Abstract

Venous and arterial thromboses have traditionally been considered distinct pathophysiologic entities. However, the two disorders have many features in common, and there is evidence that persons with venous thrombosis may be at greater risk for arterial events. The pathogenesis of both disorders includes endothelial injury, platelet activation, elevated levels of intrinsic clotting factors and inflammatory markers, increased fibrinogen, and impaired fibrinolysis. In addition, older age, obesity, dyslipidemia, and smoking predispose to both venous and arterial thrombosis. While the evidence that arterial disease is a risk factor for venous thrombosis is inconclusive, arterial disease does appear to occur with a modestly increased frequency in patients with a history of venous thromboembolism. Reported odds ratios in such patients were 1.2 for myocardial infarction, 1.3 for stroke, 2.3 for carotid plaque, and 4.3 for coronary calcification. Of note, in persons under age 40 with unprovoked venous thrombosis, the odds ratio for acute myocardial infarction was as high as 3.9. In general, however, venous disease is considered to be a weak risk factor for arterial thrombosis, and the use of agents specifically targeted to the prevention of heart attack or stroke in the majority of persons with VTE cannot be recommended at present.

Venous and arterial thromboses have traditionally been considered distinct pathophysiologic entities. Venous thrombi usually develop in low-flow vessels and consist predominantly of erythrocytes and fibrin. Arterial thrombi are found in areas of high shear stress and consist mostly of platelets and fibrin. However, the two disorders have many features in common, and there is evidence that persons with venous thrombosis may be at greater risk for arterial events. Furthermore, there are a few disorders that are characterized by having both venous and arterial thromboses: the antiphospholipid antibody syndrome, heparin-induced thrombocytopenia, myeloproliferative disorders, and hyperhomocysteinemia.

In this paper, the common pathophysiologic features of arterial and venous thrombosis will be described, and the clinical studies examining the association of the two conditions will be reviewed. The clinical studies are divided into those that examined the risk of venous thrombosis in patients with arterial disease, and those that assessed the risk of arterial thrombosis in patients with venous disease. Venous thromboembolism (VTE) may be unprovoked (spontaneous) or secondary to other factors such as trauma or surgery; most studies have focused on patients with unprovoked VTE. Some investigators have compared incidence rates between unprovoked and secondary VTE, without a non-VTE control group. However, there are important differences between patients with unprovoked and secondary VTE; only studies with well-matched controls (without VTE) are included in this review.

Commonalities Between Arterial and Venous Thrombosis

There is biological plausibility to the concept that atherosclerosis and VTE may have a similar pathogenesis. In both arterial and venous thrombosis, activation of endothelium, platelets and leukocytes can be demonstrated, setting the stage for thrombus formation in veins as well as arteries. Other factors associated with arterial and venous thrombosis are high levels of clotting components, older age, obesity, smoking, dyslipidemia, and hormonal agents (Table 1 ).

Factors VIII, IX, and XI

Elevated levels of intrinsic clotting factors are associated with both arterial and venous disease. Large prospective studies have reported an association between factor VIII and cardiovascular events. In the Atherosclerosis Risk in Communities Study, the odds ratio for prevalent cardiovascular disease was 1.15 in men and 1.14 in women (P < .05),1 and in the Cardiovascular Health Study, the hazard ratio for cardiovascular events was 1.06 (95% CI: 1.00–1.12).2 Retrospective family studies confirm this association. Bank et al3 examined 584 first-degree relatives of 177 patients with elevated factor VIII concentrations. As compared with relatives with normal factor VIII levels, those with high levels had an annual incidence of a first arterial thrombotic event that was 3-fold increased. In particular, the risks for a first myocardial infarction (odds ratio 4.3) and first peripheral arterial thrombosis (odds ratio 8.6) were significantly increased (P = .046). While this study suggests that high levels of factor VIII predispose to arterial disease, it is possible that in addition to inheriting a propensity for an elevated factor VIII level, these relatives also may have inherited other risk factors for atherosclerosis. However, in further support for a role of factors VIII, IX, and XI in arterial disease, Doggen et al4 recently reported that these factors were elevated in men with a history of myocardial infarction.

Serial measurements of factor VIII in persons with VTE demonstrate persistently high concentrations of factor VIII, although other acute phase reactants revert back to normal.5 More than 19,000 adults were prospectively evaluated in the LITE study6; 159 venous thrombotic events occurred. Factor VIII was linearly associated with an increased risk of VTE (P for trend < .0001). The same is true for elevated levels of fibrinogen.7 That raised factor VIII levels occur on a genetic basis was shown by studies of family members8; 40% of first degree relatives had increased factor VIII.3 While studies of several regions of the F8 gene were unable to identify polymorphisms,9 analysis of 13 families with thrombosis and high factor VIII levels showed linkage to imprinted loci on chromosomes 5 and 11.10 Families with inherited high concentrations of combined factors VIII, IX, and XI have an odds ratio of 4.1 for developing venous thrombotic events, confirming that these are indeed potent risk factors for VTE.11 

Age

Over the past 30 years, considerable effort has been expended to discern the changes in coagulation that may explain the increased frequency of thrombosis in the elderly. In 1980, Zahavi et al12 reported that levels of plasma β-thromboglobulin and platelet factor 4, specific platelet proteins released during platelet activation, increased with patient age. In addition, spontaneous platelet activation was found to correlate with age and was independent of hematocrit.13 These findings of platelet activation in the elderly were confirmed by Bastyr et al,14 who also observed more active platelet aggregation in response to adenosine diphosphate and increased turnover of platelet phosphoinositides with advancing age. Platelet aggregation and platelet adhesion to ex vivo umbilical artery segments were significantly correlated in elderly, but not young, blood donors.15 A mechanism that may explain the increased responsiveness of platelets in the elderly is the age-related loss of platelet receptors for the inhibitory prostacyclin, PGI2.16 Platelet activation characterizes both venous and arterial thrombosis (see accompanying article by B Furie, beginning on page 255). However, a clear role for platelets in venous thrombosis has not been established; for example, in the Women’s Health Study, long-term, low-dose aspirin had little effect on the prevention of VTE.17 

Hager et al18 performed an extensive study of blood coagulation factors in the elderly. They found that partial thromboplastin (aPTT) and thrombin clotting times were slightly shortened in older patients (age 68–92 years) than in younger patients (age 18–41 years). Plasma concentrations of fibrinogen and factors VII, VIII, X, high molecular weight kininogen, and prekalikrein were increased, whereas antithrombin was decreased. Factor IX19 and the A-subunit of factor XIII20 also increase with age. Kario et al21 confirmed the increase in factor VII in those 60 to 98 years old, and attributed this to increased hepatic synthesis and activation of the FVII zymogen. Ibbotson et al22 studied the consequences of increased clotting factor levels and activity, and observed that thrombin generation strongly correlated with age (r = −0.64). More recently, shortening of the aPTT was reported to increase the risk of VTE.23 Since all clotting factors except factor VII are reflected by the aPTT, it is perhaps not surprising that increased levels of factors VIII,24,25 IX,26 XI,27 and fibrinogen28 have been associated with a greater risk of VTE. In particular, elevated levels of fibrinogen are associated with an increased risk of VTE in those older than 45 but not in those younger than 45. Certain polymorphisms of the fibrinogen genes also appear to increase the risk of venous thrombosis. Persons homozygous for the FGG-H2 gene had decreased fibrinogen γ′ levels, and this was associated with an enhanced VTE risk, possibly by removing a binding site for thrombin.29 

Several investigators have examined the fibrinolytic system with aging. Hashimoto et al30 reported a marked increase in both tissue plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI-1) with increasing age, but a decrease in PA activity. The latter was confirmed by Hager et al,18 who also noted that levels of plasminogen and antiplasmin were unaffected by age. Levels of plasmin-antiplasmin (PAP) complexes rise with age,31 possibly reflecting increased fibrinolytic activity. This concept is supported by studies of d-dimer, a measure of fibrin degradation, which is also increased in the elderly. Lastly, thrombin activatable fibrinolysis inhibitor (TAFI) also increases with age, especially in women.32 With the exception of d-dimer, the association of other fibrinolytic factors with venous thrombosis is still tenuous.

Molecular markers of coagulation, such as prothrombin activation fragment F1+2, are increased in the elderly as compared to younger individuals.33,34 Wilkerson and Sane35 suggest that the elevated levels of F1+2 in the elderly may be due to excessive factor Xa activity. In keeping with that suggestion, levels of thrombin-antithrombin (TAT) complexes increase with age.36 However, there is no compensatory increase in natural anticoagulants such as protein C, S, or antithrombin,37 and this may tip the hemostatic balance toward thrombosis.

Lastly, cytokines associated with inflammation appear to increase with advancing age. Interleukin (IL)-6 has been most studied; it is increased in the elderly38 and has been found to be a risk factor for venous thrombosis.39 IL-6 induces the synthesis of fibrinogen, increases platelet counts, and promotes platelet aggregation and thrombosis in experimental animals (summarized by Wilkerson and Sane35).

The prevalence of chronic venous disease, especially leg ulcers, increases with age (recently summarized by Bergan et al40); this observation is consistent with the increased prevalence of VTE in the elderly, as chronic venous disease is the most common sequel of this disorder. Fronek et al41 report that the diameter of the common femoral vein declines beginning at age 60, with a decrease in flow velocity. Another factor that may predispose to venous and arterial thrombosis is the age-related decline in endothelial nitric oxide production, as observed in aged human umbilical vein endothelial cells in culture.42 

Obesity

Obesity is a risk factor for atheromatous disease, but it is also a risk factor for VTE. Abdollahi et al43 observed that obesity (body mass index [BMI] > 30) increased the risk of venous thrombosis twofold (CI: 1.5–3.4) in the 454 persons enrolled in the Leiden Thrombophilia Study. There was a larger absolute effect in older age groups. They also found that the use of oral contraceptives in women with BMI > 25 increased the risk of VTE 10-fold, an observation confirmed by Canonico et al.44 In another population-based case-control study, the risk of VTE increased linearly with BMI in postmenopausal women (OR per SD increase in BMI 1.34 [CI 1.16–1.55]).45 The basis for the association of obesity with VTE is unclear; fat is pro-inflammatory and abdominal fat, especially visceral fat, may raise venous pressure in the vena cava and distal veins as well as be a source of PAI-1, a potent inhibitor of fibrinolysis.46 However, this is not the only alteration in hemostasis; Abdollahi et al43 noted raised levels of factors VIII and IX in the obese. Thus, several factors in the obese (increased factor VIII, fibrinogen, PAI-1, as well as diabetes and dyslipidemia) predispose to arterial and venous thrombosis.

Dyslipidemia

Dyslipidemia might be a risk factor for venous as well as arterial disease. Doggen et al47 reported that elevated triglyceride levels were associated with a doubling of the risk for VTE in postmenopausal women, and another study found that elevated HDL-cholesterol decreased risk.48 However, a study of over 27,000 women could not confirm that the levels of these lipids affected the risk of incident VTE,49 and the LITE study, a prospective investigation of nearly 20,000 persons over the age of 45, also was unable to find an association of recurrent VTE with decreased apolipoprotein A1 (a major component of HDL) and lower HDL particle concentrations.50 Increased Lp(a) is a risk factor for VTE as well as atherosclerosis, although its thrombogenicity may reside in its anti-fibrinolytic activity. Lastly, several recent studies have shown that statin drugs decrease the risk of VTE.51,53 In a large, randomized, controlled trial (JUPITER), persons who took rosuvastatin were 43% less likely to experience a VTE than non-users.54 The participants in this trial had LDL cholesterol levels lower than 130 mg/dL, but C-reactive protein concentrations higher than 2.0 mg/L, suggesting that the beneficial effects of statins might be related to their anti-inflammatory effects as well as their lipid lowering activity.

Smoking

Smoking is a well-established risk factor for arterial disease, but it also contributes to VTE. The Nurses Health Study found smoking to be an independent risk factor for PE, with a relative risk of 1.9 that increased to 3.3 with more intense usage.55 In middle-aged men, smoking was associated with a relative risk for VTE of 2.8 (CI 1.3–6.1).56 Pomp et al57 performed a case-control study of more than 8000 persons, half of whom had VTE. Smoking was associated with an increased risk of VTE (current smokers: OR 1.43; CI: 1.3–1.6; former smokers: 1.2, CI: 1.1–1.4). Those with a higher number of pack-years had a larger OR (4.3), and smoking acted synergistically with oral contraceptive use and prothrombotic genetic mutations to increase risk.

VTE in Persons with Atherosclerosis

An association between VTE and atherothrombosis was observed in an autopsy study by Eliasson et al,58 who found an OR of 1.4 (CI: 1.3–1.5) adjusted for age and gender. Of note, the association was observed mainly for cervico-cranial and peripheral arterial disease; coronary artery disease had a negative association. Furthermore, the impact of this study is weakened by the fact that fatal pulmonary embolism (PE) is a common mechanism of death in hospitalized patients, and this study was limited to recording only acute thrombosis in the autopsied subjects.

The Tromso study examined the incidence of VTE in persons with a strong family history of myocardial infarction.59 The hazard ratio for total VTE was 1.25 (CI: 1.01–1.6) and for unprovoked VTE 1.46 (1.03–2.07) in multivariable analysis. The authors suggested that persons with a high risk of arterial thrombosis were also at risk for venous thrombosis, although the hazard ratio for VTE barely reached statistical significance.

In contrast to these studies pointing to a risk of VTE in persons with atherosclerosis, two observational studies could find no such association. Neither the Cardiovascular Health Study (CHS) nor the Atherosclerosis Risk in Communities (ARIC) study were able to confirm that persons with evidence of subclinical atherosclerosis (carotid ultrasound, ankle-brachial index) had a higher incidence of VTE.60,61 It should be noted that both of these studies examined only persons older than 45 years.

The conclusion from these studies is that atherosclerosis does not appear to be a risk factor for VTE, except perhaps in younger persons with an unusually large number of other risk factors.

Association of Arterial Disease with Idiopathic Venous Thromboembolism

Prandoni et al62 performed carotid ultrasound in 299 patients with VTE and no history of arterial disease. Carotid plaques were observed in 47% of those with idiopathic VTE, 27% in patients with secondary venous thrombosis, and 32% in a control group who were admitted for conditions unrelated to either arterial thrombosis or VTE, and were age/sex matched to the study group. The odds ratio (OR) for carotid plaque in patients with idiopathic VTE as compared with those with secondary thrombosis was 2.3, and 1.8 compared with controls. The relatively high frequency of carotid plaque might have been related to the age and sex of the participants (65 years, 68% men), and that about a third had hypertension or were smokers. However, the strength of the association was unaffected in multivariate analysis for atherosclerosis risk factors.

Hong et al63 performed a retrospective case-control study of patients with confirmed idiopathic VTE and well-matched controls in whom VTE had been excluded. The VTE group had a higher prevalence of coronary artery calcium, as well as diabetes and hypertension. Which of these several risk factors underlie the coronary disease is not clear from this small retrospective study.

The relationship between unprovoked VTE, age, and acute myocardial infarction was investigated by Spencer et al.64 The Canadian Institute for Health Information Database was used to identify all patients 20 to 64 years old hospitalized with an unprovoked VTE and followed up for 10 years. Controls were matched 2:1 with cases. While the cumulative rate of acute myocardial infarction was no different in the total sample, patients 20 to 39 years old had a higher rate of myocardial infarction as compared with controls (0.1 vs 0.03 per 100 patient-years; HR 3.92; CI 1.65–9.35). No association was observed in those 40 to 64 years old. Although the investigators stated that the younger patients had no atherosclerotic risk factors at baseline, it is clearly not possible to exclude all potential factors that may increase risk.

A Danish study evaluated the risk of myocardial infarction and stroke in more than 40,000 patients with deep vein thrombosis (DVT) and PE, and 160,000 controls.65 Between a third and a half of the cohorts were older than 70. At one year follow-up, those with unprovoked DVT had an HR for myocardial infarction of 1.74 and for stroke of 2.01, and patients with unprovoked PE had an HR for myocardial infarction of 2.62 and stroke of 3.17. After 2 to 20 years of follow-up, the HRs were smaller but still significant (Table 2 ). However, in contrast to previous studies, the relative risks for arterial cardiovascular events were similar for those with provoked and unprovoked VTE.

Bova et al66 conducted a small, retrospective study of 151 consecutive patients with unprovoked VTE and a similar number of controls. During a mean follow-up period of 43 months, there were 16 arterial events in the VTE patients and only 6 in the controls (adjusted HR 2.86 [1.07–7.62]).

In summary, the prevalence of arterial disease in patients with unprovoked VTE appears to be modestly increased. As Table 2  shows, the largest effect was observed in the smallest studies. It is important to note, however, that the study of Spencer et al64 did find an impressive hazard ratio of 3.92 when only persons younger than 40 years old were included.

Conclusions

Arterial and venous thromboses have many similar pathogenetic mechanisms. Endothelial injury, platelet activation, elevated levels of intrinsic clotting factors and inflammatory markers, increased fibrinogen, and impaired fibrinolysis are characteristic of the two disorders. In addition, older age, obesity, dyslipidemia, and smoking predispose to both venous and arterial thrombosis. However, the evidence that arterial disease, per se, is a risk factor for venous thrombosis is inconclusive. On the other hand, arterial disease does appear to occur with a modestly increased frequency in patients with a history of unprovoked VTE, especially in younger individuals with major risk factors. Nevertheless, venous disease is considered to be a weak risk factor for arterial thrombosis, and the use of agents specifically targeted to the prevention of heart attack or stroke in the majority of persons with VTE is not currently recommended. Some of the uncertainties regarding the value of this approach could be addressed by appropriately designed clinical trials.

Disclosures
 Conflict-of-interest disclosure: The authors declare no competing financial interests.
 Off-label drug use: None disclosed.

Acknowledgment

Support from Grant AG032136 from the National Institute on Aging, National Institutes of Health.

References

References
1
Folsom AR, Wu KK, Shahar E, Davis CE. Association of hemostatic variables with prevalent cardiovascular disease and asymptomatic carotid artery atherosclerosis. The Atherosclerosis Risk in Communities (ARIC) Study Investigators.
Arterioscler Thromb
.
1993
;
13
:
1829
–1836.
2
Zakai NA, Katz R, Jenny NS, et al. Inflammation and hemostasis biomarkers and cardiovascular risk in the elderly: the Cardiovascular Health Study.
J Thromb Haemost
.
2007
;
5
:
1128
–1135.
3
Bank I, Libourel EJ, Middeldorp S, et al. Elevated levels of FVIII:C within families are associated with an increased risk for venous and arterial thrombosis.
J Thromb Haemost
.
2004
;
3
:
79
–84.
4
Doggen CJM, Rosendaal FR, Meijers JCM. Levels of intrinsic coagulation factors and the risk of myocardial infarction among men: opposite and synergistic effects of factors XI and XII.
Blood
.
2006
;
108
:
4045
–4051.
5
O’Donnell J, Mumford AD, Manning RA, Laffan M. Elevation of factor VIII:C in venous thromboembolism is persistent and independent of the acute phase response.
Thromb Haemost
.
2000
;
83
:
10
–13.
6
Tsai AW, Cushman M, Rosamond WD, et al. Coagulation factors, inflammation markers, and venous thromboembolism: the Longitudinal Investigation of Thromboembolism Etiology (LITE).
Am J Med
.
2002
;
113
:
636
–642.
7
Kamphuisen PWW, Eikenboom JCJ, Vos HL, et al. Increased levels of factor VIII and fibrinogen in patients with venous thrombosis are not caused by acute phase reactions.
Thromb Haemost
.
1999
;
81
:
680
–683.
8
Schambeck CM, Hinney K, Haubitz I, Taleghani BM, Wahler D, Keller F. Familial clustering of high factor VIII levels in patients with venous thromboembolism.
Arterioscler Thromb Vasc Biol
.
2001
;
21
:
289
–292.
9
Mansvelt EPG, Laffan M, McVey JH, Tuddenham EGD. Analysis of the F8 gene in individuals with high plasma factor VIII:C levels and associated venous thrombosis.
Thromb Haemost
.
1998
;
80
:
561
–565.
10
Berger M, Mattheisen M, Kulle B, et al. High factor VIII levels in venous thromboembolism show linkage to imprinted loci on chromosomes 5 and 11.
Blood
.
2005
;
105
:
638
–644.
11
Lavigne G, Mercier E, Quere I, Dauzat M, Gris J-C. Thrombophilic families with inheritably associated high levels of coagulation factors VIII, IX, and XI.
J Thromb Haemost
.
2003
;
1
:
2134
–2139.
12
Zahavi J, Jones NAG, Leyton J, Dubiel M, Kakkar VV. Enhanced in vivo platelet “release reaction” in old healthy individuals.
Thromb Res
.
1980
;
17
:
329
–336.
13
Burgess-Wilson MD, Green S, Heptinstall S, Mitchell JRA. Spontaneous platelet aggregation in whole blood: dependence on age and haematocrit.
Lancet
.
1984
;
ii
:
1213
.
14
Bastyr EJ III, Kadrofske MM, Vinik AI. Platelet activity and phosphoinositide turnover increase with advancing age.
Am J Med
.
1990
;
88
:
601
–606.
15
Emery JD, Leifer DW, Moura GL, Southern P, Morrissey JH, Lawrence JB. Whole-blood platelet aggregation predicts in vitro and in vivo primary hemostatic function in the elderly.
Arterioscler Thromb Vasc Biol
.
1995
;
15
:
748
–753.
16
Modesti PA, Fortini A, Abbate R, Gensini GF. Age related changes of platelet protacyclin receptors in humans.
Eur J Clin Invest
.
1985
;
15
:
204
–208.
17
Glynn RJ, Ridker PM, Goldhaber SZ, Buring JE. Effect of low-dose aspirin on the occurrence of venous thromboembolism.
Ann Intern Med
.
2007
;
147
:
525
–533.
18
Hager K, Setzer J, Vogl T, Voit J, Platt D. Blood coagulation factors in the elderly.
Arch Gerontol Geriatr
.
1989
;
9
:
277
–282.
19
Sweeney JD, Hoerning LA. Age dependent effect on the level of factor IX.
Am J Clin Pathol
.
1993
;
687
–688.
20
Ariens RA, Kohler HP, Mansfield MW, Grant PJ. Subunit antigen and activity levels of blood coagulation factor XIII in healthy individuals. Relation to sex, age, smoking, and hypertension.
Arterioscler Thromb Vasc Biol
.
1999
;
19
:
2012
–2016.
21
Kario K, Matsuo T, Nakao K. Factor VII hyperactivity in the elderly.
Thromb Haemost
.
1991
;
65
:
25
–27.
22
Ibbotson SH, Tate GM, Davies JA. Thrombin activity by intrinsic activation of plasma in-vitro accelerates with increasing age of the donor.
Thromb Haemost
.
1992
;
67
:
377
–380.
23
Tripodi A, Chantarangkul V, Martinelli I, Bucciarelli P, Mannucci PM. A shortened activated partial thromboplastin time is associated with the risk of venous thromboembolism.
Blood
.
2004
;
104
:
3631
–3634.
24
Koster T, Blann AD, Briet E, Vandenbroucke JP, Rosendaal FR. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis.
Lancet
.
1995
;
345
:
152
–155.
25
Kraaijenhagen RA, in’t Anker PS, Koopman MMW, et al. High plasma concentration of factor VIIIc is a major risk factor for venous thromboelmbolism.
Thromb Haemst
.
2000
;
83
:
5
–9.
26
van Hylckama Vlieg A, van der Linden IK, Bertina RM, Rosendaal FR. High levels of factor IX increase the risk of venous thrombosis.
Blood
.
2000
;
95
:
3678
–3682.
27
Meijers JCM, Tekelenburg WLH, Bouma BN, Bertina RM, Rosendaal FR. High levels of coagulation factor XI as a risk factor for venous thrombosis.
N Engl J Med
.
2000
;
342
:
696
–701.
28
van Hylckama Vlieg A, Rosendaal FR. High levels of fibrinogen are associated with the risk of deep venous thrombosis mainly in the elderly.
J Thromb Haemost
.
2003
;
1
:
2677
–2678.
29
De Willige SU, de Visser MCH, Houwing-Duistermaat JJ, Rosendaal FR, Vos HL, Bertina RM. Genetic variation in the fibrinogen gamma gene increases the risk for deep venous thrombosis by reducing plasma fibrinogen γ′ levels.
Blood
.
2005
;
106
:
4176
–4183.
30
Hashimoto Y, Kobayashi A, Yamazaki N, Sugawara Y, Takada Y, Takada A. Relationship between age and plasma t-PA, PA-inhibitor, and PA activity.
Thromb Res
.
1987
;
46
:
625
–633.
31
Sakkinen PA, Cushman M, Psaty BM, et al. Relationship of plasmin generation to cardiovascular disease risk factors in elderly men and women.
Arterioscler Thromb Vasc Biol
.
1999
;
19
:
499
–504.
32
Juhan-Vague I, Renucci JF, Grimaux M, et al. Thrombin-activatable fibrinolysis inhibitor antigen levels and cardiovascular risk factors.
Arterioscler Thromb Vasc Biol
.
2000
;
20
:
2156
–2161.
33
Bauer KA, Weiss LM, Sparrow D, Vokonas PS, Rosenberg RD. Aging-associated changes in indices of thrombin generation and protein C activation in humans. Normative Aging Study.
J Clin Invest
.
1987
;
80
:
1527
–1534.
34
Van den Burg PJM, Hospers JEH, van Vliet M, Mosterd WL, Bouma BN, Huisveld JA. Changes in haemostatic factors and activation products after exercise in healthy subjects with different ages.
Thromb Haemost
.
1995
;
74
:
1457
–1464.
35
Wilkerson WR, Sane DC. Aging and thrombosis.
Sem Thromb Haemost
.
2002
;
28
:
555
–567.
36
Ofosu FA, Craven S, Dewar L, et al. Age-related changes in factor VII proteolysis in vivo.
Br J Haematol
.
1996
;
94
:
407
–412.
37
Sakkinen PA, Cushman M, Psaty BM, et al. Correlates of antithrombin, protein C, protein S, and TFPI in a healthy elderly cohort.
Thromb Haemost
.
1998
;
80
:
134
–139.
38
Ershler WB. Interleukin-6: a cytokine for gerontologists.
J Am Geriatr Soc
.
1993
;
41
:
176
–181.
39
Reitsma PH, Rosendaal FR. Activation of innate immunity in patients with venous thrombosis: the Leiden Thrombophilia Study.
J Thromb Haemost
.
2003
;
2
:
619
–622.
40
Bergan JJ, Schmid-Schonbein GW, Smith PDC, Nicolaides AN, Boisseau MR, Eklof B. Chronic venous disease.
N Engl J Med
.
2006
;
355
:
488
–498.
41
Fronek A, Criqui MH, Denenberg J, Langer RD. Common femoral vein dimensions and hemodynamics including Valsalva response as a function of sex, age, and ethnicity in a population study.
J Vasc Surg
.
2001
;
33
:
1050
–1056.
42
Hoffmann J, Haendeler J, Aicher A, et al. Aging enhances the sensitivity of endothelial cells toward apoptotic stimuli. Important role of nitric oxide.
Circ Res
.
2001
;
89
:
709
–715.
43
Abdollahi M, Cushman M, Rosendaal FR. Obesity: risk of venous thrombosis and the interaction with coagulation factor levels and oral contraceptive use.
Thromb Haemost
.
2003
;
89
:
493
–498.
44
Canonico M, Oger E, Conard J, on behalf of the Estrogen and Thromboembolism Risk Study Group. Obesity and risk of venous thromboembolism among postmenopausal women: differential impact of hormone therapy by route of estrogen administration. The ESTHER Study.
J Thromb Haemost
.
2006
;
4
:
1259
–1265.
45
Oren E, Smith NL, Doggen CJM, Heckbert SR, Lemaitre RN. Body mass index and the risk of venous thrombosis among postmenopausal women.
J Thromb Haemost
.
2006
;
4
:
2273
–2275.
46
Eriksson P, Harmelen VV, Hoffstedt J, et al. Regional variation in plasminogen activator inhibitor-1 expression in adipose tissue from obese individuals.
Thromb Haemost
.
2000
;
83
:
545
–548.
47
Doggen CJM, Smith NL, Lemaitre RN, Heckbert SR, Rosendaal FR, Psaty BM. Serum lipid levels and the risk of venous thrombosis.
Arterioscler Thromb Vasc Biol
.
2004
;
24
:
1970
–1975.
48
Eichinger S, Pecheniuk NM, Hron G, Deguchi H, Kyrle PA, Griffin JH. Risk of recurrent venous thromboembolism reduced by high density lipoproteins [abstract].
Blood
.
2006
;
108
:
84a
.
49
Everett BM, Glynn RJ, Buring JE, Ridker PM. Lipid biomarkers, hormone therapy and the risk of venous thromboembolism in women.
J Thromb Haemost
.
2009
;
7
:
588
–596.
50
Chamberlain AM, Folsom AR, Heckbert SR, Rosamond WD, Cushman M. High-density lipoprotein cholesterol and venous thromboembolism in the Longitudinal Investigation of Thromboembolism Etiology (LITE).
Blood
.
2008
;
112
:
2675
–2680.
51
Squizzato A, Romualdi E, Ageno W. Why should statins prevent venous thromboembolism. A systematic literature search and a call for action.
J Thromb Haemost
.
2006
;
4
:
1925
–1927.
52
Ramcharan AS, Van Stralen KJ, Snoep JD, Mantel-Teeuwisse AK, Rosendaal FR, Doggen CJM. HMG-CoA reductase inhibitors, other lipid-lowering medication, antiplatelet therapy, and the risk of venous thrombosis.
J Thromb Haemost
.
2009
;
7
:
514
–520.
53
Sorensen HT, Horvath-Puho E, Sogaard KK, et al. Arterial cardiovascular events, statins, low-dose aspirin and subsequent risk of venous thromboembolism: a population-based case-control study.
J Thromb Haemost
.
2009
;
7
:
521
–528.
54
Glynn RJ, Danielson E, Fonseca FAH, et al. A randomized trial of rosuvastatin in the prevention of venous thromboembolism.
N Engl J Med
.
2009
;
360
:
1851
–1861.
55
Goldhaber SZ, Grodstein F, Stampfer MJ, et al. A prospective study of risk factors for pulmonary embolism in women.
JAMA
.
1997
;
277
:
642
–645.
56
Hansson PO, Eriksson H, Welin L, Svardsudd K, Wilhelmsen L. Smoking and abdominal obesity: risk factors for venous thromboembolism among middle-aged men.
Arch Intern Med
.
1999
;
159
:
1886
–1890.
57
Pomp ER, Rosendaal FR, Doggen CJ. Smoking increases the risk of venous thrombosis and acts synergistically with oral contraceptive use.
Am J Hematol
.
2008
;
83
:
97
–102.
58
Eliasson A, Bergqvist D, Bjorck M, Acosta S, Sternby NH, Ogren M. Incidence and risk of venous thromboembolism in patients with verified arterial thrombosis: a population study based on 23,796 autopsies.
J Thromb Haemost
.
2006
;
4
:
1897
–1902.
59
Braekkan SK, Mathiesen EB, Njolstad I, Wilsgaard T, Stormer J, Hansen JB. Family history of myocardial infarction is an independent risk factor for venous thromboembolism: the Tromso study.
J Thromb Haemost
.
2008
;
6
:
1851
–1857.
60
Van der Hagen PB, Folsom AR, Jenny NS, et al. Subclinical atherosclerosis and the risk of future venous thrombosis in the Cardiovascular Health Study.
J Thromb Haemost
.
2006
;
4
:
1903
–1908.
61
Reich LM, Folsom AR, Key NS, et al. Prospective study of subclinical atherosclerosis as a risk factor for venous thromboembolism.
J Thromb Haemost
.
2006
;
4
:
1909
–1913.
62
Prandoni P, Bilora F, Marchiori A, et al. An association between atherosclerosis and venous thrombosis.
N Engl J Med
.
2003
;
348
:
1435
–1441.
63
Hong C, Zhu F, Du D, Pilgram TK, Sicard GA, Bae KT. Coronary artery calcification and risk factors for atherosclerosis in patients with venous thromboembolism.
Atherosclerosis
.
2005
;
183
:
169
–174.
64
Spencer FA, Ginsberg JS, Chong A, Alter DA. The relationship between unprovoked venous thromboembolism, age, and acute myocardial infarction.
J Thromb Haemost
.
2008
;
6
:
1507
–1513.
65
Sorenson HT, Horvath-Puho E, Pedersen L, Baron JA, Prandoni P. Venous thromboembolism and subsequent hospitalisation due to acute arterial cardiovascular events: a 20 year cohort study.
Lancet
.
2007
;
370
:
1773
–1779.
66
Bova C, Marchiori A, Noto A, et al. Incidence of arterial cardiovascular events in patients with idiopathic venous thromboembolism: a retrospective cohort study.
Thromb Haemost
.
2006
;
96
:
132
–136.

Author notes

1

Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL