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1.
Thromb Haemost ; 82(3): 1033-40, 1999 Sep.
Article in English | MEDLINE | ID: mdl-10494760

ABSTRACT

The contribution of the various components of the contact system in the generation of factor XIIa (FXIIa) and of kallikrein (KRN) on an electronegative surface and the release of the generated enzymes to the bulk phase was examined in mixtures of normal human plasma and plasmas congenitally deficient in these components. The incubation of normal human plasma in the presence of sulphatide vesicles (40 microM) resulted in a fast generation of amidolytic activities due to FXIIa and to KRN followed by slower first-order inactivation rates of FXIIa (k'FXIIa) and of KRN (k'KRN) due to the presence of esterase inhibitors. Variation of the levels of factor XII (FXII), over a wide range, showed little effect on levels of FXIIa and of KRN but no activities were detected in 100% FXII-deficient plasma. The variation of prekallikrein (PKRN) concentration showed little effect on the generation of FXIIa but the generation of KRN declined linearly with the decrease in the level of PKRN. No activities were detected on treatment of PKRN-deficient plasma. The variation in the concentration of high molecular weight kininogen (HK) showed effects on FXIIa and KRN that were qualitatively similar to those seen on variation of PKRN but 100% HK-deficient plasma generated considerable activities of both FXIIa and KRN. The variation in the concentration of factor XI (FXI) showed no effect on the generation of FXIIa, whereas KRN levels increased linearly with the contribution of FXI-deficient in normal plasma. The present results suggest that the contiguous binding of FXIIa, FXII, PKRN-HK and FXI-HK onto the electronegative surface induces a rapid generation of FXIIa and KRN. The bound PKRN-HK complex prevents the release of generated FXIIa and therefore further binding and activation of FXII from the bulk phase. Consequently, the turnover of FXII is independent of its levels in the bulk phase and is rather related to the concentration of contact surface. The generated KRN is also protected by HK. However, since the enzyme responsible for the activation of PKRN-HK is FXIIa, the levels of generated KRN are positively related to the concentration of substrate.


Subject(s)
Factor XIIa/biosynthesis , Animals , Blood Coagulation/physiology , Cattle , Electrochemistry , Factor XI/metabolism , Factor XII/metabolism , Humans , In Vitro Techniques , Kinetics , Kininogen, High-Molecular-Weight/blood , Prekallikrein/metabolism , Sulfoglycosphingolipids/metabolism , Surface Properties
2.
Thromb Res ; 94(2): 117-29, 1999 Apr 15.
Article in English | MEDLINE | ID: mdl-10230897

ABSTRACT

The incubation of normal human plasma in the presence of sulphatide vesicles results in the generation of amidolytic activity due to factor XIIa (FXIIa) and to kallikrein (KRN). The progress of the generation of the enzymes distinguished a high initial rate of enzyme generation, a decline of this rate to maximum amidolytic activity ([FXIIa]m and [KRN]m) and a negative pseudo-first-order rate attributed to enzyme inactivation by plasma C1-inhibitor (C1INH). [FXIIa]m and [KRN]m were determined after the treatment of various dilutions of plasma in the presence of 4, 15, or 40 microM sulphatide vesicles. At all levels of sulphatides, [FXIIa]m and [KRN]m initially increased with the concentration of plasma, to reach a plateau at higher concentration of plasma. The plateau activities of the generated enzymes and the optimal concentration of plasma both increased with the level of sulphatide vesicles. The pseudo-first-order inactivation rate for KRN increased progressively with the concentration of plasma but the respective rate for FXIIa was independent of the plasma concentration. The data suggest that contiguous binding of plasma FXIIa, factor XII (FXII), and the complexes of high molecular weight kininogen (HK) with prekallikrein (HK-PKRN) and factor XI (HK-FXI) to an electronegative surface induces a rapid generation of FXIIa and KRN. The concentration of the electronegative surface controls the levels of generated FXIIa and KRN and their release to the bulk phase. The released FXIIa and KRN are both inactivated by C1INH.


Subject(s)
Cerebrosides/pharmacology , Factor XII/metabolism , Kallikrein-Kinin System , Plasma/metabolism , Prekallikrein/metabolism , Activation Analysis , Animals , Cattle , Humans , Kininogens/metabolism , Regression Analysis
3.
Thromb Haemost ; 80(2): 233-8, 1998 Aug.
Article in English | MEDLINE | ID: mdl-9716144

ABSTRACT

Abetalipoproteinaemia is a rare disorder of apolipoprotein B metabolism associated with extremely low plasma concentrations of triglyceride. To discover whether the general positive association between factor VII and triglyceride levels extends to this condition, 5 patients were compared with 18 controls. All patients had a triglyceride below 100 micromol/l. Plasma unesterified fatty acid concentration was normal. Although factor IX activity was only slightly reduced (mean 88% standard) and factor IX antigen was normal, mean activated factor VII in patients was strikingly reduced to 34% of that in controls, a level similar to that found in haemophilia B. The patients' mean factor VII activity and factor VII antigen were also significantly reduced to 54% and 63% of those in controls, respectively. Mean factor XI activity and tissue factor pathway inhibitor activity were reduced in patients to 70% and 75% of control values respectively, while factor XII, factor XI antigen, factor X, prothrombin and protein C were normal.


Subject(s)
Abetalipoproteinemia/physiopathology , Antigens/blood , Factor VII/immunology , Factor VIIa/metabolism , Abetalipoproteinemia/blood , Abetalipoproteinemia/genetics , Adult , Blood Coagulation Factors/metabolism , Case-Control Studies , Fatty Acids, Nonesterified/blood , Female , Humans , Male
4.
Eur Heart J ; 18(2): 235-41, 1997 Feb.
Article in English | MEDLINE | ID: mdl-9043839

ABSTRACT

The Oxford Cholesterol Study is a randomized placebo-controlled trial designed primarily to assess the effects of simvastatin on blood cholesterol levels and side-effects in preparation for a large, long-term trial of the effects of cholesterol-lowering drug therapy on mortality. At present there is only limited evidence from randomized comparisons of the effects of HMG-CoA reductase inhibitors, such as simvastatin, on thrombogenic, as distinct from atherogenic, pathways in coronary heart disease. The present sub-study was carried out to assess the effects of simvastatin on a range of haemostatic variables, as well as on free fatty acids and on lipoprotein fractions not studied in detail previously. At an average of about 2 years after starting study treatment, non-fasting blood samples were obtained from a sequential sample of 162 participants who had been randomly allocated to receive 40 mg (54 patients) or 20 mg (57 patients) daily simvastatin or matching placebo treatment (51 patients). Only patients who reported taking their study treatment and who were not known to be diabetic or to be taking some other lipid lowering treatment were to be included. The principal comparisons were to be of those allocated simvastatin (i.e. 20 and 40 mg doses combined) vs those allocated placebo. Among patients allocated simvastatin, marginally significant lower factor VII antigen levels (12.10% +/- 6.08 of standard; 2P < 0.05) and non-significantly lower factor VII coagulant activity (8.24% +/- 4.99 of standard) and fibrinogen concentrations (0.10 +/- 0.08 g. l-1) were observed. In contrast, plasminogen activator inhibitor activity was significantly higher (2.62 +/- 1.03 IU; 2P < 0.01) among patients allocated simvastatin. No significant differences were seen in the other haemostatic factors studied (e.g. prothrombin fragment 1.2, factor XII and C1 inhibitor). Total free fatty acid concentration was marginally significantly reduced (2P = 0.02) with simvastatin, but none of the reductions in individual free fatty acids was significant. Lipoprotein fractions were only measured among patients allocated 40 mg daily simvastatin or placebo. Compared with placebo, simvastatin produced significant decreases not only in LDL cholesterol (1.74 +/- 0.15 mmol.1(-1): 2P < 0.0001) but also in VLDL cholesterol (0.28 +/- 0.08 mmol.1(-1); 2P < 0.001) and IDL cholesterol (0.17 +/- 0.03 mmol.1(-1); 2P < 0.0001). There were also lower triglyceride levels associated with LDL (0.07 +/- 0.01 mmol.1(-1); 2P < 0.0001), IDL (0.03 +/- 0.01 mmol.1(-1); 2P < 0.01) and VLDL (0.27 +/- 0.14; 2P = 0.05). The effects of simvastatin on haemostatic variables appear to be far less marked than its lipid effects. Given the associations of haemostatic factors with coronary heart disease incidence, larger randomized comparisons of the HMG-CoA reductase inhibitors (and of the newer fibrates which may produce greater effects) are needed to provide more reliable estimates of the extent to which they influence these variables.


Subject(s)
Fatty Acids, Nonesterified/blood , Hemostasis/drug effects , Hypercholesterolemia/drug therapy , Hypolipidemic Agents/therapeutic use , Lipoproteins/blood , Lovastatin/analogs & derivatives , Adult , Aged , Chromatography, Thin Layer , Coronary Disease/blood , Coronary Disease/prevention & control , Enzyme-Linked Immunosorbent Assay , Factor VII/drug effects , Factor VII/metabolism , Factor XII/drug effects , Factor XII/metabolism , Female , Fibrinogen/drug effects , Fibrinogen/metabolism , Follow-Up Studies , Humans , Hydroxymethylglutaryl CoA Reductases/blood , Hydroxymethylglutaryl CoA Reductases/drug effects , Hypercholesterolemia/blood , Lipoproteins/drug effects , Lovastatin/therapeutic use , Male , Middle Aged , Prospective Studies , Prothrombin/drug effects , Prothrombin/metabolism , Risk Factors , Simvastatin , Single-Blind Method
5.
Biochem Pharmacol ; 53(1): 27-34, 1997 Jan 10.
Article in English | MEDLINE | ID: mdl-8960060

ABSTRACT

25-Hydroxycholesterol stimulated acyl-CoA:cholesterol acyltransferase (ACAT) activity in rat liver microsomes in vitro with half-maximal stimulation at 16.8 microM oxysterol and a maximal activity that was three times that in its absence. The current study was conducted to determine the effect of 25-hydroxycholesterol on rates and extent of intervesicular cholesterol transfers within microsomes and to determine whether this activation of ACAT could be accounted for on the basis of increased cholesterol availability for the enzyme. Cholesterol transfer kinetics were assessed in systems that either enriched or depleted microsomal cholesterol. Incubation of microsomes at 37 degrees C with phosphatidylcholine:cholesterol liposomes or purified plasma membranes resulted in enrichment of microsomal cholesterol. Incubation of microsomes with just phosphatidylcholine liposomes resulted in depletion of cholesterol. The extent of cholesterol enrichment or depletion depended on incubation time and the initial concentration of cholesterol in donor and acceptor vesicles. The rate and extent of cholesterol transfer from liposomes to microsomes were slightly increased when 25-hydroxycholesterol was present during the transfer process. Irrespective of the treatment, 25-hydroxycholesterol continued to stimulate the ACAT activity of the treated microsomes. Microsomes that were enriched or depleted of cholesterol in the absence of 25-hydroxycholesterol yielded as much enzyme activities when assayed in the presence of 25-hydroxycholesterol as with the systems that contained 25-hydroxycholesterol during both the transfer process and enzyme assays. The results suggest that a major part of the activation of microsomal ACAT by 25-hydroxycholesterol is not ascribable to increased substrate availability for the enzyme.


Subject(s)
Hydroxycholesterols/pharmacology , Sterol O-Acyltransferase/metabolism , Animals , Cholesterol/metabolism , Enzyme Activation/drug effects , Male , Microsomes, Liver/enzymology , Rats , Rats, Wistar
6.
Arterioscler Thromb Vasc Biol ; 17(12): 3449-60, 1997 Dec.
Article in English | MEDLINE | ID: mdl-9437192

ABSTRACT

Modification of dietary fat composition may influence hemostatic variables, which are associated with increased risk of coronary heart disease (CHD). To address this question, we performed a controlled feeding study on 26 healthy male nonsmoking subjects with diets of differing fat composition. For the first 3 weeks, the subjects were given a diet calculated to supply 30% energy as total fat: 8% as monounsaturated, 4% as polyunsaturated, and 16% energy as saturated fatty acids, respectively (saturated diet). This was followed immediately by two diets taken in random order, each of 3-week duration and separated by an 8-week washout period on the subject's usual diet. Both diets were calculated to supply 30% of energy as fat: 14% monounsaturated, 6% as polyunsaturated, and 8% energy as saturated fatty acids. They both provided 5 g (approximately 1.7% energy) more of polyunsaturated fatty acids than the saturated fat diet; in one diet as long-chain n-3 fatty acids (n-3 diet) and in the other as linoleic acid (n-6 diet). Fasting plasma lipids, lipoproteins, and hemostatic factors were measured on the final 3 days of each dietary period. In a subset of 9 subjects the postprandial responses to a test meal were studied on the penultimate day of each period, each meal having the fat composition of its parent diet. On the n-3 diet compared with the n-6 diet, plasma triglyceride, HDL3 cholesterol, apoprotein AII, and fibrinogen concentrations were lower and HDL2 cholesterol concentration was higher (P = .0001, P = .003, P = .0001, P = .004, and P = .001, respectively). On both the n-3 and n-6 diets compared with the saturated diet, fasting plasma total and LDL cholesterol, apoprotein B, beta-thromboglobulin concentrations, and platelet counts were lower (P < .0001, P < .0001, P < .001, P < .01, and P < .05 respectively) and plasma Lp(a) and von Willebrand factor concentrations were higher (P = .02 and P < .01, respectively). Fasting factor VII coagulant activity (VIIc) was increased and apoprotein AI concentration reduced following the n-3 diet (P = .004 and P = .01, respectively) compared with the saturated diet. Plasma fibrinogen concentration was significantly greater following the n-6 diet than on the saturated diet (P = .02). Postprandially, plasma triglyceridemia was greater on the n-6 diet and lowest on the n-3 diet (P < .001) with the saturated diet being intermediate. Plasma VIIc was increased at 4 hours following the standardized test meals on the n-3 and n-6 diets (both P < .05) but not on the saturated diet. An increased intake of long chain n-3 fatty acids decreases fasting plasma triglyceride and apoprotein AII concentrations and increases HDL2 cholesterol concentrations and results in less postprandial lipemia but leads to an increase in VIIc. An increased intake of linoleic acid may raise plasma fibrinogen concentration. Decreasing the intake of saturated fatty acids reduces plasma LDL cholesterol and apoprotein B without affecting HDL cholesterol concentration independent of the type of polyunsaturated fatty acids in the diet. When advice is given to reduce saturated fat intake, it is important to ensure an appropriate ratio of n-3/n-6 fatty acids in the diet.


Subject(s)
Dietary Fats, Unsaturated , Fatty Acids, Unsaturated , Hemostasis , Lipoproteins/blood , Adult , Apolipoproteins B/blood , Cholesterol/blood , Diet , Erythrocytes/chemistry , Factor VII/metabolism , Fasting , Glycerophosphates/blood , Humans , Male , Postprandial Period , Triglycerides/blood
7.
Blood ; 87(10): 4187-96, 1996 May 15.
Article in English | MEDLINE | ID: mdl-8639777

ABSTRACT

Factor VII activity (FVIIc), a risk marker for coronary heart disease, is increased during postprandial lipemia. Factor VII activation accompanies lipolysis of triglyceride-rich lipoproteins, but the nature of this association and whether it is causal remain uncertain. To explore this issue, four patients with homozygous factor XII deficiency, four with complete factor XI deficiency, six with factor IX deficiency, and their respective age- and sex-matched controls were given two isocaloric dietary regimens, one providing on average 136 g fat and the other 19 g fat. Blood was taken before breakfast, immediately before lunch at 195 minutes, and at completion of the study at 390 minutes. All samples for each subject and matched control were assayed as one batch for FVIIc, activated factor VII, and factor VII antigen (FVIIag). Activation of factor VII was observed with the high-fat regimen but not with the low-fat regimen in all controls, factor XII-deficient patients, and factor XI-deficient patients. No factor VII activation was observed during either regimen in factor IX-deficient patients, but a normal postprandial responsiveness of factor VII to dietary fat was restored in one patient who replicated the study after factor IX therapy. Plasma FVIIag was not altered postprandially in either regimen in any group of patients or controls. Factor IX apparently plays an obligatory role in the postprandial activation of factor VII, although the mechanism remains to be determined.


Subject(s)
Dietary Fats/pharmacology , Factor VII/metabolism , Factor VIIa/biosynthesis , Factor XI Deficiency/blood , Factor XII Deficiency/blood , Hemophilia B/blood , Adult , Body Mass Index , Cholesterol/blood , Diet, Fat-Restricted , Dietary Fats/administration & dosage , Eating , Enzyme Activation/drug effects , Factor IX/pharmacology , Fasting , Female , Humans , Lipolysis , Male , Middle Aged , Risk Factors , Triglycerides/blood
8.
J Intern Med ; 238(2): 137-41, 1995 Aug.
Article in English | MEDLINE | ID: mdl-7629481

ABSTRACT

A 38-year-old Asian man presented with acute pancreatitis, marked hypertriglyceridaemia and macroproteinuria, 20 years after the diagnosis of lecithin-cholesterol acyltransferase (LCAT) deficiency. After recovery, he exhibited macroproteinuria and chylomicronaemia despite treatment with a very-low-fat diet. Infusion of normal plasma significantly increased the proportion of cholesterol esters in the patient's plasma and significantly lowered chylomicron-triglyceride levels, but not proteinuria. We conclude that renal dysfunction may be a late manifestation of LCAT deficiency and that it may lead to severe chylomicronaemia and acute pancreatitis. Infusion of normal plasma corrects the dyslipidaemia in LCAT deficiency, but in the short term does not improve renal function.


Subject(s)
Lecithin Cholesterol Acyltransferase Deficiency/diagnosis , Pancreatitis/etiology , Acute Disease , Adult , Blood Component Transfusion , Diagnosis, Differential , Humans , Lecithin Cholesterol Acyltransferase Deficiency/blood , Lecithin Cholesterol Acyltransferase Deficiency/complications , Lecithin Cholesterol Acyltransferase Deficiency/therapy , Lipoproteins/blood , Male , Pancreatitis/blood
9.
Thromb Res ; 78(1): 67-75, 1995 Apr 01.
Article in English | MEDLINE | ID: mdl-7778067

ABSTRACT

Activated factor XII (XIIa), activated factor VII (VIIa) and factor VII coagulant activity (VIIc) were determined in non-treated and in treated (cold-incubated) citrated plasmas from women in late pregnancy and from norma volunteers. All three activities were higher in the non-treated plasmas from women in late pregnancy than from normal subjects. The incubation of citrated plasmas from women in late pregnancy, on ice for 24 hours, resulted in a many-fold increase of factor XIIa activity, factor VIIa levels and VIIc. The dilution of these plasmas resulted in a sharp decrease of all three activities in the post-incubation mixture, so that in the plasmas diluted 2:1 with buffer all three activities were similar to those in fresh plasmas. Similar incubations of diluted plasmas (1:1) from normal volunteers resulted in no increase of factor XIIa activity, factor VIIa levels and VIIc. However, the presence in the incubation mixture of micellar stearate resulted in a stearate concentration-dependent increase of all three activities in treated plasmas. Levels of factor XIIa activity and factor VIIa in the treated plasmas from both groups of subjects were highly correlated (r = 0.987; p < 0.001). There was also a highly significant correlation between VIIc and factor VIIa levels (0.989; p < 0.001). These results demonstrate that the in vitro increase in factor VIIa levels is due to the activation of the contact system of coagulation and is dependent on the potency of the contact surface. Moreover, VIIc over a wide range of values, observed in the present experiments, can provide an accurate measure of factor VIIa concentration.


Subject(s)
Factor VII/metabolism , Factor XII/metabolism , Adult , Cold Temperature , Female , Humans , Male , Plasma , Pregnancy , Stearates/chemistry
10.
Br Med Bull ; 50(4): 813-32, 1994 Oct.
Article in English | MEDLINE | ID: mdl-7804733

ABSTRACT

Remnants produced on the lipolysis of triglyceride-rich lipoproteins provide a contact surface that activates the contact system of coagulation and therefrom factor VII. New evidence is reviewed suggesting that increased levels of circulating activated factor VII (VIIa) initiates coagulation and produces thrombin at higher rate at the site of an atheromatous lesion or at an injury site. This may have profound significance for the propagation of thrombus and for the thrombin-induced inflammatory and proliferative responses. Vascular homeostasis is achieved by the regulated interaction of the coagulation and fibrinolytic systems. An imbalance in this equilibrium may lead to an increased risk of thrombosis or a bleeding diathesis. The role of PAI-1, a potent inhibitor of enzymes that generate plasmin, in the regulation of fibrinolytic activity, is discussed and the evidence linking the expression of its activity to hypertriglyceridaemia is reviewed. Moreover, the association between lipoprotein (a) and coronary heart disease is attributed to its interference in the normal activation of plasminogen to plasmin.


Subject(s)
Blood Coagulation , Lipids/blood , Thrombosis/blood , Dietary Fats/metabolism , Factor VIII/metabolism , Fibrinolysis , Humans , Lipoproteins/blood , Platelet Aggregation Inhibitors/metabolism
11.
Blood Coagul Fibrinolysis ; 5(4): 583-91, 1994 Aug.
Article in English | MEDLINE | ID: mdl-7841315

ABSTRACT

The hypothesis that lipolysis of large lipoproteins by lipoprotein lipase (LPL) has an important influence on the activation of the contact system of coagulation and subsequently on factor VII activation was tested in rabbits rendered hyperlipidaemic by dietary means and/or by injection of Triton WR-1339. The dietary treatment involved a control diet and two isocaloric diets containing either a 0.5% cholesterol or 0.5% cholesterol and 7.5% safflower oil supplement. Other groups of rabbits were given either a standard diet or the standard diet supplemented with 1% cholesterol. All supplemented diets increased many-fold the concentrations of cholesterol associated with the chylomicron, very low-(VLDL), intermediate-(IDL) and low-density (LDL) lipoprotein fractions. Factor VII coagulant activity (FVIIc) increased significantly in all groups of rabbits fed the cholesterol supplement. The intravenous injection of Triton WR-1339 into rabbits fed either the standard or 1% cholesterol-supplemented diet resulted in increases of plasma cholesterol and triglyceride concentrations up to 36-48 h thereafter, followed by decreases up to completion of the experiment at 72 h. Most of these increases in plasma lipids were associated with the chylomicron and VLDL fractions. Following injection of Triton into rabbits fed either the standard or cholesterol-supplemented diet, changes in FVIIc were biphasic with a decrease in activity in the early intervals when rates of accumulation of plasma lipid were constant, and a progressive increase in activity at later intervals when rates of lipid accumulation declined and then reversed.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Antigens/metabolism , Blood Coagulation , Factor VII/metabolism , Hypercholesterolemia/blood , Lipolysis/drug effects , Lipoprotein Lipase/antagonists & inhibitors , Lipoproteins/blood , Polyethylene Glycols/pharmacology , Surface-Active Agents/pharmacology , Animals , Cholesterol/administration & dosage , Cholesterol/toxicity , Cholesterol, HDL/blood , Cholesterol, VLDL/blood , Chylomicrons/blood , Diet, Atherogenic , Dietary Fats/administration & dosage , Dietary Fats/toxicity , Enzyme Activation , Hypercholesterolemia/chemically induced , Injections, Intravenous , Polyethylene Glycols/administration & dosage , Rabbits , Safflower Oil/administration & dosage , Safflower Oil/toxicity , Surface-Active Agents/administration & dosage , Thromboplastin/metabolism , Triglycerides/blood
12.
Curr Opin Lipidol ; 5(3): 227-35, 1994 Jun.
Article in English | MEDLINE | ID: mdl-7952918

ABSTRACT

Recent evidence suggests that long-chain saturated fatty acids (i.e. stearic acid), produced on lipolysis of triglyceride-rich lipoproteins in the interface of circulating remnant particles provide a contact surface that activates the contact system of coagulation and subsequently activates factor VII. Increased level of circulating activated factor VII is probably of little consequence to a healthy individual with minimal expression of tissue factor in the vasculature. However, at a site of an atheromatous plaque or at a vascular injury site where there is tissue factor activity, increased circulating activated factor VII is expected to generate thrombin at a higher rate. Propagation of the prothrombotic environment will be facilitated on expression of additional tissue factor that is induced by the local increased concentration of thrombin. Thrombin with its receptor-mediated interactions with blood and vessel wall cells can signal inflammatory and proliferative responses such as those that occur in atheroma.


Subject(s)
Arteriosclerosis/metabolism , Blood Coagulation/physiology , Lipoproteins/metabolism , Thrombosis/metabolism , Animals , Arteriosclerosis/etiology , Blood Proteins/physiology , Factor VII/metabolism , Humans , Thrombin/biosynthesis , Thromboplastin/biosynthesis , Thrombosis/etiology
13.
Arterioscler Thromb ; 14(2): 214-22, 1994 Feb.
Article in English | MEDLINE | ID: mdl-8305411

ABSTRACT

Previous studies have demonstrated activation of the contact system of coagulation and an increase in factor VII coagulant activity (VIIc) when citrated plasma is incubated in the presence of micellar stearate. The products of contact activation, factors XIIa and IXa, were responsible in this system for the activation of factor VII, thereby increasing factor VIIc. To obtain evidence that these in vitro interactions also operate in vivo, factor VIIc was examined in relation to plasma free fatty acid concentrations in five healthy individuals during the consumption of isocaloric high-saturated fat, high-unsaturated fat, and low-fat diets, each taken for 4 weeks in random order and separated by intervals of 12 weeks. For all but the final 3 days of each phase, subjects selected appropriate foods from prepared lists to meet the dietary requirements. Experimental diets of predetermined fat content and composition were fed on days 26 through 28 in each phase. Fat supplied on average 62% of energy in two of the experimental diets and less than 20% of energy in the third. On the final day of each dietary phase, the concentrations of the various free fatty acids and factor VIIc were measured before breakfast and at three 150-minute intervals thereafter. Plasma factor VIIc was, respectively, 6.5% and 13.1% of standard higher on the unsaturated and saturated fat diets than on the low-fat diet. Furthermore, the plasma concentration of stearic acid was strongly associated with factor VIIc (r = .58; P < .0001), and this relation remained significant (P = .003) after allowance for the plasma concentrations of palmitic, oleic, and linoleic acids.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Antigens/metabolism , Dietary Fats/pharmacology , Factor VII/metabolism , Stearic Acids/blood , Adult , Blood Coagulation Factors/analysis , Cholesterol Esters/blood , Fatty Acids, Nonesterified/blood , Female , Humans , Lipids/blood , Lipoproteins/blood , Male , Multivariate Analysis , Osmolar Concentration , Triglycerides/blood
14.
Blood Coagul Fibrinolysis ; 4(6): 943-51, 1993 Dec.
Article in English | MEDLINE | ID: mdl-8148488

ABSTRACT

The prolonged incubation of dilute plasma on ice in the presence of added sulphatide vesicles or the long-chain saturated fatty acids (FA) stearic acid (C18:0) or behenic acid (C22:0) induced a concentration-dependent increase in factor VII coagulant activity (VIIc). The addition of FA at various ratios to human serum albumin showed the micellar non-bound pool to be responsible for this effect, FA bound to the high-affinity or low-affinity binding sites of albumin having no influence on VIIc. Plasma VIIc also increased following addition of behenate-enriched lipoprotein particles produced by incubation of the d < 1.006 g/ml lipoprotein fraction with this FA, or addition of lipoprotein remnants produced by pre-incubation of the d < 1.006 g/ml fraction with lipoprotein lipase. Long-chain saturated fatty acids in the interface of lipoprotein remnants, produced by the interaction of triglyceride-rich lipoprotein particles with lipoprotein lipase, appear to provide a surface that activates the contact system of coagulation and subsequently factor VII.


Subject(s)
Factor VII/metabolism , Fatty Acids/pharmacology , Lipoproteins/chemistry , Triglycerides/analysis , Anticoagulants , Citrates , Citric Acid , Fatty Acids/chemistry , Female , Humans , Hydrogen-Ion Concentration , Lipoprotein Lipase/pharmacology , Lipoproteins, VLDL/chemistry , Lipoproteins, VLDL/pharmacology , Liposomes , Plasma , Pregnancy , Serum Albumin , Sulfoglycosphingolipids
15.
Atherosclerosis ; 103(2): 231-43, 1993 Nov.
Article in English | MEDLINE | ID: mdl-8292098

ABSTRACT

Cholesterol and triglyceride in the various lipoprotein fractions were determined in five patients without functional lipoprotein lipase (LPL) while on their habitual therapeutic diet of 'low fat' content (20-25 g/day). They were also studied following 3 days on either a 'minimal fat' diet (< 15 g/day) or a 'moderate fat' diet (45-50 g/day). Values obtained were compared with the respective levels measured in five control subjects on a 'normal fat' (70-90 g/day) diet. The patients had hypertriglyceridaemia (type V hyperlipoproteinaemia) under all dietary conditions. Cholesterol and triglyceride levels in plasma and in the chylomicron fraction increased in the patients with increasing dietary fat. In the very low density lipoprotein (VLDL) fraction from the patients, triglyceride levels also increased with the dietary fat intake, but cholesterol levels were similar under all dietary conditions. In the patients, cholesterol concentrations in the low (LDL) and high density (HDL) lipoprotein fractions were significantly lower than the respective levels in controls, but the ratio of cholesterol to triglyceride levels in both of these lipoprotein fractions decreased with the dietary fat intake. VLDL apolipoprotein B-100 (apo B-100) pool size was similar in the patients on the two test diets (P = 0.95) and 3.5-fold higher than in five healthy volunteers on a normal fat diet. Using a stable isotope enrichment method, the kinetics of apo B-100 were investigated in the patients under the last two dietary conditions. The fractional and absolute secretion rates of the apolipoprotein in the patients did not vary with fat intake, but fractional secretion rates were significantly lower and the absolute secretion rates were significantly higher in the patients than the respective values in the controls. These results are consistent with the hypothesis that in the absence of LPL activity the metabolism of chylomicron and VLDL particles in the circulation results in triglyceride-rich LDL and HDL particles that are taken up by the liver at increased rates, thus reducing the plasma LDL and HDL cholesterol concentrations, whereas the products of hydrolysis of these particles induce an increased rate of synthesis of triglyceride and an increased rate of secretion of VLDL apo B-100.


Subject(s)
Apolipoproteins B/analysis , Lipoprotein Lipase/deficiency , Lipoproteins/blood , Triglycerides/blood , Adult , Apolipoprotein B-100 , Cholesterol/blood , Female , Humans , Hyperlipoproteinemia Type V/blood , Hyperlipoproteinemia Type V/enzymology , Lipoproteins, HDL/blood , Lipoproteins, LDL/blood , Lipoproteins, VLDL/blood , Male , Middle Aged
16.
Blood Coagul Fibrinolysis ; 4(2): 223-34, 1993 Apr.
Article in English | MEDLINE | ID: mdl-8499561

ABSTRACT

The contribution of various enzymes in the activation of factor VII, determined from the increase in factor VII coagulant activity (VIIc), was investigated following the exposure of citrated plasma to low temperature. The contact system of coagulation was initiated either by the contact surface present in certain plasmas (i.e. plasma from women in late pregnancy) or by micellar stearate added to plasma diluted with an equal volume of buffer (plasma from normal healthy subjects or from women in late pregnancy). With either of the contact surfaces, increase of VIIc and the concentration of enzymes derived from factor XII (XIIa) depended on the potency of the contact surface. The stearate-induced VIIc in diluted plasmas from women in late pregnancy or from normal subjects was inhibited by 60-70% in the presence of anti-factor IX monoclonal antibody. VIIc was not increased in XII-deficient plasma following the addition of stearate. The addition of purified human factor XII to this plasma restored the increase in VIIc and the activation of factor XII. In factor IX-deficient plasma, the stearate-induced increase in VIIc was only 38% of that seen in normal plasma and was restored by the addition of purified factor IX. Similarly in factor XI-deficient plasma, the stearate-induced increase in VIIc and the factor XII activation were 48% and 69% of that found in normal plasma. The addition of EDTA (2 mM) did not alter the extent of factor XII activation induced by contact surface, but it did inhibit the rise in VIIc. It is concluded that in the presence of contact surface the activation of factor XII and the sequential activation of factor XI and of factor IX results in the activation of factor VII. Activated factor IX is responsible for the major part of the factor VII activation whereas the rest may be through the direct activation by XIIa.


Subject(s)
Factor IX/physiology , Factor VII/physiology , Factor XII/physiology , Antibodies, Monoclonal/pharmacology , Blood Coagulation , Enzyme Activation , Factor IX/chemistry , Factor XII/biosynthesis , Factor XII/chemistry , Female , Humans , Pregnancy , Surface Properties
17.
Atherosclerosis ; 97(1): 67-73, 1992 Nov.
Article in English | MEDLINE | ID: mdl-1445495

ABSTRACT

In order to evaluate whether Hageman factor (XII) is increased in survivors of myocardial infarction and whether this in turn influences factor VII coagulant activity (VIIc), we examined the coagulation and lipoprotein profiles in 82 subjects, 51 of whom had a definite history of myocardial infarction and 31 healthy volunteers invited from a local general practice register for a cardiovascular screen. Both serum cholesterol (P = 0.03) and plasma fibrinogen levels (P = 0.02) were significantly elevated in cases compared with controls. There were no significant differences in coagulant activities, and in particular factor XII concentration was not significantly different between groups. Furthermore, in 47 of the subjects, 28 of whom had a history of myocardial infarction, a more detailed analysis, including measurement of VIIc after overnight incubation of plasma at 4 degrees C, was undertaken. Approximately half the subjects in either group showed some evidence of activation, though history of myocardial infarction was not in itself a significant predictor of this. All measures of XII concentration related positively to VIIc after cold activation, the strongest being the measure of amidolytic activity following activation of factor XII (XIIAm) (r = 0.5, P < 0.01). In addition, XIIa, a measure of activity due to enzymes derived from factor XII, related strongly to many of the measured lipoprotein variables, particularly VLDL cholesterol and triglycerides, supporting the hypothesis that negatively charged molecules such as free fatty acids on larger lipoprotein particles provide the contact surface necessary to activate factor XII. The findings confirm the importance of this alternative pathway in leading to activation of factor VII.


Subject(s)
Factor XII/analysis , Myocardial Infarction/blood , Aged , Antigens/analysis , Cholesterol/blood , Factor VII/analysis , Fibrinogen/analysis , Humans , Lipoproteins/blood , Male , Middle Aged , Risk Factors
18.
Atherosclerosis ; 95(2-3): 119-25, 1992 Aug.
Article in English | MEDLINE | ID: mdl-1418087

ABSTRACT

A high factor VII coagulant activity (VIIc), a marker of increased risk of coronary heart disease, is frequently found in types IIb and IV hyperlipidaemia, but its cause is not fully understood. Factor VII can be activated by factor XIIa, generated from factor XII upon activation of the contact system of coagulation. Ten patients with familial lipoprotein-lipase (LPL) deficiency and 10 healthy control subjects were therefore compared to explore the hypothesis that high concentrations of unesterified fatty acids (UFA), released from triglyceride-rich lipoproteins by LPL, are a source of factor XII activation and hence the increased VIIc that is observed post-prandially and in non-LPL-deficient hypertriglyceridaemic states. Mean plasma cholesterol and triglyceride concentrations were, respectively, 1.5- and 19-fold higher in the patients than controls, due to increases in very-low-density lipoproteins and chylomicrons. The concentration and composition of plasma UFA were similar in both groups. In conformity with the hypothesis, VIIc was not increased in the LPL-deficient group, despite their massive hypertriglyceridaemia. Furthermore, when the patients' plasma was treated with LPL, factor XII was activated promptly and substantially, whereas no similar effect was observed in the controls. These results suggest that high concentrations of circulating triglyceride-rich lipoproteins will increase VIIc in the presence of LPL.


Subject(s)
Factor XII/physiology , Lipolysis , Lipoprotein Lipase/deficiency , Lipoproteins/metabolism , Triglycerides/metabolism , Adult , Factor VII/metabolism , Factor XII/metabolism , Fatty Acids, Nonesterified/blood , Fatty Acids, Nonesterified/classification , Female , Humans , Lipoproteins/blood , Male , Middle Aged
20.
Thromb Haemost ; 66(4): 446-52, 1991 Oct 01.
Article in English | MEDLINE | ID: mdl-1796394

ABSTRACT

The incubation of purified human factor XII (Hageman factor [HF]) in the presence of long-chain saturated fatty acids (FA) like stearate (C-18) or behenate (C-22) resulted in a time-dependent increase of amidolytic activity. The HF autoactivation progress curves were sigmoidal. The first order rate for the initial period was constant; this was followed by a period of decreasing rate and a plateau of zero rate. These progress curves were similar to those obtained on the incubation of HF in the presence of sulphatide vesicles or dextran sulphate. The initial rate of autoactivation of HF was dependent on the FA concentration of contact surface and increased with increasing concentration of HF. At constant concentration of contact surface and varying concentration of HF, autoactivation rates in the presence of behenate, sulphatide vesicles or dextran sulphate followed Michaelis-Menten kinetics. The Km values for all three contact surfaces were above the physiological plasma concentration of HF whereas the catalytic efficiency in the presence of behenate (0.034 microM-1s-1) was about 2/3 of that in the presence of sulphatide vesicles (0.053 microM-1s-1) and considerably higher than that in the presence of dextran sulphate (0.004 microM-1s-1). Long-chain saturated FA bound to human serum albumin at the high- or low-affinity sites are ineffective, whereas the crystalline non-bound stearate or behenate provided a potent contact surface.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Dextran Sulfate/pharmacology , Factor XII/metabolism , Fatty Acids/pharmacology , Sulfoglycosphingolipids/pharmacology , Fatty Acids/chemistry , Humans , Hydrogen-Ion Concentration , Kinetics , Liposomes , Serum Albumin/chemistry
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