scholarly journals Role of Factor XIa and Plasma Kallikrein in Arterial and Venous Thrombosis

2020 ◽  
Vol 120 (06) ◽  
pp. 883-993 ◽  
Author(s):  
Mayken Visser ◽  
Stefan Heitmeier ◽  
Hugo ten Cate ◽  
Henri M. H. Spronk
Keyword(s):  
Venous Thrombosis ◽  
Animal Studies ◽  
Vascular Occlusion ◽  
Coagulation Factors ◽  
Human Studies ◽  
Plasma Kallikrein ◽  
Contact Activation ◽  
Charged Surfaces ◽  
Factor Xia ◽  
And Function

AbstractCardiovascular disease, including stroke, myocardial infarction, and venous thromboembolism, is one of the leading causes of morbidity and mortality worldwide. Excessive coagulation may cause vascular occlusion in arteries and veins eventually leading to thrombotic diseases. Studies in recent years suggest that coagulation factors are involved in these pathological mechanisms. Factors XIa (FXIa), XIIa (FXIIa), and plasma kallikrein (PKa) of the contact system of coagulation appear to contribute to thrombosis while playing a limited role in hemostasis. Contact activation is initiated upon autoactivation of FXII on negatively charged surfaces. FXIIa activates plasma prekallikrein (PK) to PKa, which in turn activates FXII and initiates the kallikrein–kinin pathway. FXI is also activated by FXIIa, leading to activation of FIX and finally to thrombin formation, which in turn activates FXI in an amplification loop. Animal studies have shown that arterial and venous thrombosis can be reduced by the inhibition of FXI(a) or PKa. Furthermore, data from human studies suggest that these enzymes may be valuable targets to reduce thrombosis risk. In this review, we discuss the structure and function of FXI(a) and PK(a), their involvement in the development of venous and arterial thrombosis in animal models and human studies, and current therapeutic strategies.

scholarly journals Identification of the factor XII contact activation site enables sensitive coagulation diagnostics

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Marco Heestermans ◽  
Clément Naudin ◽  
Reiner K. Mailer ◽  
Sandra Konrath ◽  
Kristin Klaetschke ◽  
...  
Keyword(s):  
Partial Thromboplastin Time ◽  
Thrombin Generation ◽  
Thrombus Formation ◽  
Coagulation Factors ◽  
Activated Partial Thromboplastin Time ◽  
Plasma Kallikrein ◽  
Factor Xii ◽  
Contact Activation ◽  
Intrinsic Pathway ◽  
Surface Binding

AbstractContact activation refers to the process of surface-induced activation of factor XII (FXII), which initiates blood coagulation and is captured by the activated partial thromboplastin time (aPTT) assay. Here, we show the mechanism and diagnostic implications of FXII contact activation. Screening of recombinant FXII mutants identified a continuous stretch of residues Gln317–Ser339 that was essential for FXII surface binding and activation, thrombin generation and coagulation. Peptides spanning these 23 residues competed with surface-induced FXII activation. Although FXII mutants lacking residues Gln317–Ser339 were susceptible to activation by plasmin and plasma kallikrein, they were ineffective in supporting arterial and venous thrombus formation in mice. Antibodies raised against the Gln317–Ser339 region induced FXII activation and triggered controllable contact activation in solution leading to thrombin generation by the intrinsic pathway of coagulation. The antibody-activated aPTT allows for standardization of particulate aPTT reagents and for sensitive monitoring of coagulation factors VIII, IX, XI.

The effects of antenatal glucocorticoid exposure on fetal and neonatal skin maturation

2017 ◽  
Vol 45 (8) ◽  
Author(s):  
Deanne August ◽  
Yogavijayan Kandasamy
Keyword(s):  
Animal Studies ◽  
Controlled Trial ◽  
Fetal Lung ◽  
Human Studies ◽  
Standard Clinical Practice ◽  
Antenatal Steroids ◽  
Improved Outcomes ◽  
Type Ii Pneumocytes ◽  
Neonatal Skin ◽  
And Function

AbstractAims:The use of antenatal glucocorticoids in women with preterm labor has dramatically improved outcomes for premature infants. The most commonly used antenatal glucocorticoids are betamethasone and dexamethasone. Glucocorticoids accelerate fetal lung growth by several mechanisms, including the maturation of type II pneumocytes enabling surfactant production. Furthermore, the lipids in the lung share similarity with those in the skin. Therefore, antenatal administration of glucocorticoids may have effects on the structure and function of the developing epidermal barrier in fetuses and neonates.Methods:We performed a systematic review to characterize these effects, identifying 11 studies (six animal and five human studies).Results:Five out of the six animal studies used a rodent model for investigating the effects of antenatally administered glucocorticoids, while the other used an ovine model. Antenatally administered glucocorticoids accelerated skin maturation in animal studies, but studies of human fetuses found conflicting results. None of the reviewed studies compared the effects of different types of glucocorticoids.Conclusions:More human studies are needed to fully understand the effects of antenatal steroids. However, as the antenatal use of glucocorticoids in preterm pregnancies has become part of standard clinical practice, it would be unethical to carry out a large randomized controlled trial. We may have to rely on animal models to improve our understanding of the effects of antenatal glucocorticoid exposure on the fetal and neonatal skin maturation.

APPLICATION OF SPECIFIC SERINE PROTEASE INHIBITORS IN ASSAYS FOR ACTIVATED CONTACT FACTORS.

1987 ◽  
Author(s):  
G Tans ◽  
T Janssen-Claessen ◽  
J Rosing ◽  
J H Griffin
Keyword(s):  
Serine Protease ◽  
Protease Inhibitors ◽  
Plasma Kallikrein ◽  
Serine Protease Inhibitors ◽  
Contact Activation ◽  
Amidolytic Activity ◽  
Efficient Inhibitor ◽  
Factor Xia ◽  
Substrate Conversion ◽  
The Individual

We developed amidolytic assays to determine human Factor Xlla, Factor XIa and plasma kallikrein in mixtures containing variable amounts of each enzyme. The commercially available chromogenic substrates pro-phe-arg-pNA (S2302 or chromozym PK), glu-pro-arg-pNA (S2366), ile-glu-(piperidyl)-gly-arg-pNA (S2337), and ile-glu-gly-arg-pNA (S2222) were tested for their suitability as substrates in these assays. 8-Factor Xlla, Factor XIa and plasma kallikrein each exhibit considerable activity towards a number of these substrates. This precludes direct quantitation of the individual enzymes when large amounts of other activated contact factors are present. Several serine protease inhibitors were tested on their ability to selectively inhibit those contact factors that may interfere with the factor tested for. Soybean trypsin inhibitor efficiently inhibits kallikrein, inhibits Factor XIa at moderate concentrations, but did not affect the amidolytic activity of Factor Xlla. Therefore, this inhibitor can be used to abolish a kallikrein and Factor XIa contribution in a Factor Xlla assay. We also report the rate constants of inhibition of contact activation factors by three different chloromethylketones. D-phe-pro-arg-CH 2 Cl was moderately active against contact factors (k - 2271 M-ls-1 at pH 8.3) but showed no differences in specif ity. D-phe-phe-arg-CH2 Cl was a very efficient inhibitor of kallikrein (k = 118,000 M-ls-1 at pH 8.3) whereas it slowly inhibited Factor Xlla (k = 1389 M-ls-1) and Factor XIa (k = 110 M-ls-1). Also dansyl-glu-gly-arg-CH2Cl was more reactive towards kallikrein (k 15,662 M-ls-1) than towards Factor Xlla (k = 462 M-ls-1) and Factor XIa (k = 63 M-ls-1). Since phe-phe-arg-CH2Cl is highly specific for kallikrein it can be used in a Factor XIa assay to selectively inhibit kallikrein. Based on the catalytic efficiencies of chromogenic substrate conversion and the inhibition characteristics of serine protease inhibitors and chloromethyl ketones we were able to develop quantitative assays for Factor Xlla, Factor XIa and kallikrein in mixtures of contact activation factors.

Mechanism, Functions, and Diagnostic Relevance of FXII Activation by Foreign Surfaces

2021 ◽  
Author(s):  
Sandra Konrath ◽  
Reiner K. Mailer ◽  
Thomas Renné
Keyword(s):  
Serine Protease ◽  
Current Knowledge ◽  
Experimental Models ◽  
Coagulation Cascade ◽  
Factor Xii ◽  
Bleeding Tendency ◽  
Contact Activation ◽  
Charged Surfaces ◽  
Coagulation Protein ◽  
And Function

AbstractFactor XII (FXII) is a serine protease zymogen produced by hepatocytes and secreted into plasma. The highly glycosylated coagulation protein consists of six domains and a proline-rich region that regulate activation and function. Activation of FXII results from a conformational change induced by binding (“contact”) with negatively charged surfaces. The activated serine protease FXIIa drives both the proinflammatory kallikrein–kinin pathway and the procoagulant intrinsic coagulation cascade, respectively. Deficiency in FXII is associated with a prolonged activated partial thromboplastin time (aPTT) but not with an increased bleeding tendency. However, genetic or pharmacological deficiency impairs both arterial and venous thrombosis in experimental models. This review summarizes current knowledge of FXII structure, mechanisms of FXII contact activation, and the importance of FXII for diagnostic coagulation testing and thrombosis.

scholarly journals Predictive Value for Increased Factor XIa and Plasma Kallikrein Activity in Acute Venous Thromboembolism

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 293-293
Author(s):  
Magdolna Nagy ◽  
Alejandro Pallares Robbles ◽  
Mayken Visser ◽  
Vincent Ten Cate ◽  
Thomas Knoeck ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Research Funding ◽  
Composite Endpoint ◽  
Coagulation Factors ◽  
Plasma Kallikrein ◽  
Plasma Samples ◽  
Limited Information ◽  
Contact Activation ◽  
Coagulation Activity ◽  
Recurrent Vte

Abstract Venous thromboembolism (VTE) is associated with increased coagulation activity, which in part can be attributed to the contact pathway of coagulation. Evidence from pre-clinical and epidemiological studies suggests that deficiency in factors of contact activation (e.g. coagulation factors (F) XI and FXII) protects against VTE. However, limited information exists regarding the activation of the contact system in the setting of acute VTE. In the current study, patients with confirmed VTE events (n=321) from the VTEval study and controls (n=300) from the population-based PREVENT-it pilot study were included. Plasma samples were collected from patients after confirmed VTE events or controls upon inclusion in the study. FXI as well as FXIa and plasma kallikrein (PKa) levels were assessed in plasma samples from all subjects using an activated thromboplastin time-based assay (FXI:c), a thrombin generation-based assay (CAT:FXIa) and by measuring inhibitory complexes (FXIa:antithrombin (AT), FXIa:alpha-1-antitrypsin (α1AT), FXIa:C1 esterase inhibitor (C1Inh) and PKa:C1Inh) using enzyme-linked immunoassay (ELISA). After a 2-year follow up period, a composite endpoint of recurrent VTE or death was determined. Increased FXI:c levels were determined in VTE patients compared to control individuals (124.08 ± 37.48% vs. 113.55 ± 27.99%), whereas CAT:FXIa levels were reduced in VTE patients (0 pM [IQR, 0-0.56] vs 0.56 pM [IQR, 0-0.88]). Levels of FXIa:α1AT and FXIa:AT inhibitory complexes were increased in VTE patients compared to controls (median[IQR]; 311.8 pM [238.2-424.0] vs. 202.5 pM [143.7 - 287.5] and 29.1 pM [23.4-38.3] vs 23.2 pM [19.7-29.8], respectively). Considering that 86% of the VTE patients were already on anticoagulant treatment (Table 1), investigation of their possible effect on the biomarkers revealed that only the CAT:FXIa was influenced by the presence of anticoagulants. Logistic regression models revealed a good discriminatory value for FXI:c and FXIa:α1AT (AUC=0.64 [0.6/0.69] and AUC=0.67 [0.62/0.71], respectively) to distinguish VTE from controls, whereas the other biomarkers were not able to distinguish between groups. The outcome recurrent VTE or death could be predicted by the inhibitory complexes, but not by the FXI(a) levels (Figure 1). Only the FXIa:α1AT complexes were able to both detect the presence of VTE (OR per SD [95%CI]: 1.28 [1.01-1.63], p=0.04) and predict recurrent VTE or death (HR per SD [95%CI]: 1.40 [1.2-1.62], p<0.0001). In summary, acute VTE is associated with both elevated FXI:c levels and increased activation of FXI and plasma prekallikrein, the latter specifically indicating contact activation. The generation of FXIa during acute VTE and its association with recurrent VTE suggests an important risk contribution of FXI activation. This study has added evidence favouring the utility of FXIa inhibition in the setting of acute VTE. Figure 1 Figure 1. Disclosures Knoeck: Bayer AG: Consultancy. ten Cate: Bayer AG: Other; Pfizer: Other; LEO Pharma: Other; Gideon Pharmaceuticals: Other; Alveron Pharma: Other. Wild: Bayer AG: Other, Research Funding; Boehringer Ingelheim: Other, Research Funding; Novartis Pharma: Other, Research Funding; Sanofi-Aventis: Other, Research Funding; Astra Zeneca: Other, Research Funding; Daiichi Sankyo Europe: Other, Research Funding.

Role of the 807 C/T Polymorphism of the α2 Gene in Platelet GP Ia Collagen Receptor Expression and Function

1999 ◽  
Vol 81 (06) ◽  
pp. 951-956 ◽  
Author(s):  
J. Corral ◽  
R. González-Conejero ◽  
J. Rivera ◽  
F. Ortuño ◽  
P. Aparicio ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Cell Types ◽  
Receptor Expression ◽  
Case Control Studies ◽  
Platelet Surface ◽  
Vitro Analysis ◽  
And Function ◽  
In Vitro Analysis

SummaryThe variability of the platelet GP Ia/IIa density has been associated with the 807 C/T polymorphism (Phe 224) of the GP Ia gene in American Caucasian population. We have investigated the genotype and allelic frequencies of this polymorphism in Spanish Caucasians. The T allele was found in 35% of the 284 blood donors analyzed. We confirmed in 159 healthy subjects a significant association between the 807 C/T polymorphism and the platelet GP Ia density. The T allele correlated with high number of GP Ia molecules on platelet surface. In addition, we observed a similar association of this polymorphism with the expression of this protein in other blood cell types. The platelet responsiveness to collagen was determined by “in vitro” analysis of the platelet activation and aggregation response. We found no significant differences in these functional platelet parameters according to the 807 C/T genotype. Finally, results from 3 case/control studies involving 302 consecutive patients (101 with coronary heart disease, 104 with cerebrovascular disease and 97 with deep venous thrombosis) determined that the 807 C/T polymorphism of the GP Ia gene does not represent a risk factor for arterial or venous thrombosis.

Amidolytic Detection of Prothrombin Activation Products after SDS-Gel Electrophoresis

1989 ◽  
Vol 61 (03) ◽  
pp. 386-391 ◽  
Author(s):  
Guido Tans ◽  
Truus Janssen-Claessen ◽  
Jan Rosing
Keyword(s):  
Gel Electrophoresis ◽  
Activated Protein C ◽  
Factor Xa ◽  
Coagulation Factors ◽  
Product Formation ◽  
Chromogenic Substrate ◽  
Nitrocellulose Membrane ◽  
Activation Products ◽  
Factor Xia ◽  
Prothrombin Activation

SummaryIn this paper we report a method via which enzymatically active products formed during prothrombin activation can be detected by simple photographic means after SDS-gel electrophoresis, blotting onto a nitrocellulose membrane and visualization with the chromogenic substrate, S2238. After amidolytic detection the same nitrocellulose membrane can also be used for immunologic detection of prothrombin activation products, thus allowing a complete description of product formation during prothrombin activation.The detection limit of the so-called “amidoblot” is approximately 3 ng thrombin per gel sample which is comparable to the sensitivity of immunoblotting.It is further shown that the amidoblot technique can also be applied to other coagulation factors for which a suitable chromogenic substrate is available (factor XIIa, kallikrein, factor XIa, factor Xa, plasmin and activated protein C).

Cold Promoted Activation of Factor VII VI. Effect of Inhibitors

1973 ◽  
Vol 29 (03) ◽  
pp. 633-643
Author(s):  
H Gjønnæss
Keyword(s):  
Soya Bean ◽  
Factor Vii ◽  
Plasma Kallikrein ◽  
Contact Activation ◽  
Activation Reaction ◽  
Hexadimethrine Bromide ◽  
Bean Trypsin Inhibitor ◽  
Plasma Arginine ◽  
Kallikrein Activity ◽  
Effect Of Inhibitors

SummaryThe cold promoted activation of factor VII occurs in parallel with an activation of a plasma arginine esterase, and, on inhibition of the cold activation of factor VII, the esterase activation also decreased. The inhibitor pattern supported our theory that the arginine esterase that is activated in the cold activation of factor VII is plasma kallikrein.The cold activation of factor VII was completely inhibited with soya bean trypsin inhibitor in doses that did not interfere with the contact activation. On the other hand, inhibition of the contact activation with hexadimethrine bromide did not interfere with the cold activation of factor VII except when this was kaolin induced. Contact and cold activation therefore appear to represent two different pathways for the activation of factor VII. The cold activation reaction is probably mediated by the activation of plasma prekallikrein, and inhibition of the plasma kallikrein activity correlates with the inhibition of the cold promoted activation of factor VII.

The Levels of the Plasma Coagulation Factors in the Post-Operative Period

1963 ◽  
Vol 10 (01) ◽  
pp. 081-087 ◽  
Author(s):  
E Davidson ◽  
S Tomlin
Keyword(s):  
Venous Thrombosis ◽  
Coagulation Factors ◽  
Plasma Coagulation ◽  
Factor I ◽  
Post Operative Period

SummaryIn the post-operative period the levels of factor I, VII—X, VIII, IX and X as well as the platelets are increased. In the immediate post-operative period there is a decrease in the levels of factors II and XI. The significance of these changes in relation to venous thrombosis is discussed.

Protective Effect of Isothiocyanates from Cruciferous Vegetables on Breast Cancer: Epidemiological and Preclinical Perspectives

2020 ◽  
Vol 20 ◽  
Author(s):  
Suong N.T. Ngo ◽  
Desmond B. Williams
Keyword(s):  
Breast Cancer ◽  
Protective Effect ◽  
Animal Studies ◽  
Cancer Survival ◽  
Breast Cancer Survival ◽  
Human Studies ◽  
In Vitro Studies ◽  
Cochrane Library ◽  
Cruciferous Vegetables

Background: The effect of cruciferous vegetable intake on breast cancer survival is controversial at present. Glucosinolates are the naturally occurring constituents found across the cruciferous vegetables. Isothiocyanates are produced from the hydrolysis of glucosinolates and this reaction is catalysed by the plant-derived enzyme myrosinase. The main isothiocyanates (ITCs) from cruciferous vegetables are sulforaphane, benzyl ITC, and phenethyl ITC, which had been intensively investigated over the last decade for their antibreast cancer effects. Objective: The aim of this article is to systematically review the evidence from all types of studies, which examined the protective effect of cruciferous vegetables and/or their isothiocyanate constituents on breast cancer. Methods: A systematic review was conducted in Pubmed, EMBASE, and the Cochrane Library from inception to 27 April 2020. Peerreviewed studies of all types (in vitro studies, animal studies, and human studies) were selected. Results: The systematic literature search identified 16 human studies, 4 animal studies, and 65 in vitro studies. The effect of cruciferous vegetables and/or their ITCs intake on breast cancer survival was found to be controversial and varied greatly across human studies. Most of these trials were observational studies conducted in specific regions, mainly in the US and China. Substantial evidence from in vitro and animal studies was obtained, which strongly supported the protective effect of sulforaphane and other ITCs against breast cancer. Evidence from in vitro studies showed sulforaphane and other ITCs reduced cancer cell viability and proliferation via multiple mechanisms and pathways. Isothiocyanates inhibited cell cycle, angiogenesis and epithelial mesenchymal transition, as well as induced apoptosis and altered the expression of phase II carcinogen detoxifying enzymes. These are the essential pathways which promote the growth and metastasis of breast cancer. Noticeably, benzyl ITC showed a significant inhibitory effect on breast cancer stem cells, a new dimension of chemoresistance in breast cancer treatment. Sulforaphane and other ITCs displayed anti-breast cancer effects at variable range of concentrations and benzyl isothiocyanate appeared to have a relatively smallest inhibitory concentration IC50. The mechanisms underlying the cancer protective effect of sulforaphane and other ITCs have also been highlighted in this article. Conclusion: Current preclinical evidence strongly supports the role of sulforaphane and other ITCs as potential therapeutic agents for breast cancer, either as adjunct therapy or combined therapy with current anti-breast cancer drugs, with sulforaphane appeared to display the greatest potential.

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