***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Tissue factor pathway inhibitor ( TFPI ) regulates factor X activation . Low TFPI is a risk factor for a first venous thrombosis . We evaluated whether low TFPI confers an increased risk of recurrent venous thromboembolism ( VTE ) . TFPI-free antigen  was measured in 611 patients with a first spontaneous VTE , and who were prospect ively followed after withdrawal of anticoagulation .  The endpoint was symptomatic recurrent VTE . The relative risk ( RR ) of recurrence increased from 1.0 ( 95 % CI 0.4 - 2.6 ) in patients with TFPI levels < or = 5th percentile to 2.7 ( 95 % CI 1.0 - 7.4 ) in patients with levels < or = 2nd percentile as compared with higher levels . At five years , the probability of recurrence was 48.6 % ( 95th CI 19.0 - 78.1 ) among patients with TFPI < or = 2nd percentile and 16.8 % ( 95th CI 13.8 - 19.8 ) among those with higher levels ( p=0.04 ) . Compared to patients with wild type factor V and high TFPI , the RR of recurrence was 1.1 ( 95 % CI 0.7 - 1.7 ) in patients with factor V Leiden and high TFPI , 2.3 ( 95 % CI 0.6 - 9.5 ) in patients with wild type factor V and low TFPI and 3.5 ( 95 % CI 0.9 - 14.3 ) in patients with factor V Leiden and low TFPI . In a multivariate analysis , the high risk of recurrence in carriers of factor V Leiden and low TFPI slightly decreased [ RR 2.8 ( 95 % CI 0.6 - 9.5 ) ] . We conclude that thrombosis patients with low levels of free TFPI are at an increased risk of recurrent VTE Background —Tissue factor pathway inhibitor ( TFPI ) , von Willebr and factor ( vWF ) , and thrombomodulin ( TM ) are 3 major hemostatic regulatory molecules synthesized by endothelium . Data from epidemiological studies aim ing to evaluate the relation between plasma levels of these molecules and the development of coronary heart disease ( CHD ) are sparse or contradictory . Methods and Results —We examined the association between these endothelial-cell markers and the incidence of  fatal or nonfatal myocardial infa rct ion ( hard CHD ) and stable or unstable angina ( angina pectoris ) in a prospect i ve cohort ( the PRIME Study ) of nearly 10 000 healthy men recruited in France and Northern Irel and . We measured baseline plasma concentration of the free form of TFPI ( f-TFPI ) , vWF , and the soluble form of TM ( sTM )  among 296 participants who subsequently developed CHD over the 5-year follow-up ( 158 with hard CHD and 142 with angina pectoris ) and in 563 control subjects by use of a nested case-control design . Individuals with plasma vWF levels in the highest quartile showed a 3.04-fold increase in the risk of hard CHD compared with those in the lowest quartile ( 95 % CI , 1.59 to 5.80 ) . Individuals with f-TFPI levels below the 10th percentile had a 2.13-fold increased risk of hard CHD compared with those with levels above it ( 95 % CI , 1.08 to 4.18 ) . The risk for both molecules persisted after control for inflammatory parameters . Individuals with vWF levels in the highest quartile and f-TFPI levels below the 10th percentile presented a 6.9-fold increased risk of hard CHD compared with those with vWF levels in the lowest quartile and f-TFPI levels above the 10th percentile ( 95 % CI , 1.3 to 37.8 ) . Conclusions —vWF and f-TFPI  plasma levels were independent risk factors for hard CHD events BACKGROUND Tissue factor ( TF ) and its specific inhibitor , tissue factor pathway inhibitor ( TFPI ) , are important contributors to the initiation of the coagulation process . OBJECTIVES To compare plasma levels of  soluble TF ( sTF )  and  free-TFPI ( f-TFPI ) between patients with stable angina pectoris ( SAP ) and acute coronary syndrome ( ACS ) and to assess the impact of the two variables on long-term prognosis . PATIENTS / METHODS Patients with SAPs ( n = 1146 ) and acute coronary syndrome ( n = 523 ) from the AtheroGene study were included and followed for 2.3 years . Because of the strong impact of unfractionated heparin ( UFH ) on f-TFPI levels , but not on sTF levels , patients having received UFH before blood drawing were excluded from the analyses on f-TFPI ( n = 226 ) . RESULTS On admission , no significant differences in sTF levels were observed between SAP and ACS patients . By comparison to patients with stable angina , f-TFPI levels significantly increased in patients with acute unstable angina and further increased in patients presenting with non-ST-elevation myocardial infa rct ion and ST-elevation myocardial infa rct ion ( P < 10(-4 ) ) . Among the 1669 individuals with a coronary artery disease , 56 died from a cardiovascular cause . In prospect i ve analyses , high sTF levels were independently associated with an increased risk of cardiovascular death in individuals with ACS ( fully adjusted hazard ratio associated with one quartile increase = 2.06 ; 95 % confidence interval 1.24 - 3.45 ; P = 0.006 ) but not in those with SAP ( hazard ratio = 1.07 ; 95 % confidence interval 0.78 - 1.46 ; P = 0.67 ) . In SAP and ACS patients , high f-TFPI levels were not independently associated with an increased risk of cardiovascular death . CONCLUSIONS Plasma sTF levels were predictive of cardiovascular mortality in individuals with ACS , whereas f-TFPI levels were associated with the severity of myocardial damage on admission but were not independently related to outcome It was recently reported from the Women 's Health Initiative that healthy women using combined hormone replacement therapy ( HRT ) for 5 years have an increased cardiovascular risk . We hypothesize that the increased risk is confined to subgroups of atherosclerotic women . Such women may have higher arterial tissue factor expression and higher thrombin formation , and changes in tissue factor pathway coagulation inhibitor ( TFPI ) and thrombin activatable fibrinolysis inhibitor ( TAFI ) may be deleterious . Healthy postmenopausal women ( n = 719 ) were r and omized to  hormone therapy [ n = 357 ; opposed ( n = 290 ) and unopposed ( n = 67 ) ] or no treatment ( n = 362 ) . Plasma TFPI and TAFI and the TFPI -287T/C and TAFI -438G/A polymorphisms were measured 5 - 6 years after r and omization . Concentrations of TFPI were significantly lower in the hormone group than in the control group ( P < 0.001 ) and in all genotypes of the TFPI polymorphism . Overall , concentrations of TAFI did not differ between the two groups but were reduced by hormone therapy in homozygotes for the rare TAFI -438 A allele ( P < 0.05 ) . The hormone effects on TFPI and TAFI were similar in smokers and non-smokers and in women using unopposed and opposed therapy . The observed decrease in TFPI may contribute to the increased cardiovascular risk associated with HRT Free-TFPI  ( f-TFPI ) presents high anticoagulant activity and its plasma level correlates with unfavorable outcomes in unstable angina .  Total TFPI ( t-TFPI ) represents mainly the lipid-bound form which seems to have a poor anticoagulant activity . Until now , it is not known whether the variations of  f-TFPI plasma levels are determined by environmental factors . The aim of our study was to evaluate the influence of cardiovascular risk factors on plasma levels of  f-TFPI  and relations with other endothelial derived molecules in a population of 626 patients ( 277 men and 349 women ) attending a metabolic ward for primary prevention of coronary disease .  Free and total TFPI plasma levels were poorly correlated .  f-TFPI levels increased with age in both sexes , t-TFPI in women only . Age-adjusted correlations of TFPI levels with conventional cardiovascular risk factors and endothelial cell markers showed different patterns for  f-TFPI  and t-TFPI . f-TFPI correlated with parameters associated with insulin resistance , particularly in females . f-TFPI was also positively associated in both genders with fibrinogen and endothelial cell markers : t-PA , thrombomodulin ( TM ) and von Willebr and factor ( vWF ) . t-TFPI correlated strongly with LDL-C in both sexes . It also correlated negatively with parameters of the insulin resistance syndrome . t-TFPI also correlated with TM but not with other endothelial cell markers . The results of the multivariate step by step analysis showed that cardiovascular risk factors poorly explained the f-TFPI variability ( 7 % and 4 % in men and women , respectively ) , whereas they explained 16 and 20 % of t-TFPI variability in men and women respectively ( mostly related to LDL-C ) . In conclusion , this study showed that free- and total-TFPI are regulated differently . f-TFPI strongly correlates with endothelial cell markers and t-TFPI is more related to conventional cardiovascular risk factors . The strong gender effect on f-TFPI levels remains to be explained The present study aim ed to determine whether four previously described polymorphisms found within the tissue factor pathway inhibitor ( TFPI ) gene are associated with free plasma TFPI levels or with TFPI activity as well as the risk of ischaemic stroke in stroke patients and control individuals . We conducted a case – control study of 162 first-ever ischaemic stroke cases and 170 r and omly selected community control individuals . The TFPI genotype was determined for the T-287C , C-399 T , Intron 7 C-33 T , and Val264Met ( G874A ) polymorphisms . Free plasma TFPI and TFPI activity were measured during the first 7 days and 3–6 months after the acute stroke event . Free plasma TFPI levels were significantly lowered 3–6 months after stroke compared with levels observed in the patient group during the acute phase of the stroke ( mean , 16.3 versus 22.46 ng/ml ; P = 0.046 ) and among the control group ( mean , 16.3 versus 22.79 ng/ml ; P < 0.0001 ) . Conversely , TFPI activity was significantly up-regulated during the acute phase ( mean , 1.30 versus 1.11 U/ml ; P = 0.0051 ) and remained elevated 3–6 months later ( mean , 1.28 versus 1.11 U/ml ; P = 0.03 ) . The TFPI gene polymorphisms studied were not significantly associated with TFPI levels or activity , nor with the risk of ischaemic stroke . In conclusion , the TFPI activity and concentration in plasma varied significantly after an ischaemic stroke ; however , these variations were not found to be due to the presence of any of the genetic mutations analysed in this study . Our results are consistent with the emerging model suggesting the lipoprotein-bound portion of TFPI has a significant influence on coagulation and diseases of haemostasis 
    Output:
    
Nonetheless , our review found robust evidence that rs5940 and rs7586970 moderate TFPI plasma levels and are c and i date risk factors for thrombosis , and that the regulation of TFPI plasma levels involves genetic factors beyond the TFPI gene