A Novel Assessment of Factor VIII Activity by Template Matching Utilizing Weighted Average Parameters from Comprehensive Clot Waveform AnalysisFunding 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).
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.
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.
An account of this work was presented at the XXVII Congress of the International Society on Thrombosis and Haemostasis, 2019, Melbourne, Australia.
Received: 11 April 2020
Accepted: 23 July 2020
22 August 2020 (online)
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- 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
- 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
- 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
- 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
- 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
- 6 Shima M, Matsumoto T, Ogiwara K. New assays for monitoring haemophilia treatment. Haemophilia 2008; 14 (Suppl. 03) 83-92
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 15 Sevenet PO, Depasse F. Clot waveform analysis: where do we stand in 2017?. Int J Lab Hematol 2017; 39 (06) 561-568
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 25 Nogami K, Shima M. Phenotypic heterogeneity of hemostasis in severe hemophilia. Semin Thromb Hemost 2015; 41 (08) 826-831
- 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
- 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
- 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
- 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
- 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
- 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