Mental Disorders and Thrombotic Risk

Abstract

Patients with psychosis, severe depression, or chronic stress are at increased risk for thromboembolism. Evidence suggests that tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) imbalance may play an important role in pathophysiology of mental and thromboembolic disorders. tPA facilitates clot dissolution and participates in several brain functions, including response to stress, learning, and memory. Depression is characterized by high PAI-1 levels, and conditions related to a hypofibrinolytic status, such as polycystic ovary syndrome and metabolic syndrome, are associated with an increased risk for both depression and cardiovascular events. Depression/psychosis may occur when estrogen and progesterone levels decrease. Estrogen inhibits synthesis of transforming growth factor-β (TGF-β), a protein increasing PAI-1 synthesis, whereas progesterone induces brain-derived neurotrophic factor release, stimulating tPA expression in neurons. Synthetic progestogens (progestins) may cause severe depression. Notably, progestin metabolites, which may prevent synthesis of natural progesterone by feedback, do not cross the blood–brain barrier. Intense suprapubic menstrual cramp, which may relate to difficulty to dissolve clots, correlates with severe premenstrual tension. Exercise, which increases tPA synthesis, has antidepressive and antithrombotic effects. We suggest that thromboembolism and some mental disorders are mechanistically related: tPA–PAI-1 imbalance seems to be a common denominator.

Keywords

venous thromboembolism - depression - schizophrenia - psychosis - mental stress - PAI-1 - plasminogen activator

• References

• 1 Thrall G, Lane D, Carroll D, Lip GY. A systematic review of the effects of acute psychological stress and physical activity on haemorheology, coagulation, fibrinolysis and platelet reactivity: Implications for the pathogenesis of acute coronary syndromes. Thromb Res 2007; 120 (6) 819-847
• 2 Austin AW, Patterson SM, von Känel R. Hemoconcentration and hemostasis during acute stress: interacting and independent effects. Ann Behav Med 2011; 42 (2) 153-173
• 3 Austin AW, Wirtz PH, Patterson SM, Stutz M, von Känel R. Stress-induced alterations in coagulation: assessment of a new hemoconcentration correction technique. Psychosom Med 2012; 74 (3) 288-295
• 4 Strike PC, Magid K, Whitehead DL, Brydon L, Bhattacharyya MR, Steptoe A. Pathophysiological processes underlying emotional triggering of acute cardiac events. Proc Natl Acad Sci U S A 2006; 103 (11) 4322-4327
• 5 Schaefer U, Machida T, Vorlova S, Strickland S, Levi R. The plasminogen activator system modulates sympathetic nerve function. J Exp Med 2006; 203 (9) 2191-2200
• 6 Geiser F, Meier C, Wegener I , et al. Association between anxiety and factors of coagulation and fibrinolysis. Psychother Psychosom 2008; 77 (6) 377-383
• 7 Räikkönen K, Lassila R, Keltikangas-Järvinen L, Hautanen A. Association of chronic stress with plasminogen activator inhibitor-1 in healthy middle-aged men. Arterioscler Thromb Vasc Biol 1996; 16 (3) 363-367
• 8 Robicsek O, Makhoul B, Klein E, Brenner B, Sarig G. Hypercoagulation in chronic post-traumatic stress disorder. Isr Med Assoc J 2011; 13 (9) 548-552
• 9 Jönsson AK, Spigset O, Hägg S. Venous thromboembolism in recipients of antipsychotics: incidence, mechanisms and management. CNS Drugs 2012; 26 (8) 649-662
• 10 Austin AW, Wissmann T, von Kanel R. Stress and hemostasis: an update. Semin Thromb Hemost 2013; 39 (8)
• 11 Dietrich-Muszalska A, Rabe-Jablonska J, Nowak P, Kontek B. The first- and second-generation antipsychotic drugs affect ADP-induced platelet aggregation. World J Biol Psychiatry 2010; 11 (2 Pt 2) 268-275
• 12 Halacheva K, Dimova S, Tolev T, Dimov D, Nikolova M. Elevated anticardiolipin antibodies in schizophrenic patients before and during neuroleptic medication. Psychiatry Res 2009; 169 (1) 51-55
• 13 Masopust J, Malý R, Andrýs C, Vališ M, Bažant J, Hosák L. Markers of thrombogenesis are activated in unmedicated patients with acute psychosis: a matched case control study. BMC Psychiatry 2011; 11: 2
• 14 Guest PC, Wang L, Harris LW , et al. Increased levels of circulating insulin-related peptides in first-onset, antipsychotic naïve schizophrenia patients. Mol Psychiatry 2010; 15 (2) 118-119
• 15 Allenet B, Schmidlin S, Genty C, Bosson JL. Antipsychotic drugs and risk of pulmonary embolism. Pharmacoepidemiol Drug Saf 2012; 21 (1) 42-48
• 16 Skrzypiec AE, Buczko W, Pawlak R. Tissue plasminogen activator in the amygdala: a new role for an old protease. J Physiol Pharmacol 2008; 59 (Suppl. 08) 135-146
• 17 Wright JW, Harding JW. Contributions of matrix metalloproteinases to neural plasticity, habituation, associative learning and drug addiction. Neural Plast 2009; 2009: 579382
• 18 Maiya R, Zhou Y, Norris EH, Kreek MJ, Strickland S. Tissue plasminogen activator modulates the cellular and behavioral response to cocaine. Proc Natl Acad Sci U S A 2009; 106 (6) 1983-1988
• 19 Yamada K, Nagai T, Nabeshima T. Drug dependence, synaptic plasticity, and tissue plasminogen activator. J Pharmacol Sci 2005; 97 (2) 157-161
• 20 Nagai T, Ito M, Nakamichi N , et al. The rewards of nicotine: regulation by tissue plasminogen activator-plasmin system through protease activated receptor-1. J Neurosci 2006; 26 (47) 12374-12383
• 21 Madani R, Hulo S, Toni N , et al. Enhanced hippocampal long-term potentiation and learning by increased neuronal expression of tissue-type plasminogen activator in transgenic mice. EMBO J 1999; 18 (11) 3007-3012
• 22 Baron A, Hommet Y, Cassé F, Vivien D. Tissue-type plasminogen activator induces plasmin-dependent proteolysis of intracellular neuronal nitric oxide synthase. Biol Cell 2010; 102 (10) 539-547
• 23 Liot G, Roussel BD, Lebeurrier N , et al. Tissue-type plasminogen activator rescues neurones from serum deprivation-induced apoptosis through a mechanism independent of its proteolytic activity. J Neurochem 2006; 98 (5) 1458-1464
• 24 Lynch MA. Long-term potentiation and memory. Physiol Rev 2004; 84 (1) 87-136
• 25 Doring TM, Kubo TT, Cruz Jr LC , et al. Evaluation of hippocampal volume based on MR imaging in patients with bipolar affective disorder applying manual and automatic segmentation techniques. J Magn Reson Imaging 2011; 33 (3) 565-572
• 26 Velakoulis D, Wood SJ, Wong MT , et al. Hippocampal and amygdala volumes according to psychosis stage and diagnosis: a magnetic resonance imaging study of chronic schizophrenia, first-episode psychosis, and ultra-high-risk individuals. Arch Gen Psychiatry 2006; 63 (2) 139-149
• 27 Chrapko WE, Jurasz P, Radomski MW, Lara N, Archer SL, Le Mellédo JM. Decreased platelet nitric oxide synthase activity and plasma nitric oxide metabolites in major depressive disorder. Biol Psychiatry 2004; 56 (2) 129-134
• 28 Enga KF, Brækkan SK, Hansen-Krone IJ, Hansen JB. Emotional states and future risk of venous thromboembolism: the Tromsø Study. Thromb Haemost 2012; 107 (3) 485-493
• 29 Vikenes K, Farstad M, Nordrehaug JE. Serotonin is associated with coronary artery disease and cardiac events. Circulation 1999; 100 (5) 483-489
• 30 Lespérance F, Frasure-Smith N, Koszycki D , et al; CREATE Investigators. Effects of citalopram and interpersonal psychotherapy on depression in patients with coronary artery disease: the Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) trial. JAMA 2007; 297 (4) 367-379
• 31 Taylor CB, Youngblood ME, Catellier D , et al; ENRICHD Investigators. Effects of antidepressant medication on morbidity and mortality in depressed patients after myocardial infarction. Arch Gen Psychiatry 2005; 62 (7) 792-798
• 32 Galan AM, Lopez-Vilchez I, Diaz-Ricart M , et al. Serotonergic mechanisms enhance platelet-mediated thrombogenicity. Thromb Haemost 2009; 102 (3) 511-519
• 33 Berger JS, Becker RC, Kuhn C, Helms MJ, Ortel TL, Williams R. Hyperreactive platelet phenotypes: relationship to altered serotonin transporter number, transport kinetics and intrinsic response to adrenergic co-stimulation. Thromb Haemost 2013; 109 (1) 85-92
• 34 McEwen BS. Glucocorticoids, depression, and mood disorders: structural remodeling in the brain. Metabolism 2005; 54 (5) (Suppl. 01) 20-23
• 35 Matthews KA, Schott LL, Bromberger J, Cyranowski J, Everson-Rose SA, Sowers MF. Associations between depressive symptoms and inflammatory/hemostatic markers in women during the menopausal transition. Psychosom Med 2007; 69 (2) 124-130
• 36 Eskandari F, Mistry S, Martinez PE , et al; POWER (Premenopausal, Odteopenia/Osteoporosis, Women, Alendronate, Depression) Study Group. Younger, premenopausal women with major depressive disorder have more abdominal fat and increased serum levels of prothrombotic factors: implications for greater cardiovascular risk. Metabolism 2005; 54 (7) 918-924
• 37 Greggersen W, Rudolf S, Fassbinder E , et al. Major depression, borderline personality disorder, and visceral fat content in women. Eur Arch Psychiatry Clin Neurosci 2011; 261 (8) 551-557
• 38 Hollinrake E, Abreu A, Maifeld M, Van Voorhis BJ, Dokras A. Increased risk of depressive disorders in women with polycystic ovary syndrome. Fertil Steril 2007; 87 (6) 1369-1376
• 39 Cibula D, Cífková R, Fanta M, Poledne R, Zivny J, Skibová J. Increased risk of non-insulin dependent diabetes mellitus, arterial hypertension and coronary artery disease in perimenopausal women with a history of the polycystic ovary syndrome. Hum Reprod 2000; 15 (4) 785-789
• 40 Huotari A, Lehto SM, Niskanen L , et al. Increased serum PAI-1 levels in subjects with metabolic syndrome and long-term adverse mental symptoms: a population-based study. Cardiovasc Psychiatry Neurol 2010; ;doi:10.1155/2010/501349
• 41 Cahill MA. Progesterone receptor membrane component 1: an integrative review. J Steroid Biochem Mol Biol 2007; 105 (1-5) 16-36
• 42 Fiumelli H, Jabaudon D, Magistretti PJ, Martin JL. BDNF stimulates expression, activity and release of tissue-type plasminogen activator in mouse cortical neurons. Eur J Neurosci 1999; 11 (5) 1639-1646
• 43 Su C, Cunningham RL, Rybalchenko N, Singh M. Progesterone increases the release of brain-derived neurotrophic factor from glia via progesterone receptor membrane component 1 (Pgrmc1)-dependent ERK5 signaling. Endocrinology 2012; 153 (9) 4389-4400
• 44 He G, Pedersen SB, Bruun JM, Richelsen B. Regulation of plasminogen activator inhibitor-1 in human adipose tissue: interaction between cytokines, cortisol and estrogen. Horm Metab Res 2000; 32 (11-12) 515-520
• 45 Peluso JJ, Yuan A, Liu X, Lodde V. Plasminogen activator inhibitor 1 RNA-binding protein interacts with progesterone receptor membrane component 1 to regulate progesterone's ability to maintain the viability of spontaneously immortalized granulosa cells and rat granulosa cells. Biol Reprod 2013; 88 (1) 20
• 46 North American Menopause Society. Estrogen and progestogen use in postmenopausal women: 2010 position statement of The North American Menopause Society. Menopause 2010; 17 (2) 242-255
• 47 Brinton RD, Thompson RF, Foy MR , et al. Progesterone receptors: form and function in brain. Front Neuroendocrinol 2008; 29 (2) 313-339
• 48 Mortola JF. Premenstrual syndrome. In: Goldman MB, Hatch M, , eds. Women and Health. San Diego, CA: Academic Press; 2000: 114-125
• 49 Sjöberg NO. Dysmenorrhea and uterine neurotransmitters. Acta Obstet Gynecol Scand Suppl 1979; 87: 57-59
• 50 Nisar N, Zehra N, Haider G, Munir AA, Sohoo NA. Frequency, intensity and impact of premenstrual syndrome in medical students. J Coll Physicians Surg Pak 2008; 18 (8) 481-484
• 51 Vichnin M, Freeman EW, Lin H, Hillman J, Bui S. Premenstrual syndrome (PMS) in adolescents: severity and impairment. J Pediatr Adolesc Gynecol 2006; 19 (6) 397-402
• 52 McColl BK, Baldwin ME, Roufail S , et al. Plasmin activates the lymphangiogenic growth factors VEGF-C and VEGF-D. J Exp Med 2003; 198 (6) 863-868
• 53 Kim DR, Czarkowski KA, Epperson CN. The relationship between bipolar disorder, seasonality, and premenstrual symptoms. Curr Psychiatry Rep 2011; 13 (6) 500-503
• 54 Yen JY, Chang SJ, Ko CH , et al. The high-sweet-fat food craving among women with premenstrual dysphoric disorder: emotional response, implicit attitude and rewards sensitivity. Psychoneuroendocrinology 2010; 35 (8) 1203-1212
• 55 Erdman Jr JW, Balentine D, Arab L , et al. Flavonoids and heart health: proceedings of the ILSI North America Flavonoids Workshop, May 31-June 1, 2005, Washington, DC. J Nutr 2007; 137 (3) (Suppl. 01) 718S-737S
• 56 Zhao X, Gu Z, Attele AS, Yuan CS. Effects of quercetin on the release of endothelin, prostacyclin and tissue plasminogen activator from human endothelial cells in culture. J Ethnopharmacol 1999; 67 (3) 279-285
• 57 Shenouda SM, Vita JA. Effects of flavonoid-containing beverages and EGCG on endothelial function. J Am Coll Nutr 2007; 26 (4) 366S-372S
• 58 Masho SW, Adera T, South-Paul J. Obesity as a risk factor for premenstrual syndrome. J Psychosom Obstet Gynaecol 2005; 26 (1) 33-39
• 59 Baptista T. Body weight gain induced by antipsychotic drugs: mechanisms and management. Acta Psychiatr Scand 1999; 100 (1) 3-16
• 60 Sartori CR, Vieira AS, Ferrari EM, Langone F, Tongiorgi E, Parada CA. The antidepressive effect of the physical exercise correlates with increased levels of mature BDNF, and proBDNF proteolytic cleavage-related genes, p11 and tPA. Neuroscience 2011; 180: 9-18
• 61 Kassam G, Le BH, Choi KS , et al. The p11 subunit of the annexin II tetramer plays a key role in the stimulation of t-PA-dependent plasminogen activation. Biochemistry 1998; 37 (48) 16958-16966
• 62 Maskall DD, Lam RW, Misri S , et al. Seasonality of symptoms in women with late luteal phase dysphoric disorder. Am J Psychiatry 1997; 154 (10) 1436-1441
• 63 Wittkowsky AK. Warfarin and other coumarin derivatives: pharmacokinetics, pharmacodynamics, and drug interactions. Semin Vasc Med 2003; 3 (3) 221-230
• 64 Hoirisch-Clapauch S, Nardi AE. Psychiatric remission with warfarin: Should psychosis be addressed as plasminogen activator imbalance?. Med Hypotheses 2013; 80 (2) 137-141
• 65 Walsh AC. Prevention of senile and presenile dementia by bishydroxycoumarin (Dicumarol) therapy. J Am Geriatr Soc 1969; 17 (5) 477-487
• 66 Bahi A, Dreyer JL. Overexpression of plasminogen activators in the nucleus accumbens enhances cocaine-, amphetamine- and morphine-induced reward and behavioral sensitization. Genes Brain Behav 2008; 7 (2) 244-256
• 67 Esse K, Fossati-Bellani M, Traylor A, Martin-Schild S. Epidemic of illicit drug use, mechanisms of action/addiction and stroke as a health hazard. Brain Behav 2011; 1 (1) 44-54
• 68 Patten SB, Barbui C. Drug-induced depression: a systematic review to inform clinical practice. Psychother Psychosom 2004; 73 (4) 207-215
• 69 van Zonneveld AJ, Curriden SA, Loskutoff DJ. Type 1 plasminogen activator inhibitor gene: functional analysis and glucocorticoid regulation of its promoter. Proc Natl Acad Sci U S A 1988; 85 (15) 5525-5529
• 70 Baars JW, de Boer JP, Wagstaff J , et al. Interleukin-2 induces activation of coagulation and fibrinolysis: resemblance to the changes seen during experimental endotoxemia. Br J Haematol 1992; 82 (2) 295-301
• 71 Cash JD, Woodfield DG, Allan AG. Adrenergic mechanisms in the systemic plasminogen active response to adrenaline in man. Br J Haematol 1970; 18 (4) 487-494
• 72 Tsai SJ, Hong CJ, Liou YJ, Yu YW, Chen TJ. Plasminogen activator inhibitor-1 gene is associated with major depression and antidepressant treatment response. Pharmacogenet Genomics 2008; 18 (10) 869-875