Background

Post-thrombotic syndrome (PTS) is a common late complication of lower extremity deep vein thrombosis (DVT).¹ The incidence of PTS is approximately 40% in adult patients with a symptomatic first episode DVT within two years.² Manifestations of PTS include chronic lower extremity pain, swelling, heaviness and/or fatigue, which may progress to stasis dermatitis or limb ulceration in a minority of patients.^1,2 Patients with advanced PTS suffer major physical limitations and impairment of health-related quality of life (QOL).³ Advanced PTS symptoms include severe pain, uncontrolled edema, venous ulcers and short-distance claudication. Venous ulcers contribute to marked impairments in QOL, rise in healthcare costs, predisposition to infections and the need for endovascular or surgical interventions.^4,5

Venous hypertension, secondary to DVT, is thought to represent a significant part of the underlying pathophysiology for development of PTS. Risk factors of PTS include recurrent ipsilateral DVT, older age, elevated body mass index (BMI) and pre-existing primary venous insufficiency. Additionally, proximal DVTs (especially with involvement of the iliofemoral venous outflow tract) portends a higher risk of PTS compared to distal (calf) DVT.¹

Medical and Compressive Therapies

The best method to prevent PTS is to prevent DVT occurrence.⁶ Therefore, using pharmacologic or mechanical thromboprophylaxis to prevent venous thromboembolism (VTE) in high risk patients, as recommended by evidence based consensus guidelines, is suggested.^7-9 In addition, the prevention of recurrent ipsilateral DVT by optimizing anticoagulant therapy may reduce the development or progression of PTS.

Many patients that suffer from PTS have other co-morbid conditions, which likely contribute to or exacerbate their PTS symptoms. Patients with right-sided heart failure, lymphedema, pulmonary hypertension, obesity and/or hepatic/renal dysfunction may all have lower extremity symptoms separate from PTS. As a result, there may be value in recommending lifestyle modifications to help alleviate some of these factors given the relatively low risk of harm and potential for benefit. Lifestyle interventions that could be considered include periodic leg elevation, supervised exercise programs, weight loss programs and smoking cessation counseling. However, these interventions have not been studied in large randomized trials for their ability to prevent or reduce PTS.

With regard to compressive therapies, the best evidence, derived from a large multicenter, double-blind, placebo-controlled randomized clinical trial, suggests that elastic compression stockings (ECS) do not prevent PTS.¹⁰ Therefore, recommendations for ECS should not be made dogmatically, but a trial of ECS for management of lower extremity swelling that is particularly bothersome may be reasonable. To encourage compliance, we suggest starting with sized-to-fit, 20-30 mmHg ECS, and increasing to higher pressure if needed to control persistent symptoms. ECS should generally be worn in the daytime.¹¹

Infusion Catheter-Directed Thrombolysis

Preliminary studies suggest that catheter-directed endovascular therapies can rapidly eliminate thrombus and resolve venous obstruction. Catheter-directed thrombolysis (CDT), in which a recombinant tissue plasminogen activator is infused into the thrombus via a multi-sidehole catheter, was studied in the CaVenT (Catheter-Directed Venous Thrombolysis in Acute Iliofemoral Vein Thrombosis) study, a multicenter open-label RCT that included 189 patients. This study demonstrated a 26% reduction (55.6% vs. 41.1%; p = 0.047) in the risk of developing PTS over two years' follow-up in patients with iliac and/or upper femoral DVT who underwent CDT in addition to anticoagulation and compression, compared with anticoagulation and compression alone. However, there was no difference in long-term venous disease-specific or general health-related quality of life.¹²

Pharmacomechanical Catheter-Directed Thrombolysis

Pharmacomechanical catheter-directed thrombolysis (PCDT) refers to the use of CDT in conjunction with a device used to aspirate/macerate thrombus, enabling faster treatment. The ATTRACT (Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis) trial was developed to determine if PCDT prevents PTS after acute proximal lower extremity DVT. The trial compared the first-line use of PCDT along with standard therapy versus standard therapy alone in 691 patients.¹³ In this study, PCDT 1) had no effect on the development of PTS over two years; 2) reduced the severity of PTS over two years; 3) decreased the degree of leg pain and swelling within the first month after treatment; and 4) increased major bleeding within 10 days of treatment (absolute risk difference 1.4%).¹⁴ The study investigators concluded that PCDT should not be used routinely as first-line DVT therapy. However, selective use to reduce PTS severity may be justified in highly symptomatic patients <65 years of age with low expected risk of bleeding who respond poorly to initial anticoagulant therapy. Those with iliofemoral DVT will most likely comprise a subgroup that benefits, since these patients have a higher baseline risk for PTS and are more likely to exhibit poor symptom response to initial anticoagulation. Furthermore, based on clinical experience, PCDT is recommended as first-line therapy for patients with DVT causing acute limb-threatening circulatory compromise.¹⁵

Conclusion

PTS is a common, late complication of DVT, which causes significant morbidity and impairs QOL. The best methods to prevent PTS are the primary prevention of DVT and ensuring optimal anticoagulant therapy after DVT. ECS may improve symptoms among those with edema, but are unlikely to prevent PTS. Endovascular thrombolytic interventions should not be routinely used as first-line therapy for acute proximal DVT in non-threatened limbs, but should be reserved for patients at low expected risk for bleeding who do not respond well to initial anticoagulation. Future studies are needed to better define which patients with DVT are most likely to benefit from endovascular thrombolysis, as well as identify new mechanisms to prevent PTS.

Table 1: Treatment Options for PTS

Lifestyle Education: avoid trauma, adequate moisturization Leg elevation when supine Exercise therapy Weight loss Smoking cessation

Compressive Stockings Edema pumps Wearable devices

Medical Anticoagulation for DVT Venoactive drugs Pentoxifylline Diuretics Professional wound care

Surgical Debridement Skin graft & substitutes Thromboendovenectomy Bypass & valvuloplasty

References

1. Kahn SR, Shrier I, Julian JA, et al. Determinants and time course of the postthrombotic syndrome after acute deep venous thrombosis. Ann Intern Med 2008;149:698-707.
2. Kahn SR, Comerota AJ, Cushman M, et al. The postthrombotic syndrome: evidence-based prevention, diagnosis, and treatment strategies: a scientific statement from the American Heart Association. Circulation 2014;130:1636-61.
3. Vedantham S, Kahn SR, Goldhaber SZ, et al. Endovascular therapy for advanced post-thrombotic sydnrome: proceedings from a multidisciplinary consensus panel. Vasc Med 016;21:400-7.
4. Delis KT, Bountouroglou D, Mansfield AO. Venous claudication in iliofemoral thrombosis: long-term effects on venous hemodynamics, clinical status, and quality of life. Ann Surg 2004;239:118-26.
5. Prandoni P, Frulla M, Sartor D, Concolato A, Girolami A. Vein abnormalities and the post-thrombotic syndrome. J Thromb Haemost 2005;3:401-2.
6. Kahn SR, Galanaud JP, Vedantham S, Ginsberg JS. Guidance for the prevention and treatment of the post-thrombotic syndrome. J Thromb Thrombolysis 2016;41:144-53.
7. 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 Clincial Practice Guidelines. Chest 2012;141:e278S-325S.
8. Gould MK, Garcia DA, Wren SM, et al. Prevention of VTE in nonorthopedic surgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clincial Practice Guidelines. Chest 2012;141:e227S.
9. Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in nonsurgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clincial Practice Guidelines. Chest 2012;141:e195S-226S.
10. Kahn SR, Shapiro S, Wells PS, et al. Compression stockings to prevent post-thrombotic syndrome: a randomised placebo-controlled trial. Lancet 2014;383:880-8.
11. Holmes CE, Bambace NM, Lewis P, Callas PW, Cushman M. Efficacy of a short course of complex lymphedema therapy or graduated compression stocking therapy in the treatment of post-thrombotic syndrome. Vasc Med 2014;19:42-8.
12. Enden T, Haig Y, Klow NE, et al. Long-term outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVenT study): a randomised controlled trial. Lancet 2012;379:31-8.
13. Vedantham S, Goldhaber SZ, Kahn SR, et al. Rationale and design of the ATTRACT study: a multicenter randomized trial to evaluate pharmacomechanical catheter-directed thrombolysis for the prevention of postthrombotic syndrome in patients with proximal deep vein thrombosis. Am Heart J 2013;165:523-30.
14. Vedantham S, Goldhaber SZ, Julian JA, et al. Pharmacomechanical catheter-directed thrombolysis for deep-vein thrombosis. N Engl J Med 2017;377:2240-52.
15. Vedantham S, Sista AK, Klein SJ, et al. Quality improvement guidelines for the treatment of lower-extremity deep vein thrombosis with use of endovascular thrombus removal. J Vasc Interv Radiol 2014;25:1317-25.

Keywords: Stockings, Compression, Tissue Plasminogen Activator, Body Mass Index, Quality of Life, Risk Factors, Varicose Ulcer, Venous Thromboembolism, Weight Reduction Programs, Smoking Cessation, Postphlebitic Syndrome, Postthrombotic Syndrome, Venous Thrombosis, Fibrinolytic Agents, Lower Extremity, Anticoagulants, Edema, Lymphedema, Heart Failure, Life Style, Hypertension, Pulmonary, Primary Prevention, Exercise Therapy, Hypertension, Dermatitis

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