The Detection of Hypercoagulability in Patients with Acute Cerebral Infarction Using a Clot Waveform Analysis.

Original Manuscript The Detection of Hypercoagulability in Patients with Acute Cerebral Infarction Using a Clot Waveform Analysis Clinical and Applied Thrombosis/Hemostasis Volume 29: 1-9 © The Author(s) 2023 Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/10760296231161591 journals.sagepub.com/home/cat Toshitaka Kamon, MD1, Shotaro Horie, MD1, Tomoya Inaba, MD1, Nobuo Ito, MDPhd1, Katsuya Shiraki2, Yuhuko Ichikawa3, Minoru Ezaki3, Hideto Shimpo, MDPhd4, Motomu Shimaoka, MDPhd5, Akisato Nishigaki, MD6, Akihiro Shindo, MDPhd6, and Hideo Wada, MDPhd2 Abstract A few studies concerning hypercoagulable states have sufficiently been reported in patients with acute cerebral infarction (ACI), as ACI is generally considered to be caused by platelet activation. Clot waveform analyses (CWA) for activated partial thromboplastin time (APTT) and small amount of tissue factor FIX activation assay (sTF/FIXa) were examined in 108 patients with ACI, 61 patients without ACI, and 20 healthy volunteers. CWA-APTT and CWA-sTF/FIXa showed that the peak heights were significantly higher in ACI patients without anticoagulant therapy than in healthy volunteers. Absorbance exceeding 78.1 mm on the 1st DPH in the CWA-sTF/FIXa showed the highest odds ratio for ACI. The peak heights were significantly lower in the CWAsTF/FIXa of ACI patients receiving argatroban therapy than in those of ACI patients without anticoagulant therapy. CWA can suggest a hypercoagulable state in ACI patients and may be useful for monitoring the need for anticoagulant therapy. Keywords CWA, APTT, sTF/FIXa, acute cerebral infarction, hypercoagulable state Date received: 3 January 2023; revised: 15 February 2023; accepted: 17 February 2023. Introduction Approximately 70% (9.5 million people) of strokes are ischemic strokes (acute cerebral infarction, [ACI]).1,2 ACI is classified into the following entities: cardioembolic ACI,3 atherosclerotic ACI,4 or lacunar ACI.5 As ACI patients still have high mortality, they require prompt treatment with antiplatelet agents (APA),1,6 direct anti-thrombin agents,8 direct oral anticoagulants (DOACs),9 unfractionated heparin (UFH), or warfarin. In Japan, most patients with atherosclerotic ACI are generally treated with argatroban.8 Cases of atherosclerotic or lacunar ACI or transient ischemic attack (TIA) are treated with aspirin or other APAs,1,6 as platelet activation may play an important role in atherosclerosis.7 Although the elevation of soluble C-type lectinlike receptor 2 (sCLEC-2) as a platelet activation marker was reported in patients with ACI,10 few biomarkers of a hypercoagulable state have been reported in ACI patients. Hypercoagulability with increased tissue factor (TF) or microparticles was proposed as a risk factor for thrombosis in patients with cancer.11 The activation of the coagulation system induced by TF may cause VTE in cancer patients through tumor growth and metastasis.12 Platelet activation 1 Department of Neurology, Mie Prefectural General Medical Center, Yokkaichi, Japan 2 Department of General and Laboratory Medicine, Mie Prefectural General Medical Center, Yokkaichi, Japan 3 Department of Central Laboratory, Mie Prefectural General Medical Center, Yokkaichi, Japan 4 Mie Prefectural General Medical Center, Yokkaichi, Japan 5 Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Tsu, Japan 6 Department of Neurology, Mie University Graduate School of Medicine, Tsu, Japan Corresponding Author: Hideo Wada, Department of General and Laboratory Medicine, Mie Prefectural General Medical Center, Yokkaichi 510-8561, Japan. Email: Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage). 2 was also proposed as a mechanism underlying thrombosis.13 Although elevated soluble fibrin (SF) and D-dimer levels are useful for detecting fibrin formation in patients with thrombosis,14,15 there are few routine tests available for hypercoagulability or thrombosis. The routine-activated partial thromboplastin time (APTT) and prothrombin time are useful for detecting bleeding tendency but are not adequate for evaluating hypercoagulability. A clot waveform analysis (CWA) including APTT and small amount of TF-induced FIX activation assay (sTF/FIXa) was recently developed; the APTT is useful for analyzing hemostatic abnormalities and monitoring anticoagulant therapy.16–18 In addition, sTF/FIXa using platelet-rich plasma (PRP) can evaluate hemostatic abnormalities, including those involving platelets.18 CWA-APTT and CWA-sTF/FIXa assays can be performed using a routine full autoblood coagulation analyzer and APTT and PT reagents. These costs are similar to those of routine APTT and PT assays. In the present study, the hypercoagulable state was examined in 108 ACI patients and 61 patients without ACI using a CWA-APTT or CWA-sTF/FIXa assay and the effects of anticoagulant therapies were also examined. Clinical and Applied Thrombosis/Hemostasis formation (FF) curve corresponded to the changes in the absorbance observed while measuring the APTT. The first derivative peak (first DP) curve corresponded to the coagulation velocity. The second derivative peak (2nd DP) curve corresponded to the coagulation acceleration. The height and time of the FF, 1st DP, and 2nd DP curves were called the FFH and FFT, 1st DPH and 1st DPT, and 2nd DPH and 2nd DPT, respectively. Statistical Analyses The data are expressed as the median (range). The significance of differences between groups was examined using the MannWhitney U-test. The cut-off values, determined as the point at which the sensitivity curve and specificity curve intersected, were examined by a receiver operating characteristic (ROC) analysis. P values of <.05 were considered to indicate statistical significance. All statistical analyses were performed using the Stat-Flex software program (Version 7; Artec Co., Ltd, Osaka, Japan). Results Treatments for ACI Materials and Methods Hemostatic abnormalities based on 155 samples in 108 ACI patients (median age, 75.0 years old: 25th-75th percentile, 65.0-82.0 years old, and 36 females and 72 males) who were admitted to Mie Prefectural General Medical Center from September 1, 2020, to April 30, 2022 were examined using a CWA. CWA examinations were also performed in 61 patients without thrombotic complications including ACI and a prothrombin time-international normalized ratio ≤1.05 (median age, 60.0 years old: 25th-75th percentile, 46.8-71.3 years old; 26 females and 35 males, and 35 with chronic hepatitis, 6 with myeloproliferative neoplasms, 6 wi (...truncated)