Platelet full length TFPI-α in healthy volunteers is not affected by sex or hormonal use

Winckers, Kristien; Thomassen, M. Christella L. G. D.; Cate, Hugo Ten; Hackeng, Tilman M.

doi:10.1371/journal.pone.0168273

Cited by 12 publications

(14 citation statements)

References 33 publications

(31 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Conversely, these therapies were associated with reduced plasma TFPIα and total TFPI, but did not influence platelet TFPIα, in agreement with the recent findings of Winckers and colleagues. 36 Finally, these therapies were associated with reduced platelet PS, but not plasma PS. The latter is somewhat surprising, given that others have reported decreased plasma total PS concentrations in response to exogenous estrogen therapy.…”

Section: | Discussionmentioning

confidence: 95%

Correlates of plasma and platelet tissue factor pathway inhibitor, factor V, and Protein S

Ellery

Hilden

Sejling

et al. 2018

Research and Practice in Thrombosis and Haemostasis

View full text Add to dashboard Cite

SummaryBackgroundPlasma Tissue Factor Pathway Inhibitor (TFPI) circulates bound to factor V (fV) and Protein S (PS). Estrogen therapy decreases plasma TFPI and PS. TFPI, fV, and PS circulate within platelets, and are released upon activation to modulate thrombus formation.ObjectiveIdentify factors affecting the concentrations of plasma and platelet TFPI, fV, and PS.MethodsBlood samples were obtained from 435 healthy individuals. Plasma total TFPI, TFPIɑ, fV, and PS, and platelet TFPI, fV, and PS were quantified. Correlations between these protein concentrations and age, gender, race, and estrogen use were established.ResultsIn males, only plasma fV increased with age, while in females, all plasma analytes increased with age. Males had higher plasma total TFPI, TFPIα, and PS than females. The platelet proteins in either sex remained relatively stable with increasing age. Platelet TFPI and PS were comparable in both sexes, while platelet fV was higher in females. Estrogen use was associated with decreased plasma total TFPI and TFPIα, and platelet PS, but not with platelet TFPI concentration. Racial differences in plasma and platelet proteins were observed, some of which were larger than inter-individual differences observed within racial groups. TFPI, fV and PS concentrations correlated in plasma, while only fV and PS correlated in platelets.ConclusionsPlasma and platelet TFPI, fV and PS differ in their: (i) in vivo association; (ii) demographic correlates; and (iii) alteration by estrogen therapies. Therefore, the plasma and platelet pools of these proteins may modulate hemostasis and thrombosis via different biochemical pathways.

show abstract

Section: | Discussionmentioning

confidence: 95%

Correlates of plasma and platelet tissue factor pathway inhibitor, factor V, and Protein S

Ellery

Hilden

Sejling

et al. 2018

Research and Practice in Thrombosis and Haemostasis

View full text Add to dashboard Cite

show abstract

“…Only 10 to 20% of plasma TFPI circulates as a free fulllength form and has previously been recognized as the active, and biologically more important, anticoagulant in vitro. [3][4][5] Free TFPI antigen levels correlate strongly with endothelial cell markers, whereas total TFPI antigen levels correlate more strongly with traditional cardiovascular risk factors (CVRFs). 6 Male sex, current smoking, diabetes mellitus, and increased low-density lipoprotein (LDL) have been proposed as positive determinants of total TFPI antigen levels, while treatment with hormone replacement therapy or oral contraceptives was strongly associated with lower total TFPI levels.…”

Section: Introductionmentioning

confidence: 99%

Relation between Tissue Factor Pathway Inhibitor Activity and Cardiovascular Risk Factors and Diseases in a Large Population Sample

et al. 2020

Self Cite

View full text Add to dashboard Cite

Objective Tissue factor pathway inhibitor (TFPI) is a potent anticoagulant protein in the extrinsic coagulation pathway. In the present study, we aim to identify the cardiovascular determinants for total TFPI activity and its association with cardiovascular disease (CVD) and total mortality. Methods Total TFPI activity was assessed in a selection of the population-based Gutenberg Health Study (n = 5,000). Statistical analysis was performed to identify the determinants for total TFPI activity as well as the associations with CVD and mortality. Results Multivariable linear regression analysis identified smoking (β 0.095 [0.054–0.136]) as a positive determinant for total TFPI activity, while diabetes (β –0.072 [–0.134 to –0.009]), obesity (β –0.063 [–0.101 to –0.024]), and history of coronary artery disease (CAD) were negatively associated with total TFPI activity, independent of age, sex, and the remaining cardiovascular risk factors. After adjustment for lipoprotein levels, the association between total TFPI activity levels and obesity and CAD was lost. The analysis additionally revealed a strong positive association between total TFPI activity levels and low-density lipoprotein (β 0.221 [0.204–0.237]). The Cox regression models revealed that a higher total TFPI activity, above 97.5th percentile of the reference group, was associated with an increased mortality risk (hazard ratio = 2.58 [95% confidence interval: 1.49–4.47]), independent of age, sex, and cardiovascular risk profile. Conclusion In the Gutenberg Health Study population-based cohort, the highest percentage of total TFPI correlated with an increased mortality risk. While elevated TFPI may reflect endothelial cell activation, the associations between total TFPI activity and obesity and CAD, points to additional mechanistic interactions.

show abstract

“…Because of its potent PS‐ and C‐terminal‐dependent inhibition of FXa, TFPIα plays the paramount anticoagulant role in in vitro assays of coagulation in human plasma. Compared with TFPIα, C‐terminal truncated forms of recombinant hTFPI and lipoprotein‐associated hTFPI containing only K1 and K2, like mouse lipoprotein‐associated TFPI, are poor inhibitors of FXa and their anticoagulant effect is difficult to detect in plasma coagulation assays, including standard thrombin generation assays . To demonstrate that the lipoprotein‐associated, C‐terminal truncated form of TFPI in mouse plasma possesses relevant anticoagulant activity, the in vitro thrombin generation assay was performed using plasma from mice with hemophilia (FVIIIKO), which reduces the dependence of the results on FXa inhibition.…”

Section: Resultsmentioning

confidence: 99%

Re‐evaluation of mouse tissue factor pathway inhibitor and comparison of mouse and human tissue factor pathway inhibitor physiology

Girard

Grunz

Lasky

et al. 2018

Journal of Thrombosis and Haemostasis

View full text Add to dashboard Cite

Essentials Mouse models are often used to define roles of tissue factor pathway inhibitor (TFPI) in man. TFPI isoform-specific KOs reveal unexpected differences between mouse and human TFPI physiology. Mouse plasma contains 20 times more TFPI than man, derived from TFPIγ, a form not found in man. TFPIγ null mice, expressing only TFPI isoforms α and β, may better reflect the human situation. SUMMARY: Background Mouse models can provide insight into the pathophysiology of human thrombosis and hemostasis. Tissue factor pathway inhibitor (TFPI) regulates coagulation through protein S (PS)-enhanced factor (F) Xa inhibition and FXa-dependent inhibition of FVIIa/tissue factor (TF) activity. TFPI is expressed as isoforms α and β in man, and α, β and γ in the mouse. Objective Assess the reliability of extending TFPI-related studies in mice to humans. Method Compare mouse and human TFPI physiology using a variety of methods. Results Mouse TFPI and human TFPI are similar in regard to: (i) the mechanisms for FVIIa/TF and FXa inhibition; (ii) TFPIα is a soluble form and TFPIβ is glycosyl phosphatidyl inositol (GPI) membrane anchored; (iii) the predominant circulating form of TFPI in plasma is lipoprotein-associated; (iv) low levels of TFPIα circulate in plasma and increase following heparin treatment; and (v) TFPIα is the isoform in platelets. They differ in that: (i) mouse TFPI circulates at a ~20-fold higher concentration; (ii) mouse lines with isolated isoform deletions show this circulating mouse TFPI is derived from TFPIγ; (iii) sequences homologous to the mouse TFPIγ exon are present in many species, including man, but in primates are unfavorable for splicing; and (iv) tandem mass spectrometry (MS/MS) detects sequences for TFPI isoforms α and β in human plasma and α and γ in mouse plasma. Conclusion To dissect the pathophysiological roles of human TFPIα and TFPIβ, studies in TFPIγ null mice, expressing only α and β, only α or only β should better reflect the human situation.

show abstract

Platelet full length TFPI-α in healthy volunteers is not affected by sex or hormonal use

Cited by 12 publications

References 33 publications

Correlates of plasma and platelet tissue factor pathway inhibitor, factor V, and Protein S

Correlates of plasma and platelet tissue factor pathway inhibitor, factor V, and Protein S

Relation between Tissue Factor Pathway Inhibitor Activity and Cardiovascular Risk Factors and Diseases in a Large Population Sample

Re‐evaluation of mouse tissue factor pathway inhibitor and comparison of mouse and human tissue factor pathway inhibitor physiology

Contact Info

Product

Resources

About