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...
SummaryTwenty patients accepted for coronary bypass surgery were randomized to receive either a concentrated ethylester compound of n-3 fatty acids, with a daily dose of 3.15 g of eicosapentaenoic acid (EPA) and 1.89 g of docosahexaenoic acid (DHA), or corn oil (controls) in a double blind study, to evaluate the effect on lipids, platelets and coagulation during the pre- and postoperative phase.Only patients with fasting triglyceride (TG) levels ≥1.6 mmol/1 at recruitment were eligible. The study was continued for 5 to 6 months. Surgery was usually performed at mid-intervention. Blood samples were collected during morning hours in fasting subjects, just prior to intervention, preoperatively and at final postoperative follow-up. Moreover, blood loss was accurately accounted for postoperatively.A threefold increase (p = 0.0001) of EPA was noted at pre-and postoperative follow-up. TG-levels were reduced 20 and 39%, respectively, in patients on n-3 fatty acids, reaching statistical significance at end of intervention (p = 0.034). TG-levels in controls remained largely unchanged. In patients on n-3 fatty acids, there was a statistically significant increase in serum total cholesterol preoperatively, but this change was no longer present at completion of the study.No significant changes were noted in platelet function, as judged by bleeding time, collagen induced platelet aggregation and release of TxB2 during aggregation. Parameters of extrinsic coagulation, including phospholipase C-sensitive factor VII (PLC-VII) and extrinsic pathway inhibitor (EPI), also remained essentially unchanged in both groups of patients. However, fibrinogen was significantly reduced in controls (p <0.05) at end of intervention. Moreover, a strong positive correlation was noted between PLC-VII and TG (r = 0.77, p = 0.0001).No significant difference in postoperative bleeding was noted between the two groups of patients.
Fourteen patients suffering from familial hypercholesterolemia (type Ha) participated in a double-blind, placebo-controlled trial that evaluated! the effects of fish oil ethyl ester (K-85, 5.7 g/day) or a hydroxymethylglutaryl coenzyme A reductase inhibitor (lovastatin, 40 mg/day) alone or in combination on lipid metabolism and bleeding time at rest and after standardized exercise. Lovastatin treatment reduced total cholesterol (-27%), low density lipoprotein cholesterol (-37%), and triglycerides (-18%), whereas high density lipoprotein cholesterol increased significantly (14%). K-85 affected total (-4%), low density lipoprotein (-9%), and high density lipoprotein (+7%) cholesterol insignificantly, whereas the triglyceride level decreased by 24% (p<0.001). The combined regimen caused an additive decrease in the triglyceride level (41%), which differed significantly (p<0.01) from that gained by lovastatin alone. Under basal conditions the bleeding time was no), influenced by the different interventions. Standardized exercise shortened the bleeding time by 19% (j7<0.001) and 16% (p<0.001) before intervention and after lovastatin treatment, respectively. After K-85 alone or in combination with lovastatin, the exerciseinduced shortening of the bleeding time was totally inhibited, which may reflect a favorable influence of fish oil on the platelet-vessel wall interaction in these high-risk patients. (Arteriosclerosis and Thrombosis 1993;13:98-104) KEYWORDS • n-3 fatty acids • lovaslatin • hydroxymethylglutaryl coenzyme A reductase inhibitor • lipoproteins • bleeding time • physical exercise • familial hypercholesterolemia • fish oil
Coronary heart disease (CHD) mortality was registered in an inland and a coastal community in Northern Norway. Subgroups of healthy males from the communities were investigated further. The daily consumption of fish in the coastal and inland areas was 132.4 g and 55.1 g respectively, and the intake of eicosapentaenoic acid was 0.9 g and 0.25 g. The content of n‐3 polyunsaturated fatty acids in platelet phospholipids and primary bleeding time were similar in the two groups. Linoleic acid was lower and saturated fatty acids were higher in phospholipids in men from the coastal ma. Collagen‐induced platelet aggregation was increased and serum triglyceride concentration was higher in men from the coastal ma. CHD mortality during a 10‐Lyear period was higher in the coastal area for both sexes. This may be associated with differences in serum triglyceride levels and platelet fatty acid composition. This study indicates that a high consumption of lean fish is not sufficient to induce changes in blood lipids and platelet function associated with low CHD mortality and it does not seem to prevent high CHD mortality.
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