|Hemostatic processes contribute to gradual fibrin deposition within atherosclerotic plaques and overt thrombus formation subsequent to plaque disruption. Activation of sympathetic nervous system (SNS) affects blood coagulation, fibrinolysis and platelet activation by several mechanisms.
Given the significance of increased hemostatic activity in atherosclerosis and thrombosis and the important role of the SNS in cardiovascular disease, sympathetic activation and catecholamine effects might contribute to arterial thrombus formation.
|In particular, chronic stimulation of the SNS and concomitant hypercoagulable changes could contribute to gradual fibrin deposition at sites of atherosclerotic lesions and, in patients with endothelial dysfunction, acute stress response could trigger rupture of an atherosclerotic plaque.
Further studies are needed to better understanding the regulation of the SNS-hemostasis axis.
|Sympathetic nervous system; Hemostasis; Blood coagulation; Fibrinolysis; Platelet activation; Fight-or-flight response
|Hemostatic processes contribute to gradual fibrin deposition within atherosclerotic plaques and overt thrombus formation subsequent to plaque disruption . It is still debated whether hypercoagulability indicates an underlying atherosclerotic process or is cause of atherosclerosis and thrombosis . Stimulation of sympathetic nervous system (SNS) increases blood clotting (by V, VIII, and Von Willebrand factors) and platelet activation with raised risk for atherothrombotic events [3-12]. The SNS regulates several homeostatic functions (e.g. cardiac, respiratory, digestion, urination, and sexual arousal) and induces physiological changes during the “fight-or-flight response”(also called the acute stress response), that is a physiological reaction occurring in response to a perceived harmful event, attack, or threat to survival .
|During acute stress response, catecholamines (adrenaline and noradrenaline) facilitate immediate physical reactions associated with a preparation for violent muscular action and increased strength and speed in anticipation of fighting or running. These physiological changes include: increased blood flow to the muscles, raised blood pressure, heart rate, blood sugars, and fats, increased muscle tension, dilation of pupil, enhanced perspiration and increase the blood clotting function of the body speeds up [14-16] (Figure 1).
|Although hastened blood coagulation the impact of SNS activation on hemostasis is not still clearly understood.
|Adrenergic nervous system and hemostasis
|Given the significance of increased hemostatic activity in atherosclerosis and the important role of the SNS in cardiovascular disease , SNS activation might contribute to arterial thrombus formation. Several studies have demonstrated that SNS activation induced procoagulant responses in patients with atherosclerotic plaques and endothelial dysfunction [18-24]. Adrenaline infusion induces platelet activity and it is higher in hypertensive individuals than in normotensive controls [25-27]. Moreover behavioral stressors, such as mental arithmetic an cold test, led to increase in fibrinogen  and platelet activity  as well as to impaired fibrinolysis [28,30] in hypertensive individuals compared with normotensive controls. In patients with heart failure, there is an higher platelet activity with acute mental stress than normal controls .
|Chronic stimulation of the SNS and concomitant hypercoagulable changes could contribute to gradual fibrin deposition at sites of atherosclerotic lesions. Once hemodynamic stress with for instance emotional arousal has triggered rupture of an atherosclerotic plaque [32,33], hypercoagulability due to catecholamine spillover with both activation of the hypothalamic-pituitary-adrenal axis  and myocardial ischemia [35-36] may promote coronary thrombus growth. Also, hypercoagulable changes with morning surge in catecholamine levels due to both circadian variation in catecholamine activity and postural change may be related to increased morning frequencies of thrombotic vascular events [37-39].
|Future studies on the effects of SNS function on hemostasis mechanisms may further help integrating arduously achieved biochemical and biological knowledge to a better understanding of the regulation of the SNS-hemostasis axis .
- Davies MJ (1996) The contribution of thrombosis to the clinical expression of coronary atherosclerosis. Thromb Res 82: 1-32.
- Koenig W (1998) Haemostatic risk factors for cardiovascular diseases. Eur Heart J 19 : C39-43.
- Redondo M, Watzke HH, Stucki B (1999) Coagulation factors II, V, VII, and X, prothrombin gene 20210GpA transition, and factor V Leiden in coronary artery disease: high factor V clotting activity is an independent risk factor for myocardial infarction. Arterioscler Thromb Vasc Biol19:1020-1025.
- Meade TW, Cooper JA, Stirling Y, Howarth DJ, Ruddock V, et al. (1994) Factor VIII, ABO blood group and the incidence of ischaemic heart disease. Br J Haematol 88: 601-607.
- Peters NS, Abrams LS, Dymond DS, Kovacs IB (1989) Platelet hyperreactivity and inefficient spontaneous thrombolysis in patients at high risk from an acute coronary event. Cardiovasc Res 23: 567-572.
- Cushman M, Lemaitre RN, Kuller LH, Psaty BM, Macy EM, et al. (1999) Fibrinolytic activation markers predict myocardial infarction in the elderly. The Cardiovascular Health Study. Arterioscler Thromb Vasc Biol 19: 493-498.
- Furman MI, Benoit SE, Barnard MR, Valeri CR, Borbone ML, et al. (1998) Increased platelet reactivity and circulating monocyte-platelet aggregates in patients with stable coronary artery disease. J Am Coll Cardiol 31: 352-358.
- Folsom AR, Wu KK, Rosamond WD, Sharrett AR, Chambless LE (1997) Prospective study of hemostatic factors and incidence of coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study. Circulation 96: 1102-1108.
- Thompson SG, Kienast J, Pyke SD, Haverkate F, van de Loo JC (1995) Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. N Engl J Med 332: 635-641.
- Cortellaro M, Boschetti C, Cofrancesco E (1992) The PLAT Study: hemostatic function in relation to atherothrombotic ischemic events in vascular disease patients. Principal results. PLAT Study Group. Progetto Lombardo Atero-Trombosi (PLAT) Study Group. Arterioscler Thromb 12:1063-70.
- Ridker PM, Vaughan DE, Stampfer MJ, Manson JE, Hennekens CH (1993) Endogenous tissue-type plasminogen activator and risk of myocardial infarction. Lancet 341: 1165-1168.
- Corbi G, Bianco A, Turchiarelli V, Cellurale M, Fatica F, et al. (2013) Potential Mechanisms Linking Atherosclerosis and Increased Cardiovascular Risk in COPD: Focus On Sirtuins. Int J Mol Sci 14: 12696-12713.
- Jansen AS, Nguyen XV, Karpitskiy V, Mettenleiter TC, Loewy AD (1995) Central command neurons of the sympathetic nervous system: basis of the fight-or-flight response. Science 270: 644-646.
- McEwen BS (2007) Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol Rev 87: 873-904.
- Korte SM, Koolhaas JM, Wingfield JC, McEwen BS (2005) The Darwinian concept of stress: benefits of allostasis and costs of allostatic load and the trade-offs in health and disease. Neurosci Biobehav Rev 29: 3-38.
- Hunt GJ (2007) Flight and fight: a comparative view of the neurophysiology and genetics of honey bee defensive behavior. J Insect Physiol 53: 399-410.
- Lymperopoulos A, Rengo G, Koch WJ (2013) Adrenergic nervous system in heart failure: pathophysiology and therapy. Circ Res 113: 739-753.
- Cines DB, Pollak ES, Buck CA, Loscalzo J, Zimmerman GA, et al. (1998) Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood 91: 3527-3561.
- Ferrara N, Komici K, Corbi G, Pagano G, Furgi G, et al. (2014) Î²-adrenergic receptor responsiveness in aging heart and clinical implications. Front Physiol 4: 396.
- Rengo G, Pagano G, Parisi V, Femminella GD, de Lucia C, et al. (2014) Changes of plasma norepinephrine and serum N-terminal pro-brain natriuretic peptide after exercise training predict survival in patients with heart failure. Int J Cardiol 171: 384-389.
- Rengo G, Galasso G, Femminella GD, Parisi V, Zincarelli C, et al. (2014) Reduction of lymphocyte G protein-coupled receptor kinase-2 (GRK2) after exercise training predicts survival in patients with heart failure. Eur J Prev Cardiol 21: 4-11.
- Paolillo S, Rengo G, Pagano G, Pellegrino T, Savarese G, et al. (2013) Impact of diabetes on cardiac sympathetic innervation in patients with heart failure: a 123I meta-iodobenzylguanidine (123I MIBG) scintigraphic study. Diabetes Care 36: 2395-2401.
- Corbi G, Conti V, Russomanno G, Longobardi G, Furgi G, et al. (2013) Adrenergic signaling and oxidative stress: a role for sirtuins? Front Physiol 4: 324.
- Conti V, Russomanno G, Corbi G, Izzo V, Vecchione C, et al. (2013) Adrenoreceptors and nitric oxide in the cardiovascular system. Front Physiol 4: 321.
- Lande K, Kjeldsen SE, Os I, Westheim A, Hjermann I, et al. (1988) Increased platelet and vascular smooth muscle reactivity to low-dose adrenaline infusion in mild essential hypertension. J Hypertens 6: 219-225.
- Lande K, Os I, Kjeldsen SE, Westheim A, Aakesson I, et al. (1986) Platelet volume, platelet release reaction and platelet response to infused adrenaline are increased in essential hypertension. Acta Med Scand Suppl 714: 129-132.
- Quartarone M, Di Cesare E, Saitta A, Cucinotta D, Coppolino E, et al. (1978) [Fibrinolysis and the cold pressor test]. Boll Soc Ital Cardiol 23: 412-421.
- Tomoda F, Takata M, Kagitani S (1999) Different platelet aggregability during mental stress in two stages of essential hypertension. Am J Hypertens;12(11Pt 1):1063-1070.
- Palermo A, Bertalero P, Pizza N, Amelotti R, Libretti A (1989) Decreased fibrinolytic response to adrenergic stimulation in hypertensive patients. J Hypertens Suppl 7: S162-163.
- Grignani G, Pacchiarini L, Zucchella M, Tacconi F, Canevari A, et al. (1992) Effect of mental stress on platelet function in normal subjects and in patients with coronary artery disease. Haemostasis 22: 138-146.
- Mittleman MA, Maclure M, Sherwood JB, Mulry RP, Tofler GH, et al. (1995) Triggering of acute myocardial infarction onset by episodes of anger. Determinants of Myocardial Infarction Onset Study Investigators. Circulation 92: 1720-1725.
- Dimsdale JE, Moss J (1980) Plasma catecholamines in stress and exercise. JAMA 243: 340-342.
- Rengo G, Pagano G, Squizzato A, Moja L, Femminella GD, et al. (2013) Oral anticoagulation therapy in heart failure patients in sinus rhythm: a systematic review and meta-analysis. PLoS One 8: e52952.
- Remme WJ (1998) The sympathetic nervous system and ischaemic heart disease. Eur Heart J 19 Suppl F: F62-71.
- Haft JI, Kranz PD, Albert FJ, Fani K (1972) Intravascular platelet aggregation in the heart induced by norepinephrine. Microscopic studies. Circulation 46: 698-708.
- Karlsberg RP, Cryer PE, Roberts R. (1981) Serial plasma catecholamine response early in the course of clinical acute myocardial infarction: relationship to infarct extent and mortality. Am Heart J;102:24-29
- Rosito GB, Tofler GH (1996) Hemostatic factors as triggers of cardiovascular events. Cardiol Clin 14: 239-250.
- Andrews NP, Goldstein DS, Quyyumi AA (1999) Effect of systemic alpha-2 adrenergic blockade on the morning increase in platelet aggregation in normal subjects. Am J Cardiol 84: 316-320.
- Buono F, Crispo S, Pagano G, Rengo G, Petitto M, et al. (2014) Determinants of left ventricular hypertrophy in patients with recent diagnosis of essential hypertension. J Hypertens 32: 166-173.
- Hawiger J (1995) Mechanisms involved in platelet vessel wall interaction. Thromb Haemost 74: 369-372.