Download PDF
Thromb Haemost 2021; 121(02): 164-173
DOI: 10.1055/s-0040-1715838
Coagulation and Fibrinolysis

A Novel Assessment of Factor VIII Activity by Template Matching Utilizing Weighted Average Parameters from Comprehensive Clot Waveform Analysis

Naruto Shimonishi
1   Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
,
Kenichi Ogiwara
1   Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
,
Yukio Oda
2   Sekisui Medical Co., Ltd., Tokyo, Japan
,
Toshiki Kawabe
2   Sekisui Medical Co., Ltd., Tokyo, Japan
,
Shinji Okazaki
2   Sekisui Medical Co., Ltd., Tokyo, Japan
,
Midori Shima
1   Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
,
Keiji Nogami
1   Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
› Author Affiliations Funding This work was partly supported by a Grant-in-Aid for Scientific Research (KAKENHI) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) to K.N. (18K07885).
› Further Information
Also available at
    Permissions and Reprints

Abstract

Background Activated partial thromboplastin time (aPTT)-based clot waveform analysis is used to evaluate the comprehensive dynamics of fibrin clot formation. In addition, the technique can be usefully utilized for the rapid assessment of factor (F)VIII procoagulant activity in various clinical settings in patients with hemophilia A (HA). We defined a novel algorithm based on the weighted average parameters from aPTT-based waveforms to devise a template-matching procedure for assessing FVIII activity (FVIII:C).

Methods The first derivatives of original clot waveforms triggered by the aPTT reagent (Coagpia APTT-N) were used to determine weighted averages of areas surrounded by the waveform at different percentages of maximum height in various clotting factor-deficient plasmas. Prepared templates based on 50 weighted average-related parameters were compared with 78 aPTT-prolonged plasmas.

Results Original nonsmoothed waveforms of the various clotting factor-deficient plasmas with prolonged aPTTs demonstrated a variety of shapes. The weighted averages were calculated after adjustments for different baselines, and the patterns seemed to be governed by the specific clotting factor deficiency. The weighted average-related parameters including baseline wedge (r 2 = 0.998) and aspect ratio (r 2 = 0.998) were highly correlated with FVIII:C levels. Template-matching analyses based on weighted average-related waveform parameters obtained from 158 samples demonstrated that the sensitivity was 97.2% and specificity was 83.3% in aPTT-prolonged plasmas (n = 78).

Conclusion This novel algorithm based on weighted averages of aPTT-based waveforms together with template-matching may support clinical usefulness for judging of HA and may aid clinical management in the patients in the absence of specific clotting factor assays.

Keywords

clot waveform analysis - weighted average - template-matching - factor VIII - hemophilia A

Authors' Contributions

N.S. performed experiments, analyzed the data, interpreted the data, prepared figures, and wrote the manuscript. K.O. analyzed the data and interpreted the data. Y.O., T.K., and S.O. performed experiments, analyzed the data, interpreted the data, and prepared figures. M.S. supervised this study. K.N. designed all experiments, interpreted the data, prepared figures, wrote and edited the manuscript.


Note

An account of this work was presented at the XXVII Congress of the International Society on Thrombosis and Haemostasis, 2019, Melbourne, Australia.




Publication History

Received: 11 April 2020

Accepted: 23 July 2020

Article published online:
22 August 2020

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Luck Jr JV, Silva M, Rodriguez-Merchan EC, Ghalambor N, Zahiri CA, Finn RS. Hemophilic arthropathy. J Am Acad Orthop Surg 2004; 12 (04) 234-245
    CrossrefPubMedGoogle Scholar
  • 2 White II GC, Rosendaal F, Aledort LM, Lusher JM, Rothschild C, Ingerslev J. Factor VIII and Factor IX Subcommittee. Definitions in hemophilia. Recommendation of the scientific subcommittee on factor VIII and factor IX of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost 2001; 85 (03) 560
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Braun PJ, Givens TB, Stead AG. et al. Properties of optical data from activated partial thromboplastin time and prothrombin time assays. Thromb Haemost 1997; 78 (03) 1079-1087
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Shima M, Thachil J, Nair SC, Srivastava A. Scientific and Standardization Committee. Towards standardization of clot waveform analysis and recommendations for its clinical applications. J Thromb Haemost 2013; 11 (07) 1417-1420
    CrossrefPubMedGoogle Scholar
  • 5 Shima M, Matsumoto T, Fukuda K. et al. The utility of activated partial thromboplastin time (aPTT) clot waveform analysis in the investigation of hemophilia A patients with very low levels of factor VIII activity (FVIII:C). Thromb Haemost 2002; 87 (03) 436-441
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Shima M, Matsumoto T, Ogiwara K. New assays for monitoring haemophilia treatment. Haemophilia 2008; 14 (Suppl. 03) 83-92
    CrossrefPubMedGoogle Scholar
  • 7 Matsumoto T, Shima M, Takeyama M. et al. The measurement of low levels of factor VIII or factor IX in hemophilia A and hemophilia B plasma by clot waveform analysis and thrombin generation assay. J Thromb Haemost 2006; 4 (02) 377-384
    CrossrefPubMedGoogle Scholar
  • 8 Katayama H, Matsumoto T, Wada H. et al. An evaluation of hemostatic abnormalities in patients with hemophilia according to the activated partial thromboplastin time waveform. Clin Appl Thromb Hemost 2018; 24 (07) 1170-1176
    CrossrefPubMedGoogle Scholar
  • 9 Nogami K, Matsumoto T, Sasai K, Ogiwara K, Arai N, Shima M. A novel simultaneous clot-fibrinolysis waveform analysis for assessing fibrin formation and clot lysis in haemorrhagic disorders. Br J Haematol 2019; 187 (04) 518-529
    CrossrefPubMedGoogle Scholar
  • 10 Solano C, Zerafa P, Bird R. A study of atypical APTT derivative curves on the ACL TOP coagulation analyser. Int J Lab Hematol 2011; 33 (01) 67-78
    CrossrefPubMedGoogle Scholar
  • 11 Matsumoto T, Nogami K, Shima M. A combined approach using global coagulation assays quickly differentiates coagulation disorders with prolonged aPTT and low levels of FVIII activity. Int J Hematol 2017; 105 (02) 174-183
    CrossrefPubMedGoogle Scholar
  • 12 Suzuki A, Suzuki N, Kanematsu T. et al. Clot waveform analysis in Clauss fibrinogen assay contributes to classification of fibrinogen disorders. Thromb Res 2019; 174: 98-103
    CrossrefPubMedGoogle Scholar
  • 13 Yoshizawa H, Nogami K, Matsumoto T. et al. Dynamic evaluation of hemostasis in the acute phase of Kawasaki disease using comprehensive coagulation functional assays. Thromb Res 2019; 174: 76-83
    CrossrefPubMedGoogle Scholar
  • 14 Nogami K, Matsumoto T, Tabuchi Y. et al. Modified clot waveform analysis to measure plasma coagulation potential in the presence of the anti-factor IXa/factor X bispecific antibody emicizumab. J Thromb Haemost 2018; 16 (06) 1078-1088
    CrossrefPubMedGoogle Scholar
  • 15 Sevenet PO, Depasse F. Clot waveform analysis: where do we stand in 2017?. Int J Lab Hematol 2017; 39 (06) 561-568
    CrossrefPubMedGoogle Scholar
  • 16 Matsumoto T, Nogami K, Tabuchi Y. et al. Clot waveform analysis using CS-2000i™ distinguishes between very low and absent levels of factor VIII activity in patients with severe haemophilia A. Haemophilia 2017; 23 (05) e427-e435
    CrossrefPubMedGoogle Scholar
  • 17 Mazurowski MA, Lo JY, Harrawood BP, Tourassi GD. Mutual information-based template matching scheme for detection of breast masses: from mammography to digital breast tomosynthesis. J Biomed Inform 2011; 44 (05) 815-823
    CrossrefPubMedGoogle Scholar
  • 18 Jing J, Dauwels J, Rakthanmanon T, Keogh E, Cash SS, Westover MB. Rapid annotation of interictal epileptiform discharges via template matching under Dynamic Time Warping. J Neurosci Methods 2016; 274: 179-190
    CrossrefPubMedGoogle Scholar
  • 19 Lee H, Tajmir S, Lee J. et al. Fully automated deep learning system for bone age assessment. J Digit Imaging 2017; 30 (04) 427-441
    CrossrefPubMedGoogle Scholar
  • 20 Buda M, Wildman-Tobriner B, Hoang JK. et al. Management of thyroid nodules seen on US images: deep learning may match performance of radiologists. Radiology 2019; 292 (03) 695-701
    CrossrefPubMedGoogle Scholar
  • 21 Aoe J, Fukuma R, Yanagisawa T. et al. Automatic diagnosis of neurological diseases using MEG signals with a deep neural network. Sci Rep 2019; 9 (01) 5057
    CrossrefPubMedGoogle Scholar
  • 22 Matsumoto T, Nogami K, Ogiwara K, Shima M. A putative inhibitory mechanism in the tenase complex responsible for loss of coagulation function in acquired haemophilia A patients with anti-C2 autoantibodies. Thromb Haemost 2012; 107 (02) 288-301
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 Yada K, Nogami K, Wakabayashi H, Fay PJ, Shima M. The mild phenotype in severe hemophilia A with Arg1781His mutation is associated with enhanced binding affinity of factor VIII for factor X. Thromb Haemost 2013; 109 (06) 1007-1015
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 Trossaërt M, Regnault V, Sigaud M, Boisseau P, Fressinaud E, Lecompte T. Mild hemophilia A with factor VIII assay discrepancy: using thrombin generation assay to assess the bleeding phenotype. J Thromb Haemost 2008; 6 (03) 486-493
    CrossrefPubMedGoogle Scholar
  • 25 Nogami K, Shima M. Phenotypic heterogeneity of hemostasis in severe hemophilia. Semin Thromb Hemost 2015; 41 (08) 826-831
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Gilmore R, Harmon S, Gannon C, Byrne M, O'Donnell JS, Jenkins PV. Thrombin generation in haemophilia A patients with mutations causing factor VIII assay discrepancy. Haemophilia 2010; 16 (04) 671-674
    PubMedGoogle Scholar
  • 27 Downey C, Kazmi R, Toh CH. Novel and diagnostically applicable information from optical waveform analysis of blood coagulation in disseminated intravascular coagulation. Br J Haematol 1997; 98 (01) 68-73
    CrossrefPubMedGoogle Scholar
  • 28 Toh CH, Giles AR. Waveform analysis of clotting test optical profiles in the diagnosis and management of disseminated intravascular coagulation (DIC). Clin Lab Haematol 2002; 24 (06) 321-327
    CrossrefPubMedGoogle Scholar
  • 29 Matsumoto T, Wada H, Nishioka Y. et al. Frequency of abnormal biphasic aPTT clot waveforms in patients with underlying disorders associated with disseminated intravascular coagulation. Clin Appl Thromb Hemost 2006; 12 (02) 185-192
    CrossrefPubMedGoogle Scholar
  • 30 Wakui M, Fujimori Y, Katagiri H. et al. Assessment of in vitro effects of direct thrombin inhibitors and activated factor X inhibitors through clot waveform analysis. J Clin Pathol 2019; 72 (03) 244-250
    CrossrefPubMedGoogle Scholar
  • 31 Hasegawa M, Wada H, Tone S. et al. Monitoring of hemostatic abnormalities in major orthopedic surgery patients treated with edoxaban by APTT waveform. Int J Lab Hematol 2018; 40 (01) 49-55
    CrossrefPubMedGoogle Scholar