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...
SUMMARY We investigated the effect of plasma low density lipoproteins (LDL), very low density lipoproteins (VLDL), and high density lipoproteins (HDL) on the platelet inhibitory effect of primary cultures of human endothelial cell monolayers (ECM). ECM incubated with lipoprotein-deficient plasma (LDP) for 2 hours at 37°C had an inhibitory effect on ADP-and collagen-induced platelet aggregation and prostaglandin production in platelet-rich plasma similar to that observed when ECM were preincubated with growth medium or plasma. Concentrations of LDL in LDP up to a protein concentration of 1600 pg/ml had an inhibitory effect on the endothelial cells' ability to modulate these platelet reactions. VLDL at the highest concentration (1600 jug/ml) had a slightly inhibitory effect, whereas HDL showed no such effect. The inhibitory effect of LDL was not observed during the first hour of incubation. When HDL in concentrations similar to or higher than LDL were combined with LDL, the inhibitory effect of LDL was partially reduced. VLDL combined with LDL or HDL did not interfere with the effects of the later fractions. The inhibitory effect of LDL was significantly reduced when LDL were diluted in whole plasma. Prostacyclin which is synthesized and released from the endothelial cells and contributes to the inhibitory effect upon platelets did not change its effect on platelet reactivity by preincubation with the various lipoprotein fractions. The current studies may indicate that LDL have a direct effect on the endothelial cells and that this effect may be partially counteracted by HDL. This effect of LDL on the endothelial cells reduces the endothelium's ability to inhibit platelet aggregation and thus could favor the tendency to thrombus formation.RECENT studies have shown that microsomal fractions of the vessel wall lining of arteries and veins are able to generate prostacyclin (PGI 2 ) from prostaglandin endoperoxides and arachidonic acid. 1 PGI 2 has a strong inhibitory effect on platelet aggregation induced by collagen, ADP, and epinephrine. It has been shown further that human endothelial cells grown in culture spontaneously release a platelet antiaggregatory principle that also inhibits malondialdehyde (MDA) production in platelets induced by collagen. 2 ' 3 These observations suggest that a normally functioning endothelial cell is able to counteract platelet aggregation and thrombus formation, and that this effect is caused partially by PGI2 4 through an inhibition of thromboxane A 2 (TXA 2 ) generation in platelets, which is the strongest naturally occurring platelet-aggregating compound described. 5 Epidemiological studies have shown a positive correlation between the plasma concentration of
Summary. Activation of factor (F)VII by tissue factor may represent a critical event during plaque rupture in acute coronary syndromes. Patients with combined hyperlipemia are at high risk for developing coronary heart disease and their tendency to thrombosis may be accelerated during postprandial hyperlipemia. In the present double-blind, placebo-controlled parallel study, 42 patients with combined hyperlipemia and serum triglycerides between 2.0 and 15.0 mmol L À1 and serum cholesterol >5.3 mmol L À1 at the end of a 3-month dietary runin period were treated with atorvastatin at 10 mg day À1 for at least 10 weeks. During the last 5 weeks the patients were randomized into two groups receiving 1.68 g day À1 omega-3 fatty acids (o-3 FA) or placebo (corn oil). The fasting levels of FVII antigen (FVII-Ag) and FVII coagulant activity (FVII:C) were high compared with healthy males. The fasting levels of activated FVII (FVIIa) and FVII-Ag correlated both to serum triglycerides and apolipoprotein A1 (apoA1). FVIIa and FVII:C increased during postprandial hyperlipemia. This increase of FVIIa correlated to the fasting triglyceride and apoA1 levels, but not to the degree of postprandial hypertriglyceridemia. The concentrations of fasting FVIIa in these patients were reduced in parallel with a reduction of fasting triglycerides by treatment with atorvastatin placebo. This treatment also reduced the postprandial level of FVIIa. o-3 FA in addition to atorvastatin further reduced FVIIa concentrations, fasting and postprandially, and also signi®cantly reduced FVII:C and FVII-Ag during postprandial hyperlipemia. Prothrombin fragment 1 2 (F1 2) increased during postprandial hyperlipemia. This increase was signi®cantly reduced after treatment with atorvastatin plus o-3 FA. The increase of F1 2 measured as incremental area under the curve (iAUC) during postprandial hyperlipemia correlated to the fasting levels of FVIIa, FVII:C and FVII-Ag and also to the levels of these factors during postprandial lipemia. In conclusion, patients with combined hyperlipemia are at risk for activation of the coagulation system, particularly during postprandial lipemia. This activation may be signi®cantly reduced by statins and o-3 FA.
This study was carried out to evaluate the effects of albumin-bound fatty acids on the anti-platelet effects of endothelial cells. Primary cultures of human endothelial cells (ECM), grown in confluent monolayers, were incubated with plasma or growth medium enriched with albumin-bound fatty acids (FA) for 2-20 h. The effects of ECM on ADP-induced platelet aggregation (PA) and collagen-induced PA and prostaglandin synthesis in platelet-rich plasma were tested. ECM released an inhibitor of platelet reactions which resembled the activity of PGI2 (prostacyclin). The inhibitory activity was increased by preincubation of ECM with arachidonic acid (AA). A moderate decrease of the activity was obtained by incubation with long-chain saturated, monoenoic and dienoic unsaturated fatty acids. A pronounced decrease of the inhibitor was obtained by incubation with di-homo-gamma-linolenic acid (DHLA). Paired combinations of AA with the other fatty acids in the incubation medium partially restored the inhibitory activity obtained by the separate FA. The stimulation of the inhibitor by AA was dose dependent and high concentrations of AA reduced this activity. The present study indicates that the quantity and quality of the plasma free fatty acids can affect the endothelial cells' ability to act as a non-thrombogenic surface.
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