Is the inhibition of both clot-associated thrombin and factor Xa more clinically relevant than either one alone?

Meddahi, Sadia; Samama, M

doi:10.1097/mbc.0b013e3283273529

Cited by 7 publications

(6 citation statements)

References 19 publications

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“…Finally, it was also shown experimentally that following hirudin treatment discontinuation, a hypercoagulation rebound occurred, possibly related to the persistence of factor Xa activity in the clot. The authors subsequently demonstrated the complementary effect of DX9065a, a clot-bound factor Xa inhibitor, and r-hirudin, which increased the antithrombotic effect in an in-vitro model for the measurement of clot-bound thrombin [30]. The combination of an antithrombin activator and thrombin inhibitor was used in a recent study on patients with ST-elevation myocardial infarction, resulting in a reduction in mortality or definite thrombosis following primary percutaneous angioplasty [31].…”

Section: Discussionmentioning

confidence: 99%

Bivalirudin in Combination with Heparin to Control Mesenchymal Cell Procoagulant Activity

et al. 2012

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Islet and hepatocyte transplantation are associated with tissue factor-dependent activation of coagulation which elicits instant blood mediated inflammatory reaction, thereby contributing to a low rate of engraftment. The aim of this study was i) to evaluate the procoagulant activity of human adult liver-derived mesenchymal progenitor cells (hALPCs), ii) to compare it to other mesenchymal cells of extra-hepatic (bone marrow mesenchymal stem cells and skin fibroblasts) or liver origin (liver myofibroblasts), and iii) to determine the ways this activity could be modulated. Using a whole blood coagulation test (thromboelastometry), we demonstrated that all analyzed cell types exhibit procoagulant activity. The hALPCs pronounced procoagulant activity was associated with an increased tissue factor and a decreased tissue factor pathway inhibitor expression as compared with hepatocytes. At therapeutic doses, the procoagulant effect of hALPCs was inhibited by neither antithrombin activators nor direct factor Xa inhibitor or direct thrombin inhibitors individually. However, concomitant administration of an antithrombin activator or direct factor Xa inhibitor and direct thrombin inhibitor proved to be a particularly effective combination for controlling the procoagulant effects of hALPCs both in vitro and in vivo. The results suggest that this dual antithrombotic therapy should also improve the efficacy of cell transplantation in humans.

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Section: Discussionmentioning

confidence: 99%

Bivalirudin in Combination with Heparin to Control Mesenchymal Cell Procoagulant Activity

et al. 2012

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“…This single ascending dose study was designed as a single-blind, randomized, and placebo-controlled study with a crossover (leapfrog) design in 3 cohorts of 10 volunteers each. Nine dose steps were planned (1,3,10,30,60,120,240,480, and 600 mg). Each volunteer in a given cohort was dosed on 3 occasions.…”

Section: Methodsmentioning

confidence: 99%

“…A direct FXa inhibitor regulates the coagulation cascade by inhibiting circulating FXa, the prothrombinase complex (FXa/F. Va), and the clot‐bound FXa 9 , 10 . Regulating the activity of FXa limits the burst of thrombin generation, thereby diminishing the thrombin‐mediated activation of coagulation and platelets without complete interruption of the basal level of thrombin necessary for primary hemostasis 11 .…”

mentioning

confidence: 99%

“…Va), and the clot-bound FXa. 9,10 Regulating the activity of FXa limits the burst of thrombin generation, thereby diminishing the thrombin-mediated activation of coagulation and platelets without complete interruption of the basal level of thrombin necessary for primary hemostasis. 11 Therefore, selective inhibition of FXa may cause less impairment of primary hemostasis and should be a safer anticoagulant therapy than direct inhibition of thrombin.…”

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confidence: 99%

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Crossover Dose Escalation Study to Assess Safety, Pharmacokinetics, and Pharmacodynamics of Single Doses of R1663, an Oral Factor Xa Inhibitor, in Healthy Male Volunteers

Schmitt¹,

Pannier²,

McIntyre³

et al. 2012

The Journal of Clinical Pharma

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This study investigated the safety, pharmacokinetics, and pharmacodynamics of single oral doses of R1663, a factor Xa inhibitor, in healthy volunteers. It was a single-blind, randomized, crossover, placebo-controlled, dose escalation study in 33 healthy male volunteers aged 18 to 45 years. Each volunteer was dosed on 3 occasions with R1663 or placebo. Single oral doses of R1663 were safe and well tolerated. R1663 did not affect bleeding time. Pharmacodynamic effects (prothrombin time [PT], activated partial thromboplastin time [aPTT]), parameters of thrombogram, and anti-factor Xa activity) and plasma concentrations of R1663 were dose-dependent and showed low to moderate (<40%) intersubject and intrasubject variability. Maximum factor Xa inhibition was achieved 3 hours post dose (time to maximum concentration of R1663): clotting times were prolonged up to 2.5-fold, whereas endogenous thrombin potential (ETP) and peak height were decreased by 48% and 85% from their baseline values, respectively. Pharmacodynamic parameters were strongly correlated to R1663 plasma concentrations, with IC50 values of 182 and 2680 ng/mL for peak height and ETP, respectively. Oral doses of R1663 up to 480 mg were well tolerated, with predictable pharmacodynamics and pharmacokinetics. R1663 prolonged clotting times (PT, aPTT) and inhibited thrombin generation without increasing bleeding time.

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“…Recent studies have investigated a combination of complementary therapies to further enhance individual anticoagulant effects. For example, employing an antithrombin inhibitor, r‐hirudin, that inhibits soluble and fibrin‐bound thrombin with a direct FXa inhibitor has been shown to enhance clotting times in vitro (Meddahi and Samama 2009). Similarly, PEGylated knob peptides may be used in conjunction with an alternative anticoagulant to target the coagulation cascade at multiple phases.…”

Section: Discussionmentioning

confidence: 99%

A new direction for anticoagulants: Inhibiting fibrin assembly with PEGylated fibrin knob mimics

Stabenfeldt

Aboujamous

Soon

et al. 2011

Biotech & Bioengineering

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Current anticoagulants target coagulation Factors upstream from fibrin assembly and polymerization (i.e. formation of fibrin clot). While effective, this approach requires constant patient monitoring since pharmacokinetics and pharmacodynamics vary from patient to patient. To address these limitations, we developed an alternative anticoagulant that effectively inhibits fibrin polymerization. Specifically, we investigated PEGylated fibrin knob `A' peptides, evaluating the effect of both PEG chain length (0, 2, 5, 10, 20, and 30 kDa) and knob peptide sequence (GPRPAAC, GPRPFPAC, and GPRPPERC) on inhibiting fibrin polymerization (i.e. clot formation). Thrombin-initiated clotting assays with purified fibrinogen were performed to compare clot formation with each peptide-PEG conjugate. Results indicated a biphasic effect of PEG chain length whereby active-PEG conjugates demonstrated increasingly enhanced inhibition of fibrin polymerization from 0 to 5 kDa PEG. However, the anticoagulant activity diminished to control levels for PEG chains above 5 kDa. Ultimately, we observed a 10-fold enhancement of anticoagulant activity with active peptides PEGylated with 5 kDa PEG compared to non-PEGylated knob peptides. The sequence of the active peptide significantly influenced the anticoagulant properties only at the highest 1:100 molar ratio where GPRPFPAC-5 kDa PEG and GPRPPERC-5 kDa PEG demonstrated significantly lower percent clottable protein than GPRPAAC-5 kDa PEG. Moreover, human plasma treated with the active 5 kDa PEG conjugate exhibited delayed the prothrombin time to within the therapeutic range specified for oral anticoagulants. Collectively, this study demonstrated the utility of PEGylated fibrin knob peptides as potential anticoagulant therapeutics.

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Is the inhibition of both clot-associated thrombin and factor Xa more clinically relevant than either one alone?

Cited by 7 publications

References 19 publications

Bivalirudin in Combination with Heparin to Control Mesenchymal Cell Procoagulant Activity

Bivalirudin in Combination with Heparin to Control Mesenchymal Cell Procoagulant Activity

Crossover Dose Escalation Study to Assess Safety, Pharmacokinetics, and Pharmacodynamics of Single Doses of R1663, an Oral Factor Xa Inhibitor, in Healthy Male Volunteers

A new direction for anticoagulants: Inhibiting fibrin assembly with PEGylated fibrin knob mimics

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