The Associations between Central Nervous System Diseases and Haemostatic Disorders

Author(s): Maria Podsiedlik*, Magdalena Markowicz-Piasecka, Elżbieta Mikiciuk-Olasik, Joanna Sikora.

Journal Name: CNS & Neurological Disorders - Drug Targets

Volume 18 , Issue 4 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


The aim of this review was to examine the relationship between the occurrence of central nervous system (CNS) diseases, the medicines used in their treatment and the blood coagulation process. The paper mainly focuses on the effects of antidepressant and antipsychotic drugs. Special attention has been paid to the influence of drugs on platelets, the vascular endothelium, plasma coagulation and fibrinolysis, regarding coagulation.

Keywords: Coagulation, haemostasis, central nervous system diseases, antidepressant drugs, antipsychotic drugs, vascular endothelium.

World Health Organization. Mental health atlas: 2011 World Health Organization 2011.
World Health Organization. Management of physical health conditions in adults with severe mental disorders WHO Guidelines World Health Organization 2018.
von Känel R, Mills PJ, Fainman C, Dimsdale JE. Effects of psychological stress and psychiatric disorders on blood coagulation and fibrinolysis: a biobehavioral pathway to coronary artery disease? Psychosom Med 2001; 63(4): 531-44.
Krystal JH, State MW. Psychiatric disorders: diagnosis to therapy. Cell 2014; 157(1): 201-14.
Hägg S, Spigset O. Antipsychotic-induced venous thromboembolism: a review of the evidence. CNS Drugs 2002; 16(11): 765-76.
Pizzi C, Santarella L, Bugiardini R. Epidemiology and the physiopathological link between depression and cardiovascular disease. IJC Metab Endocr 2014; 5: 52-5.
von Känel R, Dimsdale JE, Adler KA, Patterson TL, Mills PJ, Grant I. Effects of depressive symptoms and anxiety on hemostatic responses to acute mental stress and recovery in the elderly. Psychiatry Res 2004; 126: 253-64.
Chow V, Reddel C, Pennings G, et al. Global hypercoagulability in patients with schizophrenia receiving long-term antipsychotic therapy. Schizophr Res 2015; 162: 175-82.
Williams ED, Steptoe A. The role of depression in the etiology of acute coronary syndrome. Curr Psychiatry Rep 2007; 9: 486-92.
Paz-Filho G, Licinio J, Wong ML. Pathophysiological basis of cardiovascular disease and depression: a chicken-and-egg dilemma. Revista Brasileira de Psiquiatr 2010; 32(2): 181-91.
von Känel R, Bellingrath S, Kudielka BM. Association of vital exhaustion and depressive symptoms with changes in fibrin D-dimer to acute psychosocial stress. J Psychosom Res 2009; 67: 93-101.
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): 268-75.
Padhy SK, Sarkar S, Davuluri T, Malhotra N. Depression as a risk factor for cardiac illness - What do we know about? J Indian Coll Cardiol 2015; 5: 123-30.
Pitsavos C, Panagiotakos DB, Papageorgiou C. Anxiety in relation to inflammation and coagulation markers, among healthy adults: ATTICA. Atherosclerosis 2006; 185: 320-6.
Pluta R, Ułamek-Kozioł M, Januszewski S, Czuczwar SJ. Platelets, lymphocytes and erythrocytes from Alzheimer’s disease patients: the quest for blood cell-based biomarkers. Folia Neuropathol 2018; 56(1): 14-20.
Cortes-Canteli M, Zamolodchikov D, Ahn HJ, Strickland S, Norris EH. Fibrinogen and altered hemostasis in Alzheimer’s disease. J Alzheimers Dis 2012; 32(3): 599-608.
Zamolodchikov D, Berk-Rauch HE, Oren DA, et al. Biochemical and structural analysis of the interaction between β-amyloid and fibrinogen. Blood 2016; 128(8): 1144-51.
Chung YC, Kruyer A, Yao Y, et al. Hyperhomocysteinemia exacerbates Alzheimer’s disease pathology by way of the β-amyloid fibrinogen interaction. J Thromb Haemost 2016; 14(7): 1442-52.
Singh PK, Kawasaki M, Berk-Rauch HE, et al. Aminopyrimidine class aggregation inhibitor effectively blocks aβ-fibrinogen interaction and Aβ-induced contact system activation. Biochemistry 2018; 57(8): 1399-409.
Chen ZL, Revenko AS, Singh P, MacLeod AR, Norris EH, Strickland S. Depletion of coagulation factor XII ameliorates brain pathology and cognitive impairment in Alzheimer disease mice. Blood 2017; 129(18): 2547-56.
Kumar S, Chowdhury S, Kumar S. In silico repurposing of antipsychotic drugs for Alzheimer’s disease. BMC Neurosci 2017; 18(1): 76.
Hughes RE, Nikolic K, Ramsay RR. One for all? Hitting multiple Alzheimer’s disease targets with one drug. Front Neurosci 2016; 10: 177.
Solimini R, Rotolo MC, Pichini S, Pacifici R. Neurological disorders in medical use of cannabis: an update. CNS Neurol Disord Drug Targets 2017; 16(5): 527-33.
Uddin M. Blood-based biomarkers in depression: emerging themes in clinical research. Mol Diagn Ther 2014; 18: 469-82.
Dereli FTG, Ilhan M, Akkol EK. New drug discovery from medicinal plants and phytoconstituents for depressive disorders. CNS Neurol Disord Drug Targets 2018; 17(1)
[ 1871527317666181114141129]
de Oliveira DR, da Silva DM, Florentino IF, de Brito AF. Monoamine Involvement in the antidepressant-like effect of β-caryophyllene. CNS Neurol Disord Drug Targets 2018; 17(4): 309-20.
Małyszczak K, Rymaszewska J. Depression and anxiety in cardiovascular disease. Kardiol Pol 2016; 74(7): 603-9.
Ghoshal K, Bhattacharyya M. Overview of platelet physiology: its hemostatic and nonhemostatic role in disease pathogenesis. Sci J 2014; 2014: 7818-57.
Maes M, Van Der Planken M, Van Gastel A, Desnyder R. Blood coagulation and platelet aggregation in major depression. J Affect Disord 1996; 40: 35-40.
McAdams C, Colohan FJ, Brophy J, Leonard BE. Alteration by a plasma factor of platelet aggregation and 5HT uptake in depression. Biol Psychiatry 1992; 32: 296-8.
Schins A, Hamulyák K, Scharpé S, et al. Whole blood serotonin and platelet activation in depressed post-myocardial infarction patients. Life Sci 2004; 76: 637-50.
Schins A, Honig A, Crijns H, Baur L, Hamulyák K. Increased coronary events in depressed cardiovascular patients: 5-HT2A receptor as missing link? Psychosom Med 2003; 65: 729-37.
Nugent DF, Dinan TG, Leonard BE. Alteration by a plasma factor(s) of platelet aggregation in unmedicated unipolar depressed patients. J Affect Disord 1994; 31(1): 61-6.
Lopez-Vilchez I, Serra-Millas M, Navarro V, et al. Prothrombotic platelet phenotype in major depression: downregulation by antidepressant treatment. J Affect Disord 2014; 159: 39-45.
Aschbacher K, Roepke SK, von Känel R, et al. Persistent versus transient depressive symptoms in relation to platelet hyperactivation: a longitudinal analysis of dementia caregivers. J Affect Disord 2009; 116: 80-7.
Shimbo D, Child J, Davidson K, et al. Exaggerated serotonin-mediated platelet reactivity as a possible link in depression and acute coronary syndromes. Am J Cardiol 2002; 89: 331-3.
Burke KC, Burke JD, Regier DA, Rae DS. Age at onset of selected mental disorders in five community populations. Arch Gen Psychiatry 1990; 47(6): 511-8.
Parakh K, Sakhuja A, Bhat U, Ziegelstein RC. Platelet function in patients with depression. South Med J 2008; 101: 612-7.
Singh I, Achuthan S, Chakrabarti A, Rajagopalan S, Srinivasan A, Hota D. Influence of pre-operative use of serotonergic antidepressants (SADs) on the risk of bleeding in patients undergoing different surgical interventions: A meta-analysis. Pharmacoepidemiol Drug Saf 2015; 24: 237-45.
Laghrissi-Thode F, Wagner WR, Pollock BG, Johnson PC, Finkel MS. Elevated platelet factor 4 and beta-thromboglobulin plasma levels in depressed patients with ischemic heart disease. Biol Psychiatry 1997; 42: 290-5.
Maurer-Spurej E, Pittendreigh C, Solomons K. The influence of selective serotonin reuptake inhibitors on human platelet serotonin. Thromb Haemost 2004; 91: 119-28.
Nemeroff CB, Musselman DL. Are platelets the link between depression and ischemic heart disease? Am Heart J 2000; 140: 57-62.
Smolderen KG, Spertus JA, Reid KJ, et al. Association of somatic and cognitive depressive symptoms and biomarkers in acute myocardial infarction: insights from the translational research investigating underlying disparities in acute myocardial infarction patients’ health status registry. Biol Psychiatry 2012; 71: 22-9.
Carney RM, Freedland KE, Stein PK, et al. Heart rate variability and markers of inflammation and coagulation in depressed patients with coronary heart disease. J Psychosom Res 2007; 62: 463-7.
Geiser F, Urbach AS, Harbrecht U, et al. Anxiety and depression in patients three months after myocardial infarction: association with markers of coagulation and the relevance of age. J Psychosom Res 2017; 99: 162-8.
Ogłodek EA, Just MJ, Grzesińska AD, Araszkiewicz A, Szromek AR. The impact of antipsychotics as a risk factor for thromboembolism. Pharmacological Reports 2018; 70(3): 533-9.
Chrapko WE, Jurasz P, Radomski MW, et al. Decreased platelet nitric oxide synthase activity and plasma nitric oxide metabolites in major depressive disorder. Biol Psychiatry 2004; 56: 129-34.
Mendoza-Sotelo J, Torner C, Alvarado-Vasquez N, et al. Ultrastructural changes and immunolocalization of P-selectin in platelets from patients with major depression. Psychiatry Res 2010; 176: 179-82.
Dietrich-Muszalska A, Olas B. The changes of aggregability of blood platelets in schizophrenia. World J Biol Psychiatry 2009; 10(2): 171-6.
Dietrich-Muszalska A, Rabe-Jablonska J, Olas B. The effects of the second generation antipsychotics and a typical neuroleptic on collagen-induced platelet aggregation in vitro. World J Biol Psychiatry 2010; 11(2): 293-9.
Gajski G, Gerić M, Garaj-Vrhovac V. Evaluation of the in vitro cytogenotoxicity profile of antipsychotic drug haloperidol using human peripheral blood lymphocytes. Environ Toxicol Pharmacol 2014; 38: 316-24.
Dale GL. Coated-platelets: an emerging component of the procoagulant response. J Thromb Haemost 2005; 3: 2185-92.
Blann AD. Assessment of endothelial dysfunction: focus on atherothrombotic disease. In: Pathophysiology of Haemostasis and Thrombosis 2003; 33: 256-61.
Jobling L, Eyre L. Haemostasis, blood platelets and coagulation. Anaesth Intens Med 2013; 14(2): 51-3.
Doulalas AD, Rallidis LS, Gialernios T, et al. Association of depressive symptoms with coagulation factors in young healthy individuals. Atherosclerosis 2006; 186: 121-5.
Broadley AJM, Korszun A, Abdelaal E, et al. Metyrapone improves endothelial dysfunction in patients with treated depression. J Am Coll Cardiol 2006; 40: 170-5.
Halperin D, Reber G. Influence of antidepressants on hemostasis. Clin Neurosci 2007; 9: 47-59.
Kop WJ, Gottdiener JS, Tangen CM, et al. Inflammation and coagulation factors in persons > 65 years of age with symptoms of depression but without evidence of myocardial ischemia. Am J Cardiol 2002; 89: 419-24.
Panagiotakos DB, Pitsavos C, Chrysohoou C, et al. Inflammation, coagulation, and depressive symptomatology in cardiovascular disease-free people; the ATTICA study. Eur Heart J 2004; 25: 492-9.
Tracy RP, Arnold AM, Ettinger W, Fried L, Meilahn E, Savage P. The relationship of fibrinogen and factors VII and VIII to incident cardiovascular disease and death in the elderly: results from the cardiovascular health study. Arterioscler Thromb Vasc Biol 1999; 19: 1776-83.
Ohni M, Mishima K, Nakajima K, Yamamoto M, Hata Y. Serum triglycerides and blood coagulation factors VII and X, and plasminogen activator inhibitor-1. J Atheroscler Thromb 1995; 2: 41-6.
Malach M, Imperato PJ. Depression and acute myocardial infarction. Prev Cardiol 2004; 7: 83-92.
Jezova D, Kristova V, Slamova J, et al. Stress-induced rise in endothelaemia, von Willebrand factor and hypothalamic-pituitary-adrenocortical axis activation is reduced by pretreatment with pentoxifylline. J Physiol Pharmacol 2003; 54(3): 329-38.
Von Känel R, Kudielka BM, Preckel D, et al. Opposite effect of negative and positive affect on stress procoagulant reactivity. Physiol Behav 2005; 86: 61-8.
Kostka B, Para J, Sikora J. A multiparameter test of clot formation and fibrinolysis for in-vitro drug screening. Blood Coagul Fibrinolysis 2007; 18: 611-8.
Furie B, Furie BC. Mechanisms of thrombus formation. N Engl J Med 2008; 359: 938-49.
Januzzi JL, Stern T, Pasternak RC, DeSanctis RW. The influence of anxiety and depression on outcomes of patients with coronary artery disease. Arch Intern Med 2000; 160: 1913-21.
Denollet J, Brutsaert DL. Personality, disease severity, and the risk of long-term cardiac events in patients with a decreased ejection fraction after myocardial infarction. Circulation 1998; 97: 167-73.
Amodeo G, Fagiolini A, Sachs G, Erfurth A. Older and newer strategies for the pharmacological management of agitation in patients with bipolar disorder or schizophrenia. CNS Neurol Disord Drug Targets 2017; 16(8): 885-90.
Carrizo E, Fernández V, Quintero J, et al. Coagulation and inflammation markers during atypical or typical antipsychotic treatment in schizophrenia patients and drug-free first-degree relatives. Schizophr Res 2008; 103: 83-93.
Lane HY, Lin HN, Hu OY-P, Chen CC, Jann MW, Chang WH. Blood levels of reduced haloperidol versus clinical efficacy and extrapyramidal side effects of haloperidol. Prog Neuropsychopharmacol Biol Psychiatry 1997; 21: 299-311.
Chang-Chieh W, Fu-Ming T, Mao-Liang C. Antipsychotic drugs inhibit platelet aggregation via P2Y1 and P2Y12 receptors. Bio- Med Res Int 2016. Article ID 2532371, 12 pages.
Kahl KG, Westhoff-Bleck M, Krüger THC. Effects of psychopharmacological treatment with antipsychotic drugs on the vascular system. Vasc Pharm 2018; 100: 20-5.
de Souza TB, Farias DM, Coletti RF. Systemic Administration of Antipsychotic Asenapine Pre or Postnatal does not Induce Anxiety-like Behaviors in Mice CNS Neurol Disord Drug Target 2018; 13: 16(10): 1127-33.
Wei Z, Zhang K, Zhou Q. Differential mechanisms underlying antidepressant responses of ketamine and imipramine. CNS Neurol Disord Drug Targets 2017; 16(7): 846-53.
Abelaira HM, Maciel AL, Quevedo J, Reus GZ. Immune system modulators with antidepressant effects: evidence from animal models. CNS Neurol Disord Drug Targets 2017; 16(4): 398-406.
Hallbäck I, Hägg S, Eriksson AC, Whiss Per A. In vitro effects of serotonin and noradrenaline reuptake inhibitors on human platelet adhesion and coagulation. Pharmacol Rep 2012; 64: 979-83.
Belcher PR, Drake-Holland AJ. Serotonin reuptake inhibitors and cardiovascular disease. Coron Health Care 2001; 5: 141-7.
Ceylan ME, Alpsan-Omay MH. Bleeding induced by SSRIs. Eur Psychiatry 2005; 20: 570-1.
Kurne A, Ertugrul A, Yaǧcioǧlu AEA, Yazici KM. Venous thromboembolism and escitalopram. Gen Hosp Psychiatry 2004; 26: 481-3.
Kim DH, Daskalakis C, Whellan DJ, et al. Safety of selective serotonin reuptake inhibitor in adults undergoing coronary artery bypass grafting. Am J Cardiol 2009; 103: 1391-5.
Gerasimou C, Tsoporis JN, Siafakas N. A longitudinal study of alterations of s100b, srage and fas ligand in association to olanzapine medication in a sample of first episode patients with schizophrenia. CNS Neurol Disord Drug Targets 2018; 17(5): 383-8.
Axelsson S, Hägg S, Eriksson AC, Lindahl TL. Whiss P a. In vitro effects of antipsychotics on human platelet adhesion and aggregation and plasma coagulation. Clin Exp Pharmacol Physiol 2007; 34: 775-80.
De Clerck F, Somers Y, Mannaert E, Greenspan A, Eerdekens M. In vitro effects of risperidone and 9-hydroxy-risperidone on human platelet function, plasma coagulation, and fibrinolysis. Clin Ther 2004; 26: 1261-73.
van den Buuse M. Acute effects of antipsychotic drugs on cardiovascular responses to stress. Eur J Pharmacol 2003; 464: 55-62.
Smits JPP, Veldkamp MW, Wilde AAM. Mechanisms of inherited cardiac conduction disease. Europace 2005; 7: 122-37.
Khan H, Khattak S, Mubarak MS, Bawazeer SS, Abu-Izneid T, Kamal MA. Antidepressant potential of peptides: new insights as future therapeutic. CNS Neurol Disord Drug Targets 2018; 17(1): 9-13.
Meltzer HY. New trends in the treatment of schizophrenia. CNS Neurol Disord Drug Targets 2017; 16(8): 900-6.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [307 - 316]
Pages: 10
DOI: 10.2174/1871527318666190314101946
Price: $58

Article Metrics

PDF: 36