scholarly journals Rivaroxaban pharmacodynamics in healthy volunteers evaluated with thrombin generation and the active protein C system: Modeling and assessing interindividual variability

2019 ◽  
Vol 17 (10) ◽  
pp. 1670-1682 ◽  
Author(s):  
Virginie Siguret ◽  
Johan Abdoul ◽  
Xavier Delavenne ◽  
Emmanuel Curis ◽  
Audrey Carlo ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Protein C ◽  
Thrombin Generation ◽  
Interindividual Variability ◽  
System Modeling ◽  
Active Protein

Plasma Factor V Activation Is Prevented by Activated Protein C in the Presence of Phospholipid Vesicles, Not Platelets

1993 ◽  
Vol 69 (02) ◽  
pp. 124-129 ◽  
Author(s):  
Susan Solymoss ◽  
Kim Thi Phu Nguyen
Keyword(s):  
Western Blotting ◽  
Protein C ◽  
Thrombin Generation ◽  
Blood Platelets ◽  
Activated Protein C ◽  
Phospholipid Vesicles ◽  
Factor V ◽  
Two Stage ◽  
One Stage ◽  
Plasma Factor

SummaryActivated protein C (APC) is a vitamin K dependent anticoagulant which catalyzes the inactivation of factor Va and VIIIa, in a reaction modulated by phospholipid membrane surface, or blood platelets. APC prevents thrombin generation at a much lower concentration when added to recalcified plasma and phospholipid vesicles, than recalcified plasma and platelets. This observation was attributed to a platelet associated APC inhibitor. We have performed serial thrombin, factor V one stage and two stage assays and Western blotting of dilute recalcified plasma containing either phospholipid vesicles or platelets and APC. More thrombin was formed at a given APC concentration with platelets than phospholipid. One stage factor V values increased to higher levels with platelets and APC than phospholipid and APC. Two stage factor V values decreased substantially with platelets and 5 nM APC but remained unchanged with phospholipid and 5 nM APC. Western blotting of plasma factor V confirmed factor V activation in the presence of platelets and APC, but lack of factor V activation with phospholipid and APC. Inclusion of platelets or platelet membrane with phospholipid enhanced rather than inhibited APC catalyzed plasma factor V inactivation. Platelet activation further enhanced factor V activation and inactivation at any given APC concentration.Plasma thrombin generation in the presence of platelets and APC is related to ongoing factor V activation. No inhibition of APC inactivation of FVa occurs in the presence of platelets.

scholarly journals Quantification of von Willebrand factor and ADAMTS-13 after traumatic injury: a pilot study

2021 ◽  
Vol 6 (1) ◽  
pp. e000703
Author(s):  
Taleen A MacArthur ◽  
Julie Goswami ◽  
Laurie Moon Tasson ◽  
Alexander Tischer ◽  
Kent R Bailey ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Acute Phase ◽  
Von Willebrand Factor ◽  
Thrombin Generation ◽  
Trauma Patients ◽  
Phase Reaction ◽  
Time Points ◽  
A1 Domain ◽  
Von Willebrand ◽  
Willebrand Factor

BackgroundVon Willebrand factor (VWF) is an acute phase reactant synthesized in the megakaryocytes and endothelial cells. VWF forms ultra-large multimers (ULVWF) which are cleaved by the metalloprotease ADAMTS-13, preventing spontaneous VWF–platelet interaction. After trauma, ULVWF is released into circulation as part of the acute phase reaction. We hypothesized that trauma patients would have increased levels of VWF and decreased levels of ADAMTS-13 and that these patients would have accelerated thrombin generation.MethodsWe assessed plasma concentrations of VWF antigen and ADAMTS-13 antigen, the Rapid Enzyme Assays for Autoimmune Diseases (REAADS) activity of VWF, which measure exposure of the platelet-binding A1 domain, and thrombin generation kinetics in 50 samples from 30 trauma patients and an additional 21 samples from volunteers. Samples were analyzed at 0 to 2 hours and at 6 hours from the time of injury. Data are presented as median (IQR) and Kruskal-Wallis test was performed between trauma patients and volunteers at both time points.ResultsREAADS activity was greater in trauma patients than volunteers both at 0 to 2 hours (190.0 (132.0–264.0) vs. 92.0 (71.0–114.0), p<0.002) and at 6 hours (167.5 (108.0–312.5.0) vs. 92.0 (71.0–114.0), p<0.001). ADAMTS-13 antigen levels were also decreased in trauma patients both at 0 to 2 hours (0.84 (0.51–0.94) vs. 1.00 (0.89–1.09), p=0.010) and at 6 hours (0.653 (0.531–0.821) vs. 1.00 (0.89–1.09), p<0.001). Trauma patients had accelerated thrombin generation kinetics, with greater peak height and shorter time to peak than healthy volunteers at both time points.DiscussionTrauma patients have increased exposure of the VWF A1 domain and decreased levels of ADAMTS-13 compared with healthy volunteers. This suggests that the VWF burst after trauma may exceed the proteolytic capacity of ADAMTS-13, allowing circulating ULVWF multimers to bind platelets, potentially contributing to trauma-induced coagulopathy.Level of evidenceProspective case cohort study.

Phospholipid-bound Tissue Factor Modulates both Thrombin Generation and APC-mediated Factor Va Inactivation

1999 ◽  
Vol 82 (12) ◽  
pp. 1673-1679 ◽  
Author(s):  
Katalin Váradi ◽  
Jürgen Siekmann ◽  
Peter Turecek ◽  
H. Peter Schwarz ◽  
Victor Marder
Keyword(s):  
Tissue Factor ◽  
Surface Density ◽  
Protein C ◽  
Thrombin Generation ◽  
Feedback Inhibition ◽  
Activated Protein C ◽  
Reaction System ◽  
Inverse Correlation ◽  
High Concentration ◽  
Factor Va

SummaryHemostasis is initiated by tissue factor (TF) exposed on cellular phospholipid (PL) membranes, leading to thrombin generation. The binding of thrombin to thrombomodulin (TM), activates the protein C pathway, resulting in the inactivation of factors Va and VIIIa by activated protein C (APC) and a negative feedback effect on thrombin generation. A new assay system was developed for simultaneous measurement of thrombin and APC generation in defibrinated plasma induced by large unilamellar PL vesicles complexed with full-length recombinant TF (TF:PL). TF:PL preparations with a low TF concentration induced an initial rate of thrombin generation below 100 nM/min, and resulted in less thrombin formation in the presence of TM than in its absence. In contrast, TF:PL preparations with a high concentration of TF induced a higher rate of thrombin generation, and APC-mediated feedback inhibition did not occur, despite maximal APC generation. We used the same TF:PL surfaces to study factor Va inactivation by APC in a non-plasma reaction system, and found an inverse correlation between TF surface density and the rate of factor Va inactivation. This observation suggests a previously unrecognized hemostatic effect of TF, namely a non-enzymatic surface density-based inhibition of the anticoagulant effect of APC. In this model, high concentrations and surface density of TF exert complementary effects by promoting the regular procoagulant cascade and by inhibiting the protein C pathway, thereby maximizing hemostasis after vascular injury.

scholarly journals Intensity of thrombin formation and myocardial contractility in patients with ischemic heart disease after coronary stenting

2017 ◽  
Vol 16 (2) ◽  
pp. 63-69
Author(s):  
G. A. Berezovskaya ◽  
E. S. Klokova
Keyword(s):  
Myocardial Contractility ◽  
Protein C ◽  
Stress Echocardiography ◽  
Thrombin Generation ◽  
Wall Motion ◽  
Primary Pci ◽  
Before And After ◽  
Wall Motion Abnormalities ◽  
Artery Disease ◽  
Thrombin Formation

Objective. To study the relationship between the intensity of thrombin formation, estimated by thrombin generation test (TGT) in platelet poor plasma, and myocardial contractility in patients with coronary artery disease (CAD) before and after percutaneous coronary intervention (PCI). Methods. The study included 75 patients with coronary artery disease aged between 40 to 75 years, who underwent primary PCI (10 patients) or elective (65 patients) procedure, as well as 35 individuals matched for age and sex with no clinical signs of CAD. We investigated the venous blood obtained before and after 6 and 12 months following PCI. In the same period, stress echocardiography was performed. The intensity of thrombin formation was assessed using a TGT, formed in platelet poor plasma and the modified reaction mixture by adding human recombinant thrombomodulin (rh-TM) to assess the degree of activation of the protein C system. Results. The association between stress echocardiography parameters characterizing myocardial contractile capacity (ejection fraction (EF) of the left ventricle and a wall motion abnormalities (WMAs)) and TGT parameters, reflecting the intensity (ETP and the Peak) of the thrombin formation rate (V), was identified to be more expressed in patients undergoing primary PCI. The presence of the reverse correlation between EF and WMAs and the percentage reduction of V, ETP and Peak after the addition of rh-TM, as well as a significant association of the EF and WMAs with TGT indicators staged with rh-TM demonstrates the role of protein C system in the changes of myocardial contractility. The intensity of thrombin generation was also associated with hypertension. Conclusion. It was determined that TGT parameters were strongly associated with stress echocardiography parameters. The changes in thrombin generation rate were most closely associated with left ventricular ejection fraction, index of wall motion abnormalities and arterial hypertension, including hypertensive reaction to physical activity.

Low Protein C, Tissue Factor Pathway Inhibitor, and Antithrombin allow Sufficient Thrombin Generation in Neonatal Plasma

2004 ◽  
pp. 297-301
Author(s):  
G. Cvirn ◽  
S. Gallistl ◽  
T. Rehak ◽  
G. Jürgens ◽  
W. Muntean
Keyword(s):  
Tissue Factor ◽  
Protein C ◽  
Thrombin Generation ◽  
Tissue Factor Pathway Inhibitor ◽  
Low Protein ◽  
Tissue Factor Pathway

Evidence that the Protein C Activation Pathway Amplifies the lnhibition of Thrombin Generation by Recombinant Human Thrombomodulin in Plasma

1993 ◽  
Vol 70 (03) ◽  
pp. 423-426 ◽  
Author(s):  
Rika ohishi ◽  
Naoko watanabe ◽  
Masaharu Aritomi ◽  
Komakazu Gomi ◽  
Takao Kiyota ◽  
...  
Keyword(s):  
Protein C ◽  
Inhibitory Action ◽  
Thrombin Generation ◽  
Anticoagulant Activity ◽  
Activated Protein C ◽  
Inhibitory Effect ◽  
Phospholipid Vesicles ◽  
Activation Pathway ◽  
Activated Platelets ◽  
Rapid Generation

SummaryThrombomodulin (TM) is a cofactor for the thrombin-catalyzed activation of anticoagulant protein C. However, we have no evidence that thrombomodulin actually activates protein C during blood coagulation processing, nor do we know whether this activated protein C acts as an anticoagulant. We studied the inhibitory action of recombinant human soluble TM (rhs-TM) on thrombin generation in whole plasma. Human plasma was activated with small amounts of tissue factor using phospholipid vesicles in place of activated platelets. Thrombin generation was observed. The addition of only 2 nM of rhs-TM prevented rapid generation of thrombin and reduced the total amount of thrombin generated. In order to study the influence of the protein C activation pathway on this inhibitory action of rhs-TM, protein C-depleted plasma was used. rhs-TM had little inhibitory effect on protein C-depleted plasma. However, the addition of protein C caused a delay in thrombin generation and a reduction of the maximum thrombin concentration. We concluded that the anticoagulant activity of rhs-TM was amplified by the protein C activation pathway.

Interindividual variability of coumarin 7-hydroxylation in healthy volunteers

1992 ◽  
Vol 2 (5) ◽  
pp. 227-233 ◽  
Author(s):  
Arja Rautio ◽  
Holger Kraul ◽  
Anneli Kojo ◽  
Erja Salmela ◽  
Olavi Pelkonen
Keyword(s):  
Healthy Volunteers ◽  
Interindividual Variability ◽  
Coumarin 7

scholarly journals The Prothrombotic Phenotypes in Familial Protein C Deficiency Are Differentiated by Computational Modeling of Thrombin Generation

PLoS ONE ◽  
2012 ◽  
Vol 7 (9) ◽  
pp. e44378 ◽  
Author(s):  
Kathleen E. Brummel-Ziedins ◽  
Thomas Orfeo ◽  
Peter W. Callas ◽  
Matthew Gissel ◽  
Kenneth G. Mann ◽  
...  
Keyword(s):  
Computational Modeling ◽  
Protein C ◽  
Thrombin Generation ◽  
Protein C Deficiency
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