Decreased Tissue Factor Pathway Inhibitor Research Articles

Circadian misalignment disrupts biomarkers of cardiovascular disease risk and promotes a hypercoagulable state.

The circadian system regulates 24-h time-of-day patterns of cardiovascular physiology, with circadian misalignment resulting in adverse cardiovascular risk. Although many proteins in the coagulation-fibrinolysis axis show 24-h time-of-day patterns, it is not understood if these temporal patterns are regulated by circadian or behavioral (e.g., sleep and food intake) cycles, or how circadian misalignment influences these patterns. Thus, we utilized a night shiftwork protocol to analyze circadian versus behavioral cycle regulation of 238 plasma proteins linked to cardiovascular physiology. Six healthy men aged 26.2±5.6 years (mean ± SD) completed the protocol involving two baseline days with 8-h nighttime sleep opportunities (circadian alignment), a transition to shiftwork day, followed by 2days of simulated night shiftwork with 8-h daytime sleep opportunities (circadian misalignment). Plasma was collected for proteomics every 4h across 24 h during baseline and during daytime sleep and the second night shift. Cosinor analyses identified proteins with circadian or behavioral cycle-regulated 24-h time-of-day patterns. Five proteins were circadian regulated (plasminogen activator inhibitor-1, angiopoietin-2, insulin-like growth factor binding protein-4, follistatin-related protein-3, and endoplasmic reticulum resident protein-29). No cardiovascular-related proteins showed regulation by behavioral cycles. Within the coagulation pathway, circadian misalignment decreased tissue factor pathway inhibitor, increased tissue factor, and induced a 24-h time-of-day pattern in coagulation factor VII (all FDR <0.10). Such changes in protein abundance are consistent with changes observed in hypercoagulable states. Our analyses identify circadian regulation of proteins involved in cardiovascular physiology and indicate that acute circadian misalignment could promote a hypercoagulable state, possibly contributing to elevated cardiovascular disease risk among shift workers.

Beyond uterine atony: characterizing postpartum hemorrhage coagulopathy

Postpartum hemorrhage is a leading cause of morbidity and mortality worldwide, yet the associated early coagulopathy is not well defined. We hypothesized that women who develop postpartum hemorrhage have a distinct derangement of thrombin generation and coagulation factors compared with postpartum women without postpartum hemorrhage. This prospective study of pregnant patients with postpartum hemorrhage was completed at a single urban hospital. Blood was drawn on postpartum hemorrhage diagnosis and 2 and 4 hours later. Assays of patients with postpartum hemorrhage included thrombelastography, whole blood thrombin generation, coagulation factor activity, tissue factor levels and activity, and tissue factor pathway inhibitor levels, which were compared with that of patients without postpartum hemorrhage. A total of 81 patients were included in this study. Of those patients, 66 had postpartum hemorrhage, and 15 served as controls. Compared with patients without PPH, patients with postpartum hemorrhage had lower fibrinogen levels (469.0 mg/dL vs 411.0 mg/dL; P=.02), increased tissue plasminogen activator resistance (fibrinolysis 30 minutes after maximal clot strength: 8.7% vs 4.2%; P=.02), decreased peak thrombin concentration (150.2 nM vs 40.7 nM; P=.01), and decreased maximal rate of thrombin generation (60.1 nM/minute vs 2.8 nM/minute; P=.02). Furthermore, compared with patients without postpartum hemorrhage, patients with postpartum hemorrhage had decreased tissue factor levels (444.3 pg/mL vs 267.1 pg/mL; P=.02) and increased tissue factor pathway inhibitor levels (0.6 U/mL vs 0.8 U/mL; P=.04), with decreased tissue factor pathway inhibitor ratios (624 vs 299; P=.01). PPH is not only an issue of uterine tone and mechanical bleeding but also a distinct coagulopathy that is characterized by decreased fibrinogen level, clot breakdown resistance, and markedly low thrombin generation. This pathology seemed to be driven by low tissue factor and high tissue factor pathway inhibitor levels.

Tissue Factor Pathway Inhibitor, Activated Protein C Resistance, and Risk of Coronary Heart Disease Due To Combined Estrogen Plus Progestin Therapy.

To examine whether tissue factor pathway inhibitor or acquired activated protein C (APC) resistance influences the increased risk of coronary heart disease (CHD) due to estrogen plus progestin therapy. Prospective nested case-control study of 205 cases of CHD and 481 matched controls in the Women's Health Initiative randomized trial of estrogen plus progestin therapy. After multivariable covariate adjustment, both baseline tissue factor pathway activity (P=0.01) and APC resistance (P=0.004) were associated positively with CHD risk. Baseline tissue factor pathway activity and APC resistance singly or jointly did not significantly modify the effect of estrogen plus progestin on CHD risk. Compared with placebo, estrogen plus progestin decreased tissue factor pathway inhibitor activity and increased APC resistance but these changes did not seem to modify or mediate the effect of estrogen plus progestin on CHD risk. Tissue factor pathway inhibitor activity and APC resistance are related to CHD risk in women, but may not explain the increased CHD risk due to estrogen plus progestin therapy. The data from this study do not support the clinical use of measuring these hemostatic factors to help stratify risk before hormone therapy. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000611.

Decreased tissue factor pathway inhibitor (TFPI)‐dependent anticoagulant capacity in patients with cirrhosis who have decreased protein S but normal TFPI plasma levels

Protein S acts as a cofactor for tissue factor pathway inhibitor (TFPI) in the down regulation of thrombin generation, and acquired and congenital protein S deficiencies are associated with a concomitant TFPI deficiency. In contrast, in patients with liver diseases, decreased protein S, but normal or increased levels of TFPI have been reported. We compared TFPI and protein S plasma levels between 26 patients with cirrhosis and 20 healthy controls and found that TFPI levels were comparable between patients (111 ± 38%) and controls (108 ± 27%), despite reduced protein S levels (74 ± 23% in patients vs. 98 ± 10% in controls). Subsequently, we quantified the activity of the TFPI-protein S system by measuring thrombin generation in the absence and presence of neutralizing antibodies to protein S or TFPI. Ratios of peak thrombin generation in the absence and presence of these antibodies were calculated. Both the protein S and the TFPI ratios were increased in patients with cirrhosis compared to controls. Protein S ratios were (0·62 [0·08-0·93] in patients vs. 0·32 [0·20-0·54] in controls; TFPI ratios were 0·50 [0·05-0·90] in patients vs. 0·18 [0·11-0·49] in controls). Thus, although the acquired protein S deficiency in patients with cirrhosis is not associated with decreased TFPI levels, the TFPI/protein S anticoagulant system is functionally impaired.

Increased Thrombin-Activatable Fibrinolysis Inhibitor and Decreased Tissue Factor Pathway Inhibitor and Thrombomodulin Levels in Children with Hypothyroidism

Objective: We determined the profile of coagulation/fibrinolytic and vascular endothelial cell function parameters including plasminogen activator inhibitor (PAI) and thrombin-activatable fibrinolysis inhibitor (TAFI), tissue factor pathway inhibitor (TFPI), thrombomodulin (TM), and tissue plasminogen activator (tPA) levels in children with hypothyroidism. Methods: Forty children with hypothyroidism aged 0-16 months who presented for the first time to our hospital and 29 age-and sex-matched healthy controls were enrolled in the study. All coagulation tests were performed with ELISA method. One year after Na-L-thyroxine treatment, the study parameters were re-evaluated in 25 euthyroid children out of the 40 patients diagnosed with hypothyroidism.Results: Although no significant effect was detected regarding PAI antigen (Ag) and tPA Ag, the levels of TAFI, TM, and TFPI were consistent with subclinical hypercoagulability and hypofibrinolysis. There was a significant increase in TAFI Ag levels and a significant decrease in TFPI Ag and TM Ag levels in hypothyroid patients compared to healthy controls. As a result of correlation tests, the largest impact of hypothyroidism on coagulation system was on TFPI. In accordance with these findings, TAFI Ag levels decreased and TFPI Ag and TM Ag levels increased with hormonal replacement therapy. Conclusions: Increased TAFI and decreased TFPI and TM in patients with hypothyroidism may indicate a potential hypercoagulable and hypofibrinolytic state as well as possible endothelial dysfunction, which may increase the risk of atherosclerotic and atherothrombotic complications. Thyroid hormone levels should also be checked in patients with a predisposition to coagulation, and thyroid replacement therapy should be initiated. Conflict of interest:None declared.

Bivalirudin in Combination with Heparin to Control Mesenchymal Cell Procoagulant Activity

Islet and hepatocyte transplantation are associated with tissue factor-dependent activation of coagulation which elicits instant blood mediated inflammatory reaction, thereby contributing to a low rate of engraftment. The aim of this study was i) to evaluate the procoagulant activity of human adult liver-derived mesenchymal progenitor cells (hALPCs), ii) to compare it to other mesenchymal cells of extra-hepatic (bone marrow mesenchymal stem cells and skin fibroblasts) or liver origin (liver myofibroblasts), and iii) to determine the ways this activity could be modulated. Using a whole blood coagulation test (thromboelastometry), we demonstrated that all analyzed cell types exhibit procoagulant activity. The hALPCs pronounced procoagulant activity was associated with an increased tissue factor and a decreased tissue factor pathway inhibitor expression as compared with hepatocytes. At therapeutic doses, the procoagulant effect of hALPCs was inhibited by neither antithrombin activators nor direct factor Xa inhibitor or direct thrombin inhibitors individually. However, concomitant administration of an antithrombin activator or direct factor Xa inhibitor and direct thrombin inhibitor proved to be a particularly effective combination for controlling the procoagulant effects of hALPCs both in vitro and in vivo. The results suggest that this dual antithrombotic therapy should also improve the efficacy of cell transplantation in humans.

Increased platelet residual activity in patients treated with acetosalicylic acid is associated with increased tissue factor and decreased tissue factor pathway inhibitor plasma levels

Increased platelet residual activity in patients treated with acetosalicylic acid is associated with increased tissue factor and decreased tissue factor pathway inhibitor plasma levels

High Glucose Levels Enhance the Proinflammatory and Prothrombotic Actions of Serum Amyloid A (SAA) in Endothelial Cells

Objectives: SAA is elevated in plasma in diabetes and atherosclerosis and high levels predict adverse coronary events. We previously demonstrated proinflammatory and prothrombotic effects of SAA on human aortic endothelial cells (HAEC) but the effects of high glucose are unknown. Methods:HAECwere cultured inmedia±high glucose (25mM) for 7 days, then stimulated with SAA (10 g/ml) for 4, 8 or 24 h,±HDL (0.2mg/ml); mRNA levels of key inflammationand thrombosis-related genes were measured by q-RT-PCR. Results: SAA significantly upregulated tissue factor, interleukin-8, RAGE, and transcription factors NFB and Egr-1 mRNAs in a similar pattern. Peak levels (8 h) were consistently higher and later in glucose-treated HAEC than normal HAEC (4h peak) (figure shows RAGE). Effects of SAA were largely blocked by HDL although in high glucose, RAGE mRNA remained high at 24 h. SAA induced similar levels of eNOS, ICAM and antithrombin III in normal and high glucose-treated cells. SAA-induced VCAMmRNA levels were highest in high glucose-treated cells; both peaked at 4 h, an effect almost completely blocked by HDL. SAA slightly decreased tissue factor pathway inhibitor mRNA at 24 h in normal glucose cells, but levels were even lower in high glucose-treated cells.

Increased thrombin-activatable fibrinolysis inhibitor and decreased tissue factor pathway inhibitor in patients with hyperthyroidism

Various abnormalities of coagulation-fibrinolytic system have been reported in patients with thyroid dysfunction. Several studies indicate that coagulation and fibrinolytic system is disturbed in the patients with hyperthyroidism. The levels of plasma thrombin-activatable fibrinolysis inhibitor (TAFI) antigen and tissue factor pathway inhibitor (TFPI) have been very rarely investigated in patients with hyperthyroidism. Therefore, the main purpose of this study was to evaluate the profile of coagulation and fibrinolytic parameters including TAFI and TFPI in patients with hyperthyroidism. We also investigated the relationships between serum thyroid hormones and hemostatic parameters in these patients. Thirty patients with untreated hyperthyroidism and 25 age- and sex-matched healthy controls were included in the study. Factor V (FV), protein C, protein S, TFPI, and TAFI were measured. The relationships between serum thyroid hormones and these hemostatic parameters were examined. Compared with the control subjects, TAFI Ag levels were increased significantly in patients with hyperthyroidism [mean ± SD (ranges)] [177.03 ± 20.37 (131-206%) versus 145.9 ± 23.0 (89-169%)] (P < 0.001), whereas FV [89.8 ± 21.02 (49-124%) versus 116.1 ± 31.4 (56.4-200%)], protein C [72.8 ± 46.22 (2-149%) versus 144.0 ± 26.3 (74-158%)] and protein S [60.06 ± 42.82 (9-156%) versus 151 ± 33 (76-231%)] activities and TFPI Ag levels [69.56 ± 17.63 (39-140 ng/ml) versus 87.5 ± 15.9 (64-121 ng/ml)] were decreased significantly (P < 0.001 for all of them). We did not find a significant difference between Graves' disease and toxic nodular goiter for hemostatic parameters. In patients with Graves' disease, serum-free T₃ levels were inversely correlated with TFPI Ag levels (r: -0.57, P < 0.05). In conclusion, we found some important differences in the hemostatic parameters between the patients with hyperthyroidism and healthy controls. Increased TAFI and decreased FV, protein C, protein S, and TFPI in these patients represent a potential hypercoagulable and hypofibrinolytic state, which might augment the risk for atherosclerotic and atherothrombotic complications. Thus, disturbances of the hemostatic system may contribute to the excess mortality due to cardiovascular disease seen in patients with hyperthyroidism.

Increased plasminogen activator inhibitor-1, decreased tissue factor pathway inhibitor, and unchanged thrombin-activatable fibrinolysis inhibitor levels in patients with primary hyperparathyroidism

Primary hyperparathyroidism (PHPT) is associated with increased cardiovascular mortality and morbidity. Little is known about hemostatic features of patients with PHPT. To our knowledge, plasma tissue factor pathway inhibitor (TFPI) and thrombin-activatable fibrinolysis inhibitor (TAFI) levels in these patints have not been investigated. Therefore, the main purpose of this study was to evaluate the markers of endogenous coagulation/fibrinolysis, including TFPI and TAFI, and to investigate the relationships between serum calcium and PTH and these hemostatic parameters in patients with PHPT. Twenty-four patients with PHPT and 20 age-, sex-, and-weight-matched healthy controls were included in the study. Tissue plasminogen activator (t-PA), tissue plasminogen activator inhibitor-1 (PAI-1), TFPI, and TAFI were measured. The relationships between serum calcium, phosphorus, and PTH and these hemostatic parameters were examinated. Compared with the control subjects, t-PA, PAI-1, and PAI-1/t-PA ratios were significantly increased in patients with PHPT (P<0.0001), whereas TFPI levels were significantly decreased (P<0.0001). Plasma TAFI Ag levels did not significantly change in patients with PHPT compared with the controls. In patients with PHPT, serum phosphorus was negatively correlated with plasma PAI-1 Ag levels and PAI-1/t-PA ratio (r: -0.453, P<0.05; r: -0.580, P<0.01 respectively). There was a positive correlation between Cl/P ratio and plasma PAI-1 levels and PAI-1/t-PA ratio (r: 0.434, P<0.05; r: 0.528, P<0.05 respectively). iPTH was positively correlated with plasma PAI-1/t-PA ratio (r: 0.429, P<0.05). In conclusion, we found some important differences in the hemostatic parameters between the patients with PHPT and healthy controls. Increased PAI-1, PAI-1/t-PA ratios and decreased TFPI levels in these patients represent a potential hypercoagulable and hypofibrinolytic state, which might augment the risk for atherosclerotic and atherothrombotic complications. This condition may contribute to the excess mortality due to cardiovascular disease seen in patients with PHPT.

Blood coagulation and fibrinolysis in patients with Cushing’s syndrome: Increased plasminogen activator inhibitor-1, decreased tissue factor pathway inhibitor, and unchanged thrombin-activatable fibrinolysis inhibitor levels

Cushing's syndrome (CS) is associated with an increased cardiovascular mortality and morbidity. Chronic endogenous and exogenous hypercortisolism frequently induce a hypercoagulable and thrombotic condition. Little is known about hemostatic features of patients with CS. To our knowledge, plasma tissue factor pathway inhibitor (TFPI) and thrombin-activatable fibrinolysis inhibitor (TAFI) levels in these patients have not been investigated. Therefore, the main purpose of this study was to evaluate the markers of endogenous coagulation/fibrinolysis, including TFPI and TAFI, and to investigate the relationships between cortisol and these hemostatic parameters and serum lipid profile in patients with CS. Twenty-four patients with CS and 24 age-matched healthy controls were included in the study. Prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, factors V, VII, VIII, IX, and X activities, von Willebrand factor (vWF), antithrombin III (AT III), protein C, protein S, tissue plasminogen activator (t-PA), tissue plasminogen activator inhibitor-1 (PAI-1), TFPI and TAFI, as well as common lipid variables, were measured. The relationships between serum cortisol and these hemostatic parameters were examined. Compared with the control subjects, platelet count, PT, fibrinogen, AT-III and PAI-1 were significantly increased in patients with CS (p<0.05, p<0.0001, p<0.01, p<0.05, and p<0.0001, respectively), whereas aPTT and TFPI levels were significantly decreased (p<0.0001 and p<0.01, respectively). Plasma TAFI Ag levels did not significantly change in patients with CS compared with the controls. In patients with CS, we showed a negative correlation between serum cortisol: 08:00 h and aPTT (r:-0.469, p<0.05). Serum cortisol: 24:00 h was positively correlated with PAI-1 Ag levels (r: 0.479, p<0.05). In conclusion, we found some important differences in the hemostatic parameters between the patients with CS and healthy controls. Increased platelet count, fibrinogen, PAI-1, and decreased TFPI levels in these patients represent a potential hypercoagulable and hypofibrinolytic state, which might augment the risk for atherosclerotic and atherothrombotic complications. This condition may contribute to the excess of mortality due to cardiovascular disease seen in patients with CS.

Increased thrombin-activatable fibrinolysis inhibitor and decreased tissue factor pathway inhibitor in patients with hypothyroidism

Various abnormalities of coagulation-fibrinolytic system have been reported in patients with thyroid dysfunction. Several studies indicate that coagulation and fibrinolytic system is disturbed in the patients with hypothyroidism. Also, the influence of hypothyroidism on hemostasis is controversial; both hypocoagulable and hypercoagulable states have been reported. The levels of plasma thrombin-activatable fibrinolysis inhibitor (TAFI) antigen and tissue factor pathway inhibitor (TFPI) have been investigated only once in patients with hypothyroidism. Therefore, the main purpose of this study was to evaluate the profile of coagulation and fibrinolytic parameters including TAFI and TFPI in patients with hypothyroidism. Fifteen patients with untreated hypothyroidism and 15 age-matched healthy controls were included in the study. Factors V(FV), VII (FVII), VIII (FVIII) activities, von Willebrand factor (vWF), protein C, protein S, thrombomodulin (TM), TFPI, and TAFI were measured. The relationships between serum thyroid hormones and these hemostatic parameters were examined. Compared with the control subjects, FVII activity, and TM Ag and TAFI Ag levels were significantly increased in patients with hypothyroidism, whereas FV, FVIII, vWF, protein C and protein S activities, and TFPI Ag levels were significantly decreased. We did not find any significant correlation between serum thyroid hormones and the hemostatic parameters that we measured. In conclusion, we found some important differences in the hemostatic parameters between the patients with hypothyroidism and healthy controls. Increased FVII, TM, and TAFI and decreased FV, FVIII, vWF, protein C, protein S, and TFPI in these patients represent a potential hypercoagulable and hypofibrinolytic state, possible endothelial dysfunction, which might augment the risk for atherosclerotic and atherothrombotic complications. Thus, disturbances of the hemostatic system may contribute to the excess mortality due to cardiovascular disease seen in patients with hypothyroidism.

Blood coagulation and fibrinolysis in patients with acromegaly: increased plasminogen activator inhibitor-1 (PAI-1), decreased tissue factor pathway inhibitor (TFPI), and an inverse correlation between growth hormone and TFPI

Growth hormone/insulin-like growth factor-1(GH/IGF-1) hypersecretion may influence risk factors contributing to the increased cardiovascular morbidity and mortality associated with acromegaly However, so far little is known about the impact of GH/IGF-1 on coagulation and fibrinolysis in acromegalic patients as possible risk factors for cardiovascular disease (CVD). To our knowledge, plasma tissue factor pathway inhibitor (TFPI) and thrombin-activatable fibrinolysis inhibitor (TAFI) levels in these patients have not been investigated. Therefore, the main purpose of this study was to evaluate the markers of endogenous coagulation/fibrinolysis, including TFPI and TAFI, and to investigate the relationships between GH/IGF-1 and these hemostatic parameters and serum lipid profile in patients with acromegaly. A total of 22 patients with active acromegaly and 22 age-matched healthy controls were included in the study. Fibrinogen, factors V, VII, VIII, IX, and X activities, von-Willebrand factor (vWF), antithrombin III (AT III), protein C, protein S, tissue plasminogen activator (t-PA), tissue plasminogen activator inhibitor-I (PAI-1), TFPI and TAFI, as well as common lipid variables, were measured. The relationships between serum GH/IGF-1 and these hemostatic parameters were evaluated. Compared with the control subjects, fibrinogen, AT III, t-PA, and PAI-1 were increased significantly in patients with acromegaly (P < 0.0001, P < 0.05, P < 0.01, and P < 0.0001, respectively), whereas protein S activity and TFPI levels were decreased significantly (P < 0.05 and P < 0.01, respectively). Plasma TAFI Ag levels did not significantly change in patients with acromegaly compared with the controls. In patients with acromegaly, serum GH levels were inversely correlated with TFPI and apo AI levels (r: -0.514, P: 0.029 and r: -0.602, P: 0.014, respectively). There was also a negative correlation between insulin-like growth factor-1 (IGF-1) and PAI-1 (r: -0.455, P: 0.045). We found some important differences in the hemostatic parameters between the patients with acromegaly and healthy controls. Increased fibrinogen, t-PA, PAI-1 and decreased protein S and TFPI in acromegalic patients may represent a potential hypercoagulable and hypofibrinolytic state, which might augment the risk for atherosclerotic and atherothrombotic complications. Thus, disturbances of the hemostatic system and dyslipidemia may contribute to the excess mortality due to CVD seen in patients with acromegaly.

Sepsis-Induced Coagulation in the Baboon Lung Is Associated with Decreased Tissue Factor Pathway Inhibitor

Increased tissue factor (TF)-dependent procoagulant activity in sepsis may be partly due to decreased expression or function of tissue factor pathway inhibitor (TFPI). To test this hypothesis, baboons were infused with live Escherichia coli and sacrificed after 2, 8, or 24 hours. Confocal and electron microscopy revealed increased leukocyte infiltration and fibrin deposition in the intravascular and interstitial compartments. Large amounts of TF were detected by immunostaining in leukocytes and platelet-rich microthrombi. TF induction was documented by quantitative reverse transcriptase-polymerase chain reaction, enzyme-linked immunosorbent assay, and coagulation assays. Lung-associated TFPI antigen and mRNA decreased during sepsis, and TFPI activity diminished abruptly at 2 hours. Blocking antibodies against TFPI increased fibrin deposition in septic baboon lungs, suggesting that TF-dependent coagulation might be aggravated by reduced endothelial TFPI. Decreased TFPI activity coincided with the release of tissue plasminogen activator and the peak of plasmin generation, suggesting that TFPI could undergo proteolytic inactivation by plasmin. Enhanced plasmin produced in septic baboons by infusion of blocking antibodies against plasminogen activator inhibitor-1 led to decreased lung-associated TFPI and unforeseen massive fibrin deposition. We conclude that activation of TF-driven coagulation not adequately countered by TFPI may underlie the widespread thrombotic complications of sepsis.

Decreased Lung Cancer Survival With Hormone-Replacement Therapy: Caused by a Decreased Tissue Factor Pathway Inhibitor Level?

Decreased Lung Cancer Survival With Hormone-Replacement Therapy: Caused by a Decreased Tissue Factor Pathway Inhibitor Level?

Levels of Factor VIIc Associated With Decreased Tissue Factor Pathway Inhibitor and Increased Plasminogen Activator Inhibitor-1 in Dyslipidemias

Tissue factor pathway inhibitor (TFPI), a kunitztype inhibitor of the extrinsic coagulation pathway, factor VII coagulant (FVIIc), FVIIa, and the fibrinolytic factors plasminogen activator inhibitor-1 (PA1-1) and tissue plasminogen activator (TPA) have been studied in various hyperlipidemias. Compared with a normal lipidic group, mean TFPI activity was 70% higher (P < .001) and 36% higher (P < .001) in type IIa and IIb hyperlipidemias, respectively, and was lower by 13% in type IV hyperlipidemia (P = .05). TFPI was correlated with LDL cholesterol (P < .001), total cholesterol (P < .001), HDL cholesterol (P < .01), apolipoproteins (apo) AI (P < .001) and B (P < .001) and lipoprotein a (P < .01). TFPI was negatively correlated with the triglyceride level (P < .05); the correlation was dependent on LDL cholesterol and HDL cholesterol levels, which were decreased in type IV hyperlipidemia. FVIIc activity (P < .001) was increased by 30% in both type IV and type IIb hyperlipidemia and was correlated with triglyceride levels. FVIIa was not significantly increased in any group compared with control group. FVIIc was correlated with triglyceride level (P < .001), while FVIIa was not. Interestingly, FVIIa was correlated with FVIIc (r = .5, P < .001) in the control group as well as in the hyperlipidemic groups (r = .32, P < .01). These results favor the hypothesis that higher FVIIc concentrations in hyperlipidemic patients are likely due to enhancement of synthesis of FVII and that a part of this FVII circulates in an activated chemical form. Compared with the control group, PAI-1 activity was twofold higher (P < .08) in type IIa hyperlipidemia, threefold higher (P < .001) in type IIb hyperlipidemia, and fourfold higher in type IV hyperlipidemia (P < .001). PAI-1 activity correlated with triglyceride levels (P < .001), apoB levels (P < .001) and total cholesterol levels (P < .05). These correlations were dependent on apoB and probably reflect the correlation between PAI-1 and VLDL. In contrast, TPA level was normal in the different hyperlipidemias. No correlation was found between TFPI, FVIIc, and PAI-1. Variation of TFPI activity appears to be related to the variations of its main lipoprotein carriers: LDL, HDL, and Lp (a). The association in hypertriglycemic patients of hypercoagulability (increased FVIIc and decreased TFPI) and hypofibrinolysis (increased PAI-1) may explain thrombosis predisposition of some of these patients. However, it would be interesting to study the increased levels of endothelium-derived TFPI in plasma induced by the injection of heparin.