The association of alcohol with circulating total fibrinogen and plasma clot density is mediated by fibrinogen and FXIII genotypes

Abstract Background Alcohol consumption is associated with haemostasis and so may influence cardiovascular conditions. It is unknown whether the association of alcohol with total and γ’ fibrinogen concentrations, as well as clot structure, are modulated by fibrinogen and factor (F) XIII single nucleotide polymorphisms (SNPs). Methods Total fibrinogen, γ’ fibrinogen and clot properties of 2010 healthy Africans residing in South Africa were measured in relation to alcohol intake as well as its markers – gamma-glutamyltransferase (GGT), percentage carbohydrate deficient transferrin (%CDT), aspartate aminotransferase (AST), and alanine aminotransferase (ALT). Fourteen fibrinogen and two SNPs in the FXIII gene were genotyped to determine their influence. Results Alcohol intake and its markers correlated negatively with fibrinogen and clot lysis time (CLT) as well as with most of the clot properties. Percentage γ’ fibrinogen correlated positively with AST and negatively with alcohol intake. We then stratified for alcohol intake and found inverse associations between γ’ fibrinogen and both %CDT and GGT–CDT in consumers, but the positive association with AST remained only in abstainers. Alcohol intake and its markers modulated the influence of fibrinogen SNPs on total fibrinogen concentrations and the fibrinogen SNPs as well as an FXIII SNP on clot density (all p < 0.004). Conclusion/s We show for the first time that some individuals harbour certain genotypes that, in combination with alcohol consumption, might predispose or protect them from haemostatic factors that might lead to the development of cardiovascular disease. Studies are needed to clarify the mechanisms related to the interplay between alcohol and the gene variants observed here.

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The association of alcohol with circulating total fibrinogen and plasma clot density is mediated by fibrinogen and FXIII genotypes

10.21203/rs.3.rs-67774/v1 ◽

2020 ◽

Author(s):

Petro Hannie Rautenbach ◽

Cornelie Nienaber-Rousseau ◽

Marlien Pieters

Keyword(s):

Alcohol Consumption ◽

Alcohol Intake ◽

Positive Association ◽

Clot Lysis ◽

Nucleotide Polymorphisms ◽

Plasma Clot ◽

Lysis Time ◽

Carbohydrate Deficient Transferrin ◽

Haemostatic Factors ◽

Clot Structure

Abstract Background Alcohol consumption is associated with haemostasis and so may influence cardiovascular conditions. It is unknown whether the association of alcohol with total and γ’ fibrinogen concentrations, as well as clot structure, are modulated by fibrinogen and factor (F)XIII single nucleotide polymorphisms (SNPs). Methods Total fibrinogen, γ’ fibrinogen and clot properties of 2010 healthy black South Africans were measured in relation to alcohol intake as well as its markers – gamma-glutamyltransferase (GGT), percentage carbohydrate deficient transferrin (%CDT), aspartate aminotransferase (AST), and alanine aminotransferase (ALT). Fourteen fibrinogen and two SNPs in the FXIII gene were genotyped to determine their influence. Results Alcohol intake and its markers correlated negatively with fibrinogen and clot lysis time (CLT) as well as with most of the clot properties. Percentage γ’ fibrinogen correlated positively with AST and negatively with alcohol intake. We then stratified for alcohol intake and found inverse associations between γ’ fibrinogen and both %CDT and GGT–CDT in consumers, but the positive association with AST remained only in abstainers. Alcohol intake and its markers modulated the influence of fibrinogen SNPs on total fibrinogen concentrations and the fibrinogen SNPs as well as an FXIII SNP on clot density (all p <0.004). Conclusion/s We show for the first time that some individuals harbour certain genotypes that, in combination with alcohol consumption, might predispose or protect them from haemostatic factors that might lead to the development of cardiovascular disease. Studies are needed to clarify the mechanisms related to the interplay between alcohol and gene variants observed here.

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The association of alcohol with circulating total fibrinogen and plasma clot density is mediated by fibrinogen and FXIII genotypes

10.21203/rs.3.rs-67774/v2 ◽

2020 ◽

Author(s):

Petro Hannie Rautenbach ◽

Cornelie Nienaber-Rousseau ◽

Marlien Pieters

Keyword(s):

Alcohol Consumption ◽

Alcohol Intake ◽

Positive Association ◽

Clot Lysis ◽

Nucleotide Polymorphisms ◽

Plasma Clot ◽

Lysis Time ◽

Carbohydrate Deficient Transferrin ◽

Haemostatic Factors ◽

Clot Structure

Abstract Background: Alcohol consumption is associated with haemostasis and so may influence cardiovascular conditions. It is unknown whether the association of alcohol with total and g’ fibrinogen concentrations, as well as clot structure, are modulated by fibrinogen and factor (F)XIII single nucleotide polymorphisms (SNPs).Methods: Total fibrinogen, g’ fibrinogen and clot properties of 2010 healthy Africans residing in South Africa were measured in relation to alcohol intake as well as its markers – gamma-glutamyltransferase (GGT), percentage carbohydrate deficient transferrin (%CDT), aspartate aminotransferase (AST), and alanine aminotransferase (ALT). Fourteen fibrinogen and two SNPs in the FXIII gene were genotyped to determine their influence.Results: Alcohol intake and its markers correlated negatively with fibrinogen and clot lysis time (CLT) as well as with most of the clot properties. Percentage g’ fibrinogen correlated positively with AST and negatively with alcohol intake. We then stratified for alcohol intake and found inverse associations between g’ fibrinogen and both %CDT and GGT–CDT in consumers, but the positive association with AST remained only in abstainers. Alcohol intake and its markers modulated the influence of fibrinogen SNPs on total fibrinogen concentrations and the fibrinogen SNPs as well as an FXIII SNP on clot density (all p <0.004).Conclusion/s: We show for the first time that some individuals harbour certain genotypes that, in combination with alcohol consumption, might predispose or protect them from haemostatic factors that might lead to the development of cardiovascular disease. Studies are needed to clarify the mechanisms related to the interplay between alcohol and gene variants observed here.

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Altered fibrin clot structure/function in patients with antiphospholipid syndrome: association with thrombotic manifestation

Thrombosis and Haemostasis ◽

10.1160/th13-11-0980 ◽

2014 ◽

Vol 112 (08) ◽

pp. 287-296 ◽

Cited By ~ 21

Author(s):

Magdalena Celińska-Löwenhoff ◽

Teresa Iwaniec ◽

Agnieszka Padjas ◽

Jacek Musiał ◽

Anetta Undas

Keyword(s):

Structure Function ◽

Antiphospholipid Syndrome ◽

Thrombotic Event ◽

Fibrin Clot ◽

Clot Lysis ◽

Lag Phase ◽

Lysis Time ◽

Clot Structure ◽

Clot Lysis Time ◽

D Dimer

SummaryWe tested the hypothesis that plasma fibrin clot structure/function is unfavourably altered in patients with antiphospholipid syndrome (APS). Ex vivo plasma clot permeability, turbidity and susceptibility to lysis were determined in 126 consecutive patients with APS enrolled five months or more since thrombotic event vs 105 controls. Patients with both primary and secondary APS were characterised by 11% lower clot permeability (p<0.001), 4.8% shorter lag phase (p<0.001), 10% longer clot lysis time (p<0.001), and 4.7% higher maximum level of D-dimer released from clots (p=0.02) as compared to the controls. Scanning electron microscopy images confirmed denser fibrin networks composed of thinner fibres in APS. Clots from patients with “triple-antibody positivity” were formed after shorter lag phase (p=0.019) and were lysed at a slower rate (p=0.004) than in the remainder. Clots from APS patients who experienced stroke and/or myocardial infarction were 8% less permeable (p=0.01) and susceptible to lysis (10.4% longer clot lysis time [p=0.006] and 4.5% slower release of D-dimer from clots [p=0.01]) compared with those following venous thromboembolism alone. Multivariate analysis adjusted for potential confounders showed that in APS patients, lupus anticoagulant and “triple-positivity” were the independent predictors of clot permeability, while “triple-positivity” predicted lysis time. We conclude that APS is associated with prothrombotic plasma fibrin clot phenotype, with more pronounced abnormalities in arterial thrombosis. Molecular background for this novel prothrombotic mechanism in APS remains to be established.

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Plasma fibrin clot properties in the G20210A prothrombin mutation carriers following venous thromboembolism: the effect of rivaroxaban

Thrombosis and Haemostasis ◽

10.1160/th17-01-0060 ◽

2017 ◽

Vol 117 (09) ◽

pp. 1739-1749 ◽

Cited By ~ 8

Author(s):

Agnieszka Janion-Sadowska ◽

Joanna Natorska ◽

Jakub Siudut ◽

Michal Zabczyk ◽

Andrzej Stanisz ◽

...

Keyword(s):

Venous Thromboembolism ◽

Fibrin Clot ◽

Clot Lysis ◽

Mutation Carriers ◽

Lysis Time ◽

Prothrombin Mutation ◽

Fibrinolysis Inhibitor ◽

Heterozygous Carriers ◽

Mutation Group ◽

Clot Structure

SummaryWe sought to investigate whether the G20210A prothrombin mutation modifies plasma fibrin clot properties in patients after venous thromboembolism (VTE) and how rivaroxaban treatment affects these alterations. We studied 34 prothrombin mutation heterozygous carriers and sex- and age-matched 34 non-carriers, all at least three months since the first VTE episode, before and during treatment with rivaroxaban. Clot permeability (Ks) and clot lysis time (CLT) with or without elimination of thrombin activatable fibrinolysis inhibitor (TAFI) were assessed at baseline, 2–6 hours (h) after and 20–25 h after intake of rivaroxaban (20 mg/day). At baseline, the prothrombin mutation group formed denser clots (Ks −12 %, p=0.0006) and had impaired fibrinolysis (CLT +14 %, p=0.004, and CLT-TAFI +13 %, p=0.03) compared with the no mutation group and were similar to those observed in 15 healthy unrelated prothrombin mutation carriers. The G20210A prothrombin mutation was the independent predictor for Ks and CLT before rivaroxaban intake. At 2–6 h after rivaroxaban intake, clot properties improved in both G20210A carriers and non-carriers (Ks +38 %, and +37 %, CLT −25 % and −25 %, CLT-TAFI −20 % and −24 %, respectively, all p<0.001), but those parameters were worse in the prothrombin mutation group (Ks −12.8 %, CLT +17 %, CLT-TAFI +13 %, all p<0.001). Rivaroxaban concentration correlated with fibrin clot properties. After 20–25 h since rivaroxaban intake most clot properties returned to baseline. Rivaroxaban-related differences in clot structure were confirmed by scanning electron microscopy images. In conclusion, rivaroxaban treatment, though improves fibrin clot properties, cannot abolish more prothrombotic fibrin clot phenotype observed in prothrombin mutation carriers following VTE.

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Is carbohydrate-deficient transferrin in serum useful for detecting excessive alcohol consumption in hypertensive patients?

Clinical Chemistry ◽

10.1093/clinchem/40.11.2057 ◽

1994 ◽

Vol 40 (11) ◽

pp. 2057-2063 ◽

Cited By ~ 26

Author(s):

B Fagerberg ◽

S Agewall ◽

A Berglund ◽

M Wysocki ◽

P A Lundberg ◽

...

Keyword(s):

Alcohol Consumption ◽

Alcohol Intake ◽

High Alcohol ◽

Clinical Value ◽

Excessive Alcohol Consumption ◽

Cross Sectional ◽

Hypertensive Patients ◽

Carbohydrate Deficient Transferrin ◽

Excessive Alcohol ◽

High Alcohol Intake

Abstract The aim of this study was to examine the diagnostic usefulness of carbohydrate-deficient transferrin (CDT) in serum in a cross-sectional study of 439 treated hypertensive men. We related the results to alcohol intake by questionnaire and to biochemical and hemodynamic measurements known to reflect excessive alcohol consumption. The diagnostic sensitivity and the specificity for high alcohol intake (> or = 24 g/day of ethanol) were 44% and 87%, respectively. The group with reported high alcohol intake (n = 32) was characterized by hemodynamic and biochemical changes typical of alcohol abuse. The corresponding profile for the patients with increased serum CDT concentrations (n = 70) was different in several respects, indicating a considerable number of false-positive tests. We conclude that serum CDT determination had low sensitivity and specificity for excessive alcohol consumption in this group of hypertensive patients. The results illustrate the importance of evaluating new laboratory methods in unselected patient populations before drawing any conclusions about their clinical value.

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Disseminated Intravascular Coagulation (DIC) and Toxaemia of Pregnancy in Kuwait

10.1055/s-0039-1689367 ◽

1975 ◽

Author(s):

A. H. Youssef

Keyword(s):

Pregnant Women ◽

Disseminated Intravascular Coagulation ◽

High Plasma ◽

Plasma Fibrinogen ◽

Clot Lysis ◽

Functional Tests ◽

Plasma Clot ◽

Intravascular Coagulation ◽

Lysis Time ◽

Heparin Activity

43 patients with pre-eclampsia and 9 patients with eclampsia were studied and compared with 57 normal pregnant women and 36 healthy non pregnant women.Functional tests of Disseminated Intravascular Coagulation (DIC) were carried out on patients and controls. These tests included platelet count, plasma anti-heparin activity, serum FDPs and plasma fibrinogen levels, euglobulin plasma clot lysis time, thrombin, prothrombin and Kaolin-cephalin times. The results of the tests are presented and confirmed that DIC occurs in toxemia of pregnancy.Patients with pre-eclampsia and eclampsia had low platelet counts with high plasma anti-heparin activity, low plasma fibrinogen levels, raised serum FDPs concentrations and prolonged thrombin and euglobulin lysis times. These findings indicate that toxemia of pregnancy can be attributed to DIC.

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BβArg448Lys polymorphism is associated with altered fibrin clot structure and fibrinolysis in type 2 diabetes

Thrombosis and Haemostasis ◽

10.1160/th16-07-0554 ◽

2017 ◽

Vol 117 (02) ◽

pp. 295-302 ◽

Cited By ~ 1

Author(s):

Katie A. Greenhalgh ◽

Mark W. Strachan ◽

Saad Alzahrani ◽

Paul D. Baxter ◽

Kristina F. Standeven ◽

...

Keyword(s):

Type 2 Diabetes ◽

Fibrin Clot ◽

Clot Lysis ◽

Plasma Clot ◽

Lysis Time ◽

Increased Risk ◽

Fibrin Network ◽

Clot Lysis Time ◽

Fibrin Clots

SummaryBoth type 2 diabetes (T2DM) and Bß448Lys variant of fibrinogen are associated with dense fibrin clots, impaired fibrinolysis and increased cardiovascular risk. It was our objective to investigate whether BßArg448Lys adds to vascular risk by modulating fibrin network structure and/or fibrinolysis in diabetes. The primary aim was to study effects of BßArg448Lys on fibrin network characteristics in T2DM. Secondary aims investigated interactions between gender and BßArg448Lys substitution in relation to fibrin clot properties and vascular disease. Genotyping for BßArg448Lys and dynamic clot studies were carried out on 822 T2DM patients enrolled in the Edinburgh Type 2 Diabetes Study. Turbidimetric assays of individual plasma samples analysed fibrin clot characteristics with additional experiments conducted on clots made from purified fibrinogen, further examined by confocal and electron microscopy. Plasma clot lysis time in Bß448Lys was longer than Bß448Arg variant (mean ± SD; 763 ± 322 and 719 ± 351 seconds [s], respectively; p<0.05). Clots made from plasma-purified fibrinogen of individuals with Arg/Arg, Arg/Lys and Lys/Lys genotypes showed differences in fibre thickness (46.75 ± 8.07, 38.40 ± 6.04 and 25 ± 4.99 nm, respectively; p<0.001) and clot lysis time (419 ± 64, 442 ± 87 and 517 ± 65 s, respectively; p=0.02), directly implicating the polymorphism in the observed changes. Women with Bß448Lys genotype had increased risk of cerebrovascular events and were younger compared with Bß448Arg variant (67.2 ± 4.0 and 68.2 ± 4.4 years, respectively; p=0.035). In conclusion, fibrinogen Bβ448Lys variant is associated with thrombotic fibrin clots in diabetes independently of traditional risk factors. Prospective studies are warranted to fully understand the role of BβArg448Lys in predisposition to vascular ischaemia in T2DM with the potential to develop individualised antithrombotic management strategies.

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The effect of ethanol and its metabolism on fibrinolysis

Thrombosis and Haemostasis ◽

10.1160/th10-01-0048 ◽

2010 ◽

Vol 104 (10) ◽

pp. 724-733 ◽

Cited By ~ 9

Author(s):

Hester Vorster ◽

Johann Jerling ◽

Christine Venter ◽

Retha Kotze ◽

Elsabe Bornman ◽

...

Keyword(s):

Alcohol Consumption ◽

Coagulation Factors ◽

Ethanol Consumption ◽

Ethanol Metabolism ◽

Clot Lysis ◽

Protective Effects ◽

Plasma Clot ◽

Significant Difference ◽

Blood Clots

SummaryThe role of ethanol metabolism in possible haemostatic cardioprotective effects has not yet been determined. To this end, we investigated the effect of a moderate dose of ethanol (35 g) and its metabolism, on haemostatic variables over 14 hours (h). Eighteen Caucasian males participated in a placebo-controlled, randomised, cross-over study. Blood was collected prior to alcohol consumption, and at 10 time points for 14 h. Blood ethanol peaked at 1 h and was cleared after 8 h following ethanol consumption, significantly increasing plasma acetate (p=0.0028). Ethanol did not influence the coagulation factors significantly. PAI-1act increased (p<0.0001) and tPAact (p=0.047) decreased following alcohol consumption, reaching maximum (0.69 to 22.2 IU/ml) and minimum (0.88 to 0.33 IU/ml) levels at 5 h, respectively. Significantly increased plasma clot lysis times (46.8 to 67.6 minutes) and reduced global fibrinolytic capacity of whole blood, measured as D-dimer production during incubation of blood clots (2.26 to 0.29 μg/ml), were found at 5 h. Except for PAI-1act (borderline significance; p=0.05), there was no significant difference in the fibrinolytic markers between the two groups the following morning. Moderate ethanol consumption resulted in a significant temporary fibrinolysis inhibition. Any protective effects of moderate ethanol consumption on cardiovascular disease do not appear to be due to improvement in fibrinolytic potential within the first 14 h following consumption. The use of global fibrinolytic assays is recommended for determining the true effect of ethanol on fibrinolysis.

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