8 – Is there an association between pulmonary embolus and secondary pulmonary hypertension after major orthopaedic surgery?

8 – Is there an association between pulmonary embolus and secondary pulmonary hypertension after major orthopaedic surgery?

Mohammad S Abdelaal, Amar H Kelkar, Anita Rajasekhar, Peter F Sharkey.

Response/Recommendation: Chronic thromboembolic pulmonary hypertension (CTEPH) is strongly associated with prior pulmonary embolism (PE); however, this association has not been adequately explored following major orthopaedic surgeries.  Given that PE is a known complication following orthopaedic surgery and incidence of CTEPH after PE is between 0.1% and 9.1%, evaluation for CTEPH after post-surgical PE should be considered to allow for early treatment, particularly pulmonary endarterectomy (PEA), and to prevent downstream sequelae and mortality.

Strength of Recommendation: Limited.

Rationale: Major orthopaedic surgeries carry a high risk for venous thromboembolism (VTE) including deep venous thrombosis (DVT) and PE1.  Estimates suggest that in the contemporary era about 4.7% of patients undergoing major orthopaedic surgery will develop symptomatic VTE without prophylaxis2.  The major orthopaedic surgeries with the greatest risk for VTE include total knee arthroplasty (TKA), total hip arthroplasty (THA), and hip fracture surgery.  The risk of VTE is highest in the first 2 weeks postoperatively but may extend for 3 months postoperatively, as with other major surgeries3.

Acute PE, an obstruction of a pulmonary artery or its branches by an embolic or in-situ thrombus, is potentially life-threatening and can result in chronic complications with generally poor prognosis3.  The presumed relationship between DVT (particularly proximal DVT) and PE, has resulted in thromboprophylaxis becoming standard of care after major orthopaedic surgeries4.  Long-term consequences associated with PE include recurrent VTE, post-thrombotic syndrome, and CTEPH5–7.

CTEPH is an uncommon late complication of PE in patients who do not reestablish normal pulmonary artery perfusion and can present with disabling dyspnea, both at rest and with exertion8.  CTEPH can occur after single or recurrent symptomatic PE or as a complication of asymptomatic PE9.  After 3 months of appropriate anticoagulation, the diagnosis can be made if the following criteria are met: 1) mismatched perfusion defects on ventilation/perfusion scan or specific radiologic signs for CTEPH on computer tomography (CT)-angiography, and 2) mean pulmonary artery pressure (PAP) > 25mmHg with pulmonary capillary wedge pressure (PAWP) < 15mmHg on pulmonary angiogram.  CTEPH is clinically classified within group 4 pulmonary hypertension (PH) and pathologically distinguished by pulmonary arterial obstruction from organized fibrotic thrombus, development of small vessel disease, and resultant aberrant vascular remodeling10,11.

There is significant evidence supporting the specific link between VTE and CTEPH.  The reported cumulative incidence of CTEPH ranges from 0.1% to 9.1%, within the first 2 years after a symptomatic PE event12–15.  A large European multi-center retrospective cohort study reported history of VTE in almost 70% of patients with CTEPH compared to only 11% of patients with nonthromboembolic PH16.  Another large case-control study through the CTEPH registry reported an even stronger relationship, with risk of CTEPH being higher in those with clinical history of VTE compared to those history of VTE (odds ratio [OR] 49.01; p < 0.0001)17.  However, none of these studies included large numbers of post-surgical or trauma patients.  Discrepancies in reported incidence of CTEPH are attributable to nonspecific or absent symptoms in early CTEPH leading to delayed or missed diagnoses (median time from symptom onset to diagnosis is 14 months), difficulty discriminating acute PE symptoms from pre-existing CTEPH, underutilization of guideline-recommended ventilation-perfusion scans for screening, and different standards of practice across countries and regions18.  The Osiris Survey is one tool currently in development to predict risk of developing CTEPH.  In a large, longitudinal, prospective cohort study of 1,191 consecutive PE patients in Spanish hospitals, test sensitivity was 85% (95% confidence interval [CI]: 67.5-94), specificity was 91% (95% CI: 89-93), and negative predictive value was 99.4% (95% CI: 98.4-99.8); however, further study and survey validation are still needed19.

Several patient, disease, and treatment-related risk factors for development of CTEPH have been identified.  Large, persistent, idiopathic, and particularly recurrent PE, as well as larger perfusion defects, are all strongly associated with CTEPH5,9,16,20.  Residual pulmonary vascular obstruction at six months after the initial PE was an independent risk factor for both recurrent VTE and CTEPH21.  Other potential risk factors reported include ongoing thyroid replacement therapy, age greater than 60, underlying malignancy, and inflammatory or infections conditions including osteomyelitis and inflammatory bowel disease5,16,20,22.  Traditional risk factors for VTE, such as estrogen therapy or older age, have not been associated with CTEPH6.  Reports on the association of CTEPH with underlying thrombophilia have been mixed23.  Additionally, multiple studies have reported that subtherapeutic anticoagulation was not a risk factor for CTEPH; however, the focus of anticoagulation in these studies were vitamin K antagonists and newer anticoagulants have not been significantly studied24,25.

The natural progression of CTEPH is right heart failure, with reduced life expectancy and increased risk of sudden cardiac death13,18.  One study reported annual mortality of 6.0%26.  Early identification of CTEPH is critical as it is the only subgroup of PH that can potentially be surgically cured through PEA27.  Another study found considerable delay (median of 21 months) in diagnosis of CTEPH after acute PE, and that recurrent VTE was a predictor of longer delay which has detrimental effect on patient prognosis and healthcare utilization28.  Nonsurgical candidates are considered for PH-targeted medical therapies.  However, high healthcare utilization has been reported in these patients as well, with costs largely attributed to expensive PH-targeted medications26.  Lifelong anticoagulation is recommended in all CTEPH patients, regardless of whether PEA is performed, to prevent recurrent PE18.

In conclusion, this review reported on CTEPH as an underrecognized late complication of PE occurring within 2 years of the initial diagnosis.  While prevention of recurrent PE through initial and long-term anticoagulation are important, we did not find any evidence of association between type or duration of anticoagulation and incidence of CTEPH.  We did not find any evidence for a specific link between major orthopaedic surgery and CTEPH.  However, there are active registries and an ongoing prospective longitudinal clinical trial using “The United States Chronic Thromboembolic Pulmonary Hypertension Registry: Protocol for a Prospective, Longitudinal Study” that may shed more light on these issues in the coming years and may provide the necessary information to perform a formal decision analysis to assist in orthopaedic decision-making in the future29.


1.         Saleh J, El-Othmani MM, Saleh KJ. Deep Vein Thrombosis and Pulmonary Embolism Considerations in Orthopedic Surgery. Orthop Clin North Am. 2017;48(2):127-135. doi:10.1016/j.ocl.2016.12.003

2.         Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e278S-e325S. doi:10.1378/chest.11-2404

3.         Kim NH, Delcroix M, Jais X, et al. Chronic thromboembolic pulmonary hypertension. Eur Respir J. 2019;53(1):1801915. doi:10.1183/13993003.01915-2018

4.         Tritschler T, Kraaijpoel N, Le Gal G, Wells PS. Venous Thromboembolism: Advances in Diagnosis and Treatment. JAMA. 2018;320(15):1583-1594. doi:10.1001/jama.2018.14346

5.         Konstantinides SV. Detection and treatment of chronic thromboembolic pulmonary hypertension: Still a lot of homework to do. Hellenic J Cardiol. 2018;59(1):24-25. doi:10.1016/j.hjc.2018.02.012

6.         Piazza G, Goldhaber SZ. Chronic thromboembolic pulmonary hypertension. N Engl J Med. 2011;364(4):351-360. doi:10.1056/NEJMra0910203

7.         Klok FA, Huisman MV. Epidemiology and management of chronic thromboembolic pulmonary hypertension. Neth J Med. 2010;68(9):347-351.

8.         Gall H, Hoeper MM, Richter MJ, Cacheris W, Hinzmann B, Mayer E. An epidemiological analysis of the burden of chronic thromboembolic pulmonary hypertension in the USA, Europe and Japan. Eur Respir Rev. 2017;26(143):160121. doi:10.1183/16000617.0121-2016

9.         Pengo V, Lensing AWA, Prins MH, et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med. 2004;350(22):2257-2264. doi:10.1056/NEJMoa032274

10.       Simonneau G, Torbicki A, Dorfmüller P, Kim N. The pathophysiology of chronic thromboembolic pulmonary hypertension. European Respiratory Review. 2017;26(143). doi:10.1183/16000617.0112-2016

11.       Kim NH. Group 4 Pulmonary Hypertension: Chronic Thromboembolic Pulmonary Hypertension: Epidemiology, Pathophysiology, and Treatment. Cardiol Clin. 2016;34(3):435-441. doi:10.1016/j.ccl.2016.04.011

12.       Lang IM, Pesavento R, Bonderman D, Yuan JX-J. Risk factors and basic mechanisms of chronic thromboembolic pulmonary hypertension: a current understanding. Eur Respir J. 2013;41(2):462-468. doi:10.1183/09031936.00049312

13.       Vavera Z, Vojacek J, Pudil R, Maly J, Elias P. Chronic thromboembolic pulmonary hypertension after the first episode of pulmonary embolism? How often? Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2016;160(1):125-129. doi:10.5507/bp.2015.021

14.       Zhang M, Wang N, Zhai Z, et al. Incidence and risk factors of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism: a systematic review and meta-analysis of cohort studies. J Thorac Dis. 2018;10(8):4751-4763. doi:10.21037/jtd.2018.07.106

15.       Yang S, Yang Y, Zhai Z, et al. Incidence and risk factors of chronic thromboembolic pulmonary hypertension in patients after acute pulmonary embolism. J Thorac Dis. 2015;7(11):1927-1938. doi:10.3978/j.issn.2072-1439.2015.11.43

16.       Bonderman D, Wilkens H, Wakounig S, et al. Risk factors for chronic thromboembolic pulmonary hypertension. Eur Respir J. 2009;33(2):325-331. doi:10.1183/09031936.00087608

17.       Lang IM, Simonneau G, Pepke-Zaba JW, et al. Factors associated with diagnosis and operability of chronic thromboembolic pulmonary hypertension. A case-control study. Thromb Haemost. 2013;110(1):83-91. doi:10.1160/TH13-02-0097

18.       Galiè N, Humbert M, Vachiery J-L, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Respir J. 2015;46(4):903-975. doi:10.1183/13993003.01032-2015

19.       Incidence of Chronic Thromboembolic Pulmonary Hypertension: Results from a Longitudinal Prospective Cohort (Osiris Study). ISTH Congress Abstracts. Accessed September 7, 2021. https://abstracts.isth.org/abstract/incidence-of-chronic-thromboembolic-pulmonary-hypertension-results-from-a-longitudinal-prospective-cohort-osiris-study/

20.       Fernandes T, Auger W, Fedullo P. Epidemiology and risk factors for chronic thromboembolic pulmonary hypertension. Thromb Res. 2018;164:145-149. doi:10.1016/j.thromres.2018.01.012

21.       Pesavento R, Filippi L, Palla A, et al. Impact of residual pulmonary obstruction on the long-term outcome of patients with pulmonary embolism. Eur Respir J. 2017;49(5):1601980. doi:10.1183/13993003.01980-2016

22.       Bonderman D, Jakowitsch J, Adlbrecht C, et al. Medical conditions increasing the risk of chronic thromboembolic pulmonary hypertension. Thromb Haemost. 2005;93(3):512-516. doi:10.1160/TH04-10-0657

23.       Pepke-Zaba J, Delcroix M, Lang I, et al. Chronic thromboembolic pulmonary hypertension (CTEPH): results from an international prospective registry. Circulation. 2011;124(18):1973-1981. doi:10.1161/CIRCULATIONAHA.110.015008

24.       Boon GJAM, van Rein N, Bogaard HJ, et al. Quality of initial anticoagulant treatment and risk of CTEPH after acute pulmonary embolism. PLoS One. 2020;15(4):e0232354. doi:10.1371/journal.pone.0232354

25.       Posters Abstracts. Research and Practice in Thrombosis and Haemostasis. 2019;3(S1):1-891. doi:10.1002/rth2.12229 PB1622

26.       Schweikert B, Pittrow D, Vizza CD, et al. Demographics, clinical characteristics, health resource utilization and cost of chronic thromboembolic pulmonary hypertension patients: retrospective results from six European countries. BMC Health Serv Res. 2014;14:246. doi:10.1186/1472-6963-14-246

27.       Pepke-Zaba J, Hoeper MM, Humbert M. Chronic thromboembolic pulmonary hypertension: advances from bench to patient management. Eur Respir J. 2013;41(1):8-9. doi:10.1183/09031936.00181212

28.       Ende-Verhaar YM, van den Hout WB, Bogaard HJ, et al. Healthcare utilization in chronic thromboembolic pulmonary hypertension after acute pulmonary embolism. J Thromb Haemost. 2018;16(11):2168-2174. doi:10.1111/jth.14266

29.       Kerr KM, Elliott CG, Benza RL, et al. The United States Chronic Thromboembolic Pulmonary Hypertension Registry: Protocol for a Prospective, Longitudinal Study. JMIR Res Protoc. 2021;10(5):e25397. doi:10.2196/25397

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