Regulation of Blood Coagulation by the Protein C Anticoagulant Pathway

Dahlbäck, Björn; Villoutreix, Bruno O.

doi:10.1161/01.atv.0000168421.13467.82

Cited by 276 publications

(67 citation statements)

References 106 publications

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“…Animal models of VILI showed that high-V T ventilation increases alveolar fibrin deposition and systemic PAI-1 activity, and lung-protective mechanical ventilation decreases BALF levels of PAI-1, attenuates coagulation, and enhances fibrinolysis [14,22]. APC exerts its anticoagulant activity by inactivating procoagulant factors Va and VIIIa and promotes fibrinolysis by inactivating PAI-1 [23]. Recombinant APC was shown to significantly reduce mortality in patients with severe sepsis [24].…”

Section: Discussionmentioning

confidence: 99%

Effects of Activated Protein C on Ventilator-Induced Lung Injury in Rats

Jiang

Chou²,

Wang

et al. 2010

Respiration

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Background: Mechanical ventilation with a high tidal volume (VT) increases lung and systemic plasminogen activator inhibitor (PAI)-1 levels and alveolar fibrin deposition. Activated protein C (APC) may decrease PAI activity in endothelial cell-conditioned medium and thus enhance fibrinolysis. Objectives: The aims of this study were to test the hypothesis that APC can neutralize PAI-1 activity and improve lung function in an animal model of ventilator-induced lung injury. Methods: Rats were ventilated with a high-volume zero positive end-expiratory pressure (PEEP; HVZP) protocol by a volume-cycled ventilator for 2 h at a VT of 30 ml/kg, a respiratory rate of 25 breaths/min, and an FiO₂ of 0.21. Fifteen minutes before ventilation, the rats received intravenous APC (250 µg/kg, HVZP+APC group) or normal saline (vehicle; HVZP group). Another group that received no ventilation served as the control group. Results: Levels of arterial blood gas tension were comparable between the two ventilation groups throughout the study period. Rats treated with the HVZP protocol exhibited significantly higher total protein and macrophage inflammatory protein-2 concentrations in bronchoalveolar lavage fluid (BALF) and higher lung PAI-1 mRNA expression and plasma active PAI-1 levels than did the control group. Administration of APC tended to reduce the BALF protein content and systemic PAI-1 activity but did not improve the lung histology in the HVZP+APC group. Plasma levels of D-dimers were comparable among the three study groups. Conclusions: These results suggest that APC administered at a higher dosage might improve lung function by reducing alveolar protein leakage and systemic coagulation.

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Section: Discussionmentioning

confidence: 99%

Effects of Activated Protein C on Ventilator-Induced Lung Injury in Rats

Jiang

Chou²,

Wang

et al. 2010

Respiration

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“…FXa binds with high affinity to FVa on the surface of negatively charged phospholipid membranes, thus forming the prothrombinase (PTase) complex that efficiently converts prothrombin to thrombin. The activity of FVa is regulated by activated protein C (APC) that cleaves and degrades FVa (at R306, R506, and R679) in a process stimulated by the vitamin K‐dependent protein S 3. Intact FV also serves as an anticoagulant APC cofactor in regulation of FVIIIa in the phospholipid membrane‐bound tenase complex (FIXa+FVIIIa), functioning in synergy with protein S 2.…”

Section: Introductionmentioning

confidence: 99%

Factor V‐short and protein S as synergistic tissue factor pathway inhibitor (TFPIα) cofactors

Dahlbäck

Guo

Livaja-Koshiar

et al. 2018

Research and Practice in Thrombosis and Haemostasis

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Essentials FV‐Short, a normal splice isoform of Factor V, binds tissue factor pathway inhibitor (TFPIα) with high affinity.FV‐Short functions as a synergistic TFPIα cofactor with protein S in inhibition of Factor Xa.FV‐Short is much more efficient as TFPIα cofactor than full length FV.TFPIα‐cofactor activity of FV‐Short is lost upon activation of coagulation by thrombin‐mediated cleavage. Background FV‐Short is a normal splice variant of Factor V (FV) having a short B domain, which exposes a high affinity‐binding site for tissue factor pathway inhibitor α (TFPIα). FV‐Short and TFPIα circulate in complex in plasma.ObjectivesThe aim was to elucidate whether FV‐Short affects TFPIα as inhibitor of coagulation FXa and to test whether the TFPIα‐cofactor activity of protein S is influenced by FV‐Short.MethodsRecombinant FV, wild‐type FV‐Short and a FV‐Short thrombin‐cleavage resistant variant were expressed and purified. The influence of FV and FV‐Short variants and/or protein S on the FXa inhibitory activity of TFPIα was monitored both in a purified system and in a plasma‐based thrombin generation assay.Results FV‐Short had intrinsically weak TFPIα‐cofactor activity but with protein S present, FV‐Short yielded efficient inactivation of FXa. Protein S alone did not promote full TFPIα‐activity. Intact FV was inefficient at low protein S concentrations and had 10‐fold lower activity compared to FV‐Short at physiological protein S levels. Activation of FV‐Short by thrombin resulted in the loss of the TFPIα‐cofactor activity. The synergistic TFPIα‐cofactor activity of FV‐Short and protein S was also demonstrated in plasma using a thrombin generation assay.Conclusions FV‐Short and protein S are highly efficient, synergistic cofactors to TFPIα in the regulation of FXa activity, whereas full length FV has lower activity. Our results suggest the formation of an efficient FXa‐inhibitory complex between FV‐Short, TFPIα and protein S on the surface of negatively charged phospholipids.

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“…Thrombin cleaves PC at Arg169, removes the activation peptide and generates activated protein C (APC) [6]. In addition to its anticoagulant properties, APC has anti-inflammatory and cytoprotective functions, which are exerted when APC activating protease activated receptor-1 (PAR-1) [7], [8]. The human protein C gene ( PROC ) is located on chromosome 2q13-q14 and comprises nine exons spanning 11 kb [9], [10].…”

Section: Introductionmentioning

confidence: 99%

Genetic Background Analysis of Protein C Deficiency Demonstrates a Recurrent Mutation Associated with Venous Thrombosis in Chinese Population

et al. 2012

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BackgroundProtein C (PC) is one of the most important physiological inhibitors of coagulation proteases. Hereditary PC deficiency causes a predisposition to venous thrombosis (VT). The genetic characteristics of PC deficiency in the Chinese population remain unknown.MethodsThirty-four unrelated probands diagnosed with hereditary PC deficiency were investigated. PC activity and antigen levels were measured. Mutation analysis was performed by sequencing the PROC gene. In silico analyses, including PolyPhen-2, SIFT, multiple sequence alignment, splicing prediction, and protein molecular modeling were performed to predict the consequences of each variant identified. One recurrent mutation and its relative risk for thrombosis in relatives were analyzed in 11 families. The recurrent mutation was subsequently detected in a case (VT patients)-control study, and the adjusted odds ratio (OR) for VT risk was calculated by logistic regression analysis.ResultsA total of 18 different mutations, including 12 novel variants, were identified. One common mutation, PROC c.565C>T (rs146922325:C>T), was found in 17 of the 34 probands. The family study showed that first-degree relatives bearing this variant had an 8.8-fold (95%CI = 1.1–71.6) increased risk of venous thrombosis. The case-control (1003 vs. 1031) study identified this mutation in 5.88% patients and in 0.87% controls, respectively. The mutant allele conferred a high predisposition to venous thrombosis (adjusted OR = 7.34, 95%CI = 3.61–14.94). The plasma PC activity and antigen levels in heterozygotes were 51.73±6.92 U/dl and 75.17±4.84 U/dl, respectively.ConclusionsThis is the first study on the genetic background of PC deficiency in the Chinese population. The PROC c.565C>T mutation is the most frequent cause of PC deficiency as well as a prevalent risk factor for VT in Chinese individuals. The inclusion of this variant in routine thrombophilic detection may improve the diagnosis and prevention of venous thrombosis.

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Regulation of Blood Coagulation by the Protein C Anticoagulant Pathway

Cited by 276 publications

References 106 publications

Effects of Activated Protein C on Ventilator-Induced Lung Injury in Rats

Effects of Activated Protein C on Ventilator-Induced Lung Injury in Rats

Factor V‐short and protein S as synergistic tissue factor pathway inhibitor (TFPIα) cofactors

Genetic Background Analysis of Protein C Deficiency Demonstrates a Recurrent Mutation Associated with Venous Thrombosis in Chinese Population

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