Influence of protein C activation on blood coagulation and fibrinolysis in squirrel monkeys.

Colucci, Mario; Stassen, Jean Marie; Collen, Désiré

doi:10.1172/jci111402

Cited by 72 publications

(17 citation statements)

References 15 publications

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“…It should be noted that Colucci et al (25) were unable to detect increased fibrinolytic activity in blood after infusion of human APC into spider monkeys. This failure to demonstrate a profibrinolytic property of human APC may reflect inherent differences in the fibrinolytic system of the spider monkey as compared to that of the dog (7,8) and the cultured bovine endothelial cell.…”

Section: Resultsmentioning

confidence: 93%

“…Alternatively, the inability to measure a fibrinolytic response in the spider monkey may indicate that high circulating levels of antiactivator prevent detection of free t-PA in the euglobulin fractions prepared by Colucci et al. (25). A similar complication has been suggested for the failure to detect t-PA in the culture medium of human umbilical vein endothelial cells (24,(26)(27)(28).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Activated protein C stimulates the fibrinolytic activity of cultured endothelial cells and decreases antiactivator activity.

Sakata¹,

Curriden²,

Lawrence³

et al. 1985

Proc. Natl. Acad. Sci. U.S.A.

181

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The effects of bovine activated protein C (APC) on the fibrinolytic activity of cultured bovine aortic endothelial cells were investigated. Confluent monolayers were incubated with purified APC under various conditions and changes in total fibrinolytic activity and in the level of plasminogen activator and plasminogen activator inhibitor (antiactivator) were monitored. The addition of APC to the cells in the absence of other blood or plasma components led to a rapid, dose-dependent increase of fibrinolytic activity both in the media and in cellular extracts. For example, 3.4 jtg of APC per ml resulted in a 15-fold increase of fibrinolytic activity in the medium within 1 hour. The enhanced fibrinolytic activity reflected increases in both the urokinase-related and tissue-type plasminogen activators produced by these cells. Interestingly, treatment of-cells with APC also caused a rapid, dose-dependent decrease in antiactivator activity. Diisopropyl fluorophosphate-inactivated APC did not decrease antiactivator or increase plasminogen activator. Although a small but significant direct (i.e., cell-independent) effect of APC on both fibrinolytic activity and antiactivator activity could be demonstrated, the major portion of these changes appeared to be cellmediated. These observations indicate that the fibrinolytic potential of cultured endothelial cells is increased by APC and that the enzyme active site is essential for this change. Moreover, the results suggest that one of the primary mechanisms for this stimulation of endothelial cell fibrinolytic activity involves an APC-mediated decrease in antiactivator.

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Section: Resultsmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Activated protein C stimulates the fibrinolytic activity of cultured endothelial cells and decreases antiactivator activity.

Sakata¹,

Curriden²,

Lawrence³

et al. 1985

Proc. Natl. Acad. Sci. U.S.A.

181

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“…The acti vated form of protein C is an example of those molecules which directly interact with PAI-1 to alter its activity. Protein C is a vita min K dependent plasma protease zymogen that upon activation has been found to ex hibit both anticoagulant and profibrinolytic activities [Seegers et al, 1972;Kisiel et al, 1977;Comp and Esmon, 1981;Marlar et al, 1982;Colucci et al, 1984], Several studies have demonstrated that activated protein C (APC) directly neutralizes the PAI-1 activity through the formation of APC/PAI-1 com plexes and in so doing disrupts the fibrino lytic balance of cultured ECs [Sakata et al, 1985[Sakata et al, -1988van Hinsbergh et al, 1985;de Fouw et al, 1987]. The consequence of this interaction is a dramatic elevation in the net fibrinolytic activity of these cells.…”

Section: Regulation Of Pai-1mentioning

confidence: 99%

Fibrinolytic System of Vascular Endothelial Cells

Schleef

Loskutoff²

1988

Pathophysiol Haemos Thromb

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The regulation of the fibrinolytic system is of critical importance during hemostasis, wound repair, neoplasia, inflammation, and a variety of other biologic processes. This control is achieved in a large part through the action of specific plasminogen activator inhibitors (PAIs). Cultured endothelial cells (ECs) produce type 1 PAI (PAI-1), the physiologic inhibitor of tissue-type plasminogen activator. PAI-1 is one of the most highly regulated of the fibrinolytic components produced by ECs. Its synthesis is modulated by a variety of compounds including endotoxin, thrombin, transforming growth factor β, interleukin 1 and tumor necrosis factor α. Recent studies suggest that PAI-1 is synthesized by ECs as an active molecule, but that it spontaneously decays into a latent form in solution. Specific components present in the extracellular matrix of ECs and in plasma bind to PAI-1 and prevent this inactivation. The unexpected finding that cultured ECs also produce type 2 PAI (PAI-2) introduces a previously unsuspected level of complexity to our understanding of this system and raises the possibility that the altered fibrinolytic activity of ECs following various treatments, or of blood in certain individuals, may reflect changes in either one of these inhibitors.

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“…Infusion of thrombin into dogs (20), or thrombin production in dogs and primates secondary to infusion of a procoagulant mixture of factor Xa with phosphatidylcholine-phosphatidyl serine vesicles ( 13,(21)(22)(23), produces activation of protein C and an anticoagulant state characterized by prolonged clotting times with apparent elevation ofplasminogen activator levels and reduced levels of factor V and factor VIII procoagulant activities. Interestingly, in dogs (24), but not in at least two species of nonhuman primates (25,26) or humans (27), infusion of APC produces elevated levels of plasminogen activator activity and a profibrinolytic state. More recent studies have suggested that the activation of protein C and the release ofplasminogen activators may be independent events associated with thrombin generation in vivo (23).…”

Section: Introductionmentioning

confidence: 99%

Antithrombotic effects of thrombin-induced activation of endogenous protein C in primates.

et al. 1993

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The effects on thrombosis and hemostasis of thrombin-induced activation of endogenous protein C (PC) were evaluated in baboons. Thrombosis was induced by placing into arteriovenous shunts a segment of Dacron vascular graft, which generated arterial platelet-rich thrombus, followed by an expansion region of low-shear blood flow, which in turn accumulated fibrinrich venous-type thrombus. Thrombosis was quantified by "'In-platelet imaging and '25I-fibrinogen accumulation. Intravenous infusion of a-thrombin, 1-2 U/kg-min for 1 h, increased baseline activated PC levels (-5 ng/ml) to 250-500 ng/ml (P < 0.01). The lower thrombin dose, which did not deplete circulating platelets, fibrinogen, or PC, reduced arterial graft platelet deposition by 48% (P < 0.05), and platelet and fibrin incorporation into venous-type thrombus by > 85% (P < 0.01). Thrombin infusion prolonged the activated partial thromboplastin clotting time, elevated fibrinopeptide A (FPA), thrombin-antithrombin III complex (T:AT III), and fibrin D-dimer plasma levels (P < 0.01), but did not affect bleeding times. Thrombin's antithrombotic effects were blocked by infusing a monoclonal antibody (HPC4) which prevented PC activation in vivo, caused shunt occlusion, increased the consumption of platelets and fibrinogen, elevated plasma FPA and T:AT III levels, and reduced factor VIII (but not factor V) procoagulant activity (P < 0.05). We conclude that activated PC is a physiologic inhibitor of thrombosis, and that activation of endogenous PC may represent a novel and effective antithrombotic strategy. (J. Clin. Invest.

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Influence of protein C activation on blood coagulation and fibrinolysis in squirrel monkeys.

Cited by 72 publications

References 15 publications

Activated protein C stimulates the fibrinolytic activity of cultured endothelial cells and decreases antiactivator activity.

Activated protein C stimulates the fibrinolytic activity of cultured endothelial cells and decreases antiactivator activity.

Fibrinolytic System of Vascular Endothelial Cells

Antithrombotic effects of thrombin-induced activation of endogenous protein C in primates.

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