**4.2.2 Renal failure and VTE**

Pathophysiology and Clinical Aspects of 26 Venous Thromboembolism in Neonates, Renal Disease and Cancer Patients

Independent from other factors hyperhomocysteinemia is associated with a 4.8 fold

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

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 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

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.

More recently, increased plasma homocysteine concentration has been postulated as a risk factor for cancer and even as a novel tumor marker (Sun et al., 2002). Patients with malignancies often have an increased risk of VTE disease and as such being the second most common cause of death in cancer patients, second to the primary disease itself (Rickles et al., 1992). In 1865 Trousseau described hypercoagulability and increasing risk of »spontaneous coagulation« in patients with cancer (Trousseau, 1865). Nowadays, it is established that

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

the vessel wall leading to or at least accelerating thrombus and vascular disease.

increased risk for VTE (Köktürk et al., 2010).

**4.1 Mechanisms for thrombosis in hyperhomocysteinemia** 

because of the impact of hydrogen peroxide (Hultberg et al., 1997).

the effects of altered vessel function during hyperhomocysteinemia.

**4.2.1 Malignancies and VTE** 

Under physiological conditions, non-protein bound homocysteine is subjected to glomerular filtration, and almost completely reabsorbed in the tubuli and oxidatively catabolized to carbon dioxide and sulphate in the kidney cells. The clearance is markedly reduced in renal failure with a strong, positive correlation between homocysteine levels, serum creatinine and the glomerular filtration rate (Hultberg et al., 1993). Hyperhomocysteinemia in patients with chronic renal failure induces an oxidative stress to the vascular endothelium, causing a failure in vasodilatation and an impairment of antithrombotic properties. In patients with end-stage renal disease (ESRD) the prevalence of hyperhomocysteinemia is 85-100% and of the fifty-nine ESRD patients undergoing hemodialysis treatment with supplemented B vitamines it was concluded that the MTHFR C677T mutation is an important genetic determinant of elevated plasma homocysteine concentration level.
