This is an excerpt from Advanced Cardiovascular Exercise Physiology by Denise L. Smith & Bo Fernhall.
Hemostatic Adaptations to Aerobic Exercise Training
Aerobic exercise training has a variety of hemostatic effects that together provide a cardioprotective effect. Platelet activation and aggregation are reduced with training, while fibrinolysis is enhanced in trained compared to untrained individuals. Although training is thought to have little effect on coagulation in healthy individuals, it may play an important protective role in cardiac patients.
Acute aerobic exercise, particularly of high intensity, enhances platelet adhesion and aggregation. However, chronic exercise training serves a protective function and has been shown to reduce platelet adhesion and aggregation, both at rest and in response to an acute bout of exercise (Wang, Jen, and Chen, 1997, 1995). This has important implications for cardiovascular health, as acute bouts of exercise have been associated with myocardial infarction and sudden cardiac death (Bartsch, 1999). Thus, sedentary individuals are more susceptible to exercise-related cardiac events than trained individuals.
There are several ways in which aerobic exercise training may improve platelet function. Training increases levels of prostacyclin and NO, which inhibit platelet aggregation. Further, training decreases levels of oxidized low-density lipoproteins (LDL), which enhances platelet activation via inactivation of NO. Thus, lower levels of oxidized LDL following training may reduce platelet activation.
Coagulation potential appears to change little with endurance training in healthy adults. A number of investigators have reported no effect of training on thrombin time, prothombin time, and activated partial thromboplastin time, or on coagulation Factor VIII activity and antigen levels at rest (El-Sayed, Lin, and Rattu, 1995; Van den Burg et al., 1997) or in response to exercise (El-Sayed, Lin, and Rattu, 1995; Ferguson et al., 1987). The effect of chronic exercise on fibrinogen remains unclear, with data from cross-sectional studies supporting lower fibrinogen levels in trained compared to untrained subjects and data from training studies showing increased, decreased, or unchanged fibrinogen levels following training (Womack, Nagelkirk, and Coughlin, 2003). Endurance training, however, may play an important protective role in cardiac patients, where exercise training has been shown to lengthen activated partial thromboplastin time and decrease coagulation Factor VIII activity and fibrinogen levels (Suzuki et al., 1992)—all indices of reduced coagulability.
Fibrinolytic activity is enhanced with regular exercise. Several researchers report greater activity of tissue plasminogen activator following acute exercise in trained compared to untrained subjects (Speiser et al., 1988; Szymanski, Pate, and Durstine, 1994). Such changes may be related to the greater release of tissue plasminogen activator or the reduced formation of plasminogen activator inhibitor complexes reported in trained subjects at rest (De Paz et al., 1992). Further, plasminogen activator inhibitor activity is lower at rest, and tends to decrease more following exercise, in trained individuals compared to their untrained counterparts (Speiser et al., 1988; Szymanski, Pate, and Durstine, 1994). Interestingly, Szymanski and associates (1994) reported that plasminogen activator inhibitor activity reached zero in 30% of their active subjects, suggesting a possible floor effect that may have blunted the effect of training on this variable. Together, these changes set the stage for greater plasmin formation and subsequent fibrin degradation. Consistent with this notion, De Paz and colleagues (1992) found higher fibrin and fibrinogen degradation products in trained runners compared to inactive controls. While the majority of evidence supports enhanced fibrinolysis following aerobic training, these findings are not universal. Baynard and colleagues (2007) reported no difference in either plasminogen activator or plasminogen activator inhibitor in trained versus untrained individuals.
Implications for Cardiovascular Disease
The changes in endothelial cell function and hemostasis described here have important implications for cardiovascular health. Healthy endothelial cells support an anti-
coagulatory, antithrombotic, and antiproliferative state that is instrumental in protecting against atherosclerosis and coronary artery disease. Nitric oxide and prostacyclin released from the endothelium prevent adhesion of platelets and monocytes to the arterial wall. Further, NO inhibits proliferation and migration of smooth muscle cells and also opposes the actions of endothelin, a potent vasoconstrictor and activator of smooth muscle cell proliferation (Maeda et al., 2001; Ruschitzka, Noll, and Luscher, 1997). Healthy endothelial cell function protects against the various stages of arterial plaque formation.
Atherosclerosis is a multifaceted process that has been linked to endothelial dysfunction. Damage to endothelial cells, which may result from factors such as hypertension, hyperlipidemia, or smoking, results in abnormal expression of adhesion molecules. This, in turn, increases the binding of various leukocytes, particularly monocytes and T-lymphocytes, to the endothelial cells (Libby, Ridker, and Masari, 2002; Ruschitzka, Noll, and Luscher, 1997). Inflammatory mediators cause monocytes and T-lymphocytes to migrate into the intima of the vessel (Libby, Ridker, and Masari, 2002). Meanwhile, LDL move into the vessel wall at the site of injury and become oxidized. Subsequently, activated macrophages accumulate oxidized LDL, forming foam cells that are the base of the atherosclerotic plaque. Another important component to the plaque’s development is proliferation and migration of smooth muscle cells to the intima of the vessel.
In the early stages, remodeling of the vessel wall will accommodate the growing plaque with little change in the vessel lumen diameter (Glagov et al., 1987). Thus, blood flow may not be significantly altered at this time. As the plaque continues to grow, the vessel will narrow and stiffen progressively, increasing vascular resistance and potentially limiting coronary blood flow. Additionally, the reduced availability of NO and increased release of endothelin associated with atherosclerosis will offset the normal balance of vascular tone, causing greater vasoconstriction and a further increase in vascular resistance.
Even in the early stages of atherosclerosis, when vessel narrowing may be minimal, the plaque is vulnerable to rupture. Rupture of an atherosclerotic plaque, and subsequent thrombus formation, is one of the most common causes of acute myocardial infarction. When the plaque ruptures, collagen and various procoagulant factors released from the plaque are exposed to flowing blood, with several important consequences. First, platelets become activated, adhere to the vessel wall, and aggregate to begin the formation of a thrombus. Second, the release of procoagulant factors stimulates coagulation (see chapter 8 for a complete discussion of the process of coagulation). Platelets also transport fibrinogen to the injury site, where it can then be converted to fibrin. The fibrin matrix reinforces and strengthens the thrombus. The end result is the formation of a thrombus that may occlude flow through a coronary artery and result in a myocardial infarction.
Aerobic training can protect against atherosclerosis by maintaining normal endothelial cell function and NO release. Additionally, moderate aerobic exercise has been shown to improve endothelial cell function in patients with coronary artery disease (Edwards et al., 2004). The progression of atherosclerosis may be slowed or even reversed through lifestyle modification, including regular exercise and management of other risk factors, such as hypertension, hyperlipidemia, diabetes, smoking, and obesity. Further, positive adaptations in platelet activity, coagulation, and fibrinolysis associated with endurance training may reduce the chance of an acute cardiac event in patients with atherosclerotic disease.