**3.3.6 Age related factors**

Many studies have shown that hyperhomocysteinemia increases with age (Pennypacker et al., 1992). This is connected with inadequate nutrition, the changes in gastrointestinal function, B vitamins deficiency, enzyme defects, a higher occurance of the C677T mutation and numerous age-related physiological factors.

Pathophysiology and Clinical Aspects of 24 Venous Thromboembolism in Neonates, Renal Disease and Cancer Patients

Coffee consumption has been associated with several risk factors for coronary heart disease, including plasma total homocysteine and reduced B vitamin concentrations (Ulvike et al., 2008). Coffee drinking is associated with smoking and low intake of fruit and vegetables. Tea consumption, in contrast, was associated with lower homocysteine levels (Nygard et al.,

B vitamins have been suggested to play a critical role to maintain low homocysteine levels (Silaste et al., 2001). A diet poor in fresh fruit and vegetables or strict vegeterians may develop nutritional vitamin B12 deficiency (Miller et al., 1991). This is particulary serious in pregnancy, as the mother may not be able to supply the fetus with sufficient vitamin B12. Also modern food processing may destroy essential vitamins and it has recently been shown that microwave heating may destroy as much as 30 % of the vitamin B12 content in food (Watanabe et al., 1998). Prolonged heating may also destroy folate and vitamin B6. Besides, healthly subjects eating fish more than 3 times a week had lower homocysteine levels than

Physical activity plays an important role in our life, since it is the cheapest way of strengthening our health and reduces the risk of developing cardiovascular diseases. It has been confirmed that physical activity decreases the concentrations of total plasma homocysteine and thus the probability of developing a cardiovascular disease in healthy and already sick people. In the study called Bed rest "The influence of simulated weightlessness upon the human organism" performed in 2006, 2007 and 2008 at the Valdoltra Orthopaedic Hospital, Slovenia, in which young male participants (age 24-30 years) rested in horizontal position for 35 days, a statistically increased homocysteine concentration was documented (Plazar et al., 2008). The diet composition and the energy intake were daily supervised and monitored by a dietician. Volunteers were non-smokers, non-alcoholics, without history of cardiovascular and neuromuscular disorders*.* Several studies indicate physical activity as an independent lifestyle factor connected with lower homocysteine concentration. Besides, exercise is associated with a reduction in plasma fibrinogen concentrations, and with increasing activity levels of exercise a reduction in homocysteine was observed. So, this prolonged bed rest study confirms that increased levels of homocysteine in blood, negatively influences the cardiovascular system. Although, the precise mechanism is not well understood, similar consequences can result from prolonged

Many studies have shown that hyperhomocysteinemia increases with age (Pennypacker et al., 1992). This is connected with inadequate nutrition, the changes in gastrointestinal function, B vitamins deficiency, enzyme defects, a higher occurance of the C677T mutation

**3.3.3 Coffee consumption** 

**3.3.4 Inadequate nutrition** 

**3.3.5 Physical activity** 

those eating fish less than one a month.

physical inactivity in everyday life.

and numerous age-related physiological factors.

**3.3.6 Age related factors** 

1997b).

**MOST COMMON RISK FACTORS**  *Inherited*  CBS deficiency MTHFR deficiency MS deficiency Being male *Aquired*  Aged 40 + Deficients of folate, vitamin B6 and B12 Post menopausal status Drinking alcohol Smoking Often angry or suppress anger Physical inactivity / sedentary life-style Drinking caffeinated drinks - coffee, tea, coke Being pregnant Being strict vegetarian High fat/protein diet intake High diet salt intake Hypothyroidism Chronic kidney problems Use drugs: e.g.: phenytoin, carbamazepine, methotrexate, aminoglutethimide Suffering from chronic illnesses Digestive problems, auto-immune diseases, asthma, eczema, arthritis, osteoporosis, ulcers, diabetes, heart conditions, high blood pressure, thrombosis, cancer

Table 3. Common risk factors inducing mild hyperhomocysteinemia

#### **4. Venous thromoembolism and hyperhomocysteinemia**

It has been recognized, since the first description of hyperhomocysteinemia, that arterial and venous thrombosis are common in these patients. Patients with homocysteinuria suffered of thrombotic events, cerebrovascular occlusions, deep vein thromboses, myocardial infarctions and peripheral vascular thromboses (Mudd et al., 1985) of which a quarter of all thrombotic events occured before the age of 16 and half before the age of 28, much earlier in life than would normally be expected for these types of events. Further, patients with CBS deficiency-induced homocysteinuria have high levels of plasma homocysteine (Carey et al., 1968). Interest in the hyperhomocysteinemia condition increased when a large number of studies (mainly retrospective) showed that also mildly elevated homocysteine levels are associated with venous thromboembolism (VTE), thrombotic stroke, and peripheral vascular disease (Wilcken & Wilcken, 1976, Mudd et al., 1985, Moll, 2004).

To conclude, mild hyperhomocysteinemia can be induced by a variety of risk factors of which the most common genetic factors are heterozygous CBS gene defects and polymorphism in the MTHFR gene at position 677, while as well numerous aquired conditions might be involved (Table 3).

Hyperhomocysteinemia: Relation to Cardiovascular Disease and Venous Thromboembolism 27

breast, pancreas, and gastrointestinal cancers are associated with a higher incidence of thrombosis. With more advanced stages of cancer there is a lower overall survival rate, but, also a greater risk of venous thromboembolism, additionally influencing the survival of

The associated pathophysiology of VTE and malignancies has not been precisely defined. However, it has been reported that cancer patients show increased levels of several procoagulant factors (Falanga et al., 1993). It is well established that women with advanced breast cancer show hyperhomocysteinemia, which explains the hight rate of venous thrombosis in women with metastatic breast malignancy (Smith et al., 2008). Other established contributors to the VTE increased risk are: chemotherapy, hormonal adjuvant therapy, surgery, central venous catheters, immobility and inherited thrombophilia, with

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

Several studies have examined the relationship between hyperhomocysteinemia and retinal vein occlusion, a condition affecting approximately five out of 1000 of the general population over 64 years of age (David et al., 1988). The association between retinal vein occlusion, hyperhomocysteinemia and thermolabile MTHFR was confirmed (Janssen et al.,

Venous thrombosis in children occurs at a much lower frequency than in adults and the events are usually provoked by acquired risk factors like sepsis, cancer and central venous catheters. The association of VTE and hyperhomocysteinemia in children has been

Hyperhomocysteinemia during pregnancy, which is a consequence of perturbations in methionine and/or the folate metabolism, has been implicated in adverse outcomes such as

confirmed in two case control studies (Koch et al., 1999; Kosch et al., 2004).

the notion that oncological therapies do influence the immunological response.

determinant of elevated plasma homocysteine concentration level.

**4.2.4 Homocysteine and thrombosis in children** 

**4.2.5 Hyperhomocysteinemia and pregnancy** 

patients.

**4.2.2 Renal failure and VTE** 

**4.2.3 Retinal Vein occlusion** 

2005).

Independent from other factors hyperhomocysteinemia is associated with a 4.8 fold increased risk for VTE (Köktürk et al., 2010).
