Impact of homocysteine-thiolactone on plasma fibrin networks

Abstract

Epidemiologic studies have shown that hyperhomocysteinemia is an independent risk factor for vascular disease. Homocysteine (Hcy) circulates as different species, mostly protein bound, and approximately 1% as its reduced form and the cyclic thioester homocysteine-thiolactone (HTL). Despite the level of plasma thiolactone being markedly low, detrimental effects are related to its high reactivity. HTL reacts with proteins by acylation of free basic amino groups; in particular, the epsilon-amino group of lysine residues forms adducts and induces structural and functional changes in plasma proteins. In order to assess the effects of HTL on plasma fibrin networks, a pool of normal plasma incubated with HTL (100, 500 and 1,000 μmol/L, respectively) was evaluated by global coagulation tests and fibrin formation kinetic assays, and the resulting fibrin was observed by scanning electron microscopy. HTL significantly prolonged global coagulation tests in a concentration-dependent manner with respect to control, and increases were up to 14.5%. Fibrin formation kinetic parameters displayed statistically significant differences between HTL-treated plasma and control in a concentration-dependent way, showing higher lag phase and lower maximum reaction velocity and final network optical density. Electron microscopy analysis of HTL plasma networks revealed a compact architecture, with more branches and shorter fibers than control. We can conclude that HTL induced a slower coagulation process, rendering more tightly packed fibrin clots. Since these features of the networks have been related to impaired fibrinolysis, the N-homocysteinylation reactions would be involved in the prothrombotic effects associated to hyperhomocysteinemia.

Admission homocysteine is an independent predictor of spontaneous reperfusion and early infarct-related artery patency before primary percutaneous coronary intervention in ST-segment elevation myocardial infarction

“…HHCY has been related to impaired formation of the fibrin network [ 36 , 37 ]. HCY impairs the fibrinolysis networks by inducing slower coagulation process and rendering more tightly packed fibrin clots [ 10 ].Under the influence of HCY, fibrin networks resulted in a more compact structure with shorter, thicker and more branched fibers, these structural properties of fibrin are related to slower spontaneous lysis rate of thrombus, and proved to be less permeable and more resistant to fibrinolysis [ 38 , 39 ]. Moreover, studies have revealed that mild HHCY (>10umol/L) showed markedly relationship with decreased tissue-type plasminogen activator (t-PA) activity (which is the major activator of fibrinolysis) and impaired spontaneous thrombolysis in STEMI patients [ 40 ].…”

“…Homocysteine (HCY) is a sulfur-containing amino acid that functions as a key intermediate in methionine metabolism [ 8 ], which is believed to promote atherothrombosis through several mechanism [ 9 ], and hyperhomocystenemia (HHCY) (plasma HCY > 10 mmol/L) is currently recognized as a new independent risk factor for atherosclerotic vascualr disease. Furthermore, HHCY is related to impaired formation of the fibrin networkby inducing slower coagulation process and rendering more tightly packed fibrin clots, hence influencing the process of spontaneous thrombolysis [ 10 ]. Therefore, we speculated that HCY might be a predictor of early SR in STEMI patients.…”

Homocysteine Modification in Protein Structure/Function and Human Disease

“…The slower lysis is caused by impaired activation of plasminogen on N-Hcy-fibrin (273). Confocal microscopy of N-Hcy-fibrin clots reveals a denser structure with increased branching, relative to unmodified fibrin (75,182), which can explain why lysis of N-Hcy-fibrin is slower than control fibrin. N-Hcy-fibrinogen has the ability to form disulfide-linked complexes with albumin; this, however, has no effect on lysis of N-Hcy-fibrin clots (274).…”

Tongxinluo Prevents Endothelial Dysfunction Induced by Homocysteine ThiolactoneIn Vivovia Suppression of Oxidative Stress

“…HTL reacts with proteins by acylation of free basic amino groups. In particular, the epsilon-amino group of lysine residues forms adducts and induces structural and functional changes in plasma proteins [ 3 ]. High levels of homocysteine impair endothelial function and cause endothelial damage in humans and in animal models [ 4 , 5 ], indicating that the endothelial monolayer is very sensitive to changes in plasma homocysteine levels.…”