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 preva- lence was the same in older individuals with or with- out 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 thrombo- sis 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 mol- ecule 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 recur- rent 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 dis- eases, non-diabetic older men with no history of cardiovascular heart disease or stroke showed a sig- nifi 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-plasmino- gen activator), and blood viscosity. These relation- ships 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 asso- ciated 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 epidemio- logic 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/inser- tion 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 lev- els 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 angi- otensin-I-converting enzyme and PAI-1 gene vari- ants, 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 preva- lence 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 per- formed at baseline on a subset of 2224 CHS indi- viduals (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 cente- narians suggests that the 4G allele carriers reached longevity despite high circulating PAI-1 levels [65]. Another important gene–environment interac- tion was identifi ed by Brown et al. [66], who demon- strated 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, asso- ciated with PAI-1 antigen. As renin production decreases with age, it is not surprising that the asso- ciation between PAI-1 4G/5G genotype and myocar- dial 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 cod- ing 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 myocar- dial 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 dis- ease [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 pre- vious 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 poly- morphisms 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 pro- moter 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 sur- vival could be age- and sex-specifi c. The mortality reduction associated with the TAFI-438A/A genotype involved all causes of mor- tality, not just that from thromboembolic or cardio- vascular 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 pro- spective 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 car- diovascular 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, sim- ilar 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 geno- types 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 hyperho- mocysteinemia may be more important in the aged population. The treatment of hyperhomocysteine- mia 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 gen- eral, slightly higher values of several coagulation and fi brinolysis measurements than younger con- trols. 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 hypercoagulabil- ity associated with aging, but that this phenomenon is compatible with health and longevity. Hence, high plasma levels of the coagulation activation mark- ers 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 dis- ease, 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 pre- dictor 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 dis- ease and reached the extreme limits of human life. Homozygosity for the 4G allele, despite its associa- tion 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 insu- lin 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, with- out 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 cen- tenarians 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 mul- timers (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 success- ful 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, strik- ing 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 thou- sands of gene variations escaped the force of natural selection and thus play roles in the genesis of dif- ferent 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 hemo- static activation and hemostatic proteins [19,26]. Specifi cally, the modulation of fi brinolysis may infl uence aging and age-related diseases. For exam- ple, 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 resist- ance, 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 demon- strated that a hemostasis-associated gene can con- tribute to human longevity, in the shape of a common promoter variant of the TAFI gene [19]. 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[...]... 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 cod- ing 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