Relationship between Venous and Arterial Thrombosis: A Review of the Literature from a Causal Perspective

Willem M. Lijfering; Linda E. Flinterman; Jan P. Vandenbroucke; Frits R. Rosendaal; Suzanne C. Cannegieter

doi:10.1055/s-0031-1297367

Seminars in Thrombosis and Hemostasis, Table of Contents

Semin Thromb Hemost 2011; 37(8): 885-896
DOI: 10.1055/s-0031-1297367

Relationship between Venous and Arterial Thrombosis: A Review of the Literature from a Causal Perspective

Willem M. Lijfering¹ , Linda E. Flinterman¹ , Jan P. Vandenbroucke¹ , Frits R. Rosendaal¹ ^, ² , Suzanne C. Cannegieter¹

¹Department of Clinical Epidemiology, Leiden University Medical Center, The Netherlands
²Department of Thrombosis and Hemostasis, Leiden University Medical Center, The Netherlands

Abstract

ABSTRACT

Venous thrombosis and arterial thrombosis are traditionally regarded as two different diseases with respect to pathophysiology, epidemiology, and treatment strategies. Research findings of the past few years suggest that this categorical distinction may be too strict. However, whether the described relationship between venous and arterial thrombosis is real or a result of other factors such as confounding, chance, or bias is still unclear. In this review, we discuss the current literature while using causal diagrams to better understand possible causal relations between cardiovascular risk factors, atherosclerosis, arterial thrombosis, and venous thrombosis. Furthermore, we propose study designs to investigate the causal link between venous and arterial thrombosis. In addition, we comment on the effect of statin use on the occurrence of both arterial and venous thrombosis. The possible clinical implications of these findings are discussed.

KEYWORDS

Venous thrombosis - arterial thrombosis - atherosclerosis - vascular diseases - epidemiology

Full Text

References

REFERENCES

1 Fauci A S, Braunwald E, Kasper D L et al.. Harrison's Principles of Internal Medicine. 17th ed. New York, NY: McGraw-Hill; 2008
2 Squizzato A, Galli M, Romualdi E et al.. Statins, fibrates, and venous thromboembolism: a meta-analysis. Eur Heart J. 2010; 31 (10) 1248-1256
3 Ageno W, Becattini C, Brighton T, Selby R, Kamphuisen P W. Cardiovascular risk factors and venous thromboembolism: a meta-analysis. Circulation. 2008; 117 (1) 93-102
4 Sørensen H T, Horvath-Puho E, Søgaard K K 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 (4) 521-528
5 Sørensen H T, Horvath-Puho E, Pedersen L, Baron J A, Prandoni P. Venous thromboembolism and subsequent hospitalisation due to acute arterial cardiovascular events: a 20-year cohort study. Lancet. 2007; 370 (9601) 1773-1779
6 Becattini C, Agnelli G, Prandoni P et al.. A prospective study on cardiovascular events after acute pulmonary embolism. Eur Heart J. 2005; 26 (1) 77-83
7 Klok F A, Mos I C, Broek L et al.. Risk of arterial cardiovascular events in patients after pulmonary embolism. Blood. 2009; 114 (8) 1484-1488
8 Prandoni P, Bilora F, Marchiori A et al.. An association between atherosclerosis and venous thrombosis. N Engl J Med. 2003; 348 (15) 1435-1441
9 van der Hagen P B, Folsom A R, Jenny N S et al.. Subclinical atherosclerosis and the risk of future venous thrombosis in the Cardiovascular Health Study. J Thromb Haemost. 2006; 4 (9) 1903-1908
10 Reich L M, Folsom A R, Key N S et al.. Prospective study of subclinical atherosclerosis as a risk factor for venous thromboembolism. J Thromb Haemost. 2006; 4 (9) 1909-1913
11 Lijfering W M, Rosendaal F R, Cannegieter S C. Risk factors for venous thrombosis - current understanding from an epidemiological point of view. Br J Haematol. 2010; 149 (6) 824-833
12 Collins R, MacMahon S, Flather M et al.. Clinical effects of anticoagulant therapy in suspected acute myocardial infarction: systematic overview of randomised trials. BMJ. 1996; 313 (7058) 652-659
13 Bath P M, Iddenden R, Bath F J. Low-molecular-weight heparins and heparinoids in acute ischemic stroke : a meta-analysis of randomized controlled trials. Stroke. 2000; 31 (7) 1770-1778
14 Prandoni P. Venous thromboembolism and atherosclerosis: is there a link?. J Thromb Haemost. 2007; 5 (Suppl 1) 270-275
15 Meade T W, Mellows S, Brozovic M et al.. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study. Lancet. 1986; 2 (8506) 533-537
16 Folsom A R, Rosamond W D, Shahar E The Atherosclerosis Risk in Communities (ARIC) Study Investigators et al. Prospective study of markers of hemostatic function with risk of ischemic stroke. Circulation. 1999; 100 (7) 736-742
17 De Buyzere M, Philippé J, Duprez D, Baele G, Clement D L. Coagulation system activation and increase of D-dimer levels in peripheral arterial occlusive disease. Am J Hematol. 1993; 43 (2) 91-94
18 Becattini C, Vedovati M C, Ageno W, Dentali F, Agnelli G. Incidence of arterial cardiovascular events after venous thromboembolism: a systematic review and a meta-analysis. J Thromb Haemost. 2010; 8 (5) 891-897
19 Hansson G K. Inflammatory mechanisms in atherosclerosis. J Thromb Haemost. 2009; 7 (Suppl 1) 328-331
20 Borissoff J I, Heeneman S, Kilinç E et al.. Early atherosclerosis exhibits an enhanced procoagulant state. Circulation. 2010; 122 (8) 821-830
21 Roumen-Klappe E M, den Heijer M, van Uum S H, van der Ven-Jongekrijg J, van der Graaf F, Wollersheim H. Inflammatory response in the acute phase of deep vein thrombosis. J Vasc Surg. 2002; 35 (4) 701-706
22 Roumen-Klappe E M, Janssen M C, Van Rossum J et al.. Inflammation in deep vein thrombosis and the development of post-thrombotic syndrome: a prospective study. J Thromb Haemost. 2009; 7 (4) 582-587
23 Price P A, Faus S A, Williamson M K. Warfarin causes rapid calcification of the elastic lamellae in rat arteries and heart valves. Arterioscler Thromb Vasc Biol. 1998; 18 (9) 1400-1407
24 Rennenberg R J, van Varik B J, Schurgers L J et al.. Chronic coumarin treatment is associated with increased extracoronary arterial calcification in humans. Blood. 2010; 115 (24) 5121-5123
25 Handke M, Harloff A, Bode C, Geibel A. Patent foramen ovale and cryptogenic stroke: a matter of age?. Semin Thromb Hemost. 2009; 35 (5) 505-514
26 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 (2) 132-136
27 Abdollahi M, Cushman M, Rosendaal F R. Obesity: risk of venous thrombosis and the interaction with coagulation factor levels and oral contraceptive use. Thromb Haemost. 2003; 89 (3) 493-498
28 Pomp E R, le Cessie S, Rosendaal F R, Doggen C J. Risk of venous thrombosis: obesity and its joint effect with oral contraceptive use and prothrombotic mutations. Br J Haematol. 2007; 139 (2) 289-296
29 Lijfering W M, Christiansen S C, Naess I A et al.. The risk of venous thrombosis related to increase in body mass index is mediated by factor VIII induced APC-resistance. Blood. 2009; 114 453 (ASH Annual Meeting Abstracts)
30 Bank I, Libourel E J, 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. 2005; 3 (1) 79-84
31 Faber D R, de Groot P G, Visseren F L. Role of adipose tissue in haemostasis, coagulation and fibrinolysis. Obes Rev. 2009; 10 (5) 554-563
32 Darvall K A, Sam R C, Silverman S H, Bradbury A W, Adam D J. Obesity and thrombosis. Eur J Vasc Endovasc Surg. 2007; 33 (2) 223-233
33 Hautanen A. Synthesis and regulation of sex hormone-binding globulin in obesity. Int J Obes Relat Metab Disord. 2000; 24 (Suppl 2) S64-S70
34 Middeldorp S, Meijers J C, van den Ende A E et al.. Effects on coagulation of levonorgestrel- and desogestrel-containing low dose oral contraceptives: a cross-over study. Thromb Haemost. 2000; 84 (1) 4-8
35 Naess I A, Christiansen S C, Romundstad P, Cannegieter S C, Rosendaal F R, Hammerstrøm J. Incidence and mortality of venous thrombosis: a population-based study. J Thromb Haemost. 2007; 5 (4) 692-699
36 Mahmoodi B K, Gansevoort R T, Veeger N J Prevention of Renal and Vascular End-stage Disease (PREVEND) Study Group et al. Microalbuminuria and risk of venous thromboembolism. JAMA. 2009; 301 (17) 1790-1797
37 Tsai A W, Cushman M, Rosamond W D, Heckbert S R, Polak J F, Folsom A R. Cardiovascular risk factors and venous thromboembolism incidence: the longitudinal investigation of thromboembolism etiology. Arch Intern Med. 2002; 162 (10) 1182-1189
38 Holst A G, Jensen G, Prescott E. Risk factors for venous thromboembolism: results from the Copenhagen City Heart Study. Circulation. 2010; 121 (17) 1896-1903
39 Heit J A, Leibson C L, Ashrani A A, Petterson T M, Bailey K R, Melton III L J. Is diabetes mellitus an independent risk factor for venous thromboembolism?: a population-based case–control study. Arterioscler Thromb Vasc Biol. 2009; 29 (9) 1399-1405
40 Petrauskiene V, Falk M, Waernbaum I, Norberg M, Eriksson J W. The risk of venous thromboembolism is markedly elevated in patients with diabetes. Diabetologia. 2005; 48 (5) 1017-1021
41 Ageno W, Prandoni P, Romualdi E et al.. The metabolic syndrome and the risk of venous thrombosis: a case–control study. J Thromb Haemost. 2006; 4 (9) 1914-1918
42 Dentali F, Squizzato A, Ageno W. The metabolic syndrome as a risk factor for venous and arterial thrombosis. Semin Thromb Hemost. 2009; 35 (5) 451-457
43 Steffen L M, Cushman M, Peacock J M et al.. Metabolic syndrome and risk of venous thromboembolism: Longitudinal Investigation of Thromboembolism Etiology. J Thromb Haemost. 2009; 7 (5) 746-751
44 Borch K H, Braekkan S K, Mathiesen E B et al.. Abdominal obesity is essential for the risk of venous thromboembolism in the metabolic syndrome: the Tromsø study. J Thromb Haemost. 2009; 7 (5) 739-745
45 Chamberlain A M, Folsom A R, Heckbert S R, Rosamond W D, Cushman M. High-density lipoprotein cholesterol and venous thromboembolism in the Longitudinal Investigation of Thromboembolism Etiology (LITE). Blood. 2008; 112 (7) 2675-2680
46 Glynn R J, Rosner B. Comparison of risk factors for the competing risks of coronary heart disease, stroke, and venous thromboembolism. Am J Epidemiol. 2005; 162 (10) 975-982
47 Doll R, Peto R, Wheatley K, Gray R, Sutherland I. Mortality in relation to smoking: 40 years' observations on male British doctors. BMJ. 1994; 309 (6959) 901-911
48 Wannamethee S G, Lowe G D, Shaper A G, Rumley A, Lennon L, Whincup P H. Associations between cigarette smoking, pipe/cigar smoking, and smoking cessation, and haemostatic and inflammatory markers for cardiovascular disease. Eur Heart J. 2005; 26 (17) 1765-1773
49 Pomp E R, Rosendaal F R, Doggen C J. Smoking increases the risk of venous thrombosis and acts synergistically with oral contraceptive use. Am J Hematol. 2008; 83 (2) 97-102
50 Severinsen M T, Kristensen S R, Johnsen S P, Dethlefsen C, Tjønneland A, Overvad K. Smoking and venous thromboembolism: a Danish follow-up study. J Thromb Haemost. 2009; 7 (8) 1297-1303
51 Mulder R, van Schouwenburg I M, Mahmoodi B K et al.. Associations between high factor VIII and low free protein S levels with traditional arterial thrombotic risk factors and their risk on arterial thrombosis: results from a retrospective family cohort study. Thromb Res. 2010; 126 (4) e249-e254
52 Doggen C J, Rosendaal F R, Meijers J C. 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 (13) 4045-4051
53 Folsom A R, Wu K K, Shahar E, Davis C E. The Atherosclerosis Risk in Communities (ARIC) Study Investigators . Association of hemostatic variables with prevalent cardiovascular disease and asymptomatic carotid artery atherosclerosis. Arterioscler Thromb. 1993; 13 (12) 1829-1836
54 Ye Z, Liu E H, Higgins J P et al.. Seven haemostatic gene polymorphisms in coronary disease: meta-analysis of 66,155 cases and 91,307 controls. Lancet. 2006; 367 (9511) 651-658
55 Mahmoodi B K, Brouwer J L, Veeger N J, van der Meer J. Hereditary deficiency of protein C or protein S confers increased risk of arterial thromboembolic events at a young age: results from a large family cohort study. Circulation. 2008; 118 (16) 1659-1667
56 Rosendaal F R. Clotting and myocardial infarction: a cycle of insights. J Thromb Haemost. 2003; 1 (4) 640-642
57 Rosendaal F R, Varekamp I, Smit C et al.. Mortality and causes of death in Dutch haemophiliacs, 1973-86. Br J Haematol. 1989; 71 (1) 71-76
58 Triemstra M, Rosendaal F R, Smit C, Van der Ploeg H M, Briët E. Mortality in patients with hemophilia. Changes in a Dutch population from 1986 to 1992 and 1973 to 1986. Ann Intern Med. 1995; 123 (11) 823-827
59 Srámek A, Kriek M, Rosendaal F R. Decreased mortality of ischaemic heart disease among carriers of haemophilia. Lancet. 2003; 362 (9381) 351-354
60 Smith P, Arnesen H, Holme I. The effect of warfarin on mortality and reinfarction after myocardial infarction. N Engl J Med. 1990; 323 (3) 147-152
61 The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. JAMA. 1984; 251 (3) 351-364
62 Baigent C, Keech A, Kearney P M Cholesterol Treatment Trialists' (CTT) Collaborators et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005; 366 (9493) 1267-1278
63 Ramcharan A S, Van Stralen K J, Snoep J D, Mantel-Teeuwisse A K, Rosendaal F R, Doggen C J. HMG-CoA reductase inhibitors, other lipid-lowering medication, antiplatelet therapy, and the risk of venous thrombosis. J Thromb Haemost. 2009; 7 (4) 514-520
64 Glynn R J, Danielson E, Fonseca F A et al.. A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Engl J Med. 2009; 360 (18) 1851-1861
65 Cushman M. A new indication for statins to prevent venous thromboembolism? Not yet. J Thromb Haemost. 2009; 7 (4) 511-513
66 Morishita E, Asakura H, Saito M et al.. Elevated plasma levels of free-form of TFPI antigen in hypercholesterolemic patients. Atherosclerosis. 2001; 154 (1) 203-212
67 Musiał J, Undas A, Undas R, Brozek J, Szczeklik A. Treatment with simvastatin and low-dose aspirin depresses thrombin generation in patients with coronary heart disease and borderline-high cholesterol levels. Thromb Haemost. 2001; 85 (2) 221-225
68 Dangas G, Badimon J J, Smith D A et al.. Pravastatin therapy in hyperlipidemia: effects on thrombus formation and the systemic hemostatic profile. J Am Coll Cardiol. 1999; 33 (5) 1294-1304
69 Ridker P M, Danielson E, Fonseca F A JUPITER Study Group et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008; 359 (21) 2195-2207
70 Piazza G, Goldhaber S Z. Venous thromboembolism and atherothrombosis: an integrated approach. Circulation. 2010; 121 (19) 2146-2150
71 Heit J A, Silverstein M D, Mohr D N, Petterson T M, O'Fallon W M, Melton III L J. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case–control study. Arch Intern Med. 2000; 160 (6) 809-815
72 Heit J A, Kobbervig C E, James A H, Petterson T M, Bailey K R, Melton III L J. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med. 2005; 143 (10) 697-706
73 van Hylckama Vlieg A, Helmerhorst F M, Vandenbroucke J P, Doggen C J, Rosendaal F R. The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case–control study. BMJ. 2009; 339 b2921
74 Lidegaard Ø, Løkkegaard E, Svendsen A L, Agger C. Hormonal contraception and risk of venous thromboembolism: national follow-up study. BMJ. 2009; 339 b2890
75 Blom J W, Doggen C J, Osanto S, Rosendaal F R. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA. 2005; 293 (6) 715-722
76 Ginsberg J S, Wells P S, Brill-Edwards P et al.. Antiphospholipid antibodies and venous thromboembolism. Blood. 1995; 86 (10) 3685-3691
77 Matta F, Singala R, Yaekoub A Y, Najjar R, Stein P D. Risk of venous thromboembolism with rheumatoid arthritis. Thromb Haemost. 2009; 101 (1) 134-138
78 Brouwer J L, Bijl M, Veeger N J, Kluin-Nelemans H C, van der Meer J. The contribution of inherited and acquired thrombophilic defects, alone or combined with antiphospholipid antibodies, to venous and arterial thromboembolism in patients with systemic lupus erythematosus. Blood. 2004; 104 (1) 143-148
79 Grainge M J, West J, Card T R. Venous thromboembolism during active disease and remission in inflammatory bowel disease: a cohort study. Lancet. 2010; 375 (9715) 657-663
80 van Zaane B, Squizzato A, Huijgen R et al.. Increasing levels of free thyroxine as a risk factor for a first venous thrombosis: a case–control study. Blood. 2010; 115 (22) 4344-4349
81 Lijfering W M, Ten Kate M K, Sprenger H G, van der Meer J. Absolute risk of venous and arterial thrombosis in HIV-infected patients and effects of combination antiretroviral therapy. J Thromb Haemost. 2006; 4 (9) 1928-1930
82 Mahmoodi B K, ten Kate M K, Waanders F et al.. High absolute risks and predictors of venous and arterial thromboembolic events in patients with nephrotic syndrome: results from a large retrospective cohort study. Circulation. 2008; 117 (2) 224-230
83 Wattanakit K, Cushman M, Stehman-Breen C, Heckbert S R, Folsom A R. Chronic kidney disease increases risk for venous thromboembolism. J Am Soc Nephrol. 2008; 19 (1) 135-140
84 Ocak G, Verduijn M, Vossen C Y et al.. Chronic kidney disease stages 1-3 increase the risk of venous thrombosis. J Thromb Haemost. 2010; 8 (11) 2428-2435
85 Cannegieter S C, Doggen C J, van Houwelingen H C, Rosendaal F R. Travel-related venous thrombosis: results from a large population-based case control study (MEGA study). PLoS Med. 2006; 3 (8) e307
86 Smeeth L, Cook C, Thomas S, Hall A J, Hubbard R, Vallance P. Risk of deep vein thrombosis and pulmonary embolism after acute infection in a community setting. Lancet. 2006; 367 (9516) 1075-1079
87 Lijfering W M, Brouwer J L, Veeger N J et al.. Selective testing for thrombophilia in patients with first venous thrombosis: results from a retrospective family cohort study on absolute thrombotic risk for currently known thrombophilic defects in 2479 relatives. Blood. 2009; 113 (21) 5314-5322
88 Rosendaal F R, Koster T, Vandenbroucke J P, Reitsma P H. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood. 1995; 85 (6) 1504-1508
89 Poort S R, Rosendaal F R, Reitsma P H, Bertina R M. A common genetic variation in the 3′-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood. 1996; 88 (10) 3698-3703
90 Jick H, Slone D, Westerholm B et al.. Venous thromboembolic disease and ABO blood type. A cooperative study. Lancet. 1969; 1 (7594) 539-542
91 Lijfering W M, Mulder R, ten Kate M K, Veeger N J, Mulder A B, van der Meer J. Clinical relevance of decreased free protein S levels: results from a retrospective family cohort study involving 1143 relatives. Blood. 2009; 113 (6) 1225-1230
92 Koster T, Blann A D, Briët E, Vandenbroucke J P, Rosendaal F R. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet. 1995; 345 (8943) 152-155
93 den Heijer M, Koster T, Blom H J et al.. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med. 1996; 334 (12) 759-762
94 Meltzer M E, Lisman T, Doggen C J, de Groot P G, Rosendaal F R. Synergistic effects of hypofibrinolysis and genetic and acquired risk factors on the risk of a first venous thrombosis. PLoS Med. 2008; 5 (5) e97
95 Folsom A R, Lutsey P L, Astor B C, Cushman M. C-reactive protein and venous thromboembolism. A prospective investigation in the ARIC cohort. Thromb Haemost. 2009; 102 (4) 615-619
96 Quist-Paulsen P, Naess I A, Cannegieter S C et al.. Arterial cardiovascular risk factors and venous thrombosis: results from a population-based, prospective study (the HUNT 2). Haematologica. 2010; 95 (1) 119-125
97 Bots M L, Hoes A W, Koudstaal P J, Hofman A, Grobbee D E. Common carotid intima-media thickness and risk of stroke and myocardial infarction: the Rotterdam Study. Circulation. 1997; 96 (5) 1432-1437
98 James A H, Jamison M G, Biswas M S, Brancazio L R, Swamy G K, Myers E R. Acute myocardial infarction in pregnancy: a United States population-based study. Circulation. 2006; 113 (12) 1564-1571
99 Van Den Bosch M A, Kemmeren J M, Tanis B C et al.. The RATIO study: oral contraceptives and the risk of peripheral arterial disease in young women. J Thromb Haemost. 2003; 1 (3) 439-444
100 Tanis B C, van den Bosch M A, Kemmeren J M et al.. Oral contraceptives and the risk of myocardial infarction. N Engl J Med. 2001; 345 (25) 1787-1793
101 Yusuf S, Hawken S, Ounpuu S INTERHEART Study Investigators et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case–control study. Lancet. 2004; 364 (9438) 937-952
102 Sytkowski P A, D'Agostino R B, Belanger A, Kannel W B. Sex and time trends in cardiovascular disease incidence and mortality: the Framingham Heart Study, 1950-1989. Am J Epidemiol. 1996; 143 (4) 338-350
103 Teo K K, Ounpuu S, Hawken S INTERHEART Study Investigators et al. Tobacco use and risk of myocardial infarction in 52 countries in the INTERHEART study: a case–control study. Lancet. 2006; 368 (9536) 647-658
104 Kannel W B. Range of serum cholesterol values in the population developing coronary artery disease. Am J Cardiol. 1995; 76 (9) 69C-77C
105 Booth G L, Kapral M K, Fung K, Tu J V. Relation between age and cardiovascular disease in men and women with diabetes compared with non-diabetic people: a population-based retrospective cohort study. Lancet. 2006; 368 (9529) 29-36
106 Urbanus R T, Siegerink B, Roest M, Rosendaal F R, de Groot P G, Algra A. Antiphospholipid antibodies and risk of myocardial infarction and ischaemic stroke in young women in the RATIO study: a case–control study. Lancet Neurol. 2009; 8 (11) 998-1005
107 Peters M J, van Halm V P, Voskuyl A E et al.. Does rheumatoid arthritis equal diabetes mellitus as an independent risk factor for cardiovascular disease? A prospective study. Arthritis Rheum. 2009; 61 (11) 1571-1579
108 Barcat D, Guérin V, Ryman A et al.. Thrombophilia and thrombosis in systemic lupus erythematosus: a case–control study. Ann Rheum Dis. 2003; 62 (10) 1016-1017
109 Ha C, Magowan S, Accortt N A, Chen J, Stone C D. Risk of arterial thrombotic events in inflammatory bowel disease. Am J Gastroenterol. 2009; 104 (6) 1445-1451
110 Flynn R W, Macdonald T M, Jung R T, Morris A D, Leese G P. Mortality and vascular outcomes in patients treated for thyroid dysfunction. J Clin Endocrinol Metab. 2006; 91 (6) 2159-2164
111 Mann J F, Gerstein H C, Pogue J, Bosch J, Yusuf S. Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: the HOPE randomized trial. Ann Intern Med. 2001; 134 (8) 629-636
112 Gerstein H C, Mann J F, Yi Q HOPE Study Investigators et al. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA. 2001; 286 (4) 421-426
113 Smeeth L, Thomas S L, Hall A J, Hubbard R, Farrington P, Vallance P. Risk of myocardial infarction and stroke after acute infection or vaccination. N Engl J Med. 2004; 351 (25) 2611-2618
114 Tanis B, Algra A, van der Graaf Y, Helmerhorst F, Rosendaal F. Procoagulant factors and the risk of myocardial infarction in young women. Eur J Haematol. 2006; 77 (1) 67-73
115 Folsom A R, Rosamond W D, Shahar E The Atherosclerosis Risk in Communities (ARIC) Study Investigators et al. Prospective study of markers of hemostatic function with risk of ischemic stroke. Circulation. 1999; 100 (7) 736-742
116 Stampfer M J, Malinow M R, Willett W C et al.. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA. 1992; 268 (7) 877-881
117 Loscalzo J. Homocysteine trials—clear outcomes for complex reasons. N Engl J Med. 2006; 354 (15) 1629-1632
118 Meltzer M E, Doggen C J, de Groot P G, Rosendaal F R, Lisman T. Plasma levels of fibrinolytic proteins and the risk of myocardial infarction in men. Blood. 2010; 116 (4) 529-536
119 Meltzer M E, Doggen C J, de Groot P G, Rosendaal F R, Lisman T. The impact of the fibrinolytic system on the risk of venous and arterial thrombosis. Semin Thromb Hemost. 2009; 35 (5) 468-477
120 Snoep J D, Roest M, Barendrecht A D, De Groot P G, Rosendaal F R, Van Der Bom J G. High platelet reactivity is associated with myocardial infarction in premenopausal women: a population-based case–control study. J Thromb Haemost. 2010; 8 (5) 906-913
121 Kaptoge S, Di Angelantonio E, Lowe G Emerging Risk Factors Collaboration et al. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet. 2010; 375 (9709) 132-140

Willem M. LijferingM.D. Ph.D.

Department of Clinical Epidemiology, Leiden University Medical Centre

P.O. Box 9600, 2300 RC Leiden, The Netherlands

Email: w.m.lijfering@lumc.nl