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. 2001 Jul 20;2(4):165–170. doi: 10.1186/cvm-2-4-165

The role of dyslipidemia and statins in venous thromboembolism

Joel G Ray 1,✉, Frits R Rosendaal 2
PMCID: PMC59643  PMID: 11806791

Abstract

Recent studies have proposed an association between hyperlipidemia and venous thromboembolism (VTE). We review the epidemiological evidence linking dyslipidemia with VTE and examine several possible underlying mechanisms. We discuss the possible role of HMG CoA reductase inhibitors (statins) in the prevention and treatment of VTE and suggest future directions for research.

Keywords: HMG CoA reductase inhibitors, statins, deep vein thrombosis, venous thromboembolism, lipids, hyperlipidemia

Introduction

Any textbook of cardiovascular medicine published within the past 20 years is sure to contain a lengthy discussion of the role of dyslipidemia in the development of both atherosclerosis and acute arterial thrombosis [1]. Elevated total serum cholesterol, elevated low-density-lipoprotein cholesterol (LDL-C), and decreased high-density-lipoprotein cholesterol (HDL-C) are all well-established risk factors for coronary heart disease [1], while there is still debate about the contribution of hypertriglyceridemia to this process [2].

Perhaps it is not surprising that major textbooks of hematology [3] and thrombosis medicine [4] do not mention any role for dyslipidemia in the pathogenesis of venous thromboembolism (VTE). One reason may be the absence of pathological evidence of lipid deposition within either the venous system or the so-called 'red thrombus' that may develop therein [5]. Accordingly, there has been little hypothesis-generating research exploring the interplay between lipid dysfunction and VTE. In the following paper, we discuss the evidence linking hyperlipidemia to the formation of VTE and the possible role of HMG CoA reductase inhibitors (statins) in its prevention and treatment.

What is the epidemiological evidence linking dyslipidemia to VTE?

Two cohort [6,7] and six case–control studies [8,9,10,11,12,13] have examined the relation between dyslipidemia or serum lipoprotein (a) [Lp(a)] and VTE. Goldhaber et al retrospectively evaluated several risk factors among 46 adults diagnosed with pulmonary embolism at autopsy and 3424 individuals enrolled at baseline in the Framingham Study [6]. Total serum cholesterol was observed to be a significant risk factor for pulmonary embolism in women (P = 0.049), but not men (P > 0.05). In the Nurses' Health Study, 280 middle-aged women with a self-reported history of pulmonary embolism were compared with a cohort of 112,542 women without a history of pulmonary embolism [7] (Table 1). They found that those with a self-reported diagnosis of hypercholesterolemia were at no increased risk for pulmonary embolism (multivariate relative risk 1.1, 95% confidence interval [CI] 0.7–1.5).

Table 1.

Epidemiological studies of the associated risk between dyslipidemia and venous thromboembolism (VTE)

Prevalence
of lipid Odds
Mean age % cases risk factor ratio
No. cases/ of cases VTE with situational among (95% CI)
Study [reference] controls (years) type risk factors* Serum lipid risk factor(s) cases (%) for VTE
Goldhaber et al [7] 280/112542 30–55 PE 55 Self-reported elevated TC 18 1.1 (0.7–1.5)
Kawasaki et al [8] 109/109 50 Leg DVT 34 TC > 5.7 mmol/L and TG > 1.7 mmol/L 23 5.1 (2.0–13.0)
TC > 5.7 mmol/L and TG ≤ 1.7 mmol/L 26 2.6 (1.2–5.3)
Nowak-Gottl et al [10] 186/186 5 Any VTE 60 Lp(a) > 30 mg/dL 42 7.2 (3.7–14.5)
von Depka et al [11] 685/266 34 Any VTE 21 Lp(a) > 10 mg/dL 40 1.6 (1.2–2.2)
Lp(a) > 20 mg/dL 25 2.2 (1.5–3.3)
Lp(a) > 30 mg/dL 20 3.2 (1.9–5.3)
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*Defined as either immobilization (i.e. trauma, surgery, or bedridden) or presence of an indwelling venous catheter at the site of thrombosis. DVT = deep vein thrombosis; Lp(a) = lipoprotein (a); PE = pulmonary embolism; TC = total cholesterol; TG = triglycerides; VTE = venous thromboembolism.

Kawasaki et al were the first to demonstrate an association between hypercholesterolemia and objectively verified deep vein thrombosis (DVT) of the leg among middle-aged men and women [8]. In comparison with matched controls, the risk for DVT was greatest in the presence of elevated fasting total serum cholesterol, either with or without concomitant hypertriglyceridemia (Table 1). Among individuals whose total serum cholesterol was below 5.8 mmol/L, isolated hypertriglyceridemia was not a risk factor for DVT (odds ratio [OR] 0.9, 95% CI 0.4–2.1).

McColl and colleagues compared 62 women with objectively confirmed VTE before age 50 years with 98 healthy, age-matched controls and observed a lower mean fasting total serum cholesterol among cases versus controls (4.74 versus 5.13 mmol/L, respectively; P < 0.02) [9]. Although the mean LDL-C was also lower among the cases (2.76 versus 3.18 mmol/L, respectively; P = 0.01), serum triglycerides were slightly higher (1.29 versus 1.09 mmol/L, respectively; P = 0.02), and there was no difference seen for serum Lp(a) (P = 0.47).

Two subsequent studies, both of similar design, evaluated the risk for VTE in the presence of elevated serum Lp(a) in children [10] and adults [11] (Table 1). In the pediatric study, an Lp(a) concentration at or above the upper-quartile value of 30 mg/dL was significantly associated with VTE, in comparison with the lowest-quartile value. This effect persisted among a subgroup of children without an underlying illness (adjusted OR 7.1, 95% CI 2.7–18.6) [10]. In the study among adults, an Lp(a) concentration greater than 30 mg/dL was also associated with VTE [11], even after adjustment for the presence of other common thrombophilia risk factors (adjusted OR 2.8, 95% CI 1.6–4.9) [11]. Furthermore, the risk for VTE in that study rose linearly with increasing Lp(a) concentrations (Table 1).

In a seventh study, Lp(a) concentrations were measured in 64 patients with previous VTE and 64 matched controls with either atrial fibrillation or valvular heart disease [12]. The median Lp(a) concentrations were not significantly different between cases and controls (69 versus 83 mg/L, respectively; P = 0.34). An eighth group of investigators compared plasma Lp(a) concentrations in 40 patients with chronic thromboembolic pulmonary hypertension, 50 patients with primary pulmonary hypertension, and 50 matched disease-free controls [13]. In that study, median Lp(a) concentrations were higher in subjects with chronic thromboembolism (26.7 mg/dL) than in those with either primary pulmonary hypertension (9.7 mg/dL) or no disease (7.0 mg/dL) [13].

Although some studies suggest an association between hyperlipidemia and VTE, their results conflict somewhat. The degree of precision and moderately high effect size seen in the three positive studies (Table 1), considered in conjunction with a 20% or greater prevalence of dyslipidemia among the cases, suggests that elevated concentrations of total serum cholesterol and Lp(a) may be important risk factors for VTE in adults and children. While some studies used fasting samples, only two described collecting specimens at least 3 months after the initial thrombotic event [10,11]. Specimen collection remote from the initial VTE event may be important, since lipids are known to decline in the presence of acute vascular events, such as VTE or myocardial infarction [14,15], potentially introducing a negative confounding effect between dyslipidemia and VTE. In the two negative cohort studies, their methods for lipid measurement were not reported [6,7], while in the Nurses' Health Study, recognition of pulmonary embolism and hypercholesterolemia depended on a self-reported diagnosis of both diseases [7], thereby casting some doubt on the validity of their findings. Future studies could help to clarify whether dyslipidemia is a causal risk factor for VTE and, if so, which lipid molecule is most thrombogenic.

Why might lipids induce venous thrombosis?

Before the routine use of acetylsalicylic acid (ASA) and heparin, patients with acute myocardial infarction previously experienced high rates of VTE, often independent of their degree of immobilization during the recovery period [16,17,18]. Since then, systemic factors such as homocysteine [19,20,21] and antiphospholipid antibodies [22,23] have been shown to activate the coagulation cascade or impair the process of fibrinolysis, resulting in both arterial and venous thrombosis [21,22]. Similarly, if dyslipidemia is a risk factor for VTE, just as for arterial thrombosis, then the underlying mechanism is also probably best conceptualized as a systemic, rather than merely a depositional or 'venosclerotic' [24], disorder within the vessel wall.

Circulating lipids appear to have both prothrombotic [25] and endothelium-altering properties [26]. For example, studies in rats suggest about a 2.3-fold greater generation of thrombi in hyperlipidemic than normolipidemic controls, associated with an 8-fold higher rate of platelet activation [27]. The thrombogenic potential of Lp(a) may be explained at several levels. First, the apolipoprotein B-100 molecule that forms Lp(a) is commonly associated with circulating LDL-C and postprandial triglyceride-rich particles [28]. Ingestion of a fatty meal appears to cause venous endothelial dysfunction in healthy adults [29], while postprandial lipemia has been associated with transient changes in factor VII coagulant (FVII:C) activity in humans [30], suggesting a temporary and reversible hypercoagulable state [25]. Furthermore, among individuals with venographically proven DVT, FVII:C activity was significantly correlated with triglyc-eride concentrations (r = 0.36, P = 0.021) [31]. Since neither FVII concentrations, nor the MspI polymorphism in the FVII gene, are themselves demonstrable risk factors for VTE [32], perhaps FVII:C requires specific lipid activation to be thrombogenic, as after the ingestion of a fatty meal [30].

Lp(a) is also structurally and functionally homologous to plasminogen, leading to potential competitive binding to fibrin and hence to impaired fibrinolysis [33]. Of 136 individuals with ischemic stroke, those with a suspected car-dioembolic mechanism (i.e. atrial fibrillation or left ventricular thrombus) had significantly higher concentrations of Lp(a) than those with a noncardioembolic source, implying a greater association between Lp(a) and acute arterial thrombosis than between Lp(a) and progressive atherosclerosis [34]. Thus, it is conceivable that Lp(a) and associated lipid-rich molecules play a role in the initiation or progression of VTE. VTE formation occurs through systemic activation of platelets and specific coagulation factors, in addition to either direct or indirect impairment of the venous endothelium.

Why might statins reduce the risk of venous thrombosis?

There now exists a compelling body of evidence for both early and late benefits of statin therapy in the secondary prevention of coronary heart disease and stroke [35,36,37,38]. Because these agents are also effective in individuals with 'normal' baseline lipid measurements [37,38], it has been suggested that they may also possess antithrombotic [39] and anti-inflammatory [40] properties.

Recent studies suggest that statins may alter elements within the vascular endothelium and coagulation cascade in a manner consistent with an antithrombotic effect. For example, indirect markers of thrombin generation, such as prothrombin fragment 1+2, appear to be significantly reduced after 6 months of pravastatin therapy in women [41], with a similar effect observed with simvastatin use in men [42]. One hypothesis to explain these effects is that these agents inhibit platelet-derived protease-activated receptor-1 (PAR-1) and tissue factor upregulation, leading to thrombin generation [43]. Others have demonstrated a reduction in concentrations of both FVII:C [44] and soluble thrombomodulin [45] with statin use. There may also be a rapid biological effect of statins on endothelial barrier permeability and nitric oxide production. For example, exposure in vitro of human umbilical vein or aortic endothelial cell monolayers to simvastatin for 24 hours attenuates thrombin-induced endothelial barrier dysfunction by 55%. This effect is related to both the dose and the duration of drug exposure [46]. Exposure in vitro of isolated human endothelial cells from the saphenous vein to cervistatin has also led to a twofold rise in production of both endothelial nitric oxide synthase and nitric oxide [47].

Once a saphenous vein coronary artery bypass graft (CABG) is transplanted into the aortocoronary circulation, it typically takes on certain morphological features akin to those of native arteries [48]. However, the vessel also retains some of its original venous properties, and some venous grafts thrombose within days or weeks of transplantation [48], well in advance of the more common scenario of occlusive 'venosclerosis' [24]. This may serve as an indirect human model for the interplay between dyslipidemia, statin use, and venous thrombosis.

For example, in a retrospective series of 212 consecutive undergoing percutaneous angioplasty of occluded saphenous vein grafts, the most significant risk factor for the development of restenosis unstable angina was dyslipidemia (adjusted OR 3.55, 95% CI 1.64–8.39) [49]. Of the 118 individuals with dyslipidemia, use of lipid-lowering therapy, principally statins, was associated with a lower risk of restenosis and unstable angina (crude OR 0.41, 95% CI 0.17–0.97).

Dyslipidemia was also found to be a major prognostic risk factor for saphenous vein graft disease in the Post-coronary Artery Bypass Graft (Post-CABG) trial [50]. Among patients randomized to receive high-dose lovastatin (40 mg daily), there was a significant reduction in both the rate of progression of saphenous vein graft occlusion and the need for coronary revascularization, in comparison with patients given low-dose lovastatin (2.5 mg daily) [51]. Interestingly, lovastatin had no effect on Lp(a) concentrations, but lipoprotein B concentrations were significantly reduced in the high-dose group [52]. In a more recent clinical trial, patients with preoperative hypercholesterolemia (total serum cholesterol greater than 6.2 mmol/L) were randomized to receive either no therapy (Group1, n = 37) or 4 weeks of preoperative simvastatin, 20 mg daily (Group2, n = 40). Those assigned simvastatin continued their therapy for 1 year postoperatively. Ninety-eight percent of participants underwent routine follow-up angiography at 1 year. The rate of detectable graft disease at 1 year, the primary study endpoint, was 46% in Group1 and 10% in Group2, indicating a benefit with statin therapy (relative risk 0.30, 95% CI 0.13–0.66). The rate of myocardial infarction was also significantly higher in Group1 (5%) than in Group2 (0%) (P = 0.036). The greatest relative benefit with statin therapy was observed among those with saphenous vein grafts [53].

Perhaps the most compelling direct evidence that statins may reduce the risk for VTE comes from two recent studies [54,55]. In the Heart Estrogen Replacement Study (HERS), 1380 women were randomized to hormone replacement therapy and 1383 women to placebo [54]. During 10,985 woman-years of follow-up, 47 women developed VTE. In a post-trial analysis, it was found that statins, but not other lipid-lowering agents, reduced the risk for VTE by 50% (adjusted hazard ratio [HR] 0.5, 95% CI 0.2–0.9). The association between statin use and DVT was also evaluated, in a retrospective Canadian cohort study comprising 125,862 men and women aged 65 years and older [55]. After 190,601 person-years of observed drug use, there was an associated decreased risk of DVT among statin users compared with controls prescribed thyroid replacement hormones, even after controlling for the presence of cancer, recent hospitalizations, and ASA or warfarin use (adjusted HR 0.78, 95% CI 0.69–0.87). Just as in the HERS study, nonstatin lipid-lowering agents did not appear protective against DVT (adjusted HR 0.97, 95% CI 0.79–1.18). In both studies, however, the apparent protective effect of statins against VTE might also be explained by the possibility that statin users were healthier (i.e. healthy-user bias) or had fewer VTE risk factors that were not measured.

What further evidence is needed for clinicians?

Dyslipidemia and VTE

We argue that, at present, dyslipidemia should not be included as part of any thrombophilia work-up in persons with idiopathic VTE. Consistent epidemiological evidence is needed to demonstrate that commonly assayed lipids (e.g. total serum cholesterol, LDL-C, triglycerides), as well as other lipoproteins [e.g. Lp(a), lipoprotein B], are risk factors for VTE. In such studies, investigators should consider collecting fasting specimens remote from the time of the VTE event. Investigators in previous and future epidemiological studies and clinical trials designed to evaluate the effect of lipid reduction on cardiovascular disease might also consider evaluating data on VTE events among their study participants.

Statins and VTE

Statins cannot be recommended for use in either the prevention or the treatment of VTE. Research studies should attempt to quantify the risk reduction for VTE with statin use. A clinical trial aimed at secondary prevention of recurrent VTE may be one starting point. For example, patients who have had a first idiopathic VTE and who have completed 3 or 6 months of anticoagulant therapy could be randomized to either continue warfarin for another 12 to 18 months [56] or discontinue their war-farin and begin on statin therapy. The primary, composite endpoint of such a trial might be the development of recurrent VTE or major hemorrhage. Before such a trial can be justified, more epidemiological evidence is needed linking statin use to reduced VTE.

A greater understanding is also needed about whether there is a difference in the antithrombotic properties of the various statin agents, either in conjunction with, or independent of, their lipid-lowering properties. For example, in an audit of 126 individuals with atheroslcerosis who switched from simvastatin (mean daily dose 22 mg) to fluvastatin (mean daily dose 37 mg), there was a significant rise in total serum cholesterol, LDL-C, and triglycerides, as well as an increase in the subsequent number of arterial thrombotic events after a mean of 17 weeks [57]. In addition, researchers should focus on whether statins, in conjunction with drugs such as ASA [58], may offer an alternative and safe approach to VTE prevention among individuals at high risk for anticoagulant-related hemorrhage.

Conclusion

In summary, there is a new and growing body of epidemiological evidence supporting a possible link between dyslipidemia and the development of VTE, as well as the potential for statins to reduce the risk of VTE. The association between both elevated total serum cholesterol and Lp(a) and VTE is not consistent, although studies have shown that dyslipidemia is a significant risk factor for CABG vein graft occlusion, and that statins reduce that risk. Finally, preliminary research suggests that statins may lower the risk for VTE through several mechanisms.

Competing interests

None declared.

Abbreviations

ASA = acetylsalicylic acid; CABG = coronary artery bypass graft; CI = confidence interval; DVT = deep vein thrombosis; FVII:C = factor VII coagulant; HDL-C = high-density-lipoprotein cholesterol; HERS = Heart Estrogen Replacement Study; HMG CoA = 3-hydroxy-3-methylglutaryl coenzyme A; HR = hazard ratio; LDL-C = low-density-lipoprotein cholesterol; Lp(a) = lipoprotein (a); OR = odds ratio; VTE = venous thromboembolism.

References

  1. Falk E, Fuster V. Atherogenesis and its determinants. In Hurst's The Heart Edited by Fuster V, Alexander RW, O'Rourke RA, Roberts R, King SB III, Wellens HJ New York: McGraw-Hill, 2001. pp. 1065–1093.
  2. Avins AL, Neuhaus JM. Do triglycerides provide meaningful information about heart disease risk? Arch Intern Med. 2000;160:1937–1944. doi: 10.1001/archinte.160.13.1937. [DOI] [PubMed] [Google Scholar]
  3. Hoffman R, Benz EJ, Jr, Shattil SJ, Furie B, Cohen HJ, Silberstein LE, (Eds) Hematology: Basic Principles and Practice New York: Chruchill Livingstone. 2000.
  4. Colman RW, Hirsh J, Marder VJ, Clowes AW, George JN, (Eds) Hemostasis and Thrombosis Lippincott: Philadelphia, 1994.
  5. Kumar V, Collins Tucker, Robbins SL, (Eds) Robbins Pathological Basis of Disease Philadelphia: WB Saunders, 1999.
  6. Goldhaber SZ, Savage DD, Garrison RJ, Castelli WP, Kannel WB, McNamara PM, Gherardi G, Feinleib M. Risk factors for pulmonary embolism. The Framingham Study. Am J Med. 1983;74:1023–1028. doi: 10.1016/0002-9343(83)90805-7. [DOI] [PubMed] [Google Scholar]
  7. Goldhaber SZ, Grodstein F, Stampfer MJ, Manson JE, Colditz GA, Speizer FE, Willett WC, Hennekens CH. A prospective study of risk factors for pulmonary embolism in women. JAMA. 1997;277:642–645. doi: 10.1001/jama.277.8.642. [DOI] [PubMed] [Google Scholar]
  8. Kawasaki T, Kambayashi J, Ariyoshi H, Sakon M, Suehisa E, Monden M. Hypercholesterolemia as a risk factor for deep-vein thrombosis. Thromb Res. 1997;88:67–73. doi: 10.1016/S0049-3848(97)00192-8. [DOI] [PubMed] [Google Scholar]
  9. McColl MD, Sattar N, Ellison J, Tait RC, Walker ID, Packard CJ, Greer IA. Lipoprotein (a), cholesterol and triglycerides in women with venous thromboembolism. Blood Coagul Fibrinolysis. 2000;11:225–229. [PubMed] [Google Scholar]
  10. Nowak-Gottl U, Junker R, Hartmeier M, Koch HG, Munchow N, Assmann G, von Eckardstein A. Increased lipoprotein(a) is an important risk factor for venous thromboembolism in childhood. Circulation. 1999;100:743–748. doi: 10.1161/01.cir.100.7.743. [DOI] [PubMed] [Google Scholar]
  11. von Depka M, Nowak-Gottl U, Eisert R, Dieterich C, Barthels M, Scharrer I, Ganser A, Ehrenforth S. Increased lipoprotein (a) levels as an independent risk factor for venous thromboembolism. Blood. 2000;96:3364–3368. [PubMed] [Google Scholar]
  12. Lippi G, Bassi A, Brocco G, Manzato F, Marini M, Guidi G. Lipoprotein(a) concentration is not associated with venous thromboembolism in a case control study. Haematologica. 1999;84:726–729. [PubMed] [Google Scholar]
  13. Ignatescu M, Kostner K, Zorn G, Kneussl M, Maurer G, Lang IM, Huber K. Plasma Lp(a) levels are increased in patients with chronic thromboembolic pulmonary hypertension. Thromb Haemost. 1998;80:231–232. [PubMed] [Google Scholar]
  14. Volpato S, Palmieri E, Fellin R, Zuliani G. Acute phase markers are associated with reduced plasma lipid levels in a population of hospitalized elderly patients. Gerontology. 2000;46:22–27. doi: 10.1159/000022129. [DOI] [PubMed] [Google Scholar]
  15. Pfohl M, Schreiber I, Liebich HM, Haring HU, Hoffmeister HM. Upregulation of cholesterol synthesis after acute myocardial infarction – is cholesterol a positive acute phase reactant? Atherosclerosis. 1999;142:389–393. doi: 10.1016/S0021-9150(98)00242-1. [DOI] [PubMed] [Google Scholar]
  16. Miller RR, Lies JE, Carretta RF, Wampold DB, DeNardo GL, Kraus JF, Amsterdam EA, Mason DT. Prevention of lower extremity venous thrombosis by early mobilization. Confirmation in patients with acute myocardial infarction by 125 I-fibrinogen uptake and venography. Ann Intern Med. 1976;84:700–703. doi: 10.7326/0003-4819-84-6-700. [DOI] [PubMed] [Google Scholar]
  17. Cristal N, Stern J, Ronen M, Silverman C, Ho W, Bartov E. Identifying patients at risk for thromboembolism. Use of 125 I-labeled fibrinogen in patients with acute myocardial infarction. JAMA. 1976;236:2755–2757. doi: 10.1001/jama.236.24.2755. [DOI] [PubMed] [Google Scholar]
  18. Pitney WR, Hickey A, Gopinath A, Dean S. Is the incidence of deep vein thrombosis following myocardial infarction decreasing? Aust N Z J Med. 1980;10:167–171. doi: 10.1111/j.1445-5994.1980.tb03706.x. [DOI] [PubMed] [Google Scholar]
  19. Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA. 1995;274:1049–1057. doi: 10.1001/jama.274.13.1049. [DOI] [PubMed] [Google Scholar]
  20. Ray JG. Meta-analysis of hyperhomocysteinemia as a risk factor for venous thromboembolic disease. Arch Intern Med. 1998;158:2101–2106. doi: 10.1001/archinte.158.19.2101. [DOI] [PubMed] [Google Scholar]
  21. Langman LJ, Cole DE. Homocysteine. Crit Rev Clin Lab Sci. 1999;36:365–406. doi: 10.1080/10408369991239231. [DOI] [PubMed] [Google Scholar]
  22. Bick RL, Baker WF. Antiphospholipid syndrome and thrombosis. Semin Thromb Hemost. 1999;25:333–350. doi: 10.1055/s-2007-994935. [DOI] [PubMed] [Google Scholar]
  23. Schulman S, Svenungsson E, Granqvist S. Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy. Duration of Anticoagulation Study Group. Am J Med. 1998;104:332–338. doi: 10.1016/S0002-9343(98)00060-6. [DOI] [PubMed] [Google Scholar]
  24. Tsukamoto S, Hasegawa T, Kitamura S, Shindo S, Akiyama K, Orime Y, Harada Y, Suzuki O, Ohata M, Sezai Y. Long-term patency of aorto-coronary saphenous vein grafts. Nippon Kyobu Geka Gakkai Zasshi. 1992;40:202–208. [PubMed] [Google Scholar]
  25. Miller GJ. Lipoproteins and the haemostatic system in atherothrombotic disorders. Baillière's Best Pract Res Clin Haematol. 1999;12:555–575. doi: 10.1053/beha.1999.0040. [DOI] [PubMed] [Google Scholar]
  26. Sattar N, Petrie JR, Jaap AJ. The atherogenic lipoprotein phenotype and vascular endothelial dysfunction. Atherosclerosis. 1998;138:229–235. doi: 10.1016/S0021-9150(98)00037-9. [DOI] [PubMed] [Google Scholar]
  27. Cignarella A, Mussoni L, Mannucci L, Ferioli E, Puglisi L, Tremoli E. Platelet activation supports the development of venous thrombosis in hyperlipidemic rats. Blood Coagul Fibrinolysis. 1998;9:47–53. doi: 10.1097/00001721-199801000-00006. [DOI] [PubMed] [Google Scholar]
  28. Scanu AM. Lipoprotein(a). A genetic risk factor for premature coronary heart disease. JAMA. 1992;267:3326–3329. doi: 10.1001/jama.267.24.3326. [DOI] [PubMed] [Google Scholar]
  29. Dzeka TN, Derylo B, Arnold JMO. Endothelial function and prostaglandins in human veins [abstract]. Can J Cardiol. 2000;16:193F. [Google Scholar]
  30. Bladbjerg EM, Marckmann P, Sandstrom B, Jespersen J. Non-fasting factor VII coagulant activity (FVII:C) increased by high-fat diet. Thromb Haemost. 1994;71:755–758. [PubMed] [Google Scholar]
  31. Mukherjee M, Dawson G, Sembhi K, Kakkar VV. Triglyceride dependence of factor VII coagulant activity in deep venous thrombosis. Thromb Haemost. 1996;76:500–501. [PubMed] [Google Scholar]
  32. Koster T, Rosendaal FR, Reitsma PH, van der Velden PA, Briet E, Vandenbroucke JP. Factor VII and fibrinogen levels as risk factors for venous thrombosis. A case-control study of plasma levels and DNA polymorphisms – the Leiden Thrombophilia Study (LETS). Thromb Haemost. 1994;71:719–722. [PubMed] [Google Scholar]
  33. Atsumi T, Khamashta MA, Andujar C, Leandro MJ, Amengual O, Ames PR, Hughes GR. Elevated plasma lipoprotein(a) level and its association with impaired fibrinolysis in patients with antiphospholipid syndrome. J Rheumatol. 1998;5:69–73. [PubMed] [Google Scholar]
  34. Dahl T, Kontny F, Slagsvold CE, Christophersen B, Abildgaard U, Odegaard OR, Morkrid L, Dale J. Lipoprotein(a), other lipoproteins and hemostatic profiles in patients with ischemic stroke: the relation to cardiogenic embolism. Cerebrovasc Dis. 2000;10:110–117. doi: 10.1159/000016039. [DOI] [PubMed] [Google Scholar]
  35. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;334:383–389. [PubMed] [Google Scholar]
  36. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med. 1995;333:1301–1307. doi: 10.1056/NEJM199511163332001. [DOI] [PubMed] [Google Scholar]
  37. Tonkin AM, Colquhoun D, Emberson J, Hague W, Keech A, Lane G, MacMahon S, Shaw J, Simes RJ, Thompson PL, White HD, Hunt D. Effects of pravastatin in 3260 patients with unstable angina: results from the LIPID study. Lancet. 2000;355:1871–1875. doi: 10.1016/S0140-6736(00)03257-8. [DOI] [PubMed] [Google Scholar]
  38. Lewis SJ, Moye LA, Sacks FM, Johnstone DE, Timmis G, Mitchell J, Limacher M, Kell S, Glasser SP, Grant J, Davis BR, Pfeffer MA, Braunwald E. Effect of pravastatin on cardiovascular events in older patients with myocardial infarction and cholesterol levels in the average range. Results of the Cholesterol and Recurrent Events (CARE) Trial. Ann Intern Med. 1998;129:681–689. doi: 10.7326/0003-4819-129-9-199811010-00002. [DOI] [PubMed] [Google Scholar]
  39. Kearney D, Fitzgerald D. The anti-thrombotic effects of statins. J Am Coll Cardiol. 1999;33:1305–1307. doi: 10.1016/S0735-1097(99)00019-4. [DOI] [PubMed] [Google Scholar]
  40. Blake GJ, Ridker PM. Are statins anti-inflammatory? Current Controlled Trials in Cardiovascular Medicine. 2000;1:131–134. doi: 10.1186/CVM-1-3-161. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Dangas G, Smith DA, Badimon JJ, Unger AH, Shao JH, Meraj P, Cohen AM, Levine D, Fallon JT, Ambrose JA. Gender differences in blood thrombogenicity in hyperlipidemic patients and response to pravastatin. Am J Cardiol. 1999;84:639–643. doi: 10.1016/S0002-9149(99)00408-7. [DOI] [PubMed] [Google Scholar]
  42. Szczeklik A, Musial J, Undas A, Gajewski P, Gora P, Swadzba J, Jankowski M. Inhibition of thrombin generation by simvastatin and lack of additive effects of ASA in patients with marked hypercholesterolemia. J Am Coll Cardiol. 1999;33:1286–1293. doi: 10.1016/S0735-1097(99)00023-6. [DOI] [PubMed] [Google Scholar]
  43. Fenton JW, Jr, Shen GX. Statins as cellular antithrombotics. Haemostasis. 1999;29:166–169. doi: 10.1159/000022496. [DOI] [PubMed] [Google Scholar]
  44. Tan KCB, Janus ED, Lam KSL. Effects of fluvastatin on prothrombotic and fibrinolytic factors in type 2 diabetes mellitus. Am J Cardiol. 1999;84:934–937. doi: 10.1016/S0002-9149(99)00471-3. [DOI] [PubMed] [Google Scholar]
  45. Ambrosi P, Aillaud MF, Habib G, Kreitmann B, Metras D, Luccioni R, Bouvenot G, Juhan-Vague I. Fluvastatin decreases soluble thrombomodulin in cardiac transplant patients. Thromb Haemost. 2000;83:46–48. [PubMed] [Google Scholar]
  46. Amerongen GP, Vermeer MA, Negre-Aminou P, Lankelma J, Emeis JJ, van Hinsbergh VW. Simvastatin improves disturbed endothelial barrier function. Circulation. 2000;102:2803–2809. doi: 10.1161/01.cir.102.23.2803. [DOI] [PubMed] [Google Scholar]
  47. Yang Z, Kozai T, van der Loo B, Viswambharan H, Lachat M, Turina MI, Malinski T, Luscher TF. HMG CoA reductase inhibition improves endothelial cell function and inhibits smooth muscle cell proliferation in human saphenous veins. J Am Coll Cardiol. 2000;36:1691–1697. doi: 10.1016/S0735-1097(00)00924-4. [DOI] [PubMed] [Google Scholar]
  48. Davies MJ. Atlas of Coronary Artery Disease Philadelphia:Lippincott-Raven, 1998.
  49. Chandrasekar B, Bourassa MG. Incidence and risk factors predictive of unstable angina resulting from restenosis after percutaneous angioplasty of saphenous vein grafts. Am Heart J. 2000;140:827–833. doi: 10.1067/mhj.2000.110768. [DOI] [PubMed] [Google Scholar]
  50. Domanski MJ, Borkowf CB, Campeau L, Knatterud GL, White C, Hoogwerf B, Rosenberg Y, Geller NL, the Post-CABG Trial Investigators. Prognostic factors for atherosclerosis progression in saphenous vein grafts: the postcoronary artery bypass graft (Post-CABG) trial. Post-CABG Trial Investigators. J Am Coll Cardiol. 2000;36:1877–1883. doi: 10.1016/S0735-1097(00)00973-6. [DOI] [PubMed] [Google Scholar]
  51. The Post Coronary Artery Bypass Graft Trial Investigators. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. N Engl J Med. 1997;336:153–162. doi: 10.1056/NEJM199701163360301. [DOI] [PubMed] [Google Scholar]
  52. Alaupovic P, Fesmire JD, Hunnighake D, Domanski M, Forman S, Knatterud GL, Forrester J, Herd JA, Hoogwerf B, Campeau L, Gobel FL. The effect of aggressive and moderate lowering of LDL-cholesterol and low dose anticoagulation on plasma lipids, apolipoproteins and lipoprotein families in Post Coronary Artery Bypass Graft Trial. Atherosclerosis. 1999;146:369–379. doi: 10.1016/S0021-9150(99)00151-3. [DOI] [PubMed] [Google Scholar]
  53. Christenson JT. Preoperative lipid control with simvastatin reduces the risk for graft failure already 1 year after myocar-dial revascularization. Cardiovasc Surg. 2001;9:33–43. doi: 10.1016/S0967-2109(00)00088-0. [DOI] [PubMed] [Google Scholar]
  54. Grady D, Wenger NK, Herrington D, Khan S, Furberg C, Hunning-hake D, Vittinghoff E, Hulley S. Postmenopausal hormone therapy increases risk for venous thromboembolic disease. Ann Intern Med. 2000;132:689–696. doi: 10.7326/0003-4819-132-9-200005020-00002. [DOI] [PubMed] [Google Scholar]
  55. Ray JG, Mamdani M, Tsuyuki RT, Anderson DR, Yeo EL, Laupacis A. Use of statins and the subsequent development of deep vein thrombosis. Arch Intern Med. 2001;161:1405–1410. doi: 10.1001/archinte.161.11.1405. [DOI] [PubMed] [Google Scholar]
  56. Kearon C, Gent M, Hirsh J, Weitz J, Kovacs MJ, Anderson DR, Turpie AG, Green D, Ginsberg JS, Wells P, MacKinnon B, Julian JA. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med. 1999;340:901–907. doi: 10.1056/NEJM199903253401201. [DOI] [PubMed] [Google Scholar]
  57. Thomas M, Mann J. Increase thrombotic vascular events after change of statin. Lancet. 1998;352:1830–1831. doi: 10.1016/S0140-6736(98)04480-8. [DOI] [PubMed] [Google Scholar]
  58. Anonymous Prevention of pulmonary embolism and deep vein thrombosis with low dose ASA: Pulmonary Embolism Prevention (PEP) trial. Lancet. pp. 1295–1302. [PubMed]

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