Low levels of tissue factor pathway inhibitor (TFPI) increase the risk of venous thrombosis

Dahm, Anders Erik Astrup; Vlieg, Astrid van Hylckama; Bendz, Bjørn; Rosendaal, Frits R.; Bertina, Rogier M.; Sandset, Per Morten

doi:10.1182/blood-2002-10-3188

Cited by 226 publications

(225 citation statements)

References 44 publications

(41 reference statements)

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“…Mean f-TFPI and sTM did not differ significantly between cases and controls irrespective of the type of event. Because it was recently shown that f-TFPI levels below the 10th percentile were a risk factor for venous thrombosis, 17 supporting a threshold effect, we performed a similar analysis in the present study. Of the individuals with hard CHD, 13.3% presented values below the cutoff, compared with 8.3% of the controls (Pϭ0.07).…”

Section: Resultsmentioning

confidence: 91%

“…Quartiles were used for vWF, f-TFPI, and sTM, whereas f-TFPI was also categorized according to the 10th percentile of the distribution in controls, as previously suggested. 17 A conditional regression analysis suitable for a nested case-control design was performed to identify discriminating predictive parameters. The same analysis was used to determine the relative risk of future CHD events after control for different sets of variables: (1) body mass index (BMI), total cholesterol, HDL cholesterol, systolic blood pressure, smoking, alcohol, and diabetes; (2) further adjustment for CRP, TNF-␣, IL-6, and fibrinogen.…”

Section: Discussionmentioning

confidence: 99%

“…16 Very recently, a case-control study indicated that low levels of f-TFPI were a risk factor for deep vein thrombosis. 17 Interestingly, mean TFPI levels were not lower in patients with deep vein thrombosis, but f-TFPI levels below the 10th percentile proved to be a risk factor. This finding supported the hypothesis of a threshold effect in which low levels of TFPI increased the risk of thrombosis.…”

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confidence: 94%

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Endothelial Cell Markers and the Risk of Coronary Heart Disease

et al. 2004

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on behalf of the PRIME Study Group Background-Tissue factor pathway inhibitor (TFPI), von Willebrand factor (vWF), and thrombomodulin (TM) are 3 major hemostatic regulatory molecules synthesized by endothelium. Data from epidemiological studies aiming 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 infarction (hard CHD) and stable or unstable angina (angina pectoris) in a prospective cohort (the PRIME Study) of nearly 10 000 healthy men recruited in France and Northern Ireland. 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.

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Section: Resultsmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

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confidence: 94%

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Endothelial Cell Markers and the Risk of Coronary Heart Disease

et al. 2004

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“…15 It has been demonstrated that short-term PM exposure significantly decreased plasma TFPI level. 51 Decreased circulating TFPI levels have been linked to venous thrombosis 52 ; however, lung TFPI expression and regulation by Sirt1 after PM exposure have not been investigated. In this study, we demonstrated that lung TFPI expression was decreased after PM exposure, and Sirt1 deletion resulted in further reduction of TFPI levels in the lung, suggesting that Sirt1 could control coagulation responses by regulating TFPI expression.…”

Section: Sirt1 Controls Lung Inflammation and Coagulation 2427mentioning

confidence: 99%

Sirt1 protects against thrombomodulin down-regulation and lung coagulation after particulate matter exposure

Liu

Liang

et al. 2012

Blood

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Exposure to ambient particulate matter (PM) air pollution has been reported to trigger inflammation and thrombosis. However, molecular mechanisms underlying the modulation of coagulation pathways in PM-induced thrombosis remain largely unknown. We report here that Sirt1, a member of class III histone deacetylase, controls lung inflammation and coagulation after PM exposure. Sirt1 knock-out mice exhibited aggravated lung vascular leakage and inflammation after PM exposure, which was correlated with increased NF-B acetylation and activation. Furthermore, Sirt1 knock-out mice were highly susceptible to PM-induced lung coagulation as demonstrated by increased fibrin formation. The increased fibrin formation was associated with reduced tissue factor pathway inhibitor (TFPI) expression and increased plasminogen activator inhibitor-1 (PAI-1) activity in the lungs, thus favoring elevated coagulation and disrupted fibrinolysis responses. Thrombomodulin (TM), a central player of the anticoagulant protein C system, is regulated by Kruppel-like factor 2 (KLF2) at the transcriptional level. IntroductionExposure to ambient particulate matter (PM) air pollution has been associated with impaired pulmonary function and increased cardiovascular disease-related mortality including inflammation and thrombosis. 1-5 Acute exposure to increased ambient fine particulate matter Ͻ 2.5 m in diameter (PM 2.5 ) was estimated to cause the premature deaths of tens of thousands of people each year in the United States. 6 Urban particulate matter (UPM) PM 2.5, one of the major air pollutants closely monitored by the US Environmental Protection Agency (EPA), is a complex mixture of substances that are directly emitted into the air from dust, soot, smoke, and combustion. 6 To protect public health, the EPA issued the current 24-hour PM 2.5 standard at 35 g/m 3 . 6 Despite the enormous health problems caused by PM 2.5 exposure, there have been few studies performed to explore the molecular mechanisms of PM 2.5 -induced lung vascular dysfunction. PM 2.5 can reach deep in the lung to the small airway and alveoli, 6 and directly cause lung inflammation and injury. [7][8][9][10][11][12][13] The pulmonary complications may lead to detrimental effects on other organs, particularly cardiovascular dysfunction such as systemic microvascular dysfunction and thrombosis. 1,2,4,5,13 A recent study demonstrated that short-term UPM exposure triggered the activation of primary hemostasis in healthy mice, with no substantial secondary hemostasis activation, leading to arterial but not venous thrombosis. 5 Whereas another study showed that short-term UPM exposure may cause activation of coagulation responses and fibrin formation in the lung. 14 Tissue factor pathway inhibitor (TFPI) and plasminogen activator inhibitor-1 (PAI-1) play important roles in coagulation and fibrinolysis cascades, respectively. TFPI is an inhibitor of tissue factor (TF)-mediated coagulation responses. 15 PAI-1, on the other hand, is a major regulator of fibrinolysis, which functions by in...

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“…1 It circulates in plasma at a concentration of ;1.6 nM. 2,3 The majority (;80%) of plasma TFPI is truncated and bound to lipoproteins, ;5% is localized in storage granules within platelets, ;5% circulates as free truncated variants, and only around 10% is considered to be free full-length TFPI, 4 with this having the greatest anticoagulant activity. [5][6][7] TFPI and its cofactor protein S downregulate tissue factor (TF)-induced thrombin generation, and a deficiency of either protein has been linked to an increased risk of venous thrombosis.…”

Section: Introductionmentioning

confidence: 99%

TFPI cofactor function of protein S: essential role of the protein S SHBG-like domain

Reglińska-Matveyev

Andersson

Rezende

et al. 2014

Blood

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Key Points• The protein S SHBG-like domain and, more specifically, its LG1 subunit are important for binding and enhancement of TFPI.• TFPI binding to the protein S SHBG-like domain likely positions TFPI Kunitz domain 2 for optimal interaction with the active site of FXa.Protein S is a cofactor for tissue factor pathway inhibitor (TFPI), accelerating the inhibition of activated factor X (FXa). TFPI Kunitz domain 3 residue Glu226 is essential for enhancement of TFPI by protein S. To investigate the complementary functional interaction site on protein S, we screened 44 protein S point, composite or domain swap variants spanning the whole protein S molecule for their TFPI cofactor function using a thrombin generation assay. Of these variants, two protein S/growth arrestspecific 6 chimeras, with either the whole sex hormone-binding globulin (SHBG)-like domain (Val243-Ser635; chimera III) or the SHBG laminin G-type 1 subunit (Ser283-Val459; chimera I), respectively, substituted by the corresponding domain in growth arrest-specific 6, were unable to enhance TFPI. The importance of the protein S SHBG-like domain (and its laminin G-type 1 subunit) for binding and enhancement of TFPI was confirmed in FXa inhibition assays and using surface plasmon resonance. In addition, protein S bound to C4b binding protein showed greatly reduced enhancement of TFPI-mediated inhibition of FXa compared with free protein S. We show that binding of TFPI to the protein S SHBG-like domain enables TFPI to interact optimally with FXa on a phospholipid membrane. (Blood. 2014;123(25):3979-3987) IntroductionTissue factor pathway inhibitor (TFPI) is a ;41 kDa Kunitz-type protease inhibitor that consists of an acidic amino-terminal polypeptide, followed by 3 tandem Kunitz-type domains (Kunitz domains 1, 2, and 3) and a basic carboxy (C)-terminal tail. 1 It circulates in plasma at a concentration of ;1.6 nM. 2,3 The majority (;80%) of plasma TFPI is truncated and bound to lipoproteins, ;5% is localized in storage granules within platelets, ;5% circulates as free truncated variants, and only around 10% is considered to be free full-length TFPI, 4 with this having the greatest anticoagulant activity. [5][6][7] TFPI and its cofactor protein S downregulate tissue factor (TF)-induced thrombin generation, and a deficiency of either protein has been linked to an increased risk of venous thrombosis. [8][9][10] TFPI specifically inhibits the initiation of coagulation through direct binding and inhibition of factor Xa (FXa) and, in a FXa-dependent manner, inhibition of the TF/factor VIIa (FVIIa) complex by forming a quarternary TF/FVIIa/FXa/TFPI complex. 11,12 The P1 residue in the Kunitz domain 2 of TFPI is required for binding to FXa, whereas the P1 residue in Kunitz domain 1 is required for binding and inhibition of TF/FVIIa. 13 The kinetic mechanism of FXa inhibition by TFPI is described as a 2-step process where TFPI first forms an immediate encounter complex with FXa (FXa/TFPI), followed by a slow isomerization into a final tight complex (FXa/TFPI*...

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Low levels of tissue factor pathway inhibitor (TFPI) increase the risk of venous thrombosis

Cited by 226 publications

References 44 publications

Endothelial Cell Markers and the Risk of Coronary Heart Disease

Endothelial Cell Markers and the Risk of Coronary Heart Disease

Sirt1 protects against thrombomodulin down-regulation and lung coagulation after particulate matter exposure

TFPI cofactor function of protein S: essential role of the protein S SHBG-like domain

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