Marked increase of fibrin gel permeability with very low dose ASA treatment

Antovič, Aleksandra; Perneby, Christina; Ekman, Gunilla Jacobsson; Wallén, Håkan; Hjemdahl, Paul; Blombäck, Margareta; He, Shuting

doi:10.1016/j.thromres.2005.02.007

Cited by 43 publications

(31 citation statements)

References 16 publications

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“…77 In vivo, aspirin concentration of 37.5, 320, and 640 mg/d increased K s by 44%, 31%, and 21%, respectively, and treatment with low -dose aspirin led to formation of thicker fibrin fibers with larger pores. 78 Similar effects of low -dose aspirin were seen in patients with coronary artery disease and in those with VTE. 79 Moreover, 1 week after aspirin withdrawal, K s returned to the baseline value.…”

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confidence: 77%

Plasma fibrin clot structure and thromboembolism: clinical implications

Ząbczyk¹,

Undas²

2017

Polish Archives of Internal Medicine

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A and-much slower-B from the N -termini of the Aα and Bβ chains, respectively, resulting in the formation of fibrin monomer with exposed binding sites in the E domain. Fibrin monomers polymerize via noncovalent interactions between the D and E domains with subsequent lateral aggregation promoted mainly by intermolecular cross -linking of α chains and probably by interactions between α and γ chains.3,4 A half -staggered fibrin structure forms a protofibril.Fibrin resistance to plasmin degradation is determined largely by covalent cross -linking mediated by activated factor XIII (FXIII), a transglutaminase enzyme whose formation from zymogen FXIII is catalyzed by thrombin. Active FXIII catalyzes the formation of covalent bonds between γ -γ, γ -α, and α -α chains of contiguous fibrin polypeptide chains.5 FXIII also links α 2 -antiplasmin and plasminogen activator inhibitors to fibrin to ensure clot resistance to enzymatic degradation. 5Fibrinogen and fibrin specifically bind a variety Fibrin formation and structure Fibrin is the main protein component of a blood clot and intravascular thrombi in all locations. Efficient fibrin formation and its normal functions are essential for hemostasis.1 Fibrinogen, the soluble fibrin precursor synthesized in the liver, is a 340 -kDa glycoprotein composed of 3 paired polypeptide chains (AαBβγ) 2 that are cross -linked together by 29 disulfide bonds. Fibrinogen contains 3 main structural regions connected by α -helical coils: a central E domain composed of the N -termini of all 6 polypeptide chains and 2 outer D domains with C -termini of the Bβ and γ chains. The C -terminal of the Aα chain is a globular structure located near the central E domain. Approximately 10% of total plasma fibrinogen molecules contain γ' chain, whose presence may contribute to cardiovascular disease. [1][2][3] Fibrin formation is initiated by thrombin cleavage of the Aα and Bβ chains of fibrinogen. AbsTRACTFibrin formed as a result of fibrinogen polymerization is the main protein component of a clot in a test tube and intravascular thrombi in vivo. Fibrin clot structure characterized by fiber diameter and pore size differs between healthy persons and those with thromboembolic diseases, in part due to the quality and quantity of fibrinogen and the magnitude of thrombin generation. A key measure of plasma clot structure is its permeability, reflected by the Darcy constant (K s ). Reduced K s is a typical feature of the prothrombotic fibrin clot phenotype, which is associated with faster formation of denser fibrin mesh, relatively resistant to lysis. Low K s has been reported in patients with prior or acute myocardial infarction (MI), stroke, or venous thromboembolism (encompassing deep vein thrombosis [DVT] and pulmonary embolism [PE]), as well as in those with prothrombotic conditions (eg, in several thrombophilic states) and in the presence of cardiovascular risk factors (eg, obesity). Antithrombotic and anticoagulant agents, along with statins, have been shown to increase K s . Growing evidence indic...

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confidence: 77%

Plasma fibrin clot structure and thromboembolism: clinical implications

Ząbczyk¹,

Undas²

2017

Polish Archives of Internal Medicine

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“…10 In the study comparing 37.5 mg with 325 mg aspirin, baseline characteristics were well matched but final differences in clot structure were generally too small to draw any definitive conclusions. 11 A further limitation of these 2 studies is related to their failure to provide a mechanistic explanation for the presumed enhanced efficacy of lower aspirin dose. Interestingly, an earlier study, by the same group, has shown that a dose of 160 mg aspirin is more efficacious than 75 mg at altering fibrin gel porosity in patients with coronary artery disease, 9 and this is in agreement with findings from the current work.…”

Section: Discussionmentioning

confidence: 99%

“…Using low dose aspirin in healthy volunteers, 2 studies, conducted by 1 group, have shown that higher doses of aspirin are associated with a lesser effect on clot structure. 10,11 Unfortunately, these studies used plasma samples, rather than purified fibrinogen, and therefore it is unclear whether the described alterations in clot properties were related to a direct aspirin-fibrinogen interaction or an effect on other clotting factors. Also, the baseline starting parameters were different in individuals treated with 75 and 325 mg aspirin, posing a question mark over interpretation of the data.…”

Section: Ajjan Et Al Effects Of Aspirin On Clot Structure and Fibrinomentioning

confidence: 99%

“…14 Moreover, there is controversy regarding the effects of aspirin dosage, which may reflect the uncertainties created by the study limitations described above. 10,11 To address these issues, we investigated the effects of aspirin on recombinant fibrinogen and clot structure/ function using an in vitro cellular system, with acetylation assessed using a monoclonal antibody. The results indicate that aspirin acetylates fibrinogen and directly affects the structure of the resulting clot and its susceptibility to lysis.…”

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confidence: 99%

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Effects of Aspirin on Clot Structure and Fibrinolysis Using a Novel In Vitro Cellular System

Ajjan

Standeven

Khanbhai

et al. 2009

ATVB

101

103

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Objectives-The purpose of this study was to investigate the direct effects of aspirin on fibrin structure/function. Methods and Results-Chinese Hamster Ovary cell lines stably transfected with fibrinogen were grown in the absence (0) and presence of increasing concentrations of aspirin. Fibrinogen was purified from the media using affinity chromatography, and clots were made from recombinant protein. Mean final turbidity [OD(ϮSEM)] was 0.083(Ϯ0.03), 0.093(Ϯ0.002), 0.101(Ϯ0.005), and 0.125(Ϯ0.003) in clots made from 0, 1, 10, and 100 mg/L aspirin-treated fibrinogen, respectively (PϽ0.05). Permeability coefficient (Ks cm 2 ϫ10 Ϫ8 ) was 1.68(Ϯ0.29) and 4.13(Ϯ0.33) comparing fibrinogen produced from cells grown with 0 mg/L and 100 mg/L aspirin respectively (PϽ0.05). Scanning electron microscopy confirmed a looser clot structure and increased fiber thickness of clots made from aspirin-treated fibrinogen, whereas rheometer studies showed a significant 30% reduction in clot rigidity. Fibrinolysis was quicker in clots made from aspirin-treated fibrinogen. Ex vivo studies in 3 normal volunteers given 150 mg aspirin daily for 1 week demonstrated similar changes in clot structure/function. Conclusion-Aspirin directly altered clot structure resulting in the formation of clots with thicker fibers and bigger pores, which are easier to lyse. This study clearly demonstrates an alternative mode of action for aspirin, which should be considered in studies evaluating the biochemical efficacy of this agent. Key Words: -fibrinogen Ⅲ aspirin Ⅲ fibrin polymerization Ⅲ fibrin structure Ⅲ acetylation Ⅲ fibrinolysis T he use of antiplatelet agents for prevention of atherothrombotic events is now well established, and aspirin is often the first line agent used in individuals with stable disease. 1 Acetylation of platelet cyclo-oxygenase-1 (COX-1) by aspirin results in irreversible inhibition of thromboxane A 2 (TXA 2 ) production and reduced platelet aggregation potential. This is regarded as the main mechanism for the cardioprotective activity of this agent. However, another mode of action for aspirin, which is not widely considered, is its potential direct effect on clotting factors, including fibrinogen and factor (F) XIII, modulating in the process fibrin clot formation and fibrinolysis. 2 A key event in clot formation is the production of thrombin, which mediates the conversion of fibrinogen into a 3-dimensional network of fibrin fibers, and this is further cross-linked and stabilized by thrombin-activated factor (F)XIII. 3 Clot structure has a role in atherothrombotic disease; clots with thin fibers, small pores, and compact structure are associated with the development of premature and more severe coronary artery disease, which may be related to slower clot lysis of clots. 4,5 Although the ability of aspirin to acetylate fibrinogen has been known for 4 decades, 6 little work has been conducted to study the functional effect of fibrinogen-aspirin interactions, with poor characterization of fibrin gel properties. Limited in vit...

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“…In vitro, clots formed from purified fibrinogen show increased fibrin gel porosity when incubated with aspirin, making them relatively less thrombotic [18]. In vivo, aspirin administration to healthy volunteers favourably alters fibrin clot structure-an effect that is more pronounced with lower doses of aspirin [19,20]. Acetylation of fibrinogen is a likely mechanism for the observed in vitro and in vivo changes in clot structure after aspirin treatment [21].…”

Section: Cardiovascular Risk Reduction: Aspirin and Its Mode Of Actionmentioning

confidence: 99%