Blood Disorders in the Elderly - part 10 pptx

438 Daniela Mari compared with its prevalence in several control patient groups (older controls 66 Ϯ 8 years old, young controls 46 Ϯ 14 years old) [46]. The prevalence was the same in older individuals with or without stroke and was lower in elderly individuals than in the younger ones. In conclusion, FV Leiden does not appear to infl uence the risk of arterial thrombosis in the elderly. Factor VIII/von Willebrand factor (FVIII/VWF) It is well known that increased plasma levels of FVIII are associated with an increased risk of venous thrombosis [47]. The plasma FVIII levels are modu- lated by VWF antigen (VWF:Ag), the carrier molecule of FVIII in plasma [48,49], and ABO blood group [50]. In the CHS, FVIII concentrations showed a positive association with risk of coronary heart disease among men and risk of cerebrovascular disease, i.e., transient ischemic attacks and stroke, among women [51]. VWF has been identifi ed as a risk factor for recurrent myocardial infarction in the general population and is associated with cerebrovascular disease [52– 54]. In the Rotterdam study [55] a strong correlation was demonstrated in elderly individuals (mean age 78) between VWF and atrial fi brillation, myocardial infarction, diabetes, and smoking in a large commu- nity-based study. Seemingly, VWF concentrations were a marker of endothelial damage [55]. Recently, the results of a 20-year follow-up exami- nation of all surviving men (aged 60–79 years) enrolled in the British Regional Heart Study were published [56]. In this prospective study of cardiovascular diseases, non-diabetic older men with no history of cardiovascular heart disease or stroke showed a signifi cant association between insulin resistance and infl ammatory markers (C-reactive protein and white cell count), coagulation factors VII–IX, markers of endothelial dysfunction (VWF and tissue-plasminogen activator), and blood viscosity. These relationships were independent of age, smoking, physical activity, alcohol intake, social class, use of statin and aspirin, and persisted after further adjustment for abdominal obesity. In particular, fasting insulin was the factor associated most strongly with VWF and FVIII. Only fasting insulin was independently associated with VWF, whereas FVIII, which was highly correlated with VWF (r ϭ 0.69), showed independent relationships with blood glucose and fasting insulin. Plasminogen activator inhibitor 1 (PAI-1) PAI-1 is a major determinant of fi brinolytic activity. There is substantial experimental and epidemiologic evidence that PAI-1 might contribute to the development of ischemic cardiovascular disease [57]. Elevated PAI-1 plays a role in the metabolic syndrome [58], and strong associations have been described between PAI-1 plasma levels and excess weight, abdominal obesity, diabetes mellitus, and insulin concentration. A common deletion/insertion polymorphism (4G/5G) has been identifi ed in the 5Ј promoter region. The guanine insertion/ deletion polymorphism is located at position –675, where one allele has a sequence of four guanines (4G) and the other has a fi fth guanine inserted (5G) [59]. The 4G allele has been correlated with high levels of gene transcription and elevated PAI-1 plasma levels in comparison with the 5G allele. This PAI-1 polymorphism modulates phenotypes associated with the metabolic syndrome [60]. The Leiden 85-plus study is a population-based study including 1258 subjects aged 85 years or older [61]. Six hundred sixty-six individuals (188 men and 478 women), successfully genotyped for angiotensin-I-converting enzyme and PAI-1 gene variants, were followed up over 10 years. The primary result of this prospective study was that men у85 years old carrying the PAI-1 4G/5G genotype were at a threefold increased risk of death due to ischemic heart disease within the 10-year follow-up (95% CI 1.2–7.6). Plasma levels of PAI-1 increase with age in a population characterized by a relatively high prevalence of obesity, hypertension, and diabetes mellitus [62]. Stratifying by genotype, signifi cant associations were found between age and PAI-1 antigen in 4G/4G and in 4G/5G groups, helping to identify a subgroup of people with an increasing risk of cardiovascular disease with age. Gene–environment interactions and vascular risk 439 Recently, Reiner and coworkers examined the association between promoter polymorphisms of several thrombosis and infl ammation genes with longevity in the CHS. Genotyping assays were performed at baseline on a subset of 2224 CHS individuals (1874 whites and 350 blacks). The mean age at the study entry was 73 years (84% whites, 54% women). After 10 years of follow-up, PAI-1 4G/4G genotype was associated with increased cardiovascular mortality in women and lower non- cardiovascular mortality in men [19]. The Quebec Family Study genotyped 666 subjects for fi ve PAI-1 gene polymorphisms and is the fi rst to show an association with direct measures of fat mass and abdominal fat, thus suggesting that PAI-1 may infl uence fat mass accretion, particularly in women. Stratifi ed analyses were performed with analysis of covariance in men (n ϭ 280) and women (n ϭ 386) separately. PAI-1-675 4G/5G polymorphism was strongly associated with body mass index (p ϭ 0.01) and fat mass (p ϭ 0.05) in women. The PAI-1-675 4G/5G promoter polymorphism and the c.43G. A (p.A15T, rs6092) variant within the exon 1 were associated with abdominal visceral fat but only in postmenopausal women (p ϭ 0.05). No association was observed in men [63]. Hormone replacement therapy, in a group of postmenopausal women with coronary artery disease, decreased circulating PAI-1 levels in those with the 4G/5G phenotype [64]. From this study it is not clear whether estrogen is benefi - cial for these individuals. A study on Italian centenarians suggests that the 4G allele carriers reached longevity despite high circulating PAI-1 levels [65]. Another important gene–environment interaction was identifi ed by Brown et al. [66], who demonstrated a signifi cant interactive effect of salt intake and PAI-1 4G/5G genotype on PAI-1 antigen. The activation of the renin–angiotensin–aldosterone system increased the effects of PAI-1 genotype on the risk of thrombotic cardiovascular events, associated with PAI-1 antigen. As renin production decreases with age, it is not surprising that the association between PAI-1 4G/5G genotype and myocardial infarction was stronger in the young [67] than in the older population [68,69]. Thrombin activatable fi brinolysis inhibitor (TAFI) TAFI is a plasma carboxypeptidase that regulates fi brinolysis by removing the C-terminal lysine and arginine residues from fi brin, thereby decreasing plasminogen on its surface [70]. A single nucleotide polymorphism in the coding region of the TAFI gene, 1040C/T, results in the Thr325Ile substitution [71]. This polymorphism is of particular interest because TAFI-Ile325 has a 60% greater antifi brinolytic activity than TAFI-Thr325. Many other polymorphisms are described in the TAFI gene, nine in promoter region, two in the 3Ј untranslated region, and three in the coding region. These polymorphisms are in strong linkage disequi- librium and form four main haplotypes. Circulating levels of TAFI are strongly determined by polymor- phic variations in the promoter and the 3Ј region of the TAFI gene [72,73]. Because of its role in the fi brinolytic system, the TAFI gene may be involved in the pathogenesis of atherothrombotic diseases. However, epidemiologic data evaluating the relations between plasma TAFI levels and the risk of cardiovascular disease have given confl icting results. In some studies, high TAFI levels were found to be protective against myocardial infarction [74] and to be negatively correlated with development of refractory angina pectoris [75]. In other studies, high TAFI levels were associated with increased risk of acute coronary artery disease [76] or angina pectoris [77–79]. The difference between studies may be due to the methods used for TAFI determination, because some enzyme-linked immunosorbent assays (ELISA) had decreased antibody reactivity towards the TAFI-Ile325 isoform and consequently produced abnormally low result of TAF1. From 1991 until 1994 the Prospective Epidemio- logical Study of Myocardial Infarction (PRIME) recruited 9758 men aged 50–59 years with no previous cardiovascular events, living in France and Northern Ireland, and they were followed up for 5 years. A total of 248 cases of cardiovascular disease and 493 matched controls were used for the genetic 440 Daniela Mari study. TAFI levels, when measured with a truly reliable method, were strongly infl uenced by polymorphisms of the TAFI gene but not associated with risk of cardiovascular heart disease [80]. The results of CHS [19] highlighted the role of TAFI-438A/A genotype in predicting mortality from all causes. Older white men (mean age at enroll- ment was 73) with this genotype had a reduced 10-year mortality rate. Survival was increased by 0.9 years, and they had 1.1 additional years of active life expectancy. No signifi cant effect of TAFI-438G/A on survival was observed in women. It should be noted that the prevalence of the TAFI-438G/A promoter genotype in this population was signifi cantly different from that reported in another study of a healthy middle-aged population of European descent [74]. The infl uence of TAFI genotype on survival could be age- and sex-specifi c. The mortality reduction associated with the TAFI-438A/A genotype involved all causes of mortality, not just that from thromboembolic or cardiovascular disease. Activated TAFI may cleave different substrates and regulate the course of infl ammation [81]. This enzyme signifi cantly contributes to the inactivation of C5a, the most potent of complement- derived anaphylatoxins [82]. This TAFI-438A/A genotype may have provided our ancestors with enhanced anti-infl ammatory and anti-thrombotic mechanisms, to improve wound healing and facili- tate reproduction. Hyperhomocysteinemia Homocysteine is a sulfur-containing amino acid, which results from the hydrolysis of S-adenosyl- homocysteine in the methionine metabolic cycle. Several conditions may determine an increase of blood homocysteine, such as an inadequate folate intake with diet, smoking, drugs (i.e., methotrexate, hormones, antiepileptic), renal failure, and inher- ited gene polymorphism of methylene-tetra-hydro- folate reductase (MTHFR). This common functional polymorphism, C677T, is associated with decreased enzymatic activity and increased homocysteine concentration. Increased levels of circulating homocysteine may trigger endothelial dysfunction through oxidative damage and induce increased oxidation of low- density lipoprotein, stimulation of smooth mus- cle cell proliferation, and hypercoagulable state. Hyperhomocysteinemia represents a modifi able cardiovascular risk factor, since vitamin supplemen- tation has been shown to effectively lower plasma homocysteine levels. The association between moderately high plasma levels of total homocysteine (tHcy) with the risk of cardiovascular disease, coronary artery disease, cerebrovascular disease, peripheral artery disease, and venous thromboembolism has been reported in several case–control, cross-sectional, and prospective studies reviewed by Cattaneo [83]. In the Homocysteine Studies Collaboration meta-analysis [84] a weak association was observed between tHcy and coronary heart disease, and in the prospective studies considered a plasma tHcy reduction of 25% was associated with an 11% lower risk of ischemic heart disease (OR 0.89, 95% CI 0.83–0.96). A recent meta-analysis presents new evidence that an increased tHcy may be a causal risk factor for stroke [85]. If homocysteine increases the risk of stroke, MTHFR polymorphism should increase the risk of stroke by increasing circulating levels of homocysteine. Among 15 635 people without cardiovascular disease, the weighted mean difference in homocysteine concentration between TT and CC homozygotes was 1.93 µmol/L (95% CI 1.38–2.47). The expected odds ratio for stroke corresponding to this difference, based on previous observational studies, was 1.20 (1.10–1.31). In this genetic meta- analysis (n ϭ 13 928) the odds ratio for stroke was 1.26 (1.14–1.40) for TT versus CC homozygotes, similar to the expected odds ratio (p ϭ 0.29). Many ongoing clinical trials have the aim to dem- onstrate that decreasing tHcy with folic acid (with or without B vitamins) is associated with a reduction in cardiovascular risk [86]. The infl uence of age on tHcy plasma levels in patients with different genotypes has been investigated in three North American studies: a study of mothers of children with spina bifi da (three age groups, Ͻ34 years, 34–40 years, Gene–environment interactions and vascular risk 441 Ͼ40 years), the National Heart, Lung, and Blood Family Heart Study (three age groups, Ͻ45 years, 45–59 years, Ͼ60 years) and a Mayo Clinic study of patients undergoing coronary angiography (three age groups, Ͻ56 years, 56–67 years, Ͼ67 years) [87]. Plasma homocysteine levels increased with age in the C/C and C/T genotype groups (p Ͻ 0.0001 and p Ͻ 0.001, respectively), but not in the T/T genotype. Genotype was signifi cantly associated with plasma homocysteine levels in the whole population and in the youngest group (p ϭ 0.002 and p ϭ 0.005, respectively), but not in the two older age groups. The subjects of these studies were highly selected. The family heart study and the Mayo Clinic study involved individuals at high risk for cardiovascular disease, while only mothers of children with spina bifi da were involved in the spina bifi da study. The prevalence of MTHFR genotypes in this selected population may not refl ect the prevalence in the general population. Higher plasma homocysteine levels have been associated with low vitamin status in the elderly [88], and thus the non-genetic causes of hyperhomocysteinemia may be more important in the aged population. The treatment of hyperhomocysteinemia in older individuals is safe and not expensive [89,90]. The Nutrition Committee of the American Heart Association has recommended 0.4 mg of folic acid, 2 mg of vitamin B 6 , and 6 mg of vitamin B 12 daily. The centenarians All studies on coagulation factors in elderly subjects have been performed in individuals under the age of 80. In general aging is associated with increased concentration of clotting factors, which may be a harbinger of increased coagulability, or alterna- tively may represent a harmless manifestation of the aging process. The study of centenarians, who present a natural model of successful aging, may help to identify the biological basis of longevity. In 1995 Mari et al. [91] for the fi rst time showed the results of an extended study of coagulation and fi brinolysis in 25 Italian centenarians. The results were compared with those obtained in two control groups of healthy adults, 25 aged 18–50 years and 25 aged 51–69 years. Older controls had, in general, slightly higher values of several coagulation and fi brinolysis measurements than younger controls. Centenarians had striking signs of heightened coagulation enzyme activity, as assessed directly by measuring activated FVII in plasma (p Ͻ 0.01, compared with either control group) or indirectly by measuring the plasma levels of the activation peptides of prothrombin, FIX, FX, and thrombin– antithrombin complexes (all p Ͻ 0.001). Heightened coagulation enzyme activity was accompanied by signs of fi brin formation (high fi brinopeptide A, p Ͻ 0.001) and secondary hyperfi brinolysis (high D-dimer and plasmin–antiplasmin complex [PAP], p Ͻ 0.001). Plasma concentrations of fi brinogen and FVIII were higher than in controls, whereas other coagulation factors were not elevated. In conclusion, this study showed that the very elderly did not escape the state of hypercoagulability associated with aging, but that this phenomenon is compatible with health and longevity. Hence, high plasma levels of the coagulation activation markers in older populations do not necessarily predict a high risk of arterial or venous thrombosis. Gene polymorphisms associated with the plasma levels of fi brinogen, FVII, and PAI-1, hemostasis proteins that help to predict the risk of atherothrombotic disease, were compared in 124 healthy individuals over 100 years old and 130 young, healthy individuals to identify genetic infl uences on extreme longevity [65]. The restriction fragment length polymorphism GA-455, located in the promoter of the β-fi brinogen gene, the guanine insertion/deletion polymorphism 4G/5G in the promoter of the PAI-1 gene, and the R353Q substitution polymorphism in exon 8 of the FVII gene have been investigated. Alleles and genotypes associated with elevated plasma levels of fi brinogen and FVII were found with similar fre- quencies in centenarians and in the comparison group. However, in centenarians there was a signifi - cantly higher frequency of the 4G allele and of the homozygous 4G/4G genotype associated with high 442 Daniela Mari PAI-1 levels. Since high PAI-1 is considered a predictor of recurrent myocardial infarction in young men, it is intriguing that the corresponding genetic marker is more frequent in centenarians who have escaped major age-related atherothrombotic disease and reached the extreme limits of human life. Homozygosity for the 4G allele, despite its association with impaired fi brinolysis, is compatible with successful aging. Rizzo et al. [92] showed that healthy centenarians have signifi cantly higher plasma PAI- 1 levels than non-centenarians, but these levels were not associated with the same degree of insulin resistance found in non-centenarians. Bladbjerg et al. [93] showed that polymorphisms of hemostasis genes do not predict longevity because the allele dis- tributions were similar in Danish centenarians and younger individuals. We described the same allele frequency of mutant F/V, an established risk factor for idiopathic and recurrent venous thrombosis, in Italian centenarians and in non-centenarians, without thrombotic events [94]. A slightly lower allele frequency in French centenarians was detected [95], unchanged allele frequency was found with low prevalence of venous thrombosis in Danish centenarians and one female homozygous for the FV mutation gene without history of thrombosis [96]. Regarding endothelial integrity, we have described signifi cantly higher levels of VWF:Ag and VWF:Rco in centenarians than in controls without signifi cant difference between blood group O and non-O. Fifty- one percent of centenarians have a reduction of the relative proportion of high-molecular-weight multimers (HMV); furthermore VWF-cleaving protease was lower than in young controls [97]. The fi nding that the VWF:CP levels are low when VWF levels are high in centenarians could be a corol- lary of the previously described paradox of successful aging [90], adding another marker of increased risk of atherothrombosis to the scenario. The labo- ratory evidence of heightened coagulation enzyme activity does not necessarily indicate an increased thrombotic risk. Among centenarians, striking biochemical signs of hypercoagulability have been documented, as assessed by measurements of plasma-activated FVII, F1ϩ2, the activation peptides of FIX and FX, TAT, FpA, and DD. The accelerated generation of activated FX, resulting in increased conversion of prothrombin into thrombin and eventually in fi brin formation, may be due to enhanced FVII–tissue factor interaction at the site of endothelial damage, or may be a consequence of impaired availability of glycosaminoglycans that modulate antithrombin III activity in vivo on the vascular surface. In addition, centenarians display high immune-reactivity against human beta-2-glyc- oprotein I, but low binding to the bovine molecule in the anticardiolipin assay. In spite of the presence of antibodies comparable to those found in patients with the antiphospholipid syndrome, no vascular events were reported, suggesting the presence of unknown protective factors and/or the lack of trig- gering factors [98]. Centenarians possess also high- risk alleles for many polymorphisms related to the cardiovascular diseases, even in homozygous form [65, 92–95]. Thus, the state of hypercoagulability and the pos- session of several high-risk alleles and well-known atherothrombotic risk markers [97] appear to be compatible with longevity and/or health. In the oldest old, the risk factors may play a different role than in young-adult subjects: for example, high total cholesterol concentrations are associated with longevity owing to lower mortality from cancer and infection [99]. Conclusions Atherosclerotic disease has reached epidemic proportions only within the last century. In fact, given that genetic polymorphisms have surely been present between populations for thousands of years, it is only the quite recent development of adverse genetic and environmental interactions that can explain the incidence and prevalence of this disorder. Gene–environment interactions are important because genes produce their effects in an indirect way (through proteins) and, therefore, the Gene–environment interactions and vascular risk 443 ultimate outcome of gene action may be different in different circumstances. In addition, perhaps thousands of gene variations escaped the force of natural selection and thus play roles in the genesis of different patterns of aging in humans. The study of environmental factors is important especially when behavioral or rehabilitative interventions may com- pensate for the functional decline of aging. The recent studies of cardiovascular risk factors, assessed late in life, have highlighted some novel, promising candidates among markers of hemostatic activation and hemostatic proteins [19,26]. Specifi cally, the modulation of fi brinolysis may infl uence aging and age-related diseases. For example, PAI-1 links two pathophysiological situations, obesity and diabetes, both of which are conditions at risk for cardiovascular diseases. On the other hand, numerous studies indicate that the increase in cardiovascular risk cannot be ascribed solely to the role of PAI-1 in either obesity or insulin resistance, but many environmental factors could inter- fere with PAI-1 plasma levels and 4G/5G genotype, including salt intake, physical activity, and triglycer- ide levels [66,69,100]. Oral antidiabetic drugs, such as metformin, reduce plasma PAI-1 levels [101]. The use of a small-molecule PAI-1 antagonist to reduce plasma PAI-1 activity and tissue remodeling would appear to be a promising strategy [102]. Recently, for the fi rst time, it has been demonstrated that a hemostasis-associated gene can contribute to human longevity, in the shape of a common promoter variant of the TAFI gene [19]. This fact suggests that the modulation of fi brinolysis may result in longevity, perhaps because reduced plasma levels of TAFI are associated with reduced infl ammatory activity. To a large extent genetics infl uences the levels of clotting factors that predict increased risk of cardiovascular disease even in elderly individuals. The combination of genotype and environmental factors determines individual disease susceptibility. Future studies, including of the oldest old, will help to clarify the importance of traditional and newer risk factors and lead to better estimates of individual cardiovascular risk. REFERENCES 1. Meade TW. Haemostatic function, arterial disease and the prevention of arterial thrombosis. Baillieres Clin Haematol 1994; 7: 733–55. 2. Green F, Humphries S. Genetic determinants of arterial thrombosis. Baillieres Clin Haematol 1994; 7: 675–92. 3. Voetsch B, Loscalzo J. Genetic determinants of arterial thrombosis. Arterioscler Thromb Vasc Biol 2004; 24: 216–29. 4. Cauley JA, Dorman JS, Ganguli M. Genetic and aging epidemiology: the merging of two disciplines. Neurol Clin 1996; 14: 467–75. 5. Franceschi C, Bonafe M, Valensin S, et al. Infl amm- aging: an evolutionary perspective on immunosenes- cence. Ann NY Acad Sci 2000; 908: 244–54. 6. Meade TW, Mellows S, Brozovic M, et al. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study. Lancet 1986; 2: 533–7. 7. MacCallum PK, Meade TW. Haemostatic function, arterial disease and the prevention of arterial thrombosis. Baillieres Best Pract Res Clin Haematol 1999; 12: 577–9. 8. Wilhelmsen L, Svardsudd K, Korsan-Bengsten K, Larsson B, Welin L, Tibblin G. Fibrinogen as a risk factor for stroke and myocardial infarction. N Engl J Med 1984; 31: 501–5. 9. Balleisen L, Bailey J, Epping PH, Schulte H, van De Loo J. Epidemiological study on factor VII, factor VIII and fi brinogen in industrial population: baseline data on the relation to age, gender, body-weight, smoking, alcohol, pill-using and menopause. Thromb Haemost 1985; 54: 475–9. 10. Maresca G, Di Blasio A, Marchioli R, Di Minno G. Measuring plasma fi brinogen to predict stroke and myocardial infarction: an update. Arterioscleros Thromb Vasc Biol 1999; 19: 1368–77. 11. Heinrich J, Balleisen L, Schulte H, Assmann G, van de Loo J. Fibrinogen and factor VII in the prediction of coronary risk: results from the PROCAM study in healthy men. Arterioscler Thromb 1994; 14: 54–9. 12. Crawford VLS, McNerlan SE, Stout RS. Seasonal changes in platelets, fi brinogen, and factor VII in elderly people. Age Ageing 2003; 32: 661–5. 13. Duan HO, Simpson-Haidaris PJ. Functional analysis of interleukin 6 response elements (IL-6REs) on the human gamma-fi brinogen promoter: binding of hepatic stat3 444 Daniela Mari correlates negatively with transactivation potential of type II IL-6REs. J Biol Chem 2003; 17: 41270–81. 14. Thomas A, Green F, Kelleher C, et al. Variation in the promotor region of the β fi brinogen gene is associated with plasma fi brinogen levels in smokers and non- smokers. Thromb Haemost 1991; 65: 487–90. 15. Thomas AE, Green FR, Humphries SE. Association of genetic variation at the beta-fi brinogen gene locus and plasma fi brinogen levels: interaction between allele frequency of the G/A-455 polymorphism, age and smoking. Clin Genet 1996; 50: 184–90. 16. Diehr P, Patrick DL, Bild DE, Burke GL, Williamson JD. Predicting future years of healthy life for older adults. J Clin Epidemiol 1998; 51: 343–53. 17. Diehr P, Newman AB, Jackson SA, Kuller L, Powe N. Weight modifi cation trials in older adults: what should the outcome measure be? Curr Control Trials Cardiovasc Med 2002; 3: 1–8. 18. Tracy RP, Arnold AM, Ettinger W, Fried L, Meilahn E, Savage P. The relationship of fi brinogen and factors VII and VIII to incident cardiovascular disease and death in the elderly: results from the Cardiovascular Health Study. Arterioscler Thromb Vasc Biol 1999; 19: 1776–83. 19. Reiner AP, Diehr P, Browner WS, et al. Common promoter polymorphisms of infl ammation and thrombosis genes and longevity in older adults: the Cardiovascular Health Study. Atherosclerosis 2005; 181: 175–83. 20. Yano K, Grove JS, Chen R, Rodriguez BL, Curb JD, Tracy RP. Plasma fi brinogen as a predictor of total and cause- specifi c mortality in elderly Japanese-American men. Arterioscler Thromb Vasc Biol 2001; 2: 1065–70. 21. de Maat MP, Bladbjerg EM, Hjelmborg JB, Bathum L, Jespersen J, Christensen K. Genetic infl uence on infl ammation variables in the elderly. Arterioscler Thromb Vasc Biol 2004; 24: 2168–73. 22. Leander K, Wyman B, Hallqvist J, Falk G, De Faire U. The G-455A polymorphism of the fi brinogen beta-gene relates to plasma fi brinogen in male cases, but does not interact with environmental factors in causing myocardial infarction in either men or women. J Intern Med 2002; 252: 332–41. 23. Balleisen L, Bailey J, Epping PH, Schulte H, van De Loo J. Epidemiological study on factor VII, factor VIII and fi brinogen in industrial population: baseline data on the relation to age, gender, body-weight, smoking, alcohol, pill-using and menopause. Thromb Haemost 1985; 54: 475–9. 24. Meade TW, Chakrabarti R, Haines AP, North Y, Thompson SG, Brozovic M. Haemostatic function and cardiovascular death: early results of a prospective study. Lancet 1980; 1: 1050–5. 25. Folsom AR, Wu KK, Rosamond WD, Sharrett AR, Chambless LE. Prospective study of hemostatic factors and incidence of coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) study. Circulation 1997; 96: 1102–8. 26. Tracy RP, Arnold AM, Ettinger W, Fried L, Meilahn E, Savage P. The relationship of fi brinogen and factors VII and VIII to incident cardiovascular disease and death in the elderly: results from the Cardiovascular Health Study. Arterioscler Thromb Vasc Biol 1999; 19: 1776–8. 27. Humphries SE, Green FR, Temple A, et al. Genetic factors determining thrombosis and fi brinolysis. Ann Epidemiol 1992; 2: 371–85. 28. Iacoviello L, Di Castelnuovo A, De Knijff P, et al. Polymorphisms in the coagulation factor VII gene and the risk of myocardial infarction. N Engl J Med 1998; 338: 79–85. 29. Di Castelnuovo A, D’Orazio A, Amore C, Falanga A, Donati MB, Iacoviello L. The decanucleotide insertion/deletion polymorphism in the promoter region of the coagulation factor VII gene and the risk of familial myocardial infarction. Thromb Res 2000; 98: 9–17. 30. Girelli D, Russo C, Ferraresi P, et al. Polymorphisms in the factor VII gene and the risk of myocardial infarction in patients with coronary artery disease. N Engl J Med 2000; 343: 774– 80. 31. Doggen CJ, Manger Cats V, Bertina RM, Reitsma PH, Vandenbroucke JP, Rosendaal FR. A genetic propensity to high factor VII is not associated with the risk of myocardial infarction in men. Thromb Haemost 1998; 80: 281–5. 32. Lane A, Green F, Scarabin PY, et al. Factor VII Arg/Gln353 polymorphism determines factor VII coagulant activity in patients with myocardial infarction (MI) and control subjects in Belfast and in France but is not a strong indicator of MI risk in the ECTIM study. Atherosclerosis 1996; 119: 119–27. 33. Lievers KJ, Mennen LI, Rattink AP, et al. The -323Ins10 polymorphism for factor VII is not associated with coronary atherosclerosis in symptomatic men. The REGRESS Study Group. Thromb Res 2000; 97: 275–80. 34. Wang XL, Wang J, McCredie RM, Wilcken DE. Polymorphisms of factor V, factor VII, and fi brinogen genes: relevance to severity of coronary artery disease. Arterioscler Thromb Vasc Biol 1997; 17: 246–51. 35. Feng D, Tofl er GH, Larson MG, et al. Factor VII gene polymorphism, factor VII levels, and prevalent Gene–environment interactions and vascular risk 445 cardiovascular disease: the Framingham Heart Study. Arterioscler Thromb Vasc Biol 2000; 20: 593–600. 36. Stessman J, Maaravi Y, Hammerman-Rozenberg R, et al. Candidate genes associated with ageing and life expectancy in the Jerusalem longitudinal study. Mech Ageing Dev 2005; 126: 333–9. 37. Jeffery S, Poloniecki J, Leatham E, et al. A protective contribution of the Q allele of the R353Q polymorphism of the factor VII gene in individuals with chronic stable angina? Int J Cardiol 2005; 100: 395–9. 38. Mennen LI, De Maat MPM, Schouten EG, et al. Dietary effects on coagulation factor VII vary across genotypes of the R/Q353 polymorphism in elderly people. J Nutr 1998; 128: 870–4. 39. Ariens RA, Lai TS, Weisel JW, Greenberg CS, Grant PJ. A role of factor XIII in fi brin clot formation and effects of genetic polymorphisms. Blood 2002; 100: 743–75. 40. Lim B, Ariens R, Carter A, Weisel J, Grant P. Genetic regulation of fi brin structure and function: complex gene–environment interactions may modulate vascular risk. Lancet 2003; 361: 1424–31. 41. Elbaz A, Poirier O, Canaple S, Chedru F, Cambien F, Amarenco P. The association between the Val34Leu polymorphism in the factor XIII gene and brain infarction. Blood 2000; 95: 586–91. 42. Bertina RM, Koeleman BP, Koster T, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64–7. 43. Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Eisenberg PR, Miletich JP. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. N Engl J Med 1995; 332: 912–17. 44. Cushman M, Kuller LH, Prentice R, et al. Estrogen plus progestin and risk of venous thrombosis. JAMA 2004; 292: 1573–80. 45. Reiner AP, Siscovick DS, Rosendaal FR. Hemostatic risk factors and arterial thrombotic disease. Thromb Haemost 2001; 85: 584–95. 46. Press RD, Liu XY, Beamer N, Coull BM. Ischemic stroke in the elderly: role of the common factor V mutation causing resistance to activated protein C. Stroke 1996; 27: 44–8. 47. Kamphuisen PW, Eikenboom JCJ, Bertina, RM. Elevated factor VIII levels and the risk of thrombosis. Arterioscler Thromb Vasc Biol 2001; 21: 731–8. 48. Weiss HJ, Hoyer IW. Von Willebrand factor: dissocia- tion from antihemophilic factor procoagulant activity. Science 1973; 182: 1149–51. 49. Wise RJ, Dorner AJ, Krane M, Pittman DD, Kaufman RJ. The role of von Willebrand factor multimers and propeptide cleavage in binding and stabilization of factor VIII. J Biol Chem 1991; 266: 21948–55. 50. Orstavik KH, Magnus P, Reisner H, Berg K, Graham JB, Nance W. Factor VIII and factor IX in a twin population: evidence for a major effect of ABO locus on factor VIII level. Am J Hum Genet 1985; 37: 89–101. 51. Tracy RP, Arnold AM, Ettinger W, Fried L, Meilahn E, Savage P. The relationship of fi brinogen and factors VII and VIII to incident cardiovascular disease and death in the elderly: results from the cardiovascular health study. Arterioscler Thromb Vasc Biol 1999; 19: 1776–83. 52. Lip GY, Blann AD. Von Willebrand factor and its relevance to cardiovascular disorders. Br Heart J 1995; 74: 580–3. 53. Catto AJ, Carter AM, Barrett JH, Bamford J, Rice PJ, Grant PJ. Von Willebrand factor and factor VIII:C in acute cerebrovascular disease: relationship to stroke subtype and mortality. Thromb Haemost 1997; 77: 1104–8. 54. Jansson JH, Nilsson TK, Johnson O. Von Willebrand factor in plasma: a novel risk factor for recurrent myocardial infarction and death. Br Heart J 1991; 66: 351–5. 55. Conway DS, Heeringa J, Van Der Kuip DA, et al. Atrial fi brillation and the prothrombotic state in the elderly: the Rotterdam study. Stroke 2003; 34: 413–17. 56. Wannamethee SG, Lowe GD, Shaper AG, Rumley A, Lennon L, Whincup PH. The metabolic syndrome and insulin resistance: relationship to haemostatic and infl ammatory markers in older non-diabetic men. Atherosclerosis 2005; 181: 101–8. 57. Kohler HP, Grant PJ. Plasminogen-activator inhibitor type 1 and coronary artery disease. N Engl J Med 2000; 342: 1792–801. 58. Juhan-Vague I, Alessi MC, Vague P. Increased plasma plasminogen activator inhibitor 1 levels: a possible link between insulin resistance and atherothrombosis. Diabetologia 1991; 34: 457–62. 59. Dawson S, Wiman B, Hamsten A, Green F, Humphries S, Henney AM. The two allele sequences of a common polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene responds differ- ently to IL-1 in Hep G2 cells. J Biol Chem 1993; 268: 10739–45. 60. Juhan-Vague I, Morange PE, Frere C, et al. The plasminogen activator inhibitor-1-675 4G/5G genotype infl uences the risk of myocardial infarction associated with elevated plasma proinsulin and insulin 446 Daniela Mari concentrations in men from Europe: the HIFMECH study. J Thromb Haemost 2003; 1: 2322–9. 61. Heijmans BT, Westendorp RG, Knook DL, Kluft C, Slagboom PE. Angiotensin I-converting enzyme and plasminogen activator inhibitor-1 gene variants: risk of mortality and fatal cardiovascular disease in an elderly population-based cohort. J Am Coll Cardiol 1999; 34: 1176–83. 62. Bonfi gli AR, Sirolla C, Cenerelli S, et al. Plasminogen activator inhibitor-1 plasma level increases with age in subjects with the 4G allele at position -675 in the promoter region. Thromb Haemost 2004; 92: 1164–5. 63. Bouchard L, Mauriege P, Vohl MC, Bouchard C, Perusse L. Plasminogen-activator inhibitor-1 polymorphisms are associated with obesity and fat distribution in the Quebec family study: evidence of interactions with menopause. Menopause 2005; 12: 136–43. 64. Grancha S, Estelles A, Tormo G, et al. Plasminogen activator inhibitor-1 (PAI-1) promoter 4G/5G genotype and increased PAI-1 circulating levels in postmenopausal women with coronary artery disease. Thromb Haemost 1999; 81: 516–21. 65. Mannucci PM, Mari D, Merati G, et al. Gene polymorphisms predicting high plasma levels of coagulation and fi brinolysis proteins: a study in centenarians. Arterioscler Thromb Vasc Biol 1997; 17: 755–9. 66. Brown NJ, Murphey LJ, Srikuma N, Koschachuhanan N, Williams GH, Vaughan DE. Interactive effect of PAI- 1 4G/5G genotype and salt intake on PAI-1 antigen. Arterioscler Thromb Vasc Biol 2001; 21: 1071–7. 67. Iacoviello L, Burzotta F, Di Castelnuovo A, Zito F, Marchioli R, Donati MB. The 4G/5G polymorphism of PAI-1 promoter gene and the risk of myocardial in farction: a meta-analysis. Thromb Haemost 1998; 80: 1029–30. 68. Roest M, van der Schouw YT, Banga JD, et al. Plasminogen activator inhibitor 4G polymorphism is associated with decreased risk of cerebrovascular mortality in older women. Circulation 2000; 101: 67–70. 69. Vaisanen SB, Humphries SE, Luong LA, Penttila I, Bouchard C, Rauramaa R. Regular exercise, plasminogen activator inhibitor-1 (PAI-1) activity and the 4G/5G promoter polymorphism in the PAI-1 gene. Thromb Haemost 1999; 82: 1117–20. 70. Bouma BN, Meijers JC. New insights into factors affect- ing clot stability: a role for thrombin activatable fi brinolysis inhibitor (TAFI; plasma procarboxypeptidase B, plasma procarboxypeptidase U, procarboxypeptidase R). Semin Hematol 2004; 41: 13–19. 71. Brouwers GJ, Vos HL, Leebeek FW, et al. A novel, possibly functional, single nucleotide polymorphism in the coding region of the thrombin-activatable fi brinolysis inhibitor (TAFI) gene is also associated with TAFI levels. Blood 2001; 98: 1992–3. 72. Henry M, Aubert H, Morange PE, et al. Identifi cation of polymorphisms in the promoter and the 3Ј region of the TAFI gene: evidence that plasma TAFI antigen levels are strongly genetically controlled. Blood 2001; 97: 2053–8. 73. Crainich P, Tang Z, Macy EM. A polymorphism at position -438 in the promoter region of thrombin- activatable fi brinolysis inhibitor (TAFI) is strongly associated with plasma antigen levels in healthy older men and women. Circulation 2000; 102: 866. 74. Juhan-Vague I, Morange PE, Aubert H, et al. Plasma thrombin-activatable fi brinolysis inhibitor antigen concentration and genotype in relation to myocardial infarction in the north and south of Europe. Arterioscler Thromb Vasc Biol 2002; 22: 867–73. 75. Brouwers GJ, Leebeek FW, Tanck MW, Wouter Jukema J, Kluft C, de Maat MP. Association between thrombin- activatable fi brinolysis inhibitor (TAFI) and clinical outcome in patients with unstable angina pectoris. Thromb Haemost 2003; 90: 92–100. 76. Santamaria A, Martinez-Rubio A, Borrell M, Mateo J, Ortin R, Fontcuberta J. Risk of acute coronary artery disease associated with functional thrombin activatable fi brinolysis inhibitor plasma level. Haematologica 2004; 89: 880–1. 77. Silveira A, Schatteman K, Goossens F, et al. Plasma procarboxypeptidase U in men with symptomatic coronary artery disease. Thromb Haemost 2000; 84: 364–8. 78. Morange PE, Juhan-Vague I, Scarabin PY, et al. Association between TAFI antigen and Ala147Thr polymorphism of the TAFI gene and the angina pectoris incidence: the PRIME study (Prospective Epidemiological Study of MI). Thromb Haemost 2003; 89: 554–60. 79. Schroeder V, Chatterjee T, Mehta H, et al. Thrombin activatable fi brinolysis inhibitor (TAFI) levels in patients with coronary artery disease investigated by angiography. Thromb Haemost 2002; 88: 1020–5. 80. Morange PE, Tregouet DA, Frere C, et al. TAFI gene haplotypes, TAFI plasma levels and future risk of coronary heart disease: the PRIME study. J Thromb Haemost 2005; 3: 1503–10. 81. Bajzar L, Jain N, Wang P, Walker JB. Thrombin activatable fi brinolysis inhibitor: not just an inhibitor of fi brinolysis. Crit Care Med 2004; 32: S320–S324. Gene–environment interactions and vascular risk 447 82. Campbell WD, Lazoura E, Okada N, Okada H. Inactivation of C3a and C5a octapeptides by carboxypeptidase R and carboxypeptidase N. Microbiol Immunol 2002; 46: 131–4. 83. Cattaneo M. Hyperhomocysteinemia and thrombosis. Lipids 2001; 36: S13–S26. 84. Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta- analysis. JAMA 2002; 288: 2015–22. 85. Casas JP, Bautista LE, Smeeth L, Sharma P, Hingorani AD. Homocysteine and stroke: evidence on a causal link from Mendelian randomisation. Lancet 2005; 365: 224–32. 86. Yap S, Boers GH, Wilcken B, et al. Vascular outcome in patients with homocystinuria due to cystathionine beta-synthase defi ciency treated chronically: a multi- center observational study. Arterioscler Thromb Vasc Biol 2001; 21: 2080–5. 87. Spotila LD, Jacques PF, Berger PB, Ballman KV, Ellison RC, Rozen R. Age dependence of the infl uence of methylenetetrahydrofolate reductase genotype on plasma homocysteine level. Am J Epidemiol 2003; 158: 871–7. 88. Selhub J, Jacques PF, Wilson PW, Rush D, Rosenberg IH. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA 1993; 270: 2693–8. 89. Malinow MR, Bostom AG, Krauss RM. Homocyst(e)ine, diet, and cardiovascular diseases: a statement for healthcare professionals from the Nutrition Committee, American Heart Association. Circulation 1999; 99: 178–82. 90. Cattaneo M. Homocysteine and cardiovascular diseases. Circulation 1999; 100: e151. 91. Mari D, Mannucci PM, Coppola R, Bottasso B, Bauer KA, Rosenberg RD. Hypercoagulability in centenarians: the paradox of successful aging. Blood 1995; 85: 3144–9. 92. Rizzo MR, Ragno E, Barbieri M, et al. Elevated plasma activator inhibitor 1 is not related to insulin resistance and to gene polymorphism in healthy centenarians. Atherosclerosis 2002; 160: 385–90. 93. Bladbjerg EM, Andersen-Ranberg K, de Maat MPM, et al. Longevity is independent of common variations in genes associated with cardiovascular risk. Thromb Haemost 1999; 82: 1110–15. 94. Mari D, Duca F, Mannucci PM, Franceschi C. Mutant factor V (Arg506Gln) in healthy centenarians. Lancet 1996; 347: 1044. 95. Faure-Delanef, Quéré I, Zouali H, Cohen D. Human longevity and R506Q factor V gene mutation. Thromb Haemost 1997; 78: 1160. 96. Kristensen SR, Andersen-Ranberg K, Bathum L, Jeune B. Factor V Leiden and venous thrombosis in Danish centenarians. Thromb Haemost 1998; 80: 860–1. 97. Coppola R, Mari D, Lattuada A, Franceschi C. Von Willebrand factor in Italian centenarians. Haematologica 2003; 88: 39–43. 98. Meroni PL, Mari D, Monti D, et al. Anti-beta 2 glyco- protein I antibodies in centenarians. Exp Gerontol 2004; 39: 1459–65. 99. Weverling-Rijnsburger AW, Blauw GJ, Lagaay AM, Knook DL, Meinders AE, Westendorp RG. Total cholesterol and risk of mortality in the oldest old. Lancet 1997; 350: 1119–23. 100. De Taeye B, Smith LH, Vaughan DE. Plasminogen activator inhibitor-1: a common denominator in obesity, diabetes and cardiovascular disease. Curr Opin Pharmacol 2005; 5: 149–54. 101. Grant PJ, Stickland MH, Booth NA, Prentice CR. Metformin causes a reduction in basal and post- venous occlusion plasminogen activator inhibitor-1 in type 2 diabetic patients. Diabet Med 1991; 8: 361–5. 102. Weisberg AD, Albornoz F, Griffi n JP, et al. Pharmaco- logical inhibition and genetic defi ciency of plasminogen activator inhibitor-1 attenuates angiotensin II/salt-induced aortic remodeling. Arterioscler Thromb Vasc Biol 2004; 25: 365–71. [...]... 0.05) In all other patients, the ICH rates were similar between the two groups remains uncertain whether this is due in part to the prehospital administration of fibrinolysis and the initial non-weight-adjusted bolus of enoxaparin therapy given to the generally older and higher-risk population included in the trial, who presumably had reduced renal function (the dose of enoxaparin was not adjusted for in. .. observed in the other clinical trials of warfarin in patients with AF is likely related to the intensity of anticoagulant therapy: virtually all intracranial hemorrhages in SPAF II, as in the other clinical trials, were associated with an INR Ͼ3.0 [60] In contrast, in the SPAF III trial (targeted INR, 2.0–3.0), the mean age was 71 years and the rate of intracranial hemorrhage was 0.5% per year [35] The. .. Antithrombotic therapy The pharmacology and management of the vitamin K antagonists Initiation and maintenance dosing Following the administration of warfarin, an initial effect on the prothrombin time (PT) usually occurs within the first two or three days, depending on the dose administered, and an antithrombotic effect occurs within the next several days [11,12] Heparin should be administered concurrently... anticipated maintenance dose of 4–5 mg per day Initiation of anticoagulation in the elderly The dose required to maintain a therapeutic range for patients over 60 years of age decreases with increasing age [13–15], possibly because of a reduction in the clearance of warfarin with age [16,17] Therefore in the elderly the initial dose of warfarin should not be more than 5 mg [18], and in some cases (i.e., in patients... POACH cytogenetics in ALL 260–1 in AML 238–40 in ATLL 319–20 in CLL 347–8 in MDSs 105 in myeloproliferative disorders 371, 375 cytokine-associated anemia 208 cytokines age-related changes 133, 207 dysregulation 106 , 166 hemopoiesis and 209 10 HSC mobilization 62 iron transport and 208–9 in MDS 103 , 106 in MGUS 139–43 pro -in ammatory 203 see also in ammatory cytokines cytomegalovirus (CMV) infection 87 cytoplasmic... that may increase in the elderly (e.g., the baseline risk for a stroke in patients with AF increases in the elderly, and the risk for ICH may increase in elderly patients receiving thrombolysis) However, if this increase is either linear or proportional for both wanted and unwanted outcomes, then the clinical net benefit will be higher for many interventions in the elderly Thus, extrapolation of results... reported two ICHs in the INR 2.0–3.0 arm, for an annual rate of 0.6%, compared to 0–0.3% in the three other treatment arms during a shorter period of follow-up The reasons for the high ICH rate in the SPAF II trial [40] in patients over the age of 75, as compared with the other studies, are not entirely clear, but the patients were older than in any other AF trial, and the target anticoagulation intensity... significant The SPAF II study [60] included the experience of patients who had participated in group 1 of SPAF I [71], in which aspirin-treated patients had an extremely low event rate; moreover, many of the strokes in the warfarin arm of SPAF II occurred in individuals who had stopped warfarin Antithrombotic therapy for AF in clinical practice Despite the extensive data from randomized trials demonstrating the. .. Trial and the UK Doctors Trial [119], there were trends toward a lower number of total strokes with aspirin in the TPT and virtually no difference in the fourth trial (HOT) [120] A main distinguishing characteristic between the first two trials and the other three was the considerably lower dose of aspirin, 75 mg/day in the TPT and HOT trials and 100 mg in the Primary Prevention Project [121] There is... higher risk than participants in the other trials on account of the inclusion of large proportions of older men The higher risk of cardiovascular and coronary events in the TPT was due to the inclusion of a larger number of risk factors for defining eligibility than for the other trials Thrombolysis and adjunctive therapy in acute myocardial infarction Streptokinase The Fibrinolytic Therapy Trialists’ . surface. In addition, centenarians display high immune-reactivity against human beta-2-glyc- oprotein I, but low binding to the bovine molecule in the anticardiolipin assay. In spite of the presence. and arginine residues from fi brin, thereby decreasing plasminogen on its surface [70]. A single nucleotide polymorphism in the coding region of the TAFI gene, 104 0C/T, results in the Thr325Ile. healing and facili- tate reproduction. Hyperhomocysteinemia Homocysteine is a sulfur-containing amino acid, which results from the hydrolysis of S-adenosyl- homocysteine in the methionine metabolic

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