The Coagulation and Fibrinolytic Responses of Baboons after In Vivo Thrombin Generation – Effect of Interleukin 6

Kruithof, Egbert K. O.; Mestries, J.C.; Gascon, Marie-Paule; Ythier, Arnaud

doi:10.1055/s-0038-1656076

Cited by 42 publications

(44 citation statements)

References 20 publications

(25 reference statements)

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“…Experimental induction of disseminated intravascular coagulation in chimpanzees or baboons results in a 50-fold increase in t-PA plasma levels within a few minutes. 7,8 The rapidity and the magnitude of the increase in the t-PA concentration, as well as the rapid return to normal levels, are consistent only with a massive release of t-PA from storage pools. The findings that injection of vasoactive agents such as thrombin or calcium ionophore leads to an acute increase of t-PA in isolated vascular systems are also consistent with an endothelial t-PA storage pool.…”

mentioning

confidence: 91%

Storage of Tissue-Type Plasminogen Activator in Weibel-Palade Bodies of Human Endothelial Cells

Rosnoblet¹,

Vischer²,

Gerard³

et al. 1999

ATVB

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Abstract-Tissue-type plasminogen activator (t-PA) is acutely released by endothelial cells. Although its endothelial storage compartment is still not well defined, t-PA release is often accompanied by release of von Willebrand factor (vWf), a protein stored in Weibel-Palade bodies. We investigated, therefore, whether t-PA is stored in these secretory organelles. Under basal culture conditions, a minority of human umbilical vein endothelial cells (HUVEC) exhibited immunofluorescent staining for t-PA, which was observed only in Weibel-Palade bodies. To increase t-PA expression, HUVEC were infected with a t-PA recombinant adenovirus (AdCMVt-PA issue-type plasminogen activator (t-PA) is a key enzyme for the removal of incipient thrombi in the vascular system, and recombinant t-PA is now widely used for the thrombolytic therapy of myocardial infarction. Endothelial cells (EC) are the main source for plasma t-PA. 1-4 Although a variety of stimuli such as venous occlusion, exercise, or injection of vasoactive substances are known to acutely increase plasma levels of t-PA, the precise mechanisms responsible for this increase are poorly defined. They may involve an acute release of t-PA from EC, variations in the rate of production of t-PA by EC, or changes in the clearance rate. 5,6 Several in vivo and ex vivo studies give clear evidence for the occurrence of acute release of t-PA. Experimental induction of disseminated intravascular coagulation in chimpanzees or baboons results in a 50-fold increase in t-PA plasma levels within a few minutes. 7,8 The rapidity and the magnitude of the increase in the t-PA concentration, as well as the rapid return to normal levels, are consistent only with a massive release of t-PA from storage pools. The findings that injection of vasoactive agents such as thrombin or calcium ionophore leads to an acute increase of t-PA in isolated vascular systems are also consistent with an endothelial t-PA storage pool. 9 -11

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mentioning

confidence: 91%

Storage of Tissue-Type Plasminogen Activator in Weibel-Palade Bodies of Human Endothelial Cells

Rosnoblet¹,

Vischer²,

Gerard³

et al. 1999

ATVB

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“…Fibrinogen production in the liver is regulated by cytokines and is greatly enhanced in the acute phase response to infection and other inflammatory processes. [8][9][10][11] It is therefore possible that moderately elevated fibrinogen levels simply report a state of inflammation associated with vascular disease. On the other hand, augmented fibrinogen levels, per se, could alter the hemodynamic properties of blood or enhance concentration driven enzyme-substrate interactions between thrombin, fibrinogen, and platelets, and thus lead to increased intravascular fibrin deposition and thrombosis.…”

Section: Introductionmentioning

confidence: 99%

Cause-effect relation between hyperfibrinogenemia and vascular disease

Kerlin

Cooley

Isermann

et al. 2004

Blood

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Elevated plasma levels of fibrinogen are associated with the presence of cardiovascular disease, but it is controversial whether elevated fibrinogen causally imparts an increased risk, and as such is a true modifier of cardiovascular disease, or is merely associated with disease. By investigating a transgenic mouse model of hyperfibrinogenemia, we show that elevated plasma fibrinogen concentration IntroductionNumerous epidemiological studies have documented the association of elevated plasma fibrinogen levels with cardiovascular disease. [1][2][3][4][5][6][7] Cross-sectional prospective studies imply that elevated plasma fibrinogen levels are an independent and predictive parameter for increased risk of coronary artery disease, stroke, and peripheral vascular disease. The magnitude of the increase in fibrinogen levels correlates with the presence and severity of peripheral arterial disease, the extent of myocardial necrosis in infarcted patients, and cerebrovascular accidents. The disease risk associated with hyperfibrinogenemia is disproportionally augmented in those individuals with the highest fibrinogen levels, indicating a threshold effect. Notwithstanding its recognized value as a marker for the presence of cardiovascular disease, it remains controversial whether an elevated fibrinogen level itself imparts an increased risk, and therefore represents a true modifier of vascular disease, or is merely associated with disease. Fibrinogen production in the liver is regulated by cytokines and is greatly enhanced in the acute phase response to infection and other inflammatory processes. [8][9][10][11] It is therefore possible that moderately elevated fibrinogen levels simply report a state of inflammation associated with vascular disease. On the other hand, augmented fibrinogen levels, per se, could alter the hemodynamic properties of blood or enhance concentration driven enzyme-substrate interactions between thrombin, fibrinogen, and platelets, and thus lead to increased intravascular fibrin deposition and thrombosis. These views are not mutually exclusive, as augmentation of fibrinogen levels secondary to an inflammatory challenge could nevertheless amplify or accelerate the disease process. Moreover, fibrinogen and fibrin degradation products might in turn enhance the inflammatory aspect of vascular lesions by regulating cytokine production and leukocyte-endothelial interactions. [12][13][14][15][16][17] Recently described genetically altered mice with chronically increased plasma fibrinogen levels in the absence of underlying inflammation provide a novel experimental tool to investigate the cause-effect relationship between hyperfibrinogenemia and vascular disease. 18 The mutant mouse strain (hereafter referred to as Hifib mice) was derived by pronuclear oocyte microinjection of the entire mouse fibrinogen locus, including all 3 fibrinogen chains as well as several kilobases of flanking sequence. The added transgenic fibrinogen allele is inherited in a Mendelian fashion, and the mice were reported to exhibit...

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“…9 ACE inhibitors and calcium antagonists may affect fibrinolysis, because both angiotensin II and cellular calcium regulate the production of PAI-1 either directly 10 or by modulating the inflammatory response, which in turn promotes secretion of PAI-1. 11 Clinical data on the effects of ACE inhibitors and calcium antagonists on fibrinolysis are limited, 4,12 and information in hypertensive patients with type 2 diabetes mellitus is virtually lacking. The primary objective of this randomized controlled trial was to compare the effects of the ACE inhibitor fosinopril with the calcium antagonist amlodipine on plasma PAI-1 antigen in persons with type 2 diabetes and hypertension.…”

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confidence: 99%

Fosinopril Versus Amlodipine Comparative Treatments Study

et al. 2002

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Background-ACE inhibitors and calcium antagonists may modulate fibrinolysis. We conducted a randomized controlled trial to assess the effects of these drugs on plasminogen activator inhibitor-1 (PAI-1) antigen, an inhibitor of fibrinolysis. Methods and Results-Participants with hypertension and type 2 diabetes mellitus (nϭ96, 51% black) were randomized after an initial 4 weeks of placebo to double-blind 20 or 40 mg fosinopril or 5 or 10 mg amlodipine daily for 4 weeks in a fixed-dose regimen. After 4 weeks of placebo washout, the patients received 4 weeks of crossover treatments. After treatment with placebo, systolic and diastolic blood pressure were 143Ϯ2 and 86Ϯ1 mm Hg and plasma PAI-1 was 43.4Ϯ2.3 ng/mL. Amlodipine achieved a greater systolic and diastolic blood pressure reduction than fosinopril (10 mm Hg versus 8 mm Hg, Pϭ0.029, and 5 mm Hg versus 3 mm Hg, Pϭ0.040, respectively) but tended to increase PAI-1, whereas fosinopril tended to decrease PAI-1 (5.4Ϯ3.6 versus Ϫ3.8Ϯ2.5 ng/mL, Pϭ0.045). The PAI-1 changes depended on drug dose (6.5Ϯ6.1 and 3.4Ϯ3.9 ng/mL with amlodipine 10 and 5 mg, respectively, and Ϫ0.4Ϯ3.1 and Ϫ7.4Ϯ4.0 ng/mL with fosinopril 20 and 40 mg, respectively, P for trend 0.024). No significant differences between fosinopril and amlodipine were found for short-term changes in tissue plasminogen activator antigen, fibrinogen, C-reactive protein, and interleukin-6. The findings were similar in black and white participants. Conclusions-Short-term treatment with fosinopril significantly reduced PAI-1 compared with amlodipine in a dosedependent fashion. This effect, which was independent of blood pressure reduction, may account for the improved clinical outcomes achieved with ACE inhibitors compared with calcium antagonists. (Circulation. 2002;105:457-461.)

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The Coagulation and Fibrinolytic Responses of Baboons after In Vivo Thrombin Generation – Effect of Interleukin 6

Cited by 42 publications

References 20 publications

Storage of Tissue-Type Plasminogen Activator in Weibel-Palade Bodies of Human Endothelial Cells

Storage of Tissue-Type Plasminogen Activator in Weibel-Palade Bodies of Human Endothelial Cells

Cause-effect relation between hyperfibrinogenemia and vascular disease

Fosinopril Versus Amlodipine Comparative Treatments Study

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