Effects of homocysteine thiol group on fibrin networks: another possible mechanism of harm

Lauricella, Ana María; Quintana, Irene; Kordich, L

doi:10.1016/s0049-3848(02)00191-3

Cited by 39 publications

(24 citation statements)

References 14 publications

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“…98 In vitro, clots formed in the presence of homocysteine have thicker, shorter fibers with a more compact structure. 99 Clots formed with fibrinogen from homocysteinemic plasma are more resistant to lysis. 100 In addition, homocysteine binds to circulating fibronectin and hinders fibrin/fibronectin binding.…”

Section: Homocysteinementioning

confidence: 99%

Genetic and Environmental Determinants of Fibrin Structure and Function

Scott

Ariëns

Grant

2004

ATVB

139

129

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Abstract-The formation of a fibrin clot is one of the key events in atherothrombotic vascular disease. The structure of the fibrin clot and the genetic and environmental factors that modify it have effects on its biological function. Alterations in fibrin structure and function have implications for the clinical presentation of vascular disease. This review briefly describes the key features involved in the formation of a fibrin clot, its typical structure, and function. This is followed by a review of the current literature on genetic and environmental influences on fibrin structure/function and the relationship to clinical disease. Key Words: fibrin Ⅲ hemostatis Ⅲ genetic Ⅲ environment Ⅲ atherothrombosis D iseases associated with the development of thrombosis are a major cause of morbidity and mortality in the developed world. Atherothrombotic vascular disorders develop over many decades and involve the interaction of classic atherogenic risk factors such as diabetes, hyperlipidemia, and hypertension with abnormalities of the inflammatory and hemostatic systems. Arterial disease develops in a high-pressure, high-flow system, with lipid deposition and smooth muscle hyperplasia occurring to form an atherosclerotic plaque. 1 Subsequently, the plaque becomes unstable and ruptures exposing a prothrombotic lipid core activating the clotting cascade and leading to the development of a platelet-rich fibrin blood clot and arterial thrombotic occlusion. The extent of this process determines clinical outcome, ranging from no clinically noticeable event to acute coronary artery syndromes including myocardial infarction (MI), cerebrovascular and peripheral vascular disease, or sudden death. The Formation of a Fibrin ClotFibrin is the major protein constituent of the blood clot and is formed from fibrinogen, a glycoprotein that circulates largely inactively, in the blood stream. Fibrinogen consists of 6 polypeptide chains (A␣, B␤, ␥) 2 held together by disulphide bonds in a molecule with bilateral symmetry (Figure 1). The molecule consists of 3 main structural regions, 2,3 including a central region (E), which contains fibrinopeptides A and B and the amino acid termini of all 6 polypeptide chains, 2 distal regions (D) connected to the E region by 2 ␣-helical coiled segments and the D regions containing the carboxyl termini of the B␤ and ␥ chains, and those of the A␣ chain, which extend to form relatively flexible ␣C-domains, each ending in a globular domain. 2,3 In situations of tissue injury and inflammation, thrombin is generated after cleavage of prothrombin by the Xase complex. Thrombin subsequently binds to fibrinogen and cleaves the amino termini of the fibrinogen A␣ and B␤ chains at region E. This results in the release of fibrinopeptides A and B from fibrinogen, producing fibrin and initiating fibrin clot formation. Release of fibrinopeptide A by thrombin is fast and exposes a polymerization site on the E region of fibrin. 4,5 This combines with a complementary binding site on the ␥ chain in the D region of an adjac...

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Section: Homocysteinementioning

confidence: 99%

Genetic and Environmental Determinants of Fibrin Structure and Function

Scott

Ariëns

Grant

2004

ATVB

139

129

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“…Coagulation factor Va is also S-homocysteinylated (Undas et al 2001) and this modification could play a role in the modulation of hemostasis process. Clots formed from human plasma incubated in vitro with Hcys (at the high concentration -3 mmol/l) have been more compact structure, with shorter and more frequently branched fibers, than those formed in the absence of Hcys (Lauricella et al 2002(Lauricella et al , 2006. Harpel et al (1992) observed that Hcys (< 8 µmol/l) enhances the binding of lipoprotein(a) to fibrin, and this results may suggest a biochemical relationship between thiol compound metabolism, thrombosis and atherogenesis.…”

mentioning

confidence: 92%

May modifications of human plasma proteins stimulated by homocysteine and its thiolactone induce changes of hemostatic function of plasma in vitro?

Olas¹,

Kołodziejczyk²,

Malinowska³

2010

gpb

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Abstract. Homocysteine (Hcys) may be implicated in different diseases, especially in cardiovascular illnesses. The most reactive form of Hcys is its cyclic thioester -homocysteine thiolactone (HTL), which is formed in plasma and represents up to 0.29% of plasma total Hcys. Recently, it has been observed that Hcys and HTL may modify plasma proteins, including albumin, hemoglobin or fibrinogen, but the role of this process is not yet well known. The aim of our study in vitro was to investigate the modifications of human plasma total proteins after incubation with the reduced form of Hcys in concentrations 10-100 µmol/l, and HTL in concentrations 1-0.1 µmol/l, which correspond to levels found in human plasma during hyperhomocysteinemia in vivo. The aim of our study was also to explain the effects of Hcys and HTL on coagulation activity of human plasma. We showed that in model system in vitro Hcys and HTL change the level of thiol, amino and carbonyl groups in plasma total proteins. Moreover, our studies reported that not only Hcys (10-100 µmol/l), but also HTL (at lower concentrations than Hcys) modulates the coagulation properties of human plasma.

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“…13 Clots formed from human plasma incubated in vitro with Hcy have also been reported to have a more compact structure, with shorter and more frequently branched fibers, than those formed in the absence of Hcy. 14 However, it is unclear whether elevated Hcy levels can influence clot properties in human subjects.…”

mentioning

confidence: 99%

Plasma Homocysteine Affects Fibrin Clot Permeability and Resistance to Lysis in Human Subjects

Undas

Brožek

Jankowski

et al. 2006

ATVB

112

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Objective-Homocysteine (Hcy) is a risk factor for thrombosis. We investigated a hypothesis that the clot permeability and its resistance to fibrinolysis is associated with plasma total Hcy (tHcy) in human subjects. Methods and Results-We studied healthy men not taking any medication (nϭ76), male patients with advanced coronary artery disease (CAD) taking low-dose aspirin (nϭ33), men with diabetes mellitus diagnosed recently (median hemoglobin A 1c 7.65%; nϭ16), and patients with isolated hypercholesterolemia (Ͼ7.0 mmol/L; nϭ15). We assessed clot permeability and turbidimetric lysis time as the determinants of fibrin clot structure. In a regression model, including age and fibrinogen, plasma tHcy was an independent predictor of clot permeation and fibrinolysis time in healthy subjects (R 2 ϭ0.88, PϽ0.0001 and R 2 ϭ0.54, PϽ0.0001, respectively). In CAD patients, tHcy and fibrinogen were stronger predictors of the permeation coefficient (R 2 ϭ0.84; PϽ0.0001) than was fibrinogen alone (R 2 ϭ0.66; PϽ0.0001), whereas tHcy was the only predictor of lysis time (R 2 ϭ0.69; PϽ0.0001). Elevated tHcy levels observed after methionine load were not associated with any of the fibrin clot properties. In patients with diabetes or hypercholesterolemia, the influence of Hcy on permeation and, to a lesser extent, on the lysis time was obscured by dominant effects of glucose and cholesterol. In 20 asymptomatic men with hyperhomocysteinemia treated with folic acid, reduction in tHcy levels resulted in increased clot permeability (Pϭ0.0002) and shorter lysis time (PϽ0.0001). Conclusions-Our results indicate that plasma tHcy predicts clot permeation and susceptibility to fibrinolysis in healthy men and CAD patients. Our data are consistent with a mechanism of thrombosis in hyperhomocysteinemia, which involves modification of fibrinogen by Hcy-thiolactone.

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Effects of homocysteine thiol group on fibrin networks: another possible mechanism of harm

Cited by 39 publications

References 14 publications

Genetic and Environmental Determinants of Fibrin Structure and Function

Genetic and Environmental Determinants of Fibrin Structure and Function

May modifications of human plasma proteins stimulated by homocysteine and its thiolactone induce changes of hemostatic function of plasma in vitro?

Plasma Homocysteine Affects Fibrin Clot Permeability and Resistance to Lysis in Human Subjects

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