REVIEW ARTICLE Effects of Lifestyle on Hemostasis, Fibrinolysis, and Platelet Reactivity A Systematic Review Kaeng W. Lee, MRCP; Gregory Y. H. Lip, MD, FRCP he pathophysiology of atherothrombosis in cardiovascular disease is complex and mul- tifactorial. No doubt, lifestyle habits such as exercise, smoking, diet, and alcohol con- sumption may have significant influence on cardiovascular disease. As the hemostatic system is assuming an increasingly prominent role in the pathogenesis and progres- Tsion of atherovascular diseases, this review evaluates the effects of lifestyle habits (or lifestyle modi- fications) on blood coagulation, fibrinolysis, and platelet reactivity. Arch Intern Med. 2003;163:2368-2392 The process of initiation, progression, and tions and the effects of exercise or physical complication of atherothrombosis in car- activity, psychosocial stress, diet, and other diovascular disease is complex and can be lifestyle habits on plasma indicators of influenced by multiple factors. Ischemic thrombogenesis are less well established. coronary syndromes such as unstable an- Further evidence of the influence of gina, myocardial infarction (MI), and sud- lifestyle changes on cardiovascular risk fac- den ischemic death share common patho- tors and clinical outcomes is illustrated by physiologic processes characterized by data from salt restriction and blood pres- coronary plaque rupture with superim- sure reduction11 and improved mortality posed thrombus formation.1,2 Indeed, there by diets rich in oily fish. In the Gruppo is substantial experimental and clinical evi- Italiano per lo Studio della Sopravvive- dence that blood hypercoagulability or nza nell’Infarto Miocardico Prevenzione thrombogenicity promotes thrombus for- (GISSI Prevenzione)12 trial and the Diet mation in the circulation, systemically and and Reinfarction Trial (DART),13 there was locally at the exposed atherogenic sur- a significant reduction in mortality after face of the disrupted plaque.3 MI by increasing dietary n-3 polyunsatu- A wide range of factors has been iden- rated fatty acids (n-3 PUFA) and fish in- tified in prospective epidemiologic studies take, respectively, and the mortality re- to have a systemic effect on blood throm- duction has been partly attributed to a bogenicity. Certainly, there is increasing evi- reduction in sudden cardiac death. In- dence of a close relationship between the deed, the recent reanalysis of the course traditional cardiovascular risk factors such of appearance of the effects of n-3 PUFA as diabetes mellitus, hypertension or hy- has showed an early and highly signifi- perlipidemia, and the increased thrombo- cant reduction of sudden cardiac death.14 genicity, which is characterized by hyper- However, many instances of sudden death coagulability, hypofibrinolysis, or increased have a thrombotic basis,15 with evidence platelet reactivity.4-6 Conversely, improve- of thrombus in the left main coronary ar- ments of these cardiovascular risk factors tery, and sudden death is not simply an have been associated with a lower prothrom- arrhythmogenic phenomenon. The aim of bic tendency.7-10 However, the associa- this review is to evaluate the effects of life- style habits (or lifestyle modifications) on From the Haemostasis, Thrombosis, and Vascular Biology Unit, University Department the plasma indices of the 3 main systems of Medicine, City Hospital, Birmingham, England. The authors have no relevant of thrombosis: blood coagulation, fibri- financial interest in this article. nolysis, and platelet reactivity. (REPRINTED) ARCH INTERN MED/ VOL 163, OCT 27, 2003 WWW.ARCHINTERNMED.COM 2368 ©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 SEARCH STRATEGY of fibrin within the thrombus, disin- antigen (a marker of cross-linked fi- tegrating clots and hence maintain- brin turnover), and tPA antigen, We performed a search using elec- ing vascular patency. Fibrin de- have been identified as indepen- tronic databases (MEDLINE, grades into soluble fibrin degradation dent predictors of subsequent car- EMBASE, and DARE), and addition- products, including D-dimers. The diovascular events in prospective ally, abstracts from national and in- primary inhibitor of the fibrinolytic studies in both healthy subjects18-22 ternational cardiovascular meet- process is the plasminogen activa- and those with cardiovascular risk ings were reviewed to identify tor inhibitor type 1 (PAI-1), which factors23,24 or established coronary unpublished studies. Relevant au- inhibits plasminogen activation by heart disease (CHD).25 In addition, thors of these studies were con- binding with tPA to form the PAI/ platelet hyperaggregation,26,27 plasma tacted to obtain further data. tPA complexes. Therefore, im- viscosity,28-30 and PAI-1 levels31-34 paired fibrinolytic function may be re- have also been associated with car- BASIC PATHOPHYSIOLOGY flected in high plasma levels of PAI-1 diovascular morbidity and mortal- AND CLINICAL PERSPECTIVES or tPA antigen (which evaluates ity in both men and women in pro- mainly the inactive PAI-1/tPA com- spective studies. Thus, the potential The process of hemostasis and plexes) and/or indicated by low modifications of these hemostatic or thrombus formation depends on plasma levels of tPA activity or acti- thrombogenic factors by simple life- the fine balance between the co- vation products such as D-dimer and style changes as both primary and agulation and fibrinolysis systems plasmin 2–antiplasmin complex. Re- secondary prevention have at- (Figure). The slower intrinsic clot- duced plasmin generation leads to tracted considerable interest from ting pathway depends on circulat- suppression of fibrinolytic activity, the public health perspective. ing coagulation factors, such as fac- thus favoring fibrin persistence and The recognition that the onset tors IXa and VIIIa. The more rapid thrombosis. of cardiovascular events is fre- extrinsic pathway is activated when Most of these variables in the quently triggered by physical exer- blood is exposed to an extravascu- coagulation and fibrinolytic sys- tion or mental stresses has lead to a lar factor such as tissue factor. Fac- tems can be readily assayed using the possible link between neurohor- tor VII (FVII) plays a key role in the enzyme-linked immunosorbent as- monal activation and coronary ath- initiation of this coagulation mecha- say (ELISA) technique. It is impor- nism when it forms complexes with tant to distinguish the difference be- tissue factor from a disrupted ath- tween the measurement of activity Coagulation System eromatous plaque. Activation of the and antigen levels of these mol- coagulation system induces the for- ecules. Although the antigen levels Intrinsic Pathway Extrinsic Pathway mation of thrombin from prothrom- refer to the total amount of the cir- X IXa VIIa VII bin. Thrombin converts fibrinogen culating proteins (both bound and VIIIa TF into (insoluble) fibrin and induces free), activity levels refer to the func- platelet activation. tionally active portions of the pro- Xa The binding of fibrinogen to teins. Thus, elevated antigen levels platelet glycoprotein IIb/IIIa recep- of a particular molecule do not nec- Prothrombin Thrombin TAT tor leads to platelet aggregation. Fi- essarily reflect an increase in its func- PTF 1+ 2 brinogen is also the major determi- tional activity. For example, el- Platelets Platelet nant of blood and plasma viscosity, evated tPA antigen levels are often Activation explaining 50% of the latter. Hence, a reflection of high levels of circu- increased tendency of hemostasis lating PAI-1, resulting in a large por- Fibrin Fibrinogen Platelet and thrombosis may be reflected in tion of tPA antigens being bound to Aggregation high levels of plasma fibrinogen, PAI-1 and thereby rendering it in- FPA + B Plasma Viscosity FVII, factor VIII (FVIII), thrombin active.16 generation, platelet reactivity, and Many of these systemic throm- Plasmin Plasminogen high plasma viscosity. Increased bogenic factors may be involved in PAI-1 PAP α2AP thrombin generation may be indi- the initiation of early atheroscle- cated by high activation markers, rotic lesions and contribute to the PAI/tPA Complex such as prothrombin activation frag- progression of coronary thrombo- FDPs, Including D-Dimers tPA ment 1+2 (F1+2) and thrombin- sis, plaque growth, and its clinical antithrombin complex (TAT), asso- sequelae. For example, plasma fi- Fibrinolytic System ciated with a decrease in clotting brinogen has been shown to stimu- time. late vascular smooth muscle migra- On the other hand, activation tion and proliferation, promote Summary of the coagulation and fibrinolysis pathways. TF indicates tissue factor; TAT, of the fibrinolytic system induces the platelet aggregation, and contrib- thrombin-antithrombin complex; PTF, 17 conversion of plasminogen to plas- ute to blood viscosity and thrombi. prothrombin fragments; FPA+B, fibrinopeptides min by plasminogen activators. Tis- Many of these indices, including fi- A and B; PAP, plasmin-antiplasmin complex; ␣ ␣ sue plasminogen activator (tPA) is brinogen, FVII, von Willebrand fac- 2AP, 2-antiplasmin; PAI-1, plasminogen activator inhibitor 1; tPA, tissue plasminogen the main fibrinolytic stimulator. tor (vWf, a marker of endothelial activator; and FDPs, fibrinogen degradation Plasmin promotes the degradation damage or dysfunction), D-dimer products. Solid arrowhead denotes activation. (REPRINTED) ARCH INTERN MED/ VOL 163, OCT 27, 2003 WWW.ARCHINTERNMED.COM