Semin Thromb Hemost 2018; 44(07): 624-631
DOI: 10.1055/s-0038-1657779
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Hemostasis and Thrombosis in the Oldest Old

Inna Tzoran
1   Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel
2   Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
,
Ron Hoffman
1   Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel
2   Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
,
Manuel Monreal
3   Department of Internal Medicine, Hospital Universitari Germans Trias i Pujol, Barcelona, Spain
› Author Affiliations
Further Information

Publication History

Publication Date:
19 June 2018 (online)

Abstract

There is a growing proportion of the elderly population in the Western world, and these individuals require special considerations regarding a broad variety of aspects, including treatment approaches to illnesses that affect all age groups. The hemostatic system in individuals changes considerably with aging. Specifically, changes in levels of procoagulant and natural anticoagulant factors along with thrombopathy simultaneously create a hypercoagulable state and hemostatic difficulties. Underlying morbidities, such as congestive heart failure, chronic obstructive pulmonary disease, diabetes mellitus, and cancer, increase the risk for venous and arterial thrombosis. This population is also increasingly affected by acquired bleeding disorders, including acquired hemophilia and acquired von Willebrand syndrome, as well as mild congenital bleeding disorders. Real-life data demonstrate that recurrent and fatal venous thromboembolism is the major hemostatic concern in the elderly. The fact that treatment of thrombotic complications increases the bleeding risk also has to be taken into consideration, particularly in the older age group. This remains true in the era of direct oral anticoagulants. In conclusion, maintaining a delicate balance between thrombosis and bleeding risks is the key issue in providing qualified treatment to elderly patients.

 
  • References

  • 1 United Nations Department of Economic and Social Affairs. Population Division. World Population Ageing. Available at: http://www.un.org/en/development/desa/population/publications/pdf/ageing/WorldPopulationAgeing2013.pdf . Accessed November 1, 2017
  • 2 Engbers MJ, van Hylckama Vlieg A, Rosendaal FR. Venous thrombosis in the elderly: incidence, risk factors and risk groups. J Thromb Haemost 2010; 8 (10) 2105-2112
  • 3 Martinelli I. Risk factors in venous thromboembolism. Thromb Haemost 2001; 86 (01) 395-403
  • 4 Roger VL, Jacobsen SJ, Weston SA. , et al. Trends in the incidence and survival of patients with hospitalized myocardial infarction, Olmsted County, Minnesota, 1979 to 1994. Ann Intern Med 2002; 136 (05) 341-348
  • 5 Spencer FA, Gore JM, Lessard D. , et al. Venous thromboembolism in the elderly. A community-based perspective. Thromb Haemost 2008; 100 (05) 780-788
  • 6 Tofler GH, Massaro J, Levy D. , et al. Relation of the prothrombotic state to increasing age (from the Framingham Offspring Study). Am J Cardiol 2005; 96 (09) 1280-1283
  • 7 Mari D, Mannucci PM, Coppola R, Bottasso B, Bauer KA, Rosenberg RD. Hypercoagulability in centenarians: the paradox of successful aging. Blood 1995; 85 (11) 3144-3149
  • 8 Favaloro EJ, Soltani S, McDonald J, Grezchnik E, Easton L. Cross-laboratory audit of normal reference ranges and assessment of ABO blood group, gender and age on detected levels of plasma coagulation factors. Blood Coagul Fibrinolysis 2005; 16 (08) 597-605
  • 9 Dolan G, Neal K, Cooper P, Brown P, Preston FE. Protein C, antithrombin III and plasminogen: effect of age, sex and blood group. Br J Haematol 1994; 86 (04) 798-803
  • 10 Gleerup G, Winther K. The effect of ageing on platelet function and fibrinolytic activity. Angiology 1995; 46 (08) 715-718
  • 11 Eren M, Boe AE, Klyachko EA, Vaughan DE. Role of plasminogen activator inhibitor-1 in senescence and aging. Semin Thromb Hemost 2014; 40 (06) 645-651
  • 12 Yamamoto K, Takeshita K, Kojima T, Takamatsu J, Saito H. Aging and plasminogen activator inhibitor-1 (PAI-1) regulation: implication in the pathogenesis of thrombotic disorders in the elderly. Cardiovasc Res 2005; 66 (02) 276-285
  • 13 Balduini CL, Noris P. Platelet count and aging. Haematologica 2014; 99 (06) 953-955
  • 14 Jones CI. Platelet function and ageing. Mamm Genome 2016; 27 (7–8): 358-366
  • 15 Mohebali D, Kaplan D, Carlisle M, Supiano MA, Rondina MT. Alterations in platelet function during aging: clinical correlations with thromboinflammatory disease in older adults. J Am Geriatr Soc 2014; 62 (03) 529-535
  • 16 Favaloro EJ, Franchini M, Lippi G. Aging hemostasis: changes to laboratory markers of hemostasis as we age - a narrative review. Semin Thromb Hemost 2014; 40 (06) 621-633
  • 17 Righini M, Van Es J, Den Exter PL. , et al. Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism: the ADJUST-PE study. JAMA 2014; 311 (11) 1117-1124
  • 18 Fuchs E, Asakly S, Karban A, Tzoran I. Age-adjusted cutoff D-dimer level to rule out acute pulmonary embolism: a validation cohort study. Am J Med 2016; 129 (08) 872-878
  • 19 Migliacci R, Becattini C, Pesavento R. , et al. Endothelial dysfunction in patients with spontaneous venous thromboembolism. Haematologica 2007; 92 (06) 812-818
  • 20 Chopard RP, Miranda Neto MH, Biazotto W, Molinari SL. Age-related changes in the human renal veins and their valves. Ital J Anat Embryol 1994; 99 (02) 91-101
  • 21 Brooks EG, Trotman W, Wadsworth MP. , et al. Valves of the deep venous system: an overlooked risk factor. Blood 2009; 114 (06) 1276-1279
  • 22 van den Akker M, Buntinx F, Metsemakers JF, Roos S, Knottnerus JA. Multimorbidity in general practice: prevalence, incidence, and determinants of co-occurring chronic and recurrent diseases. J Clin Epidemiol 1998; 51 (05) 367-375
  • 23 Fried LP, Bandeen-Roche K, Kasper JD, Guralnik JM. Association of comorbidity with disability in older women: the Women's Health and Aging Study. J Clin Epidemiol 1999; 52 (01) 27-37
  • 24 Chew HK, Davies AM, Wun T, Harvey D, Zhou H, White RH. The incidence of venous thromboembolism among patients with primary lung cancer. J Thromb Haemost 2008; 6 (04) 601-608
  • 25 Heit JA, O'Fallon WM, Petterson TM. , et al. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study. Arch Intern Med 2002; 162 (11) 1245-1248
  • 26 Samama MM. An epidemiologic study of risk factors for deep vein thrombosis in medical outpatients: the Sirius study. Arch Intern Med 2000; 160 (22) 3415-3420
  • 27 Howell MD, Geraci JM, Knowlton AA. Congestive heart failure and outpatient risk of venous thromboembolism: a retrospective, case-control study. J Clin Epidemiol 2001; 54 (08) 810-816
  • 28 Beemath A, Stein PD, Skaf E, Al Sibae MR, Alesh I. Risk of venous thromboembolism in patients hospitalized with heart failure. Am J Cardiol 2006; 98 (06) 793-795
  • 29 Alikhan R, Cohen AT, Combe S. , et al. Prevention of venous thromboembolism in medical patients with enoxaparin: a subgroup analysis of the MEDENOX study. Blood Coagul Fibrinolysis 2003; 14 (04) 341-346
  • 30 Tillie-Leblond I, Marquette CH, Perez T. , et al. Pulmonary embolism in patients with unexplained exacerbation of chronic obstructive pulmonary disease: prevalence and risk factors. Ann Intern Med 2006; 144 (06) 390-396
  • 31 Kim V, Goel N, Gangar J. , et al; COPD Gene Investigators. Risk factors for venous thromboembolism in chronic obstructive pulmonary disease. Chronic Obstr Pulm Dis (Miami) 2014; 1 (02) 239-249
  • 32 Piazza G, Goldhaber SZ, Kroll A, Goldberg RJ, Emery C, Spencer FA. Venous thromboembolism in patients with chronic obstructive pulmonary disease. Am J Med 2012; 125 (10) 1010-1018
  • 33 Tsai AW, Cushman M, Rosamond WD, Heckbert SR, Polak JF, Folsom AR. Cardiovascular risk factors and venous thromboembolism incidence: the longitudinal investigation of thromboembolism etiology. Arch Intern Med 2002; 162 (10) 1182-1189
  • 34 Stein PD, Goldman J, Matta F, Yaekoub AY. Diabetes mellitus and risk of venous thromboembolism. Am J Med Sci 2009; 337 (04) 259-264
  • 35 Petrauskiene V, Falk M, Waernbaum I, Norberg M, Eriksson JW. The risk of venous thromboembolism is markedly elevated in patients with diabetes. Diabetologia 2005; 48 (05) 1017-1021
  • 36 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
  • 37 Piazza G, Goldhaber SZ, Kroll A, Goldberg RJ, Emery C, Spencer FA. Venous thromboembolism in patients with diabetes mellitus. Am J Med 2012; 125 (07) 709-716
  • 38 Blom JW, Doggen CJ, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 2005; 293 (06) 715-722
  • 39 Blom JW, Vanderschoot JP, Oostindiër MJ, Osanto S, van der Meer FJ, Rosendaal FR. Incidence of venous thrombosis in a large cohort of 66,329 cancer patients: results of a record linkage study. J Thromb Haemost 2006; 4 (03) 529-535
  • 40 Levitan N, Dowlati A, Remick SC. , et al. Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy. Risk analysis using Medicare claims data. Medicine (Baltimore) 1999; 78 (05) 285-291
  • 41 Paneesha S, McManus A, Arya R. , et al; VERITY Investigators. Frequency, demographics and risk (according to tumour type or site) of cancer-associated thrombosis among patients seen at outpatient DVT clinics. Thromb Haemost 2010; 103 (02) 338-343
  • 42 Carpentier P, Priollet P. Epidemiology of chronic venous insufficiency [in French]. Presse Med 1994; 23 (05) 197-201
  • 43 Carpentier PH, Maricq HR, Biro C, Ponçot-Makinen CO, Franco A. Prevalence, risk factors, and clinical patterns of chronic venous disorders of lower limbs: a population-based study in France. J Vasc Surg 2004; 40 (04) 650-659
  • 44 Folsom AR, Cushman M, Tsai MY. , et al. A prospective study of venous thromboembolism in relation to factor V Leiden and related factors. Blood 2002; 99 (08) 2720-2725
  • 45 Ridker PM, Hennekens CH, Miletich JP. G20210A mutation in prothrombin gene and risk of myocardial infarction, stroke, and venous thrombosis in a large cohort of US men. Circulation 1999; 99 (08) 999-1004
  • 46 Bikdeli B, Jiménez D, Hawkins M. , et al; RIETE Investigators. Rationale, design and methodology of the computerized registry of patients with venous thromboembolism (RIETE). Thromb Haemost 2018; 118 (01) 214-224
  • 47 López-Jiménez L, Montero M, González-Fajardo JA. , et al; RIETE Investigators. Venous thromboembolism in very elderly patients: findings from a prospective registry (RIETE). Haematologica 2006; 91 (08) 1046-1051
  • 48 Vasco B, Villalba JC, Lopez-Jimenez L. , et al; RIETE Investigators. Venous thromboembolism in nonagenarians. Findings from the RIETE registry. Thromb Haemost 2009; 101 (06) 1112-1118
  • 49 Lacruz B, Tiberio G, Núñez MJ. , et al; RIETE Investigators. Venous thromboembolism in centenarians: findings from the RIETE registry. Eur J Intern Med 2016; 36: 62-66
  • 50 Spirk D, Husmann M, Hayoz D. , et al. Predictors of in-hospital mortality in elderly patients with acute venous thrombo-embolism: the SWIss Venous ThromboEmbolism Registry (SWIVTER). Eur Heart J 2012; 33 (07) 921-926
  • 51 Kruse-Jarres R, Singleton TC, Leissinger CA. Identification and basic management of bleeding disorders in adults. J Am Board Fam Med 2014; 27 (04) 549-564
  • 52 Kruse-Jarres R. Acquired bleeding disorders in the elderly. Hematology (Am Soc Hematol Educ Program) 2015; 2015 (15) 231-236
  • 53 Boggio LN, Green D. Acquired hemophilia. Rev Clin Exp Hematol 2001; 5 (04) 389-404 , quiz 431
  • 54 Hauser I, Lechner K. Solid tumors and factor VIII antibodies. Thromb Haemost 1999; 82 (03) 1005-1007
  • 55 Kruse-Jarres R, Kempton CL, Baudo F. , et al. Acquired hemophilia A: updated review of evidence and treatment guidance. Am J Hematol 2017; 92 (07) 695-705
  • 56 Franchini M, Vaglio S, Marano G. , et al. Acquired hemophilia A: a review of recent data and new therapeutic options. Hematology 2017; 22 (09) 514-520
  • 57 Kruse-Jarres R, St-Louis J, Greist A. , et al. Efficacy and safety of OBI-1, an antihaemophilic factor VIII (recombinant), porcine sequence, in subjects with acquired haemophilia A. Haemophilia 2015; 21 (02) 162-170
  • 58 Mingot-Castellano ME, Núñez R, Rodríguez-Martorell FJ. Acquired haemophilia: Epidemiology, clinical presentation, diagnosis and treatment [in Spanish]. Med Clin (Barc) 2017; 148 (07) 314-322
  • 59 W Collins P, Chalmers E, Hart D. , et al; United Kingdom Haemophilia Centre Doctors' Organization. Diagnosis and management of acquired coagulation inhibitors: a guideline from UKHCDO. Br J Haematol 2013; 162 (06) 758-773
  • 60 Baudo F, Collins P, Huth-Kühne A. , et al; EACH2 registry contributors. Management of bleeding in acquired hemophilia A: results from the European Acquired Haemophilia (EACH2) Registry. Blood 2012; 120 (01) 39-46
  • 61 Tiede A, Klamroth R, Scharf RE. , et al. Prognostic factors for remission of and survival in acquired hemophilia A (AHA): results from the GTH-AH 01/2010 study. Blood 2015; 125 (07) 1091-1097
  • 62 Kessler CM, Knöbl P. Acquired haemophilia: an overview for clinical practice. Eur J Haematol 2015; 95 (Suppl. 81) 36-44
  • 63 Mital A. Acquired von Willebrand syndrome. Adv Clin Exp Med 2016; 25 (06) 1337-1344
  • 64 Jennes E, Guggenberger D, Zotz R. , et al. Perioperative intravenous immunoglobulin treatment in a patient with severe acquired von Willebrand syndrome: case report and review of the literature. Clin Case Rep 2017; 5 (05) 664-670
  • 65 Budde U, Scheppenheim S, Dittmer R. Treatment of the acquired von Willebrand syndrome. Expert Rev Hematol 2015; 8 (06) 799-818
  • 66 Kanakry JA, Gladstone DE. Maintaining hemostasis in acquired von Willebrand syndrome: a review of intravenous immunoglobulin and the importance of rituximab dose scheduling. Transfusion 2013; 53 (08) 1730-1735
  • 67 Wheeler AP, Gailani D. Why factor XI deficiency is a clinical concern. Expert Rev Hematol 2016; 9 (07) 629-637
  • 68 Puy C, Rigg RA, McCarty OJ. The hemostatic role of factor XI. Thromb Res 2016; 141 (Suppl. 02) S8-S11
  • 69 James P, Salomon O, Mikovic D, Peyvandi F. Rare bleeding disorders - bleeding assessment tools, laboratory aspects and phenotype and therapy of FXI deficiency. Haemophilia 2014; 20 (Suppl. 04) 71-75
  • 70 Batty P, Honke A, Bowles L. , et al. Ongoing risk of thrombosis with factor XI concentrate: 5 years experience in two centres. Haemophilia 2015; 21 (04) 490-495
  • 71 Duga S, Salomon O. Congenital factor XI deficiency: an update. Semin Thromb Hemost 2013; 39 (06) 621-631
  • 72 Shearer MJ, Fu X, Booth SL. Vitamin K nutrition, metabolism, and requirements: current concepts and future research. Adv Nutr 2012; 3 (02) 182-195
  • 73 Greer FR. Vitamin K the basics--what's new?. Early Hum Dev 2010; 86 (Suppl. 01) 43-47
  • 74 Parker RI. Etiology and treatment of acquired coagulopathies in the critically ill adult and child. Crit Care Clin 1997; 13 (03) 591-609
  • 75 Kearon C. Natural history of venous thromboembolism. Semin Vasc Med 2001; 1 (01) 27-37
  • 76 Go AS, Hylek EM, Phillips KA. , et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. JAMA 2001; 285 (18) 2370-2375
  • 77 Vidaillet H, Granada JF, Chyou Po. , et al. A population-based study of mortality among patients with atrial fibrillation or flutter. Am J Med 2002; 113 (05) 365-370
  • 78 Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001; 285 (22) 2864-2870
  • 79 Zhu W, He W, Guo L, Wang X, Hong K. The HAS-BLED score for predicting major bleeding risk in anticoagulated patients with atrial fibrillation: a systematic review and meta-analysis. Clin Cardiol 2015; 38 (09) 555-561
  • 80 Ruíz-Giménez N, Suárez C, González R. , et al; RIETE Investigators. Predictive variables for major bleeding events in patients presenting with documented acute venous thromboembolism. Findings from the RIETE registry. Thromb Haemost 2008; 100 (01) 26-31
  • 81 Heidbuchel H, Verhamme P, Alings M. , et al; ESC Scientific Document Group. Updated European Heart Rhythm Association practical guide on the use of non-vitamin-K antagonist anticoagulants in patients with non-valvular atrial fibrillation: executive summary. Eur Heart J 2017; 38 (27) 2137-2149
  • 82 Sharma M, Cornelius VR, Patel JP, Davies JG, Molokhia M. Efficacy and harms of direct oral anticoagulants in the elderly for stroke prevention in atrial fibrillation and secondary prevention of venous thromboembolism: systematic review and meta-analysis. Circulation 2015; 132 (03) 194-204
  • 83 Veltkamp R, Rizos T, Horstmann S. Intracerebral bleeding in patients on antithrombotic agents. Semin Thromb Hemost 2013; 39 (08) 963-971
  • 84 van Es N, Coppens M, Schulman S, Middeldorp S, Büller HR. Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. Blood 2014; 124 (12) 1968-1975
  • 85 Di Minno A, Frigerio B, Spadarella G. , et al. Old and new oral anticoagulants: food, herbal medicines and drug interactions. Blood Rev 2017; 31 (04) 193-203
  • 86 Na KS, Jung HY, Cho SJ, Cho SE. Can we recommend mirtazapine and bupropion for patients at risk for bleeding? A systematic review and meta-analysis. J Affect Disord 2018; 225: 221-226
  • 87 Roose SP, Rutherford BR. Selective serotonin reuptake inhibitors and operative bleeding risk: a review of the literature. J Clin Psychopharmacol 2016; 36 (06) 704-709
  • 88 Laporte S, Chapelle C, Caillet P. , et al. Bleeding risk under selective serotonin reuptake inhibitor (SSRI) antidepressants: a meta-analysis of observational studies. Pharmacol Res 2017; 118: 19-32
  • 89 Steffens DC, Fisher GG, Langa KM, Potter GG, Plassman BL. Prevalence of depression among older Americans: the aging, demographics and memory study. Int Psychogeriatr 2009; 21 (05) 879-888