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DOI: 10.1055/a-2778-9810
Decoding Clot Waveform Analysis: Toward Better Understanding and Harmonization
Authors
Abstract
Clot waveform analysis (CWA) extends routine coagulation assays (activated partial thromboplastin time [aPTT] and prothrombin time [PT]) by incorporating continuous optical monitoring to generate kinetic profiles of clot formation. This method provides both qualitative and quantitative information on hemostasis, with increasing evidence for its clinical utility in detecting factor deficiencies and characterizing thrombotic and bleeding disorders. Despite the growing body of evidence, translation of CWA into routine clinical practice remains limited.
This review identifies three principal barriers: (1) variability arising from differences in optical detection methods (absorbance vs. transmittance), (2) interreagent variation even within the same analyzer platform, and (3) lack of a clear distinction between standard CWA, performed with commercially available reagents, and modified CWA, incorporating in-house adjustments. To address these challenges, we encourage adopting distinct nomenclature for detection modalities (CWA-A; A for absorbance and CWA-T; T for transmittance), establishing standardized reporting requirements including reagent and platform details, and establishing quality assurance frameworks for CWA.
Standardization of terminology and reporting will enhance reproducibility, enable cross-study comparisons, and accelerate the clinical translation of CWA from the laboratory bench to the bedside.
Authors' Contributions
J.Y.T., M.R.T.D.G., and C.W.T. contributed to the original draft and manuscript revision. W.H.W., C.K.Y., G.H.G., and H.J.N. contributed to manuscript revision.
* These authors contributed equally and share primary co-authorship of this article.
Publication History
Received: 06 October 2025
Accepted: 23 December 2025
Accepted Manuscript online:
08 January 2026
Article published online:
21 January 2026
© 2026. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
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References
- 1 Lancé MD. A general review of major global coagulation assays: thrombelastography, thrombin generation test and clot waveform analysis. Thromb J 2015; 13 (01) 1
- 2 Nogami K. Clot waveform analysis for monitoring hemostasis. Semin Thromb Hemost 2023; 49 (06) 592-599
- 3 Wada H, Shiraki K, Matsumoto T, Shimpo H, Shimaoka M. Clot waveform analysis for hemostatic abnormalities. Ann Lab Med 2023; 43 (06) 531-538
- 4 Wada H, Shiraki K, Ichikawa Y, Matsumoto T, Shimpo H, Shimaoka M. Clinical application of clot waveform analysis. Clin Appl Thromb Hemost 2025; 31: 10 760296251331606
- 5 Marongiu F, Ruberto MF, Marongiu S, Barcellona D. Clot waveform analysis: from hypercoagulability to hypocoagulability: a review. Arch Pathol Lab Med 2024; 148 (12) 1371-1375
- 6 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
- 7 Onishi T, Shimonishi N, Takeyama M. et al. The balance of comprehensive coagulation and fibrinolytic potential is disrupted in patients with moderate to severe COVID-19. Int J Hematol 2022; 115 (06) 826-837
- 8 Wada H, Shiraki K, Matsumoto T. et al. A clot waveform analysis of thrombin time using a small amount of thrombin is useful for evaluating the clotting activity of plasma independent of the presence of emicizumab. J Clin Med 2022; 11 (20) 6142
- 9 Tsuchida T, Hayakawa M, Kumano O. Characterization and usefulness of clot-fibrinolysis waveform analysis in critical care patients with enhanced or suppressed fibrinolysis. Thromb Haemost 2024; 124 (01) 40-48
- 10 Masuda J, Wada H, Kato T. et al. Enhanced hypercoagulability using clot waveform analysis in patients with acute myocardial infarction and acute cerebral infarction. J Clin Med 2024; 13 (23) 7181
- 11 Zaidi A, Green L. Physiology of haemostasis. Anaesth Intensive Care Med 2025; 26 (01) 41-47
- 12 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
- 13 Siegemund T, Scholz U, Schobess R, Siegemund A. Clot waveform analysis in patients with haemophilia A. Hamostaseologie 2014; 34 (Suppl. 01) S48-S52
- 14 Sevenet PO, Depasse F. Clot waveform analysis: where do we stand in 2017?. Int J Lab Hematol 2017; 39 (06) 561-568
- 15 Wakui M, Fujimori Y, Ozaki Y. et al. Comparison of clot waveform analysis with or without adjustment between prothrombin time and activated partial thromboplastin time assays to assess in vitro effects of direct oral anticoagulants. Clin Chim Acta 2024; 562: 119887
- 16 Hasegawa M, Tone S, Wada H. et al. The evaluation of hemostatic abnormalities using a CWA-small amount tissue factor induced FIX activation assay in major orthopedic surgery patients. Clin Appl Thromb Hemost 2021; 27: 10 760296211012094
- 17 Kadu A, Shah AM, Goswami H. Clot waveform analysis of prolonged activated partial thromboplastin time in various disorders. Indian J Pathol Microbiol 2025; 68 (01) 137-140
- 18 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
- 19 Nesheim M, Samis J, Walker J. et al. Lipoprotein-complexed C-reactive protein and the biphasic transmittance waveform in critically ill patients. Blood Rev 2002; 16 (Suppl. 01) S15-S22
- 20 Toh CH, Samis J, Downey C. et al. 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 (07) 2522-2529
- 21 Dempfle CEH, Lorenz S, Smolinski M. et al. Utility of activated partial thromboplastin time waveform analysis for identification of sepsis and overt disseminated intravascular coagulation in patients admitted to a surgical intensive care unit. Crit Care Med 2004; 32 (02) 520-524
- 22 Tokunaga N, Inoue C, Sakata T. et al. Usefulness of the second-derivative curve of activated partial thromboplastin time on the ACL-TOP coagulation analyzer for detecting factor deficiencies. Blood Coagul Fibrinolysis 2016; 27 (04) 474-476
- 23 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
- 24 Kato K, Hatayama Y, Shimohiro H, Ichikawa H, Fukuda T. Differences in the composition of activated partial thromboplastin time (APTT) reagents affect clot waveform analysis. Yonago Acta Med 2022; 65 (03) 226-230
- 25 Kanouchi K, Narimatsu H, Shirata T, Morikane K. Diagnostic analysis of lupus anticoagulant using clot waveform analysis in activated partial thromboplastin time prolonged cases: a retrospective analysis. Health Sci Rep 2021; 4 (02) e258
- 26 Mair G, Dunhill S, Tiplady C. Prognostic implications of a biphasic waveform for APTT analysis in a district general hospital. Int J Lab Hematol 2008; 30 (06) 467-472
- 27 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
- 28 U.S. Food and Drug Administration. 510(k) Substantial Equivalence Determination Decision Summary: K173202 [Internet]. U.S. Food and Drug Administration; 2017 . Available from: https://www.accessdata.fda.gov/cdrh_docs/reviews/K173202.pdf
- 29 Wong WH, Tan CW, Abdul Khalid NB. et al. Reagent effects on the activated partial thromboplastin time clot waveform analysis: a multi-centre study. Diagnostics (Basel) 2023; 13 (14) 2447
- 30 Wada H, Shiraki K, Matsumoto T. et al. Evaluating factor VIII concentrates using clot waveform analysis. J Clin Med 2024; 13 (13) 3857
- 31 Chu YMH. Comparison of APTT and APTT-based clot waveform analysis parameters between SYSMEX CN3000 analyzer and SYSMEX CS2500 analyzer. In Singapore; 2025 . p. 27. Available from: https://ssh.org.sg/wp-content/uploads/2025/05/SSH-ASM-2025-Program-Booklet-Final.pdf
- 32 Ichikawa J, Okazaki R, Fukuda T, Ono T, Ishikawa M, Komori M. Evaluation of coagulation status using clot waveform analysis in general ward patients with COVID-19. J Thromb Thrombolysis 2022; 53 (01) 118-122
- 33 Fan BE, Ramanathan K, Sum CLL. et al. Global haemostatic tests demonstrate the absence of parameters of hypercoagulability in non-hypoxic mild COVID-19 patients: a prospective matched study. J Thromb Thrombolysis 2022; 53 (03) 646-662
- 34 Tan CW, Tan JY, Wong WH. et al. Clinical and laboratory features of hypercoagulability in COVID-19 and other respiratory viral infections amongst predominantly younger adults with few comorbidities. Sci Rep 2021; 11 (01) 1793
- 35 Fan BE, Ng J, Chan SSW. et al. COVID-19 associated coagulopathy in critically ill patients: A hypercoagulable state demonstrated by parameters of haemostasis and clot waveform analysis. J Thromb Thrombolysis 2021; 51 (03) 663-674
- 36 Tan CW, Low JGH, Wong WH, Chua YY, Goh SL, Ng HJ. Critically ill COVID-19 infected patients exhibit increased clot waveform analysis parameters consistent with hypercoagulability. Am J Hematol 2020; 95 (07) E156-E158
- 37 Shimura T, Kurano M, Kanno Y. et al. Clot waveform of APTT has abnormal patterns in subjects with COVID-19. Sci Rep 2021; 11 (01) 5190
- 38 Tan JY, Wong WH, Liu W. et al. Effect of lupus anti-coagulant and antiphospholipid antibodies on clot waveform analysis parameters. Thromb Res 2025; 247: 109268
- 39 Tan CW, Cheen MHH, Wong WH. et al. Elevated activated partial thromboplastin time-based clot waveform analysis markers have strong positive association with acute venous thromboembolism. Biochem Med (Zagreb) 2019; 29 (02) 020710
- 40 Ruberto MF, Marongiu F, Mandas A. et al. The venous thromboembolic risk and the clot wave analysis: a useful relationship?. Clin Chem Lab Med 2018; 56 (03) 448-453
- 41 Ng CL, Uy FM, Cheong MA. et al. Activated partial thromboplastin time-based clot waveform analysis: a potential for application in acute myocardial infarction and its complications. Sci Rep 2024; 14 (01) 20917
- 42 Mannan KA, Kumar N, Ahluwalia J. et al. The activated partial thromboplastin time-clot waveform analysis in hemophilia: does it help in differentiation?. Int J Lab Hematol 2023; 45 (02) 241-249
- 43 Hartmann R, Feenstra T, Knappe S, Schrenk G, Scheiflinger F, Dockal M. A bispecific antibody demonstrates limited measurability in routine coagulation assays. Blood Coagul Fibrinolysis 2020; 31 (06) 353-365
- 44 Dave RG, Geevar T, Mammen JJ, Vijayan R, Mahasampath G, Nair SC. Clinical utility of activated partial thromboplastin time clot waveform analysis and thrombin generation test in the evaluation of bleeding phenotype in hemophilia A. Indian J Pathol Microbiol 2021; 64 (01) 117-122
- 45 Yoo KY, Jung SY, Hwang SH, Lee SM, Park JH, Nam HJ. Global hemostatic assay of different target procoagulant activities of factor VIII and factor IX. Blood Res 2018; 53 (01) 41-48
- 46 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
- 47 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
- 48 Shimomura D, Matsumoto T, Sugimoto K. et al. The first-derivative curve of the coagulation waveform reveals the cause of aPTT prolongation. Clin Appl Thromb Hemost 2020; 26: 1076029620978810
- 49 Drissi E, Ben Lakhal F, Ghali O. et al. Clot waveform analysis in hemophilia carriers. Blood Coagul Fibrinolysis 2025; 36 (01) 8-13
- 50 Suzuki A, Suzuki N, Okamoto S. et al. Prevalence estimation of dysfibrinogenemia using the Clauss-CWA approach. Int J Lab Hematol 2025; 47 (02) 297-303
- 51 Horner K, Kitchen S. Evaluation of Clauss fibrinogen assay clot waveform analysis for the detection of dysfibrinogenemia on Sysmex CN-6000. Int J Lab Hematol 2025; 47 (05) 915-922
- 52 Suzuki A, Suzuki N, Kanematsu T. et al. Development and validation of a novel qualitative test for plasma fibrinogen utilizing clot waveform analysis. Sci Rep 2022; 12 (01) 434
- 53 Arai S, Kamijo T, Kaido T. et al. Automated screening procedure for the phenotypes of congenital fibrinogen disorders using novel parameters, |min1|c and Ac/|min1|c, obtained from clot waveform analysis using the Clauss method. Clin Chim Acta 2021; 521: 170-176
- 54 Arai S, Kamijo T, Hayashi F. et al. Screening method for congenital dysfibrinogenemia using clot waveform analysis with the Clauss method. Int J Lab Hematol 2021; 43 (02) 281-289
- 55 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
- 56 Chanthong S, Choed-Amphai C, Manowong S. et al. Rotational thromboelastometry and clot waveform analysis as point-of-care tests for diagnosis of disseminated intravascular coagulation in critically ill children in Thailand. Pediatr Crit Care Med 2024; 25 (05) e221-e231
- 57 Abraham SV, Rafi AM, Krishnan SV. et al. Utility of clot waveform analysis in Russell's viper bite victims with hematotoxicity. J Emerg Trauma Shock 2018; 11 (03) 211-216
- 58 Chikasawa Y, Amano K, Shinozawa K. et al. Comprehensive comparison of global coagulation assays to differentiate lupus anticoagulant from acquired hemophilia A in patients with prolonged APTT. Int J Hematol 2023; 118 (05) 577-588
- 59 Wakui M, Fujimori Y, Nakamura S. et al. Characterisation of antithrombin-dependent anticoagulants through clot waveform analysis to potentially distinguish them from antithrombin-independent inhibitors targeting activated coagulation factors. J Clin Pathol 2021; 74 (04) 251-256
- 60 Cheong MA, Tan CW, Wong WH. et al. A correlation of thrombin generation assay and clot waveform analysis in patients on warfarin. Hematology 2022; 27 (01) 337-342
- 61 Evrard J, Siriez R, Bouvy C. et al. Comparison of analytical performances between clot waveform analysis and FibWave in edoxaban-treated patients and healthy controls. Res Pract Thromb Haemost 2022; 6 (07) e12804
- 62 Wakui M, Fujimori Y, Nakamura S. et al. Distinct features of bivalent direct thrombin inhibitors, hirudin and bivalirudin, revealed by clot waveform analysis and enzyme kinetics in coagulation assays. J Clin Pathol 2019; 72 (12) 817-824
- 63 Ichikawa J, Okazaki R, Fukuda T, Yoon D, Komori M. Effects of hemodilution on clot waveform analysis parameters, clotting factors, and thrombin generation assays in a dilutional model based on analysis of 11 healthy male blood donors. Med Sci Monit 2022; 28: e937368
- 64 Tan CW, Wong WH, Cheen MHH. et al. Assessment of aPTT-based clot waveform analysis for the detection of haemostatic changes in different types of infections. Sci Rep 2020; 10 (01) 14186
- 65 Maeda K, Wada H, Shinkai T, Tanemura A, Matsumoto T, Mizuno S. Evaluation of hemostatic abnormalities in patients who underwent major hepatobiliary pancreatic surgery using activated partial thromboplastin time-clot waveform analysis. Thromb Res 2021; 201: 154-160
- 66 Ruberto MF, Marongiu F, Sorbello O, Civolani A, Demelia L, Barcellona D. Are prothrombin time and clot waveform analysis useful in detecting a bleeding risk in liver cirrhosis?. Int J Lab Hematol 2019; 41 (01) 118-123
- 67 Terras M, El Borgi W, Betbout W. et al. Clot waveform analysis in acute promyelocytic leukemia. Blood Coagul Fibrinolysis 2024; 35 (01) 27-31
- 68 Di Pino M, Ruberto MF, Costanzo G. et al. Chronic spontaneous urticaria: a low-grade disseminated intravascular coagulation only partially reversed by omalizumab. Clin Exp Med 2023; 23 (02) 495-502
- 69 Ruberto MF, Sorbello O, Civolani A, Barcellona D, Demelia L, Marongiu F. Clot wave analysis and thromboembolic score in liver cirrhosis: two opposing phenomena. Int J Lab Hematol 2017; 39 (04) 369-374
- 70 Yamada K, Nakajima Y, Ogiwara K, Sakai T, Fukuda K, Nogami K. ROTEM could be useful for lupus anticoagulant hypoprothrombinemia syndrome. Pediatr Int 2024; 66 (01) e15773