Inhibition of the tissue factor-factor vii complex: involvement of factor xa and lipoproteins

Hubbard, A. R.; Jennings, C.A.

doi:10.1016/0049-3848(87)90154-x

Cited by 77 publications

(43 citation statements)

References 20 publications

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“…Our data confirmed the observations of Hubbard and Jennings, 13 but we could not find any significant association of TFPI with HDL or apoA-II particles as reported by Novotny et al 14 The distribution pattern of gel filtration reported in the present study was somewhat different from that reported by others.…”

Section: Discussionsupporting

confidence: 68%

“…If this assumption is correct, lovastatin treatment, which caused a specific drop in apoB-TFPI complexes, would not affect the anticoagulant potential in plasma. However, in vitro studies have indicated 13 that apoBassociated material is of major importance in the inhibition of the procoagulant activity of TF-factor VII complexes in the presence of factor Xa.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Tissue-factor pathway inhibitor and lipoproteins. Evidence for association with and regulation by LDL in human plasma.

Hansen

Huseby

Sandset

et al. 1994

Arterioscler Thromb

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Tissue-factor pathway inhibitor (TFPI) is a potent inhibitor of extrinsic coagulation, which is mainly associated with lipoproteins in circulating blood. Gel filtration of human plasma confirmed the presence of three peaks in which approximately 10%, 70%, and 20% of total TFPI activity was retained. Precipitation of very-low-density lipoproteins and low-density lipoproteins (LDLs) in plasma by polyethylene glycol almost completely abolished peaks I and II. LDL isolated by ultracentrifugation revealed two peaks of TFPI after gel filtration that coeluted with peaks I and II, respectively, from gel filtration of total plasma. TFPI activity in peaks I and II was also precipitated by anti-apolipoprotein B antibodies. Fourteen patients with familial hypercholesterolemia had higher plasma TFPI activity than did age-and sexmatched normolipemic control subjects (1.45±0.27 U/mL versus 0.80±0.09 U/mL, i><.001). Plasma TFPI was correlated with LDL cholesterol (r=.73, Z'<.001) and apolipoprotein B (r=.69, P<.001). No association was found with high-density lipoprotein cholesterol or apolipoprotein A-I. In a doubleblind, placebo-controlled trial among the familial hypercholesterolemia patients, lovastatin alone or in combination with fish oil concentrate lowered plasma TFPI in parallel with LDL cholesterol. Gel filtration of plasma from these patients demonstrated a specific drop in apolipoprotein B-TFPI complexes, whereas TFPI not associated with lipoproteins was unchanged. This study demonstrated that plasma TFPI was associated with and regulated by LDL in plasma from healthy subjects and patients with familial hypercholesterolemia. (Arterioscler Thromb. 1994;14:223-229.) Key Words • lovastatin • HMG-CoA reductase inhibitors • familial hypercholesterolemia • tissue-factor pathway inhibitor • lipoproteins I ncreasing evidence suggests that tissue factor (TF) provides the initial trigger for blood coagulation in normal hemostasis 1 and most likely plays a major role in thrombogenesis associated with atherosclerosis. Tissue-factor pathway inhibitor (TFPI) is a protease inhibitor that may function as a natural anticoagulant regulating TF-induced coagulation.3 TFPI needs factor Xa for its action and exerts its function by neutralizing factor Xa catalytic activity and by inactivating factor VIIa-TF catalytic activity. - 5TFPI has been established as the major plasma inhibitor of the factor VIIa-TF activity formed either in vitro with TF in suspension 6 or with TF expressed on the surface membrane of perturbed endothelial cells. 7 ' 8 In vivo studies in the rabbit also indicate that TFPI functions as a natural anticoagulant by inhibiting the factor VIIa-TF catalytic activity formed in circulating blood exposed to a iow concentration of TF. 9 Recently, Almus et al 10 have shown that moderate variation in plasma TFPI activity affects the ability of TFPI to inhibit factor VIIa-TF activity during hemostasis in an umbilical vein model. Received April 28, 1993; revision accepted October 25, 1993. Studies of normal individual...

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Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Tissue-factor pathway inhibitor and lipoproteins. Evidence for association with and regulation by LDL in human plasma.

Hansen

Huseby

Sandset

et al. 1994

Arterioscler Thromb

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“…12,13 The heparin infusion allowed us to measure the total intravascular TFPI levels, including the EC-TFPI concentration, which was 7.7 to 11.2 times greater than the preheparin free TFPI level, as previously reported. 5 As determined by comparison of preheparin and postheparin plasmas, the distribution of intravascular TFPI in the CAD patients studied consisted of Ͻ10% as the circulating preheparin free fraction (6% to 9%), 30% as the Lp-bound form (27% to 32%), and 60% as the EC-TFPI fraction (60% to 64%) regardless of the patients' dyslipidemic profiles.…”

Section: Discussionmentioning

confidence: 99%

“…The free form of TFPI inhibits tissue factor-induced coagulation more effectively than Lp-bound TFPI. 12,13 Consequently, EC-TFPI is physiologically the more important pool, mediating the major antithrombotic activity on the endothelial surface. EC-TFPI is believed to bind to heparan sulfate on the cell surface, as does lipoprotein lipase (LPL).…”

mentioning

confidence: 99%

Intravascular Free Tissue Factor Pathway Inhibitor Is Inversely Correlated With HDL Cholesterol and Postheparin Lipoprotein Lipase but Proportional to Apolipoprotein A-II

Kawaguchi¹,

Miyao²,

Noguchi³

et al. 2000

ATVB

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Abstract-To elucidate the distribution and clinical implications of tissue factor pathway inhibitor (TFPI) concentrations, we measured TFPI levels consisting of preheparin free, lipoprotein-bound (Lp-bound), and endothelial cell-anchor pools in 156 patients with coronary artery disease (average age, 61.2Ϯ9.1 years; range, 32 to 78 years) by heparin infusion (50 IU/kg) and compared them with the preheparin TFPI levels of 229 healthy subjects (average age, 59.6Ϯ9.4 years; range, 41 to 80 years). The patients had lower preheparin free TFPI and lower HDL cholesterol (HDL-C) levels than the healthy subjects with equivalent Lp-bound forms (free TFPI, 15.9Ϯ6.5 versus 19.2Ϯ8.1 ng/mL). In a partial correlation analysis, the preheparin free TFPI levels were shown to be inversely correlated with the HDL-C concentrations in both the patients (rϭϪ0.454, PϽ0.001) and the healthy subjects (rϭϪ0.136, PϽ0.05). As determined by comparison of preheparin and postheparin plasma, the patients generally showed preheparin free TFPI Ͻ10%, Lp-bound TFPI at 30%, and endothelial cell-anchor TFPI at 60%. When the patients were divided into 4 categories by their LDL cholesterol (LDL-C, 130 mg/dL) and HDL-C (40 mg/dL) levels to specify their coronary risks, the low-HDL-C groups had significantly increased preheparin and postheparin free TFPI levels and decreased postheparin LPL levels, whereas the high-LDL-C groups showed increased levels of Lp-bound TFPI. In a partial correlation analysis, we found a proportional relation between postheparin free TFPI and apolipoprotein A-II (rϭ0.5327) and between HDL-C and LPL (rϭ0.4906), whereas postheparin free TFPI was inversely correlated with HDL-C (rϭϪ0.4280) and postheparin LPL (rϭϪ0.4791). The inverse relationship between TFPI and LPL suggests that increased free TFPI concentrations as a compensatory response of the endothelium to prevent atherothrombotic processes compete with and displace LPL on endothelial surface, resulting in reduced LPL and low HDL-C. T issue factor pathway inhibitor (TFPI) plays an important role in the antithrombotic properties of vessel walls by inhibiting extrinsic coagulation processes. 1,2 Intravascular TFPI consists of free and lipoprotein-bound (Lp-bound) forms. 3 The free form includes 2 subfractions except in platelets, 4 ie, a circulating free TFPI fraction without carrier in preheparin plasma and a heparin-releasable TFPI fraction from endothelial cells. 5 Exogenous administration of recombinant TFPI to experimental animals prevents thrombosis, 6 whereas increased TFPI levels have been observed in patients with acute myocardial infarction. 7 Although the alteration of serum lipids by cholesterol-lowering therapy influences Lpbound TFPI profiles, 8 -11 little is known about the clinical implications of the TFPI level and its regulation in relation to lipid risk profiles.In the present study, we compared TFPI subfractions in preheparin plasmas of normal healthy subjects and patients with coronary artery disease (CAD). Significant negative correlations were observed ...

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“…Thus, the relative dependencies of these reactions on shear rate when all other conditions are held constant would be indicative of the importance of the diffusion of factor VIII to the surface. In addition, LACI, which circulates mainly as a lipoprotein (32), was used in its free, purified form. The relative effectiveness of free and lipoprotein-bound LACI is not known, but we have observed the LACI effects considerably below its estimated plasma concentration of 2.3 nM (Fig.…”

Section: Discussionmentioning

confidence: 99%

Hemophilia as a defect of the tissue factor pathway of blood coagulation: effect of factors VIII and IX on factor X activation in a continuous-flow reactor.

Repke

Gemmell

Guha

et al. 1990

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

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The effect offactors VIII and IX on the ability of the tissue factor-factor Vila complex to activate factor X was studied in a continuous-flow tubular enzyme reactor. Tissue factor immobilized in a phospholipid bilayer on the inner surface of the tube was exposed to a perfusate containing factors VIla, VIII, IX, and X flowing at a wall shear rate of 57, 300, or 1130 sec'1. Factor Xa in the effluent was determined by chromogenic assay. The flux of factor Xa (moles formed per unit surface area per unit time) was strongly dependent on wall shear rate, increasing about 3-fold as wail shear rate increased from 57 to 1130 sec-1. The addition of factors VIII and IX at their respective plasma concentrations resulted in a further 2-to 3-fold increase. The direct activation of factor X by tissue factor-factor Vila could be virtually eliminated by the lipoprotein-associated coagulation inhibitor; however, when factors VIII and IX were present at their approximate plasma concentrations, factor Xa production rates were enhanced 15-to 20-fold. These results suggest that the tissue factor pathway, mediated through factors VIII and IX, produces significant levels of factor Xa even in the presence of an inhibitor of the tissue factor-factor VIa complex; moreover, the activation is dependent on local shear conditions. These findings are consistent both with a model of blood coagulation in which initiation of the system results from tissue factor and with the bleeding observed in hemophilia.There is considerable evidence that the initiation of coagulation in vivo may be the result of the formation of a catalytic complex between tissue factor (TF), a transmembrane protein found in many cell types, and factor VII or VIIa, a zymogen of a serine protease and a serine protease, respectively (for a recent review see ref. 1). The TF-factor VII complex (TF:VII) is rapidly converted to TF:VIIa by activated factors X and IX, both products of the TF pathway of coagulation (2, 3). Thus, apart from the first catalytic cycles, the active promoter of coagulation appears to be TF:VIIa.This complex catalyzes two reactions, the conversion of factor X to Xa and offactor IX to IXa. Each ofthese products leads to the formation of prothrombinase (4), the first directly and the latter indirectly (5-7); the indirect reaction involves factor VIIIa, the activated form of the antihemophilic factor, and factor IXa (8, 9).If coagulation is initiated by TF:VIIa, then the clinical manifestations of hemophilia (a deficiency of factor VIII or IX) dictate that the indirect path to factor Xa production must be the dominant one in vivo; yet direct measurements of the rates of factor IX and X activation in vitro have shown the latter to be a much more efficient reaction (6, 7). This observation has led to difficulty in integrating hemophilia into a formulation in which TF is the essential initiator of coagulation. Indeed, this very observation has lent credence to the concept of "contact" activation in which coagulation is initiated by factors XII and XI.Unti...

show abstract

Inhibition of the tissue factor-factor vii complex: involvement of factor xa and lipoproteins

Cited by 77 publications

References 20 publications

Tissue-factor pathway inhibitor and lipoproteins. Evidence for association with and regulation by LDL in human plasma.

Tissue-factor pathway inhibitor and lipoproteins. Evidence for association with and regulation by LDL in human plasma.

Intravascular Free Tissue Factor Pathway Inhibitor Is Inversely Correlated With HDL Cholesterol and Postheparin Lipoprotein Lipase but Proportional to Apolipoprotein A-II

Hemophilia as a defect of the tissue factor pathway of blood coagulation: effect of factors VIII and IX on factor X activation in a continuous-flow reactor.

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