Agustin García-Mansilla, Fernando Holc, Martin Buttaro.
Response/Recommendation: Although it is not entirely clear whether venous thromboembolism (VTE) should be monitored after orthopaedic surgery, in selected patients suffering VTE due to persistent risk factors, the preferred method should be serial ultrasonography with or without previous serum D-dimer quantification.
Strength of Recommendation: Limited.
Rationale: VTE includes two clinical entities, deep venous thrombosis (DVT) and, pulmonary embolism (PE).It occurs in 1 to 2 individuals per 1000 each year1. VTE can be categorized broadly as either provoked or unprovoked. VTE is considered provoked when it is in conjunction with major temporary risk factors such as surgery or trauma and also be provoked by major persistent risk factors such as cancer2–6. While unprovoked are those produced in the absence of risk factors and without an identifiable cause2–5. Although a patient submitted to an orthopaedic surgery could suffer a provoked VTE secondary to a previous condition, it’s more likely to suffer a transient provoked VTE in relation to the surgical event.
Initially, treatment of a provoked VTE from a temporary risk factor such as surgery should receive a limited course of anticoagulation7,8. In this case, the American Society of Hematology (ASH) guidelines suggest with moderated strength that after 3- to 6-months of treatment, anticoagulation should stop7. Substantial literature has reported the low-risk of recurrence of a provoked VTE9–14. In this scenario, the need of monitoring patients during or after treatment is not entirely clear. This should be in accordance with the risk of recurrence of VTE, which can occur in 1% to 3% of patients2–5 after removal of the provoking factor. However, when the VTE is unprovoked, the cumulative risk of recurrence reaches 10% to 30% at 2 and 10 years, respectively2–5,15.
The monitoring of patients with a provoked VTE by transient risk factors is not required after the finalization of the primary treatment due to the improbable risk of recurrence of VTE in these individuals7. Is not clear if the same condition in provoked VTE by chronic risk factors such as active cancer, inflammatory bowel disease, autoimmune disorders, chronic infections, and chronic immobility, will necessarily need extended anticoagulation, and with that, closer monitoring of the VTE16–20. The third condition would be an unprovoked VTE.
Serum D-dimer levels are easily tested and have proven to be effective in the assessment of residual thrombosis after VTE provoked by orthopaedic18 and non-orthopaedic procedures21–23. Despite having low specificity, they are considered useful for excluding diagnoses due to their high negative predictive values for DVT and PE16,24,25. However, by themselves, they are not an infallible tool and must be accompanied by imaging studies to confirm the presence of VTE. Kumagai et al18, have reported that combined D-dimer and ultrasound screening in patients with acute spinal cord injury (persistent risk factor) improved the detection of VTE, including PE, compared with D-dimer screening alone. Moreover, it is important to emphasize that the evidence is not sustainable when proposing a cut-off point or the ideal time to measure postoperative D-dimer levels. In a randomized trial, Palareti et al.26, included 223 individuals with an elevated D-dimer 1 month after completing 3- to 6-months of anticoagulation. In this study, participants were randomized to stop anticoagulation or to continue it for up to 18 months. They found that patients with an abnormal D-dimer level, 1 month after the discontinuation of anticoagulation had a significant incidence of recurrent VTE, which is reduced by the resumption of anticoagulation.
Ultrasonography is a less invasive procedure which besides the ability of monitoring also could diagnose recurrent VTE in selective patients. Prandoni et al., performed a randomized trial to evaluate the efficacy of tailoring the duration of anticoagulation based on recanalization or persistence of residual venous thrombosis as determined by ultrasound imaging17. Their criteria for a recanalized vein were a vein thrombosis 2 mm in diameter with probe compression or 3 mm in diameter on two consecutive examinations. Participants randomized to ultrasonography received anticoagulation for an average of 4- to 5-months longer than did individuals randomized to the control group. Consequently, the investigators observed a non-significant reduction in the risk of PE in the intervention group. Unfortunately, this method is operator-dependent and the main problem in extrapolating these data to clinical practice is the criteria for determining recanalization of a thrombosed vein which can vary from one observer to another. Furthermore, ultrasound criteria to quantify residual venous thrombosis is not widely used.
The ASH guideline panel provides a conditional recommendation against the routine use of any of these modalities for all patients with VTE but acknowledges the potential utility of 1 (or more) of these approaches for management of selected patients7. We agree with subjective inclination to serial ultrasonography due to its inherent capacity to confirm the potentially suspicion of VTE. However, the lack of strong evidence in relation to this topic does not allow us to recommend one over the other.
2. Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galiè N, et al. 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014 Nov 14;35(43):3033–69, 3069a.
4. Ageno W, Farjat A, Haas S, Weitz JI, Goldhaber SZ, Turpie AGG, et al. Provoked versus unprovoked venous thromboembolism: Findings from GARFIELD-VTE. Res Pract Thromb Haemost. 2021 Feb 20;5(2):326–41.
5. Kearon C, Ageno W, Cannegieter SC, Cosmi B, Geersing GJ, Kyrle PA, et al. Categorization of patients as having provoked or unprovoked venous thromboembolism: guidance from the SSC of ISTH. J Thromb Haemost. 2016 Jun 7;14(7):1480–3.
6. Brownson KE, Brahmandam A, Huynh N, Reynolds J, Fares WH, Lee AI, et al. Characteristics of provoked deep venous thrombosis in a tertiary care center. J Vasc Surg Venous Lymphat Disord. 2017 Jul;5(4):477–84.
7. Ortel TL, Neumann I, Ageno W, Beyth R, Clark NP, Cuker A, et al. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. Blood Adv. 2020 Oct 13;4(19):4693–738.
9. Agnelli G, Prandoni P, Becattini C, Silingardi M, Taliani MR, Miccio M, et al. Extended oral anticoagulant therapy after a first episode of pulmonary embolism. Ann Intern Med. 2003 Jul 1;139(1):19–25.
10. Belcaro G, Laurora G, Cesarone MR, De Sanctis MT. Prophylaxis of recurrent deep venous thrombosis. A randomized, prospective study using indobufen and graduated elastic compression stockings. Angiology. 1993 Sep;44(9):695–9.
11. Couturaud F, Sanchez O, Pernod G, Mismetti P, Jego P, Duhamel E, et al. Six Months vs Extended Oral Anticoagulation After a First Episode of Pulmonary Embolism: The PADIS-PE Randomized Clinical Trial. JAMA. 2015 Jul 7;314(1):31–40.
12. Eischer L, Gartner V, Schulman S, Kyrle PA, Eichinger S, AUREC-FVIII investigators. 6 versus 30 months anticoagulation for recurrent venous thrombosis in patients with high factor VIII. Ann Hematol. 2009 May;88(5):485–90.
15. Boutitie F, Pinede L, Schulman S, Agnelli G, Raskob G, Julian J, et al. Influence of preceding length of anticoagulant treatment and initial presentation of venous thromboembolism on risk of recurrence after stopping treatment: analysis of individual participants’ data from seven trials. BMJ. 2011 May 24;342:d3036.
16. Ageno W, Cosmi B, Ghirarduzzi A, Santoro R, Bucherini E, Poli D, et al. The negative predictive value of D-dimer on the risk of recurrent venous thromboembolism in patients with multiple previous events: a prospective cohort study (the PROLONG PLUS study). Am J Hematol. 2012 Jul;87(7):713–5.
17. Prandoni P, Prins MH, Lensing AWA, Ghirarduzzi A, Ageno W, Imberti D, et al. Residual thrombosis on ultrasonography to guide the duration of anticoagulation in patients with deep venous thrombosis: a randomized trial. Ann Intern Med. 2009 May 5;150(9):577–85.
18. Kumagai G, Wada K, Kudo H, Asari T, Ichikawa N, Ishibashi Y. D-dimer monitoring combined with ultrasonography improves screening for asymptomatic venous thromboembolism in acute spinal cord injury. J Spinal Cord Med. 2020 May;43(3):353–7.
19. Prandoni P, Barbar S, Milan M, Vedovetto V, Pesavento R. The risk of recurrent thromboembolic disorders in patients with unprovoked venous thromboembolism: new scenarios and opportunities. Eur J Intern Med. 2014 Jan;25(1):25–30.
20. Bhatt M, Braun C, Patel P, Patel P, Begum H, Wiercioch W, et al. Diagnosis of deep vein thrombosis of the lower extremity: a systematic review and meta-analysis of test accuracy. Blood Adv. 2020 Apr 14;4(7):1250–64.
21. Palareti G, Legnani C, Cosmi B, Guazzaloca G, Pancani C, Coccheri S. Risk of venous thromboembolism recurrence: high negative predictive value of D-dimer performed after oral anticoagulation is stopped. Thromb Haemost. 2002 Jan;87(1):7–12.
22. Verhovsek M, Douketis JD, Yi Q, Shrivastava S, Tait RC, Baglin T, et al. Systematic review: D-dimer to predict recurrent disease after stopping anticoagulant therapy for unprovoked venous thromboembolism. Ann Intern Med. 2008 Oct 7;149(7):481–90, W94.
23. Bruinstroop E, Klok FA, Van De Ree MA, Oosterwijk FL, Huisman MV. Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism: a meta-analysis. J Thromb Haemost. 2009 Apr;7(4):611–8.
24. Yamashita Y, Wada H, Nomura H, Mizuno T, Saito K, Yamada N, et al. Elevated fibrin-related markers in patients with malignant diseases frequently associated with disseminated intravascular coagulation and venous thromboembolism. Intern Med. 2014;53(5):413–9.