Distinct features of bivalent direct thrombin inhibitors, hirudin and bivalirudin, revealed by clot waveform analysis and enzyme kinetics in coagulation assays

Wakui, Masatoshi; Fujimori, Yuta; Nakamura, Shoko; Kondo, Yoshino; Kuroda, Yuko; Oka, Shusaku; Nakagawa, Terumichi; Katagiri, Hisako; Murata, Mitsuru

doi:10.1136/jclinpath-2019-205922

Cited by 17 publications

(15 citation statements)

References 24 publications

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“… 36 , 37 The basic analysis of the APTT-CWA demonstrated pharmacological evidence of the blockade of thrombin-positive feedback by antithrombin and anti-Xa inhibitors and differences in anticoagulant cooperativity between them. 38 , 39 …”

Section: Monitoring For Anticoagulant Therapymentioning

confidence: 99%

Update on the Clot Waveform Analysis

Wada

Matsumoto

Ohishi

et al. 2020

Clin Appl Thromb Hemost

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The activated partial thromboplastin time (APTT)–clot waveform analysis (CWA) was previously reported to be associated with the early detection of disseminated intravascular coagulation and was also reported to be able to measure very low levels of coagulation factor VIII activity. The software program for the analysis for the APTT-CWA allows the associated first and second derivative curves (first and second DCs) to be displayed. The first and second DC reflect the velocity and acceleration, respectively. The height of the first DC reflects the “thrombin burst” and bleeding risk, while that of the second DC is useful for detecting any coagulation factor deficiency and abnormal enhancement of coagulation by phospholipids. Activated partial thromboplastin time-CWA aids in making a differential diagnosis which is difficult to do using only the routine APTT. The CWA is currently used for many applications in the clinical setting, including the monitoring of hemophilia patients and patients receiving anticoagulant therapy and the differential diagnosis of diseases.

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Section: Monitoring For Anticoagulant Therapymentioning

confidence: 99%

Update on the Clot Waveform Analysis

Wada

Matsumoto

Ohishi

et al. 2020

Clin Appl Thromb Hemost

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“…Activated partial thromboplastin time (APTT) is an important parameter for measuring both the therapeutic effect and the bleeding risk of hirudin, thus assisting in altering the therapeutic dose. Previous experiments have shown that hirudin significantly prolonged APTT, prothrombin time (PT), and thrombin time (TT), and the value of APTT was positively correlated with the plasma concentration of hirudin 26,27 . In this study, the prolongation of APTT was only observed in the 0.2 mg group (one subject) of the single‐dose trial and in two subjects each from the continuous administration trial groups (0.30 and 0.45 mg/kg/h).…”

Section: Discussionmentioning

confidence: 46%

“…Previous experiments have shown that hirudin significantly prolonged APTT, prothrombin time (PT), and thrombin time (TT), and the value of APTT was positively correlated with the plasma concentration of hirudin. 26,27 In this study, the prolongation of of APTT in 4 subjects form the continuous administration trial occurred on the day of administration, which could be related to the action of EH. However, the symptoms were all mild and the subjects recovered on the same day or the next day without any treatment.…”

Section: Activated Partial Thromboplastin Time (Aptt) Is An Import-mentioning

confidence: 68%

A phase I, single and continuous dose administration study on the safety, tolerability, and pharmacokinetics of neorudin, a novel recombinant anticoagulant protein, in healthy subjects

Liu

Wang

Dong

et al. 2021

Pharmacology Res & Perspec

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The aim of this study was to evaluate the tolerability, safety, and pharmacokinetics of single and continuous dose administration of recombinant neorudin (EPR‐hirudin, EH) by intravenous administration in healthy subjects, and to provide a safe dosage range for phase II clinical research. Forty‐four subjects received EH as a single dose of between 0.2 and 2.0 mg/kg by intravenous bolus and drip infusion. In addition, 18 healthy subjects were randomly divided into three dose groups (0.15, 0.30, and 0.45 mg/kg/h) with 6 subjects in each group for the continuous administration trial. Single or continuous doses of neorudin were generally well tolerated by healthy adult subjects. There were no serious adverse events (SAEs), and all adverse events (AEs) were mild to moderate. Moreover, no subjects withdrew from the trial because of AEs. There were no clinically relevant changes in physical examination results, clinical chemistry, urinalysis, or vital signs. The incidence of adverse events was not significantly related to drug dose or systemic exposure. After single‐dose and continuous administration, the serum EH concentration reached its peak at 5 min, and the exposure increased with the increase in the administered dose. The mean half‐life (T 1/2 ), clearance (Cl), and apparent volume of distribution (Vd) of EH ranged from 1.7 to 2.5 h, 123.9 to 179.7 ml/h/kg, and 402.7 to 615.2 ml/kg, respectively. The demonstrated safety, tolerability, and pharmacokinetic characteristics of EH can be used to guide rational drug dosing and choose therapeutic regimens in subsequent clinical studies. Clinical trial registration: Chinadrugtrials.org identifier: CTR20160444.

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“…Laboratory instruments used for routine coagulation‐related tests based on optical detection of turbidity changes allow us to perform CFWA if having software to simultaneously analyze clotting and fibrinolytic reaction curves by making their successive derivatives. We have previously verified the usability of CWA for assessment of in vitro anticoagulation with DTIs and FXa inhibitors including DOACs . This experience led us to apply CFWA to assessment of in vitro their effects on fibrinolysis.…”

Section: Discussionmentioning

confidence: 87%

“…5 We have previously verified the usability of CWA for assessment of in vitro anticoagulation with DTIs and FXa inhibitors including DOACs. 5,15 This experience led us to apply CFWA to assessment of in vitro their effects on fibrinolysis.…”

Section: Effects Of Doacs On Fibrinolysis Observed Through Aptt-cfwamentioning

confidence: 99%

Application of clot‐fibrinolysis waveform analysis to assessment of in vitro effects of direct oral anticoagulants on fibrinolysis

Oka

Wakui

Fujimori

et al. 2020

Int J Lab Hematology

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Introduction: Acceleration of fibrinolysis by direct oral anticoagulants (DOACs) has been reported by several groups, suggesting contribution of not only anticoagulant but also fibrinolytic effects to the therapeutic efficacy. The present study aims to evaluate the usability of clot-fibrinolysis waveform analysis (CFWA) for assessment of in vitro effects of DOACs on fibrinolysis. Methods:The experimental conditions were optimized according to how t-PA concentrations and a time length after t-PA adjustment affect parameters of CFWA.Addition of the activated partial thromboplastin time (APTT) reagent followed by that of calcium and t-PA was done to obtain clotting and fibrinolytic reaction curves which were mathematically differentiated for CFWA (APTT-CFWA). The positive and negative modes of waveforms were defined as the direction toward fibrin generation and that toward fibrin degradation, respectively. The maximum positive and negative values (Max p 1 and Max n 1) correspond to the maximum coagulation velocity and the maximum fibrinolysis velocity, respectively. Plasma spiked with each of DOACs (rivaroxaban, apixaban, edoxaban, and dabigatran) was subjected to APTT-CFWA.Results: Optimization of t-PA use was based on Max n 1. Roughly biphasic effects of rivaroxaban and dabigatran but not apixaban or edoxaban on fibrinolysis were observed through Max n 1 and the fibrinolysis peak time, which was defined as a time length from the time when Max p 1 (Max p 1 time) to the time when Max n 1 appears (Max n 1 time). Conclusion:The results suggest the usability of CFWA for assessment of DOAC effects and provide insights into relevance of anticoagulation to therapeutic efficacy and bleeding risk from the perspective of fibrinolysis. K E Y W O R D Sactivated partial thromboplastin time, clot-fibrinolysis waveform analysis, direct oral anticoagulants, maximum fibrinolysis velocity, tissue plasminogen activator

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Distinct features of bivalent direct thrombin inhibitors, hirudin and bivalirudin, revealed by clot waveform analysis and enzyme kinetics in coagulation assays

Cited by 17 publications

References 24 publications

Update on the Clot Waveform Analysis

Update on the Clot Waveform Analysis

A phase I, single and continuous dose administration study on the safety, tolerability, and pharmacokinetics of neorudin, a novel recombinant anticoagulant protein, in healthy subjects

Application of clot‐fibrinolysis waveform analysis to assessment of in vitro effects of direct oral anticoagulants on fibrinolysis

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