A Hypothesis to Explain the Reported Association of the α-fibrinogen A312 Allele with Thromboembolic Disease

Curran, JM; Fatah-Ardalani, K; Tornvall, Per; Humphries, SE; Green, FR

doi:10.1055/s-0037-1615977

Cited by 9 publications

(7 citation statements)

References 2 publications

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“…Equally, and in support of this, there was no difference in permeability between the variants, suggesting again a similar measure of pore size. These results are in contrast to those reported by Curran et al, 18 who found a decrease in plasma clot permeability associated with Ala312. Because the amount of fibrinogen in clots is a major determinant of fibrin structure, 13 it is difficult to determine accurately the influence of genotypes in plasma samples.…”

Section: Discussioncontrasting

confidence: 99%

“…13 For instance, we have previously shown that the FXIII Val34Leu polymorphism has a significant influence on clot structure. 9 We evaluated the influence of Thr312Ala on clot structure/function in a purified system from subjects only possessing the FXIII Val34 genotype to exclude the influence of this variable, which could represent one of the reasons for the difference in results between our study and that by Curran et al 18 We have previously hypothesized that the Ala312 allele predisposes clots to embolization by influencing ␣-fibrin monomer cross-linking. 7 In this study, we have shown that the fibrinogen A␣ Thr312Ala polymorphism indeed affects clot structure and stiffness and changes FXIII-induced crosslinking of ␣-chains.…”

Section: Discussionmentioning

confidence: 94%

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Functional Analysis of the Fibrinogen Aα Thr312Ala Polymorphism

et al. 2003

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Background-The fibrinogen A␣ Thr312Ala polymorphism occurs within the ␣C domain of fibrinogen, which is important for lateral aggregation and factor XIII-induced cross-linking of fibrin fibers. We have previously shown an association of Ala312 fibrinogen with poststroke mortality in subjects with atrial fibrillation and with pulmonary embolism in subjects with venous thrombosis. Methods and Results-We studied the properties of clots formed from purified Ala312 and Thr312 fibrinogen and found that Ala312 fibrinogen produces stiffer clots, associated with increased ␣ chain cross-linking, as demonstrated by SDS-Page. On electron microscopy analysis, we found larger fiber diameters in the Ala312 clots and observed a lower number of fibers per square micrometer. The number of branch points per square micrometer was similar between genotypes. Conclusions-Our study shows that Ala312 influences clot structure and properties by increased factor XIII cross-linking and formation of thicker fibrin fibers. These findings may provide a mechanism by which Ala312 fibrinogen could predispose to clot embolization.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 94%

Functional Analysis of the Fibrinogen Aα Thr312Ala Polymorphism

et al. 2003

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“…Clot formed from Ala/Ala subjects demonstrates more extensive a-chain cross-linking, increased fibre thickness and greater clot stiffness than is seen in Thr/Thr controls [40]. Such clot also shows less permeability to flow, which, in turn, permits less access to fibrinolytic factors in vivo [41]. These properties suggest that the Ala substitution enhances lateral aggregation of fibrin protofibrils and encourages formation of a more tightly packed fibrin structure.…”

Section: Discussionmentioning

confidence: 93%

Fibrinogen A Thr312Ala polymorphism is associated with chronic thromboembolic pulmonary hypertension

Suntharalingam¹,

Goldsmith

Marion³

et al. 2008

European Respiratory Journal

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Although chronic thromboembolic pulmonary hypertension (CTEPH) is characterised by the persistence of organised thrombus, few pro-thrombotic risk factors have been identified in subjects with the disease. The aim of the present study was to compare the prevalence of eight functionally relevant haemostatic polymorphisms between CTEPH subjects and healthy controls.Genomic DNA was isolated from 214 CTEPH subjects and 200 healthy controls, and analysed for Factor V Leiden, prothrombin guanine (G) to adenine (A) substitution at nucleotide 20210 (20210G.A), plasminogen activator inhibitor-1 4G/5G, tissue plasminogen activator 7351 cytosine (C).thymidine (T), Factor XIII 100G.T, fibrinogen Aa substitution of threonine with alanine at position 312 (Thr312Ala), fibrinogen Bb substitution of arginine with lysine at position 448 (Arg448Lys) and fibrinogen Bb 455G.A polymorphisms.A significant difference was demonstrated in fibrinogen Aa Thr312Ala genotype and allele frequencies between CTEPH subjects and controls. The presence of the alanine allele significantly increased the risk of CTEPH.The fibrinogen Aa alanine 312 allele alters fibrinogen a-a chain cross-linkage and has previously been associated with both increased risk of embolisation and increased resistance to thrombolysis. An association between this polymorphism and chronic thromboembolic pulmonary hypertension, therefore, supports an embolic aetiology for this disease, and may provide a mechanism by which thrombus persists following an acute event.

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“…In fact, the fibrinogen reduction in carriers explained most of the effect on thrombin generation with or without platelets. In literature, the 312Ala allele influences clot stability 32 and predisposes clots to embolization, 25 but the relation with fibrinogen expression is still unclear. This polymorphism is relatively abundant among whites with an estimated frequency of 35% to 40%.…”

Section: Discussionmentioning

confidence: 99%

Variable Hypocoagulant Effect of Fish Oil Intake in Humans

Vanschoonbeek

Feijge

Paquay

et al. 2004

ATVB

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Objective-The beneficial effect of dietary fish oil, rich in omega-3 polyunsaturated fatty acids (PUFAs), on cardiovascular disease is multifactorial and may partly rely on their anticoagulant action. We studied how fish oil intake influenced thrombin generation in plasma and which factors were involved herein. Methods and Results-Twenty-five healthy males with borderline overweight received 3.0 g omega-3 PUFAs daily for 4 weeks. Fish oil intake reduced plasma triglycerides and lowered platelet integrin activation, as well as plasma levels of fibrinogen and factor V, but had no effect on vitamin K-dependent coagulation factors. Before fish oil intake, thrombin generation (reflecting the coagulant potential) considerably varied between plasmas from individual subjects, which were partly explained by variation in prothrombin, antithrombin, fibrinogen, and factor V levels. Fish oil intake reduced thrombin generation in the presence and absence of platelets. This reduction correlated with the fish oil effect on fibrinogen and factor V levels. Interestingly, the lowering effect of fish oil on thrombin generation and fibrinogen clustered around subjects with high fibrinogen carrying a structural fibrinogen ␣-chain polymorphism. Conclusions-Dietary omega-3 PUFAs provoke a hypocoagulant, vitamin K-independent effect in humans, the degree of which may depend on fibrinogen level. Key Words: coagulation Ⅲ factor V Ⅲ fibrinogen Ⅲ fish oil Ⅲ thrombin generation S ince the 1970s, fish oil has been studied as a nutritional component with antithrombotic potential. 1 The protective effect on thrombosis has been attributed to the omega-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid, and docosahexaenoic acid, which are abundantly present in fish oil. Early epidemiological and intervention studies pointed to a strong association between consumption of omega-3 PUFAs and a reduced risk of coronary heart disease, even with only 2 fish dishes per week. 2,3 Currently, a daily intake of 0.3 g of omega-3 PUFAs is recommended for healthy adults, and a daily dose up to 1 to 3 g is recommended for patients with coronary heart disease or hypertriglyceridemia. 4 Despite 30 years of study, the precise mechanisms of action of omega-3 PUFAs are still a matter of debate. 5 Established effects include an altered heart and vessel function, a decreased risk for arrhythmias, and lowering of blood pressure. Many reports also describe effects on plasma hemostatic variables, but usually with high interstudy variation. Best documented is that omega-3 PUFA intake reduces plasma triglycerides levels, whereas plasma cholesterol is decreased in only few studies. 6 -8 Part of published studies show, often mild, lowering effects of omega-3 PUFA on platelet activation and bleeding time. 9 With respect to coagulation, some trials point to a moderate reduction by fish oil of the plasma levels of fibrinogen and coagulation factors V, VII, and X, 10 -12 whereas other studies fail to detect this. 5,9 Because some of these factors require vitami...

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A Hypothesis to Explain the Reported Association of the α-fibrinogen A312 Allele with Thromboembolic Disease

Cited by 9 publications

References 2 publications

Functional Analysis of the Fibrinogen Aα Thr312Ala Polymorphism

Functional Analysis of the Fibrinogen Aα Thr312Ala Polymorphism

Fibrinogen A Thr312Ala polymorphism is associated with chronic thromboembolic pulmonary hypertension

Variable Hypocoagulant Effect of Fish Oil Intake in Humans

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