrow GB, Carlier MSA, Dasgupta S, Craigen FB, Mutch NJ, Curry N. Fibrinogen replacement therapy for traumatic coagulopathy: does the fibrinogen source matter?. Int J Mol Sci 2021; 22 (04) 2185
    CrossrefPubMedSuche in Google Scholar
  • 34 Undas A. Fibrin clot properties and their modulation in thrombotic disorders. Thromb Haemost 2014; 112 (01) 32-42
    PubMedSuche in Google Scholar
  • 35 Undas A. How to assess fibrinogen levels and fibrin clot properties in clinical practice?. Semin Thromb Hemost 2016; 42 (04) 381-388
    Thieme ConnectPubMedSuche in Google Scholar
  • 36 Peyvandi F, Palla R, Menegatti M. et al; European Network of Rare Bleeding Disorders Group. Coagulation factor activity and clinical bleeding severity in rare bleeding disorders: results from the European Network of Rare Bleeding Disorders. J Thromb Haemost 2012; 10 (04) 615-621
    CrossrefPubMedSuche in Google Scholar
  • 37 Haas T, Cushing MM, Asmis LM. Comparison of the efficacy of two human fibrinogen concentrates to treat dilutional coagulopathy in vitro. Scand J Clin Lab Invest 2018; 78 (03) 230-235
    CrossrefPubMedSuche in Google Scholar
  • 38 Wolberg AS. Thrombin generation and fibrin clot structure. Blood Rev 2007; 21 (03) 131-142
    CrossrefPubMedSuche in Google Scholar