Andrew J. Hughes, Emanuele Chisari, Javad Parvizi., Geoffrey Westrich, David Beverland.

Response/Recommendation: Deep venous thrombosis (DVT) propagation, causing pulmonary embolus (PE), has been described in patients with unprovoked clots and attributed to the prothrombotic phenotype of the individual. While it is recognized that a PE may arise from a DVT, a direct relationship between DVT propagation and a PE does not appear to exist for orthopaedic surgery patients that undergo total joint arthroplasty (TJA).

Strength of Recommendation: Moderate.

Rationale: Understanding the natural history, prognosis, and implications of venous thromboembolism (VTE) occurring as a consequence of orthopaedic procedures is imperative. Despite DVT rates falling to as low as 0.4% post total hip arthroplasty (THA), and 0.8% post total knee arthroplasty (TKA), consensus is lacking regarding the risk of propagation of distal DVT to the lungs^1-4. Much of the literature pertaining to the natural history of VTE reports on unprovoked DVT or those provoked in the setting of prothrombotic risk factors, the pathophysiology of which differ from the provoked postoperative DVT^5-7. A causal relationship between DVT and PE has not been proven in patients undergoing lower limb TJA)^1,8,9.

Surgery has been reported as a major, but transient, trigger for VTE^10-12. Local activation of the clotting cascade begins intraoperatively following endothelial injury and the release of tissue thromboplastin, which promotes an inflammatory feedback loop involving procoagulant proteins and fibrin strands^13,14. This transient prothrombotic environment, encompassing distal venous valve pockets that provide a nidus for clot formation, predispose orthopaedic patients to a higher rate of ipsilateral DVT than those undergoing major non-orthopaedic procedures^7,13,15. Amongst surgical specialties, however, retrospective research has shown that PE rates in the arthroplasty cohort are no higher than those undergoing gastrointestinal, vascular, or gynecological procedures¹⁶. If a DVT was to consistently propagate to cause a PE post arthroplasty, the literature would appreciate a significantly elevated PE incidence compared to other surgical specialties, in proportion to that of DVT rates, however, this is not the case.

PE are thought to most commonly arise by way of an established distal thrombus becoming dislodged, travelling within the returning circulatory system to the lungs, obstructing arterioles within the pulmonary vasculature, and causing ischemia⁵. Thrombosis can also arise directly within the pulmonary vasculature. Patients at risk of in-situ pulmonary artery thrombosis display a pronounced prothrombotic phenotype, with contributions from abnormal fibrinogen variants, family history, autoimmune disease, endocrine dysregulation, and active cancer^5,17,18. Separate to both hematological pathophysiological pathways, increased intramedullary pressure during arthroplasty procedures has been shown to embolize prothrombotic fat, bone marrow, and cement fragments through systemic veins into the pulmonary vascular system13,19,20. Activation of extremity and pulmonary thrombogenesis, by way of thromboplastin exposure, has been hypothesized to contribute to DVT and PE rates following TJA, however, intraoperative steps have been taken to mitigate this process^13,20. Manifestation of symptomatic PE is a complex, multifactorial process, with multiple pathophysiological pathways likely coexisting in genetically susceptible patients, however propagation of an extremity thrombus does not appear to consistently contribute to the burden of arthroplasty-related PE disease^21-23.

Little exists in the literature to clarify the evolution of incidental asymptomatic DVT, as evidenced by the lack of consensus within published guidelines^7,24-26. Observational studies have confirmed that the majority of isolated deep DVT display an uneventful clinical course, without embolization²⁷. Half of such thrombi arise at the time of surgery and resolve spontaneously within the first 72 hours postoperatively²⁷. Whereas unprovoked, proximal DVT are concerning given their tendency to propagate to cause a PE, and risk of recurrence^27-32. In the provoked postoperative setting, however, PE rates do not appear to correlate with the observed incidence of proximal DVT, which have been identified in 27% of all DVT post-THA, and 15% of all DVT post TKA^33,34. An increased proximal DVT rate in those undergoing THA has not translated into a heightened burden of PE compared to those post TKA^22,35.

Perioperative prophylaxis and early mobilization have made significant progress in the fight against VTE, which can be appreciated via the falling incidence of post-arthroplasty DVT^6,36,37. In contrast, due to radiological advancements, and the ability to now discern even smaller emboli, the incidence of PE has been seen to increase the last two decades^38,39. Highly sensitive multi-detector row computer tomography (CT) pulmonary angiography scanning allows for the detection of clinically insignificant disease in the postoperative setting, arising within the periphery of the pulmonary vasculature^39-41. Despite prophylaxis and enhanced recovery pathways, the rate of clinically significant PE persists between 0.2 – 1.1% of all arthroplasty patients^22,42-44. The proportion of TJA patients at risk of PE development has remained consistent over the past two decades, regardless of compliance with guidelines directed towards reducing the venographic evidence of DVT^7,44.

Whilst unprovoked lower extremity DVT carries a risk of propagation, this has not been proven to occur in the provoked perioperative orthopaedic setting^1,4. PE are thought to arise via multiple interacting pathophysiological processes, most likely within genetically susceptible patients undergoing TJA. Robust scientific evidence, investigating the propagation tendencies of the provoked postoperative DVT, is lacking. Carefully designed, prospective research will play a vital role in clarifying our understanding of perioperative VTE as a disease, most notably its natural history and prognosis in the arthroplasty patient.

References:

1.         Parvizi J, Jacovides CL, Bican O, Purtill JJ, Sharkey PF, Hozack WJ, et al. Is Deep Vein Thrombosis a Good Proxy for Pulmonary Embolus? J Arthroplasty. 2010;25(No. 6 Suppl):138-44.

2.         Warren JA, Sundaram K, Anis HK, Kamath AF, Higuera CA, Piuzzi NS. Have Venous Thromboembolism Rates Decreased in Total Hip and Knee Arthroplasty? J Arthroplasty. 2020 Jan;35(1):259-64.

3.         Keller K, Hobohm L, Barco S, Schmidtmann I, Münzel T, Engelhardt M, et al. Venous thromboembolism in patients hospitalized for knee joint replacement surgery. Nature Sci Rep. 2020;10:22440.

4.         Callaghan JJ, Dorr LD, Engh GA, Hanssen AD, Healy WL, Lachiewicz PF, et al. Prophylaxis for thromboembolic disease: recommendations from the American College of Chest Physicians—are they appropriate for orthopaedic surgery? J Arthroplasty. 2005;20:273.

5.         Huisman MV, Barco S, Cannegieter SC, Le Gal G, Konstantinides SV, Reitsma PH, et al. Pulmonary embolism. Nat Rev Dis Primers. 2018;4:18028.

6.         Anderson DR, Morgano GP, Bennett C, Dentali F, Francis CW, Garcia DA, et al. American Society of Hematology 2019 guidelines for management of venous thromboembolism: prevention of venous thromboembolism in surgical hospitalized patients. Blood Adv. 2019 Dec 10;3(23):3898-944.

7.         Nicholson M, Chan N, Bhagirath V, Ginsberg J. Prevention of Venous Thromboembolism in 2020 and Beyond. J Clin Med. 2020 Aug;9(8):2467.

8.         Della Valle CJ, Steiger DJ, DiCesare PE. Duplex ultrasonography in patients suspected of postoperative pulmonary embolism following total joint arthroplasty. Am J Orthop. 2003;32(8):386-8.

9.         Westrich GH, Farrell C, Bono JV, Ranawat CS, Salvati EA, Sculco TP. The incidence of venous thromboembolism after total hip arthroplasty: a specific hypotensive epidural anesthesia protocol. J Arthroplasty. 1999;14(4):456-63.

10.       White RH, Zhou H, Romano PS. Incidence of symptomatic venous thromboembolism after different elective or urgent surgical procedures. Thromb Haemost. 2003 Sep;90(3):446-55.

11.       Caprini JA. Thrombosis risk assessment as a guide to quality patient care. Dis Mon. 2005 Feb-Mar;51(2-3):70-8.

12.       White RH, Romano PS, Zhou H, Rodrigo J, Bargar W. Incidence and time course of thromboembolic outcomes following total hip or knee arthroplasty. Arch Intern Med. 1998 Jul;158(14):1525-31.

13.       Pitto RP, Hamer H, Fabiani R, Radespiel-Troeger M, Koessler M. Prophylaxis Against Fat and Bone-Marrow Embolism During Total Hip Arthroplasty Reduces the Incidence of Postoperative Deep-Vein Thrombosis. J Bone Joint Surg. 2002;84(1):39-48.

14.       Salvati EA, Pellegrini Jr VD, Sharrock NE, Lotke PA, Murray DW, Potter H, et al. Recent advances in venous thromboembolic pro- phylaxis during and after total hip replacement. J Bone Joint Surg. 2000;82:252-70.

15.       Dahl OE. Thromboprophylaxis in hip arthroplasty. New frontiers and future strategy. Acta Orthop Scand. 1998;69:339-42.

16.       Caron A, Depas N, Chazard E, Yelnik C, Jeanpierre E, Paris C, et al. Risk of Pulmonary Embolism More Than 6 Weeks After Surgery Among Cancer-Free Middle-aged Patients. JAMA Surg. 2019 Dec;154(12):1126-32.

17.       Quarck R, Wynants M, Verbeken E, Meyns B, Delcroix M. Contribution of inflammation and impaired angiogenesis to the pathobiology of chronic thromboembolic pulmonary hypertension. Eur Respir J. 2015;46:431–43.

18.       Cao Y, Geng C, Li Y, Zhang Y. In situ Pulmonary Artery Thrombosis: A Previously Overlooked Disease. Front Pharmacol. 2021;12:671589.

19.       Malhotra R, Singla A, Lekha C, Kumar V, Karthikeyan G, Malik V, et al. A prospective randomized study to compare systemic emboli using the computer- assisted and conventional techniques of total knee arthroplasty. J Bone Joint Surg. 2015;97(11):889-94.

20.       Rothberg DL, Makarewich CA. Fat Embolism and Fat Embolism Syndrome. J Am Acad Orthop Surg. 2019;27:e346-e55.

21.       Heit JA, Lahr BD, Ashrani AA, Petterson TM, Bailey KR. Predictors of venous thromboembolism recurrence, adjusted for treatments and interim exposures: a population-based case-cohort study. Thromb Res. 2015 Aug;136(2):298-307.

22.       Kahn SR, Shivakumar S. What’s new in VTE risk and prevention in orthopedic surgery. Res Pract Thromb Haemost. 2020 Mar;4(3):366-76.

23.       Zöller B, Svensson PJ, Sundquist J, Sundquist K, Pirouzifard M. Postoperative Joint Replacement Complications in Swedish Patients With a Family History of Venous Thromboembolism. JAMA Netw Open. 2018;1:e181924.

24.       Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, 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 Feb;141(2 Suppl):e419S-e96S.

25.       Palareti G, Schellong S. Isolated distal deep vein thrombosis: what we know and what we are doing. J Thromb Haemost. 2012 Jan;10(1):11-9.

26.       Drew Fleck, Albadawi H, Wallace A, Knuttinen G, Naidu S, Oklu R. Below-knee deep vein thrombosis (DVT): diagnostic and treatment patterns. Cardiovasc Diagn Ther. 2017 Dec;7(Suppl 3):S134-S9.

27.       Kearon C. Natural History of Venous Thromboembolism. Circulation. 2003 Jun 17;107(23 Suppl 1):122-30.

28.       Masuda EM, Kessler DM, Kistner RL, Eklof B, Sato DT. The natural history of calf vein thrombosis: lysis of thrombi and development of reflux. J Vasc Surg. 1998;28:67-74.

29.       Kazmers A, Groehn H, Meeker C. Acute calf vein thrombosis: outcomes and implications. Am Surg 1999; 65: 1124–7. Am Surg. 1999;65(1124-7).

30.       Palareti G, Cosmi B, Lessiani G, Rodorigo G, Guazzaloca G, Brusi C, et al. Evolution of untreated calf deep vein thrombosis in high risk symptomatic outpatients: the blind, prospective CALTHRO study. Thromb Haemost. 2010;104(1063-1070).

31.       Eichinger S, Heinze G, Jandeck LM, Kyrle PA. Risk assessment of recurrence in patients with unprovoked deep vein thrombosis or pulmonary embolism: the Vienna prediction model. Circulation. 2010;121:1630-6.

32.       Baglin T, Douketis J, Tosetto A, Marcucci M, Cushman M, Kyrle P, et al. Does the clinical presentation and extent of venous thrombosis predict likelihood and type of recurrence? A patient-level meta-analysis. J Thromb Haemost. 2010;8:2436-342.

33.       Ciccone 2nd WJ, Fox P, Neumyer M, Rubens D, Parrish WM, Pellegrini Jr VD. Ultrasound surveillance for asymptomatic deep venous thrombosis after total joint replacement. J Bone Joint Surg Am. 1998;80(8):1167-74.

34.       Ciccone 2nd WJ, Reid JS, Pellegrini Jr VD. The Role of Ultrasonography in Thromboembolic Disease Management in the Orthopaedic Patient. Iowa Orthop J. 1999;19:18-25.

35.       Januel J-M, Chen G, Ruffieux C, Quan H, Douketis JD, Crowther MA, et al. Symptomatic In-Hospital Deep Vein Thrombosis and Pulmonary Embolism Following Hip and Knee Arthroplasty Among Patients Receiving Recommended Prophylaxis: A Systematic Review. JAMA. 2012;307(3):294-303.

36.       Falck-Ytter Y, Francis CW, Johanson NA, Curley C, Dahl OE, Schulman S, 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 Feb;141(2 Suppl):e278S-e325S.

37.       Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008 Jun;133(6 Suppl):381S-453S.

38.       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(829-39).

39.       D’Apuzzo MR, Keller TC, Novicoff WM, Browne JA. CT Pulmonary Angiography After Total Joint Arthroplasty: Overdiagnosis and Iatrogenic Harm? Clin Orthop Related Res. 2013;471(9):2737-42.

40.       Messerschmidt C, Friedman RJ. Clinical experience with novel oral anticoagulants for thromboprophylaxis after elective hip and knee arthroplasty. Arterioscler Thromb Vasc Biol. 2015;35:771-8.

41.       Karayiannis PN, Hill JC, Stevenson C, Finnegan S, Armstrong L, Beverland D. CT pulmonary angiography in lower limb arthroplasty: A retrospective review of 11 249 patients over 11 years. Bone Joint J. 2018;100-B(7):938-44.

42.       Jacobs JJ, Mont MA, Bozic KJ, Della Valle CJ, Goodman SB, Lewis CG, et al. American Academy of Orthopaedic Surgeons clinical practice guideline on: preventing venous thromboembolic disease in patients undergoing elective hip and knee arthroplasty. J Bone Joint Surg. 2012 Apr 18;94(8):746-7.

43.       Parvizi J, Huang R, Raphael IJ, Arnold WV, Rothman RH. Symptomatic Pulmonary Embolus After Joint Arthroplasty: Stratification of Risk Factors. Clin Orthop Related Res. 2014;472(3):903-12.

44.       Lieberman JR, Cheng V, Cote MP. Pulmonary Embolism Rates Following Total Hip Arthroplasty With Prophylactic Anticoagulation: Some Pulmonary Emboli Cannot Be Avoided. J Arthroplasty. 2017;32:980-6.