Thrombosis homocysteine

Homocysteine arises from dietary methionine. High levels of homocysteiae (hyperhomocysteinemia) are a risk factor for occlusive vascular diseases including atherosclerosis and thrombosis (81—84). In a controlled study, semm folate concentrations of <9.2 nmol/L were linked with elevated levels of plasma homocysteiae. Elevated homocysteine levels have beea associated also with ischemic stroke (9). The mechanism by which high levels of homocysteine produce vascular damage are, as of yet, aot completely uaderstood. lateractioa of homocysteiae with platelets or eadothehal cells has beea proposed as a possible mechanism. Clinically, homocysteine levels can be lowered by administration of vitamin B, vitamin B 2> foHc acid. 

Supplements of 400 Ig/d of folate begun before conception result in a significant reduction in the incidence of neural mbe defects as found in spina bifida. Elevated blood homocysteine is an associated risk factor for atherosclerosis, thrombosis, and hypertension. The condition is due to impaired abihty to form methyl-tetrahydrofolate by methylene-tetrahydrofolate reductase, causing functional folate deficiency and resulting in failure to remethylate homocysteine to methionine. People with the causative abnormal variant of methylene-tetrahydrofolate reductase do not develop hyperhomocysteinemia if they have a relatively high intake of folate, but it is not yet known whether this affects the incidence of cardiovascular disease. 

Answer A. Homocysteine, the substrate for the enzyme, accumulates increasing the risk of deep vein thrombosis and disrupting the normal crosslinking of fibrillin. Deficiency of homocysteine methyl transferase would cause homocystinuria, but would also predispose to megaloblastic anemia. 

Figure 22.6 How various factors increase the risk of atherosclerosis, thrombosis and myocardial infarction. The diagram provides suggestions as to how various factors increase the risk of development of the trio of cardiovascular problems. The factors include an excessive intake of total fat, which increases activity of clotting factors, especially factor VIII an excessive intake of saturated or trans fatty acids that change the structure of the plasma membrane of cells, such as endothelial cells, which increases the risk of platelet aggregation or susceptibility of the membrane to injury excessive intake of salt - which increases blood pressure, as does smoking and low physical activity a high intake of fat or cholesterol or a low intake of antioxidants, vitamin 6 2 and folic acid, which can lead either to direct chemical damage (e.g. oxidation) to the structure of LDL or an increase in the serum level of LDL, which also increases the risk of chemical damage to LDL. A low intake of folate and vitamin B12 also decreases metabolism of homocysteine, so that the plasma concentration increases, which can damage the endothelial membrane due to formation of thiolactone.

In a totally different field, studies were being carried out on children who had a deficiency of methionine synthase and an impaired ability to convert homocysteine to methionine, so that they had increased blood levels of homocysteine. It was noted that these children had an increased incidence of thrombosis in cerebral and coronary arteries. This led to a study which eventually showed that an increased level of homocysteine was a risk factor for coronary artery disease in adults. Since methionine synthase requires the vitamins, folic acid and B12, for its catalytic activity, it has been suggested that an increased intake of these vitamins could encourage the conversion of homocysteine to methionine and hence decrease the plasma level of homocysteine. This is particularly the case for the elderly who are undernourished (see Chapter 15 for a discussion of nutrition in the elderly). 

In the light of three further cases of thrombosis, it has been suggested that there may be a particular predisposition to this complication in patients with high circulating concentrations of homocysteine, and that these should be checked for in advance of treatment (33). 

Sauls DL, Wolberg AS, Hoffman M. Elevated plasma homocysteine leads to alterations in fibrin clot structure and stability implications for the mechanism of thrombosis in hyperhomocysteinemia. J Thromb Haemost 2003 l(2) 300-306. 

On the day of admission, the patient had developed a deep venous thrombosis in his right calf, a site not involved in the injury. In investigating the underlying cause of the deep venous thrombosis, serum homocysteine was measured and found to be 17.4 pmol/L (normal is < 14 pmol/I.).To distinguish between folic acid and vitamin B12 deficiencies, a serum methylmalonic acid (MMA) assay was performed it yielded a result of 0.59 pmol/I. MMA (normal is < 0.30 pmol/L). This confirmed the presence of vitamin B12 deficiency, despite a serum B12 concentration that was within the normal range. 

There is an association between the rare inborn recessive condition of homocystinemia and arterial and venous thrombosis, and observational data link coronary heart disease, stroke, and venous thromboembolism with increasing plasma homocysteine (Wald et al. 2002, 2004). This led to trials of foUc acid and pyridoxine supplementation to lower homocysteine levels (Hankey 2002 Hankey and Eikelboom 2005). Results from such trials have so far been disappointing the Vitamin Intervention for Stroke Prevention Study (VISP) and the Norwegian Vitamin Trial (NORVIT) (Toole et al. 2004 Bonaa et al. 2006) trials showed no treatment effect on recurrent stroke, coronary events or deaths. Preliminary results from the Study of Vitamins to Prevent Stroke (VITATOPS) trial have shown no evidence of reduced levels of iirflammation, endothelial dysfunction, or the hypercoagulability postulated to be increased by elevated homocysteine levels in patients with previous TIA or stroke treated with foUc acid, vitamin B12 and vitamin Bs... 

Additional parameters Decreased serum values of zinc (105, 196) and selenium (27, 181), thrombopenia or throm-bopathy (128) as well as increased values of endotoxins (33, 35) and homocysteine are also considered to be important laboratory parameters. Increased values of anticardiolipin antibodies are a hint of existing portal vein thrombosis. Determination of aj-foetoprotein (s. pp 106, 778) or des-gamma-carboxy prothrombin (s. p. 779) should be carried out to obtain a basic value, then checked at longer intervals if values increase, they must be monitored at shorter intervals. This also applies if there is a progressive rise in AP and y-GT. 

In plasma, homocysteine is present as both free (< 1 %) and oxidized forms (>99%). The oxidized forms include protein (primarily albumin)-bound homocysteine mixed disulfide (80-90%), homocysteine-cysteine mixed disulfide (5-10%), and homocystine (5-10%). Several studies have shown the relationship between homocysteine and altered endothelial cell function leading to thrombosis. Thus, hyperhomocysteinemia appears to be an independent risk factor for occlusive vascular disease. Five to ten percent of the general population have mild hyperhomocysteinemia. 

Folate deficiency has been implicated in neural tube defects, including spina bifida, encephalo-celes, and anencephaly. This is true even in the absence of folate-deficient anemia or alcoholism. An inadequate intake of folate also can result in elevations in plasma homocysteine. Since even moderate hyperhomocysteinemia is considered an independent risk factor for coronary artery and peripheral vascular disease and for venous thrombosis, the role of folate as a methyl donor in the homocysteine-to-methionine conversion is getting increased attention. Patients who are heterozygous for one or another enzymatic defect and have high normal to moderate elevations of plasma homocysteine may improve with foUc acid therapy. 

Cystathionine fisynthase (EC 4.2.1.22). Failure to form cystathionine from homocysteine and serine. Elevated homocysteine and methionine in serum. Urine contains homocystine and homocysteine-cysteine disulfide. Cystathionine virtually absent from brain, where it is normally present in significant quantities. Mental retardation. Lens detachment. Skeletal abnormalities (tall stature, arachnodactyly). Arterial and venous thrombosis. 

Venous thrombosis Vitamin Be Homocysteine reduction RCT no reduction of risk in disease recurrence den Heijer et al. (2007)... 

Lussana, F., Zighetti, M.L., and Bucciarelli, P., 2003. Blood levels homocysteine, folate, vitamin B6 and B12 in women using oral contraceptives compared to non-users. Thrombosis Research. 112 37-41. 

B vitamins. Among the 13 vitamins, B vitamins are eight water-soluble vitamins (vitamin Bp thiamine vitamin B2 riboflavin vitamin B3 niacin vitamin B5 pantothenic acid vitamin Bg pyridoxine, pyridoxal or pyridoxamine vitamin B7 biotin vitamin B9 folic acid or folate and vitamin B cyanoco-balamin). Folate and vitamins Bg and B12 have joint effects on homocysteine. Cardiovascular disease. Cardiovascular disease (CVD) is a group of disorders of the heart and blood vessels and includes coronary heart disease, cerebrovascular disease, peripheral arterial disease, rheumatic heart disease, congenital heart disease (malformations of heart structure existing at birth) and deep vein thrombosis and pulmonary embolism. 

Large meta-analyses have demonstrated that the homozygous C677T MTHFR polymorphism is associated with a higher risk of ischemic heart disease, stroke and deep vein thrombosis, which probably is mediated through raised homocysteine. 

Elevated homocysteine levels are associated with vascular diseases, stroke and thrombosis. 

In 1969, McCully proposed the homocysteine hypothesis of vascular disease after demonstrating extensive atherosclerosis and arterial thrombosis at... 

Mansoor, M.A., Bergmark, C., Svardal, A.M., Lonning, P.E., and Ueland, P.M., 1995. Redox status and protein binding of plasma homocysteine and other aminothiols in patients with early-onset peripheral vascular disease. Homocysteine and peripheral vascular disease. Arteriosclerosis, Thrombosis, and Vascular Biology. 15 232-240. 

Elevated blood homocysteine is a significant risk factor for atherosclerosis, thrombosis and hypertension, independent of factors such as dietary lipids and plasma lipoproteins (section 7.3.2). About 10-15% of the population, and almost 30% of people with ischaemic heart disease, have an abnormal variant of methylene-tetrahydrofolate reductase (Figure 11.23) that is unstable and loses activity faster than normal. 

Diet and nutrition have been extensively investigated as risk factors for CHD. Many dietary factors have been linked directly to an increased or decreased risk of CHD or to major established risk factors of CHD like high blood pressure, disordered blood fats (dyslipidemia), diabetes and metabolic syndrome, overweight and obesity, and also to emerging risk factors like inflammatory markers and homocysteine. Nutrition influences atherogen-esis, thrombosis, and inflammation - all of which are interconnected pathways that lead to CHD. 

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