Semin Thromb Hemost 2018; 44(07): 632-639
DOI: 10.1055/s-0038-1661385
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Hemostasis at Extremes of Body Weight

Beverley J. Hunt
1   Thrombosis and Haemostasis, King's College, London, United Kingdom
2   Thrombosis and Haemophilia Centre, Guy's and St Thomas' NHS Trust, London, United Kingdom
› Author Affiliations
Further Information

Publication History

Publication Date:
09 July 2018 (online)

Abstract

Extremes of body weight are not uncommon in the modern world and include anorexia nervosa (AN) and obesity. Both conditions are associated with increased morbidity and mortality: AN has the highest mortality rate of all mental illnesses and unfortunately obesity has reached epidemic proportions and is a well-recognized risk factor for cardiovascular disease including venous thromboembolism (VTE). This article summarizes the current understanding of hemostatic changes of these extremes of body weight. The hemostatic changes of AN have not been well described. Severe AN is associated with pancytopenia with decreased bone marrow cellularity, which causes a mild thrombocytopenia. Platelet hyperaggregability has been recognized in AN and has been attributed at least in part to increased adrenoceptor density. Obesity and the metabolic syndrome are associated with prothrombotic changes, which have been well characterized and related to complex adipocyte-induced inflammatory changes, including increased levels of plasminogen activator inhibitor type 1, von Willebrand factor, fibrinogen, and other evidence of increased coagulation and platelet activation. Accumulating evidence suggests a significant role for increased tissue factor expression and signaling in this relationship, with increased tissue factor expression present in adipose and possibly systemic tissues, induced by adipose-generated cytokines. Intriguingly, the hemostatic changes do not seem to increase with increasing BMI, although the risk of VTE increases with BMI, suggesting that decreased venous flow due to venous enlargement may play the most important role in increased VTE risk with obesity.

 
  • References

  • 1 Smink FR, van Hoeken D, Hoek HW. Epidemiology of eating disorders: incidence, prevalence and mortality rates. Curr Psychiatry Rep 2012; 14 (04) 406-414
  • 2 WHO fact sheet on obesity and overweight, January 2015. Available at: www.who.int/mediacentre/factsheets/fs311/en . Accessed May 5, 2018
  • 3 Arcelus J, Mitchell AJ, Wales J, Nielsen S. Mortality rates in patients with anorexia nervosa and other eating disorders. A meta-analysis of 36 studies. Arch Gen Psychiatry 2011; 68 (07) 724-731
  • 4 Di Cola G, Jacoangeli F, Jacoangeli F, Lombardo M, Iellamo F. Cardiovascular disorders in anorexia nervosa and potential therapeutic targets. Intern Emerg Med 2014; 9 (07) 717-721
  • 5 Devuyst O, Lambert M, Rodhain J, Lefebvre C, Coche E. Haematological changes and infectious complications in anorexia nervosa: a case-control study. Q J Med 1993; 86 (12) 791-799
  • 6 Vande Zande VL, Mazza JJ, Yale SH. Hematologic and metabolic abnormalities in a patient with anorexia nervosa. WMJ 2004; 103 (02) 38-40
  • 7 Ogston D, Ogston WD. The fibrinolytic enzyme system in anorexia nervosa. Acta Haematol 1976; 55 (04) 230-233
  • 8 Luck P, Mikhailidis DP, Dashwood MR. , et al. Platelet hyperaggregability and increased alpha-adrenoceptor density in anorexia nervosa. J Clin Endocrinol Metab 1983; 57 (05) 911-914
  • 9 Barron LJ, Barron RF, Johnson JCS. , et al. A retrospective analysis of biochemical and haematological parameters in patients with eating disorders. J Eat Disord 2017; 5: 32
  • 10 Mikhailidis DP, Barradas MA, Jeremy JY, Gracey L, Wakeling A, Dandona P. Heparin-induced platelet aggregation in anorexia nervosa and in severe peripheral vascular disease. Eur J Clin Invest 1985; 15 (06) 313-319
  • 11 Wöckel L, Koch S, Stadler C, Meyer-Keitel AE, Schmidt MH. Serotonin-induced platelet intracellular Ca2+ response in patients with anorexia nervosa. Pharmacopsychiatry 2008; 41 (01) 10-16
  • 12 Ageno W, Becattini C, Brighton T, Selby R, Kamphuisen PW. Cardiovascular risk factors and venous thromboembolism: a meta-analysis. Circulation 2008; 117 (01) 93-102
  • 13 National Institute for Health and Care Excellence. Obesity: identification, assessment and management. London, 2014. Available at: www.nice.org.uk/guidance/cg189 . Accessed February 22, 2018
  • 14 Public Health England. Available at: http://webarchive.nationalarchives.gov.uk/20170110171101/https://www.noo.org.uk/NOO_about_obesity/maternal_obesity_2015/prevalence . Accessed February 22, 2018
  • 15 Births in Scottish Hospitals. Available at: http://www.isdscotland.org/Health-Topics/Maternity-and-Births/Publications/2014-08-26/2014-08-26-Births-Report.pdf . Accessed February 22, 2018
  • 16 Ibrahim MM. Subcutaneous and visceral adipose tissue: structural and functional differences. Obes Rev 2010; 11 (01) 11-18
  • 17 Mendis S. The contribution of the Framingham Heart Study to the prevention of cardiovascular disease: a global perspective. Prog Cardiovasc Dis 2010; 53 (01) 10-14
  • 18 Lakka HM, Laaksonen DE, Lakka TA. , et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002; 288 (21) 2709-2716
  • 19 Hubert HB, Feinleib M, McNamara PM, Castelli WP. Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study. Circulation 1983; 67 (05) 968-977
  • 20 Després JP, Lemieux I, Bergeron J. , et al. Abdominal obesity and the metabolic syndrome: contribution to global cardiometabolic risk. Arterioscler Thromb Vasc Biol 2008; 28 (06) 1039-1049
  • 21 Van Gaal LF, Mertens IL, De Block CE. Mechanisms linking obesity with cardiovascular disease. Nature 2006; 444 (7121): 875-880
  • 22 Yusuf S, Hawken S, Ôunpuu S. , et al; INTERHEART Study Investigators. Obesity and the risk of myocardial infarction in 27,000 participants from 52 countries: a case-control study. Lancet 2005; 366 (9497): 1640-1649
  • 23 Mente A, Yusuf S, Islam S. , et al; INTERHEART Investigators. Metabolic syndrome and risk of acute myocardial infarction a case-control study of 26,903 subjects from 52 countries. J Am Coll Cardiol 2010; 55 (21) 2390-2398
  • 24 National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002; 106 (25) 3143-3421
  • 25 Grundy SM, Brewer Jr HB, Cleeman JI, Smith Jr SC, Lenfant C. ; American Heart Association; National Heart, Lung, and Blood Institute. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation 2004; 109 (03) 433-438
  • 26 Alberti KG, Zimmet P, Shaw J. ; IDF Epidemiology Task Force Consensus Group. The metabolic syndrome--a new worldwide definition. Lancet 2005; 366 (9491): 1059-1062
  • 27 Alberti KG, Eckel RH, Grundy SM. , et al; International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; International Association for the Study of Obesity. Harmonizing the metabolic syndrome: a joint interim statement of the international diabetes federation task force on epidemiology and prevention; National heart, lung, and blood institute; American heart association; World heart federation; International atherosclerosis society; And international association for the study of obesity. Circulation 2009; 120 (16) 1640-1645
  • 28 Koh KK, Park SM, Quon MJ. Leptin and cardiovascular disease: response to therapeutic interventions. Circulation 2008; 117 (25) 3238-3249
  • 29 Napoleone E, DI Santo A, Amore C. , et al. Leptin induces tissue factor expression in human peripheral blood mononuclear cells: a possible link between obesity and cardiovascular risk?. J Thromb Haemost 2007; 5 (07) 1462-1468
  • 30 Rafail S, Ritis K, Schaefer K. , et al. Leptin induces the expression of functional tissue factor in human neutrophils and peripheral blood mononuclear cells through JAK2-dependent mechanisms and TNFalpha involvement. Thromb Res 2008; 122 (03) 366-375
  • 31 Samad F, Pandey M, Loskutoff DJ. Regulation of tissue factor gene expression in obesity. Blood 2001; 98 (12) 3353-3358
  • 32 Kopp CW, Kopp HP, Steiner S. , et al. Weight loss reduces tissue factor in morbidly obese patients. Obes Res 2003; 11 (08) 950-956
  • 33 Russo I, Traversa M, Bonomo K. , et al. In central obesity, weight loss restores platelet sensitivity to nitric oxide and prostacyclin. Obesity (Silver Spring) 2010; 18 (04) 788-797
  • 34 Diamant M, Nieuwland R, Pablo RF, Sturk A, Smit JW, Radder JK. Elevated numbers of tissue-factor exposing microparticles correlate with components of the metabolic syndrome in uncomplicated type 2 diabetes mellitus. Circulation 2002; 106 (19) 2442-2447
  • 35 Müller I, Klocke A, Alex M. , et al. Intravascular tissue factor initiates coagulation via circulating microvesicles and platelets. FASEB J 2003; 17 (03) 476-478
  • 36 Nomura S, Suzuki M, Katsura K. , et al. Platelet-derived microparticles may influence the development of atherosclerosis in diabetes mellitus. Atherosclerosis 1995; 116 (02) 235-240
  • 37 Goichot B, Grunebaum L, Desprez D. , et al. Circulating procoagulant microparticles in obesity. Diabetes Metab 2006; 32 (01) 82-85
  • 38 Esposito K, Ciotola M, Schisano B. , et al. Endothelial microparticles correlate with endothelial dysfunction in obese women. J Clin Endocrinol Metab 2006; 91 (09) 3676-3679
  • 39 Agouni A, Lagrue-Lak-Hal AH, Ducluzeau PH. , et al. Endothelial dysfunction caused by circulating microparticles from patients with metabolic syndrome. Am J Pathol 2008; 173 (04) 1210-1219
  • 40 Renovato-Martins M, Matheus ME, de Andrade IR. , et al. Microparticles derived from obese adipose tissue elicit a pro-inflammatory phenotype of CD16+, CCR5+and TLR8+monocytes. Biochim Biophys Acta 2017; 1863 (01) 139-151
  • 41 Koenig W. Fibrin(ogen) in cardiovascular disease: an update. Thromb Haemost 2003; 89 (04) 601-609
  • 42 Kakafika AI, Liberopoulos EN, Mikhailidis DP. Fibrinogen: a predictor of vascular disease. Curr Pharm Des 2007; 13 (16) 1647-1659
  • 43 Conlan MG, Folsom AR, Finch A. , et al. Associations of factor VIII and von Willebrand factor with age, race, sex, and risk factors for atherosclerosis. The Atherosclerosis Risk in Communities (ARIC) Study. Thromb Haemost 1993; 70 (03) 380-385
  • 44 Landin K, Stigendal L, Eriksson E. , et al. Abdominal obesity is associated with an impaired fibrinolytic activity and elevated plasminogen activator inhibitor-1. Metabolism 1990; 39 (10) 1044-1048
  • 45 Meigs JB, Mittleman MA, Nathan DM. , et al. Hyperinsulinemia, hyperglycemia, and impaired hemostasis: the Framingham Offspring Study. JAMA 2000; 283 (02) 221-228
  • 46 Mertens I, Van Gaal LF. Obesity, haemostasis and the fibrinolytic system. Obes Rev 2002; 3 (02) 85-101
  • 47 Collen D, Lijnen HR. Basic and clinical aspects of fibrinolysis and thrombolysis. Blood 1991; 78 (12) 3114-3124
  • 48 Lijnen HR. Pleiotropic functions of plasminogen activator inhibitor-1. J Thromb Haemost 2005; 3 (01) 35-45
  • 49 Leurs J, Hendriks D. Carboxypeptidase U (TAFIa): a metallocarboxypeptidase with a distinct role in haemostasis and a possible risk factor for thrombotic disease. Thromb Haemost 2005; 94 (03) 471-487
  • 50 Bouma BN, Mosnier LO. Thrombin activatable fibrinolysis inhibitor (TAFI) at the interface between coagulation and fibrinolysis. Pathophysiol Haemost Thromb 2003; 33 (5-6): 375-381
  • 51 Juhan-Vague I, Pyke SDM, Alessi MC, Jespersen J, Haverkate F, Thompson SG. Fibrinolytic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. ECAT Study Group. European Concerted Action on Thrombosis and Disabilities. Circulation 1996; 94 (09) 2057-2063
  • 52 Hamsten A, de Faire U, Walldius G. , et al. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 1987; 2 (8549): 3-9
  • 53 Sobel BE, Woodcock-Mitchell J, Schneider DJ, Holt RE, Marutsuka K, Gold H. Increased plasminogen activator inhibitor type 1 in coronary artery atherectomy specimens from type 2 diabetic compared with nondiabetic patients: a potential factor predisposing to thrombosis and its persistence. Circulation 1998; 97 (22) 2213-2221
  • 54 Thompson SG, Kienast J, Pyke SD, Haverkate F, van de Loo JC. ; European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. N Engl J Med 1995; 332 (10) 635-641
  • 55 Hulthe J, Bokemark L, Wikstrand J, Fagerberg B. The metabolic syndrome, LDL particle size, and atherosclerosis: the Atherosclerosis and Insulin Resistance (AIR) study. Arterioscler Thromb Vasc Biol 2000; 20 (09) 2140-2147
  • 56 Van Guilder GP, Hoetzer GL, Greiner JJ, Stauffer BL, DeSouza CA. Metabolic syndrome and endothelial fibrinolytic capacity in obese adults. Am J Physiol Regul Integr Comp Physiol 2008; 294 (01) R39-R44
  • 57 Skurk T, Hauner H. Obesity and impaired fibrinolysis: role of adipose production of plasminogen activator inhibitor-1. Int J Obes Relat Metab Disord 2004; 28 (11) 1357-1364
  • 58 Lijnen HR. Role of fibrinolysis in obesity and thrombosis. Thromb Res 2009; 123 (Suppl. 04) S46-S49
  • 59 Bełtowski J. Adiponectin and resistin--new hormones of white adipose tissue. Med Sci Monit 2003; 9 (02) RA55-RA61
  • 60 Schneider DJ, Sobel BE. Synergistic augmentation of expression of plasminogen activator inhibitor type-1 induced by insulin, very-low-density lipoproteins, and fatty acids. Coron Artery Dis 1996; 7 (11) 813-817
  • 61 Ekström M, Liska J, Eriksson P, Sverremark-Ekström E, Tornvall P. Stimulated in vivo synthesis of plasminogen activator inhibitor-1 in human adipose tissue. Thromb Haemost 2012; 108 (03) 485-492
  • 62 Arenillas JF, Sandoval P, Pérez de la Ossa N. , et al. The metabolic syndrome is associated with a higher resistance to intravenous thrombolysis for acute ischemic stroke in women than in men. Stroke 2009; 40 (02) 344-349
  • 63 Aubert H, Frère C, Aillaud MF, Morange PE, Juhan-Vague I, Alessi MC. Weak and non-independent association between plasma TAFI antigen levels and the insulin resistance syndrome. J Thromb Haemost 2003; 1 (04) 791-797
  • 64 Hori Y, Nakatani K, Morioka K. , et al. Insulin enhanced thrombin-activable fibrinolysis inhibitor expression through PI3 kinase/Akt pathway. Int J Mol Med 2005; 15 (02) 265-268
  • 65 Sato T, Miwa T, Akatsu H. , et al. Pro-carboxypeptidase R is an acute phase protein in the mouse, whereas carboxypeptidase N is not. J Immunol 2000; 165 (02) 1053-1058
  • 66 Boffa MB, Hamill JD, Maret D. , et al. Acute phase mediators modulate thrombin-activable fibrinolysis inhibitor (TAFI) gene expression in HepG2 cells. J Biol Chem 2003; 278 (11) 9250-9257
  • 67 Kopelman PG. Obesity as a medical problem. Nature 2000; 404 (6778): 635-643
  • 68 Cushman M, O'Meara ES, Heckbert SR, Zakai NA, Rosamond W, Folsom AR. Body size measures, hemostatic and inflammatory markers and risk of venous thrombosis: The Longitudinal Investigation of Thromboembolism Etiology. Thromb Res 2016; 144: 127-132
  • 69 Heit JA, Kobbervig CE, James AH, Petterson TM, Bailey KR, Melton III LJ. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med 2005; 143 (10) 697-706
  • 70 Pomp ER, Lenselink AM, Rosendaal FR, Doggen CJ. Pregnancy, the postpartum period and prothrombotic defects: risk of venous thrombosis in the MEGA study. J Thromb Haemost 2008; 6 (04) 632-637
  • 71 James AH, Jamison MG, Brancazio LR, Myers ER. Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors, and mortality. Am J Obstet Gynecol 2006; 194 (05) 1311-1315
  • 72 Cantwell R, Clutton-Brock T, Cooper G. , et al. Saving mothers' lives: reviewing maternal deaths to make motherhood safer: 2006-2008. The Eighth Report of the Confidential Enquiries into Maternal Deaths in the United Kingdom. BJOG 2011– 2008; 118 (Suppl. 01) 1-203
  • 73 Knight M. ; UKOSS. Antenatal pulmonary embolism: risk factors, management and outcomes. BJOG 2008; 115 (04) 453-461
  • 74 RCOG. Green-Top Guideline No 37. Reducing the Risk of Thrombosis and Embolism during Pregnancy and the Puerperium. Royal College of Obstetricians and Gynaecologists; 2009
  • 75 Sharma SK, Philip J, Wiley J. Thromboelastographic changes in healthy parturients and postpartum women. Anesth Analg 1997; 85 (01) 94-98
  • 76 Karlsson O, Sporrong T, Hillarp A, Jeppsson A, Hellgren M. Prospective longitudinal study of thromboelastography and standard hemostatic laboratory tests in healthy women during normal pregnancy. Anesth Analg 2012; 115 (04) 890-898
  • 77 Sharma S, Uprichard J, Moretti A, Boyce H, Szydlo R, Stocks G. Use of thromboelastography to assess the combined role of pregnancy and obesity on coagulation: a prospective study. Int J Obstet Anesth 2013; 22 (02) 113-118
  • 78 Morgan ES, Wilson E, Melody T. , et al. An observational study of haemostatic changes, leptin and soluble endoglin during pregnancy in women with different BMIs. Blood Coagul Fibrinolysis 2017; 28 (01) 50-55
  • 79 Stewart FM, Freeman DJ, Ramsay JE, Greer IA, Caslake M, Ferrell WR. Longitudinal assessment of maternal endothelial function and markers of inflammation and placental function throughout pregnancy in lean and obese mothers. J Clin Endocrinol Metab 2007; 92 (03) 969-975
  • 80 Misra VK, Trudeau S. The influence of overweight and obesity on longitudinal trends in maternal serum leptin levels during pregnancy. Obesity (Silver Spring) 2011; 19 (02) 416-421
  • 81 Engelberger RP, Indermühle A, Baumann F. , et al. Diurnal changes of lower leg volume in obese and non-obese subjects. Int J Obes 2014; 38 (06) 801-805