**4.1 Mechanisms for thrombosis in hyperhomocysteinemia**

Homocysteine impairs intrinsic thrombolysis and endothelium function (Dalton et al., 1997; Nishio & Watanabe; 1997). Studies of cultured cells in vitro indicate that homocysteine has prothrombotic effects on the endothelium and vascular smooth muscle. *In vitro* test results show that endothelial cells are damaged by moderate hyperhomocysteinemia mainly because of the impact of hydrogen peroxide (Hultberg et al., 1997).

Homocysteine though oxidative stress, probably directly damages endothelial cells by: (1) the direct oxidation of low density lipoproteins (2) its cytoplasmic oxidation products like homocystine, mixed disulfides and homocysteine thiolactone, which lead to the development of reactive oxidative species ROS such as hydrogen peroxide, superoxide anion and hydroxide radical (3) acceleration of fibrin and collagen accumulation in endothelial cells and smooth muscle cells, stimulating their proliferation and thus changes the vessel wall leading to or at least accelerating thrombus and vascular disease.

The metabolism of homocysteine is connected with the cellular level of S-adenosyl methionine (SAM) which is a co-substrate involved in methyl group transfers of both the transsulfuration and remethylation metabolic pathways (Fig.2) by the enzyme methyltransferase. At the same time, SAM is the methyl group donor in the methylation of DNA, proteins, phospholipids and biogenic amines. Therefore, the methyltransferase function depends on the cell concentration of both SAM and S-adenosyl homocysteine (SAH). Effectively, high cellular homocysteine levels inhibit vital methylation reactions, affecting the maintenance of the DNA structure; without repair mutations can occur and the structure can collapse. The close connection of homocysteine metabolism with methyl transfer reactions imply, that changed methyl transfer reactions are responsible for some of the effects of altered vessel function during hyperhomocysteinemia.

It is very likely that the mechanisms by which homocysteine changes vessel function are oxidative stress and alterations of cell methylation (Lentz, 1998). The proposed pathogenetic mechanisms which associate hyperhomocysteinemia and vascular injury are oxidative damage of the endothelium through suppression of the vasodilator nitric oxide, increasing the level of asymmetric dimethylarginine, impairing methylation, proliferation of vascular smooth muscle, and disruption of the normal procoagulant balance in favor of thrombosis.

#### **4.2 Homocysteine and thrombosis in malignancies, renal failure, retina veins**
