Epidemiology, Pathophysiology, and Natural History of Pulmonary Embolism

 

 Permissions and Reprints

Abstract

Pulmonary embolism (PE) is a common and potentially deadly form of venous thromboembolic disease. It is the third most common cause of cardiovascular death and is associated with multiple inherited and acquired risk factors as well as advanced age. The prognosis from PE depends on the degree of obstruction and hemodynamic effects of PE and understanding the pathophysiology helps in risk-stratifying patients and determining treatment. Though the natural history of thrombus is resolution, a subset of patients have chronic residual thrombus, contributing to the post-PE syndrome.

• References

• 1 Raskob GE, Angchaisuksiri P, Blanco AN. , et al. Thrombosis: a major contributor to global disease burden. Semin Thromb Hemost 2014; 40 (07) 724-735
  Article in Thieme ConnectPubMedGoogle Scholar
• 2 Anderson Jr FA, Zayaruzny M, Heit JA, Fidan D, Cohen AT. Estimated annual numbers of US acute-care hospital patients at risk for venous thromboembolism. Am J Hematol 2007; 82 (09) 777-782
  CrossrefPubMedGoogle Scholar
• 3 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
  CrossrefPubMedGoogle Scholar
• 4 Silverstein MD, Heit JA, Mohr DN, Petterson TM, O'Fallon WM, Melton III LJ. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998; 158 (06) 585-593
  CrossrefPubMedGoogle Scholar
• 5 Anderson Jr FA, Wheeler HB, Goldberg RJ. , et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med 1991; 151 (05) 933-938
  CrossrefPubMedGoogle Scholar
• 6 Goldhaber SZ, Hennekens CH, Evans DA, Newton EC, Godleski JJ. Factors associated with correct antemortem diagnosis of major pulmonary embolism. Am J Med 1982; 73 (06) 822-826
  CrossrefPubMedGoogle Scholar
• 7 Smith SB, Geske JB, Kathuria P. , et al. Analysis of national trends in admissions for pulmonary embolism. Chest 2016; 150 (01) 35-45
  CrossrefPubMedGoogle Scholar
• 8 Wiener RS, Schwartz LM, Woloshin S. Time trends in pulmonary embolism in the United States: evidence of overdiagnosis. Arch Intern Med 2011; 171 (09) 831-837
  CrossrefPubMedGoogle Scholar
• 9 Sheh SH, Bellin E, Freeman KD, Haramati LB. Pulmonary embolism diagnosis and mortality with pulmonary CT angiography versus ventilation-perfusion scintigraphy: evidence of overdiagnosis with CT?. AJR Am J Roentgenol 2012; 198 (06) 1340-1345
  CrossrefPubMedGoogle Scholar
• 10 Huang W, Goldberg RJ, Anderson FA, Kiefe CI, Spencer FA. Secular trends in occurrence of acute venous thromboembolism: the Worcester VTE study (1985-2009). Am J Med 2014; 127 (09) 829-39.e5
  CrossrefPubMedGoogle Scholar
• 11 Naess IA, Christiansen SC, Romundstad P, Cannegieter SC, Rosendaal FR, Hammerstrøm J. Incidence and mortality of venous thrombosis: a population-based study. J Thromb Haemost 2007; 5 (04) 692-699
  CrossrefPubMedGoogle Scholar
• 12 Horlander KT, Mannino DM, Leeper KV. Pulmonary embolism mortality in the United States, 1979-1998: an analysis using multiple-cause mortality data. Arch Intern Med 2003; 163 (14) 1711-1717
  CrossrefPubMedGoogle Scholar
• 13 Alikhan R, Peters F, Wilmott R, Cohen AT. Fatal pulmonary embolism in hospitalised patients: a necropsy review. J Clin Pathol 2004; 57 (12) 1254-1257
  CrossrefPubMedGoogle Scholar
• 14 Lilienfeld DE. Decreasing mortality from pulmonary embolism in the United States, 1979-1996. Int J Epidemiol 2000; 29 (03) 465-469
  PubMedGoogle Scholar
• 15 Tagalakis V, Patenaude V, Kahn SR, Suissa S. Incidence of and mortality from venous thromboembolism in a real-world population: the Q-VTE Study Cohort. Am J Med 2013; 126 (09) 832.e13-832.e21
  PubMedGoogle Scholar
• 16 Anderson Jr FA, Wheeler HB. Physician practices in the management of venous thromboembolism: a community-wide survey. J Vasc Surg 1992; 16 (05) 707-714
  CrossrefPubMedGoogle Scholar
• 17 Allaart CF, Poort SR, Rosendaal FR, Reitsma PH, Bertina RM, Briët E. Increased risk of venous thrombosis in carriers of hereditary protein C deficiency defect. Lancet 1993; 341 (8838): 134-138
  CrossrefPubMedGoogle Scholar
• 18 Demers C, Ginsberg JS, Hirsh J, Henderson P, Blajchman MA. Thrombosis in antithrombin-III-deficient persons. Report of a large kindred and literature review. Ann Intern Med 1992; 116 (09) 754-761
  CrossrefPubMedGoogle Scholar
• 19 Heijboer H, Brandjes DP, Büller HR, Sturk A, ten Cate JW. Deficiencies of coagulation-inhibiting and fibrinolytic proteins in outpatients with deep-vein thrombosis. N Engl J Med 1990; 323 (22) 1512-1516
  CrossrefPubMedGoogle Scholar
• 20 Rosendaal FR, Koster T, Vandenbroucke JP, Reitsma PH. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood 1995; 85 (06) 1504-1508
  PubMedGoogle Scholar
• 21 Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3′-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88 (10) 3698-3703
  PubMedGoogle Scholar
• 22 Stulberg BN, Insall JN, Williams GW, Ghelman B. Deep-vein thrombosis following total knee replacement. An analysis of six hundred and thirty-eight arthroplasties. J Bone Joint Surg Am 1984; 66 (02) 194-201
  CrossrefPubMedGoogle Scholar
• 23 Shin WC, Woo SH, Lee S-J, Lee JS, Kim C, Suh KT. Preoperative prevalence of and risk factors for venous thromboembolism in patients with a hip fracture: an indirect multidetector CT venography study. J Bone Joint Surg Am 2016; 98 (24) 2089-2095
  CrossrefPubMedGoogle Scholar
• 24 Sevitt S, Gallagher NG. Prevention of venous thrombosis and pulmonary embolism in injured patients. A trial of anticoagulant prophylaxis with phenindione in middle-aged and elderly patients with fractured necks of femur. Lancet 1959; 2 (7110): 981-989
  PubMedGoogle Scholar
• 25 Kearon C, Akl EA, Comerota AJ. , et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2, Suppl): e419S-e496S
  CrossrefPubMedGoogle Scholar
• 26 Blom JW, Doggen CJ, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 2005; 293 (06) 715-722
  CrossrefPubMedGoogle Scholar
• 27 Chew HK, Wun T, Harvey D, Zhou H, White RH. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med 2006; 166 (04) 458-464
  CrossrefPubMedGoogle Scholar
• 28 Ahlbrecht J, Dickmann B, Ay C. , et al. Tumor grade is associated with venous thromboembolism in patients with cancer: results from the Vienna Cancer and Thrombosis Study. J Clin Oncol 2012; 30 (31) 3870-3875
  CrossrefPubMedGoogle Scholar
• 29 Stein PD, Beemath A, Meyers FA, Skaf E, Sanchez J, Olson RE. Incidence of venous thromboembolism in patients hospitalized with cancer. Am J Med 2006; 119 (01) 60-68
  CrossrefPubMedGoogle Scholar
• 30 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
  CrossrefPubMedGoogle Scholar
• 31 Spencer FA, Gore JM, Lessard D, Douketis JD, Emery C, Goldberg RJ. Patient outcomes after deep vein thrombosis and pulmonary embolism: the Worcester Venous Thromboembolism Study. Arch Intern Med 2008; 168 (04) 425-430
  CrossrefPubMedGoogle Scholar
• 32 Beam DM, Courtney DM, Kabrhel C, Moore CL, Richman PB, Kline JA. Risk of thromboembolism varies, depending on category of immobility in outpatients. Ann Emerg Med 2009; 54 (02) 147-152
  CrossrefPubMedGoogle Scholar
• 33 Lapostolle F, Surget V, Borron SW. , et al. Severe pulmonary embolism associated with air travel. N Engl J Med 2001; 345 (11) 779-783
  CrossrefPubMedGoogle Scholar
• 34 Cruickshank JM, Gorlin R, Jennett B. Air travel and thrombotic episodes: the economy class syndrome. Lancet 1988; 2 (8609): 497-498
  PubMedGoogle Scholar
• 35 Chandra D, Parisini E, Mozaffarian D. Meta-analysis: travel and risk for venous thromboembolism. Ann Intern Med 2009; 151 (03) 180-190
  CrossrefPubMedGoogle Scholar
• 36 Brenner B. Haemostatic changes in pregnancy. Thromb Res 2004; 114 (5-6): 409-414
  CrossrefPubMedGoogle Scholar
• 37 Cerneca F, Ricci G, Simeone R, Malisano M, Alberico S, Guaschino S. Coagulation and fibrinolysis changes in normal pregnancy. Increased levels of procoagulants and reduced levels of inhibitors during pregnancy induce a hypercoagulable state, combined with a reactive fibrinolysis. Eur J Obstet Gynecol Reprod Biol 1997; 73 (01) 31-36
  CrossrefPubMedGoogle Scholar
• 38 James AH. Venous thromboembolism in pregnancy. Arterioscler Thromb Vasc Biol 2009; 29 (03) 326-331
  CrossrefPubMedGoogle Scholar
• 39 James AH, Tapson VF, Goldhaber SZ. Thrombosis during pregnancy and the postpartum period. Am J Obstet Gynecol 2005; 193 (01) 216-219
  CrossrefPubMedGoogle Scholar
• 40 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
  CrossrefPubMedGoogle Scholar
• 41 Petitti DB. Clinical practice. Combination estrogen-progestin oral contraceptives. N Engl J Med 2003; 349 (15) 1443-1450
  CrossrefPubMedGoogle Scholar
• 42 Lidegaard Ø, Løkkegaard E, Svendsen AL, Agger C. Hormonal contraception and risk of venous thromboembolism: national follow-up study. BMJ 2009; 339: b2890
  CrossrefPubMedGoogle Scholar
• 43 Miller J, Chan BK, Nelson HD. Postmenopausal estrogen replacement and risk for venous thromboembolism: a systematic review and meta-analysis for the U.S. Preventive Services Task Force. Ann Intern Med 2002; 136 (09) 680-690
  CrossrefPubMedGoogle Scholar
• 44 Lowe GD, Rumley A, Woodward M. , et al. Epidemiology of coagulation factors, inhibitors and activation markers: the Third Glasgow MONICA Survey. I. Illustrative reference ranges by age, sex and hormone use. Br J Haematol 1997; 97 (04) 775-784
  CrossrefPubMedGoogle Scholar
• 45 Silverstein RL, Bauer KA, Cushman M, Esmon CT, Ershler WB, Tracy RP. Venous thrombosis in the elderly: more questions than answers. Blood 2007; 110 (09) 3097-3101
  CrossrefPubMedGoogle Scholar
• 46 Goldhaber SZ, Grodstein F, Stampfer MJ. , et al. A prospective study of risk factors for pulmonary embolism in women. JAMA 1997; 277 (08) 642-645
  CrossrefPubMedGoogle Scholar
• 47 Stein PD, Matta F, Goldman J. Obesity and pulmonary embolism: the mounting evidence of risk and the mortality paradox. Thromb Res 2011; 128 (06) 518-523
  CrossrefPubMedGoogle Scholar
• 48 Cervera R, Piette J-C, Font J. , et al; Euro-Phospholipid Project Group. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum 2002; 46 (04) 1019-1027
  CrossrefPubMedGoogle Scholar
• 49 Schved JF, Dupuy-Fons C, Biron C, Quére I, Janbon C. A prospective epidemiological study on the occurrence of antiphospholipid antibody: the Montpellier Antiphospholipid (MAP) Study. Haemostasis 1994; 24 (03) 175-182
  PubMedGoogle Scholar
• 50 Prandoni P, Bilora F, Marchiori A. , et al. An association between atherosclerosis and venous thrombosis. N Engl J Med 2003; 348 (15) 1435-1441
  CrossrefPubMedGoogle Scholar
• 51 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
  CrossrefPubMedGoogle Scholar
• 52 Glynn RJ, Rosner B. Comparison of risk factors for the competing risks of coronary heart disease, stroke, and venous thromboembolism. Am J Epidemiol 2005; 162 (10) 975-982
  CrossrefPubMedGoogle Scholar
• 53 Hansson P-O, Sörbo J, Eriksson H. Recurrent venous thromboembolism after deep vein thrombosis: incidence and risk factors. Arch Intern Med 2000; 160 (06) 769-774
  CrossrefPubMedGoogle Scholar
• 54 Ouriel K, Green RM, Greenberg RK, Clair DG. The anatomy of deep venous thrombosis of the lower extremity. J Vasc Surg 2000; 31 (05) 895-900
  CrossrefPubMedGoogle Scholar
• 55 McLachlin AD, McLachlin JA, Jory TA, Rawling EG. Venous stasis in the lower extremities. Ann Surg 1960; 152 (04) 678-685
  CrossrefPubMedGoogle Scholar
• 56 Sevitt S. Organization of valve pocket thrombi and the anomalies of double thrombi and valve cusp involvement. Br J Surg 1974; 61 (08) 641-649
  CrossrefPubMedGoogle Scholar
• 57 Sajid MS, Ahmed N, Desai M, Baker D, Hamilton G. Upper limb deep vein thrombosis: a literature review to streamline the protocol for management. Acta Haematol 2007; 118 (01) 10-18
  CrossrefPubMedGoogle Scholar
• 58 Kucher N, Tapson VF, Goldhaber SZ. ; DVT FREE Steering Committee. Risk factors associated with symptomatic pulmonary embolism in a large cohort of deep vein thrombosis patients. Thromb Haemost 2005; 93 (03) 494-498
  Article in Thieme ConnectPubMedGoogle Scholar
• 59 Stein PD, Matta F, Musani MH, Diaczok B. Silent pulmonary embolism in patients with deep venous thrombosis: a systematic review. Am J Med 2010; 123 (05) 426-431
  CrossrefPubMedGoogle Scholar
• 60 Muñoz FJ, Mismetti P, Poggio R. , et al; RIETE Investigators. Clinical outcome of patients with upper-extremity deep vein thrombosis: results from the RIETE Registry. Chest 2008; 133 (01) 143-148
  CrossrefPubMedGoogle Scholar
• 61 Huisman MV, Büller HR, ten Cate JW. Utility of impedance plethysmography in the diagnosis of recurrent deep-vein thrombosis. Arch Intern Med 1988; 148 (03) 681-683
  CrossrefPubMedGoogle Scholar
• 62 Masuda EM, Kistner RL, Musikasinthorn C, Liquido F, Geling O, He Q. The controversy of managing calf vein thrombosis. J Vasc Surg 2012; 55 (02) 550-561
  CrossrefPubMedGoogle Scholar
• 63 Overton DT, Bocka JJ. The alveolar-arterial oxygen gradient in patients with documented pulmonary embolism. Arch Intern Med 1988; 148 (07) 1617-1619
  CrossrefPubMedGoogle Scholar
• 64 Stein PD, Goldhaber SZ, Henry JW. Alveolar-arterial oxygen gradient in the assessment of acute pulmonary embolism. Chest 1995; 107 (01) 139-143
  CrossrefPubMedGoogle Scholar
• 65 Santolicandro A, Prediletto R, Fornai E. , et al. Mechanisms of hypoxemia and hypocapnia in pulmonary embolism. Am J Respir Crit Care Med 1995; 152 (01) 336-347
  CrossrefPubMedGoogle Scholar
• 66 Huet Y, Lemaire F, Brun-Buisson C. , et al. Hypoxemia in acute pulmonary embolism. Chest 1985; 88 (06) 829-836
  CrossrefPubMedGoogle Scholar
• 67 Manier G, Castaing Y, Guenard H. Determinants of hypoxemia during the acute phase of pulmonary embolism in humans. Am Rev Respir Dis 1985; 132 (02) 332-338
  PubMedGoogle Scholar
• 68 D'Angelo E. Lung mechanics and gas exchange in pulmonary embolism. Haematologica 1997; 82 (03) 371-374
  PubMedGoogle Scholar
• 69 D'Alonzo GE, Bower JS, DeHart P, Dantzker DR. The mechanisms of abnormal gas exchange in acute massive pulmonary embolism. Am Rev Respir Dis 1983; 128 (01) 170-172
  CrossrefPubMedGoogle Scholar
• 70 Jaff MR, McMurtry MS, Archer SL. , et al; American Heart Association Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation; American Heart Association Council on Peripheral Vascular Disease; American Heart Association Council on Arteriosclerosis, Thrombosis and Vascular Biology. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation 2011; 123 (16) 1788-1830
  CrossrefPubMedGoogle Scholar
• 71 Elliott CG. Pulmonary physiology during pulmonary embolism. Chest 1992; 101 (4, Suppl): 163S-171S
  CrossrefPubMedGoogle Scholar
• 72 Tsang JY, Lamm WJ. Estimation of endothelin-mediated vasoconstriction in acute pulmonary thromboembolism. Pulm Circ 2012; 2 (01) 67-74
  CrossrefPubMedGoogle Scholar
• 73 Smulders YM. Pathophysiology and treatment of haemodynamic instability in acute pulmonary embolism: the pivotal role of pulmonary vasoconstriction. Cardiovasc Res 2000; 48 (01) 23-33
  CrossrefPubMedGoogle Scholar
• 74 Matthews JC, McLaughlin V. Acute right ventricular failure in the setting of acute pulmonary embolism or chronic pulmonary hypertension: a detailed review of the pathophysiology, diagnosis, and management. Curr Cardiol Rev 2008; 4 (01) 49-59
  CrossrefPubMedGoogle Scholar
• 75 McIntyre KM, Sasahara AA. Determinants of right ventricular function and hemodynamics after pulmonary embolism. Chest 1974; 65 (05) 534-543
  CrossrefPubMedGoogle Scholar
• 76 Wood KE. Major pulmonary embolism: review of a pathophysiologic approach to the golden hour of hemodynamically significant pulmonary embolism. Chest 2002; 121 (03) 877-905
  CrossrefPubMedGoogle Scholar
• 77 Lualdi JC, Goldhaber SZ. Right ventricular dysfunction after acute pulmonary embolism: pathophysiologic factors, detection, and therapeutic implications. Am Heart J 1995; 130 (06) 1276-1282
  CrossrefPubMedGoogle Scholar
• 78 Konstantinides S, Torbicki A, Agnelli G. , et al. 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J 2014; 35 (43) 3033-3069
  CrossrefPubMedGoogle Scholar
• 79 Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W. ; Management Strategies and Prognosis of Pulmonary Embolism-3 Trial Investigators. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med 2002; 347 (15) 1143-1150
  CrossrefPubMedGoogle Scholar
• 80 Meyer G, Vicaut E, Danays T. , et al; PEITHO Investigators. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med 2014; 370 (15) 1402-1411
  CrossrefPubMedGoogle Scholar
• 81 Prandoni P, Noventa F, Ghirarduzzi A. , et al. The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients. Haematologica 2007; 92 (02) 199-205
  CrossrefPubMedGoogle Scholar
• 82 Kyrle PA, Rosendaal FR, Eichinger S. Risk assessment for recurrent venous thrombosis. Lancet 2010; 376 (9757): 2032-2039
  CrossrefPubMedGoogle Scholar
• 83 Sanchez O, Helley D, Couchon S. , et al. Perfusion defects after pulmonary embolism: risk factors and clinical significance. J Thromb Haemost 2010; 8 (06) 1248-1255
  CrossrefPubMedGoogle Scholar
• 84 Cosmi B, Nijkeuter M, Valentino M, Huisman MV, Barozzi L, Palareti G. Residual emboli on lung perfusion scan or multidetector computed tomography after a first episode of acute pulmonary embolism. Intern Emerg Med 2011; 6 (06) 521-528
  CrossrefPubMedGoogle Scholar
• 85 Sista AK, Klok FA. Late outcomes of pulmonary embolism: the post-PE syndrome. Thromb Res 2018; 164: 157-162
  CrossrefPubMedGoogle Scholar
• 86 Klok FA, van Kralingen KW, van Dijk AP, Heyning FH, Vliegen HW, Huisman MV. Prospective cardiopulmonary screening program to detect chronic thromboembolic pulmonary hypertension in patients after acute pulmonary embolism. Haematologica 2010; 95 (06) 970-975
  CrossrefPubMedGoogle Scholar
• 87 Pengo V, Lensing AW, Prins MH. , et al; Thromboembolic Pulmonary Hypertension Study Group. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004; 350 (22) 2257-2264
  CrossrefPubMedGoogle Scholar
• 88 Delcroix M, Kerr K, Fedullo P. Chronic thromboembolic pulmonary hypertension. Epidemiology and risk factors. Ann Am Thorac Soc 2016; 13 (Suppl. 03) S201-S206
  CrossrefPubMedGoogle Scholar