Clot waveform analysis in Clauss fibrinogen assay contributes to classification of fibrinogen disorders

Published:December 18, 2018DOI:


      • It is difficult to classify fibrinogen disorders by Clauss fibrinogen assay (CFA) alone.
      • We developed clot waveform analysis (CWA) to distinguish fibrinogen abnormalities.
      • We found the “Min1” value to be a surrogate marker for fibrinogen antigen.
      • CWA of CFA could be a novel screening test for fibrinogen disorders.



      Clauss fibrinogen assay (CFA) is widely used as a screening test to detect fibrinogen disorders. However, CFA alone cannot distinguish quantitative and qualitative defects because it depends on functional fibrinogen activity (Ac), and fibrinogen antigen (Ag) determination is required to classify fibrinogen disorders.


      To establish a novel approach to classify fibrinogen disorders, we investigated the potential of clot waveform analysis (CWA) of CFA and searched for a surrogate marker for fibrinogen Ag.

      Materials and methods

      We analyzed CWA parameters obtained from CFA using plasma from normal patients (n = 91) and those with fibrinogen disorders (n = 27, including 15 hypofibrinogenemia, 6 dysfibrinogenemia and 6 hypodysfibrinogenemia) with a CS-5100 autoanalyzer.


      We found that maximum coagulation velocity (Min1) levels were most strongly correlated with fibrinogen Ag in both normal and fibrinogen disorders. Hence, Min1 appeared to function as a surrogate for fibrinogen Ag. Although the Ac/Min1 ratio did not simply reflect the measured Ac/Ag ratio, we found that the Ac/Min1 ratio was significantly higher than normal in hypofibrinogenemia and hypodysfibrinogenemia, but not in dysfibrinogenemia. On the other hand, we could distinguish type II deficiency from type I using estimated fibrinogen Ag (eAg) predicted from Min1. The Ac/eAg ratios of dysfibrinogenemia and hypodysfibrinogenemia were significantly lower than those of normal and hypofibrinogenemia.


      The CWA of CFA could distinguish fibrinogen disorders using a combination of Ac/Min1 and Ac/eAg values. This analysis allows the qualitative detection of fibrinogen disorder easily and represents a novel screening test for fibrinogen disorders.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Thrombosis Research
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • de Moerloose P.
        • Casini A.
        • Neerman-Arbez M.
        Congenital fibrinogen disorders: an update.
        Semin. Thromb. Hemost. 2013; 39: 585-595
        • Casini A.
        • Neerman-Arbez M.
        • Ariens R.A.
        • de Moerloose P.
        Dysfibrinogenemia: from molecular anomalies to clinical manifestations and management.
        J. Thromb. Haemost. 2015; 13: 909-919
        • Clauss A.
        Rapid physiological coagulation method in determination of fibrinogen.
        Acta Haematol. 1957; 17: 237-246
        • Chantarangkul V.
        • Tripodi A.
        • Mannucci P.M.
        Evaluation of a fully automated centrifugal analyzer for performance of hemostasis tests.
        Clin. Chem. 1987; 33: 1888-1890
        • Rossi E.
        • Mondonico P.
        • Lombardi A.
        • Preda L.
        Method for the determination of functional (clottable) fibrinogen by the new family of ACL coagulometers.
        Thromb. Res. 1988; 52: 453-468
        • Haku J.
        • Nogami K.
        • Matsumoto T.
        • Ogiwara K.
        • Shima M.
        Optimal monitoring of bypass therapy in hemophilia a patients with inhibitors by the use of clot waveform analysis.
        J. Thromb. Haemost. 2014; 12: 355-362
        • Milos M.
        • Coen Herak D.
        • Zupancic-Salek S.
        • Zadro R.
        New quantitative aPTT waveform analysis and its application in laboratory management of haemophilia a patients.
        Haemophilia. 2014; 20: 898-904
        • Casini A.
        • Undas A.
        • Palla R.
        • Thachil J.
        • de Moerloose P.
        • Subcommittee on Factor X and Fibrinogen
        Diagnosis and classification of congenital fibrinogen disorders: communication from the SSC of the ISTH.
        J. Thromb. Haemost. 2018; 16: 1887-1890
        • Shima M.
        • Thachil J.
        • Nair S.C.
        • Srivastava A.
        • Scientific and Standardization Committee
        Towards standardization of clot waveform analysis and recommendations for its clinical applications.
        J. Thromb. Haemost. 2013; 11: 1417-1420
        • Shima M.
        • Matsumoto T.
        • Ogiwara K.
        New assays for monitoring haemophilia treatment.
        Haemophilia. 2008; 14: 83-92
        • Downey C.
        • Kazmi R.
        • Toh C.H.
        Early identification and prognostic implications in disseminated intravascular coagulation through transmittance waveform analysis.
        Thromb. Haemost. 1998; 80: 65-69
        • Toh C.H.
        • Samis J.
        • Downey C.
        • Walker J.
        • Becker L.
        • Brufatto N.
        • Tejidor L.
        • Jones G.
        • Houdijk W.
        • Giles A.
        • Koschinsky M.
        • Ticknor L.O.
        • Paton R.
        • Wenstone R.
        • Nesheim M.
        Biphasic transmittance waveform in the APTT coagulation assay is due to the formation of a Ca++-dependent complex of C-reactive protein with very-low-density lipoprotein and is a novel marker of impending disseminated intravascular coagulation.
        Blood. 2002; 100: 2522-2529
        • Tan V.
        • Doyle C.J.
        • Budzynski A.Z.
        Comparison of the kinetic fibrinogen assay with the von Clauss method and the clot recovery method in plasma of patients with conditions affecting fibrinogen coagulability.
        Am. J. Clin. Pathol. 1995; 104: 455-462
        • Jacquemin M.
        • Vanlinthout I.
        • Van Horenbeeck I.
        • Debasse M.
        • Toelen J.
        • Schoeters J.
        • Lavend'homme R.
        • Freson K.
        • Peerlinck K.
        The amplitude of coagulation curves from thrombin time tests allows dysfibrinogenemia caused by the common mutation FGG-Arg301 to be distinguished from hypofibrinogenemia.
        Int. J. Lab. Hematol. 2017; 39: 301-307
        • Krammer B.
        • Anders O.
        • Nagel H.R.
        • Burstein C.
        • Steiner M.
        Screening of dysfibrinogenaemia using the fibrinogen function versus antigen concentration ratio.
        Thromb. Res. 1994; 76: 577-579
        • Casini A.
        • Blondon M.
        • Lebreton A.
        • Koegel J.
        • Tintillier V.
        • de Maistre E.
        • Gautier P.
        • Biron C.
        • Neerman-Arbez M.
        • de Moerloose P.
        Natural history of patients with congenital dysfibrinogenemia.
        Blood. 2015; 125: 553-561
        • Shapiro S.E.
        • Phillips E.
        • Manning R.A.
        • Morse C.V.
        • Murden S.L.
        • Laffan M.A.
        • Mumford A.D.
        Clinical phenotype, laboratory features and genotype of 35 patients with heritable dysfibrinogenaemia.
        Br. J. Haematol. 2013; 160: 220-227
        • Miesbach W.
        • Schenk J.
        • Alesci S.
        • Lindhoff-Last E.
        Comparison of the fibrinogen Clauss assay and the fibrinogen PT derived method in patients with dysfibrinogenemia.
        Thromb. Res. 2010; 126: e428-e433
        • Brennan S.O.
        • Mosesson M.W.
        • Lowen R.
        • Frantz C.
        Dysfibrinogenemia (fibrinogen Wilmington) due to a novel Aalpha chain truncation causing decreased plasma expression and impaired fibrin polymerisation.
        Thromb. Haemost. 2006; 96: 88-89
        • de Raucourt E.
        • Fischer A.M.
        • Meyer G.
        • de Mazancourt P.
        A Bbeta 14 Arg → Cys fibrinogen variant in a patient with thrombotic complications (fibrinogen St-Germain III).
        J. Thromb. Haemost. 2006; 4: 2722-2723
        • Dempfle C.E.
        • George P.M.
        • Borggrefe M.
        • Neumaier M.
        • Brennan S.O.
        Demonstration of heterodimeric fibrinogen molecules partially conjugated with albumin in a novel dysfibrinogen: fibrinogen Mannheim V.
        Thromb. Haemost. 2009; 102: 29-34