Review Article

Deep venous thrombosis and postthrombotic syndrome: Invasive management

Phlebology 2015, Vol. 30(1S) 59–66 ! The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0268355514568846 phl.sagepub.com

AJ Comerota

Abstract Invasive management of postthrombotic syndrome encompasses the two ends of the deep vein thrombosis spectrum, patients with acute iliofemoral deep vein thrombosis and those with chronic postthrombotic iliofemoral venous obstruction. Of all patients with acute deep vein thrombosis, those with involvement of the iliofemoral segments have the most severe chronic postthrombotic morbidity. Catheter-based techniques now permit percutaneous treatment to eliminate thrombus, restore patency, potentially maintain valvular function, and improve quality of life. Randomized trial data support an initial treatment strategy of thrombus removal. Failure to eliminate acute thrombus from the iliofemoral system leads to chronic postthrombotic obstruction of venous outflow. Debilitating chronic postthrombotic symptoms of the long-standing obstruction of venous outflow can be reduced by restoring unobstructed venous drainage from the profunda femoris vein to the vena cava.

Keywords Deep vein thrombosis, postthrombotic syndrome, iliofemoral venous obstruction, catheter-directed thrombolysis, venous outflow

Introduction A 22-year-old woman was referred for severe, postthrombotic venous claudication. As a high school student, she was the state champion in the 400 and 800 m runs for three consecutive years. She was awarded a full college scholarship to a big ten women’s track team. Three months after starting to take oral birth control, she developed an extensive iliofemoral venous thrombosis which was treated with subcutaneous low-molecular-weight heparin (LMWH) and converted to warfarin targeting an international normalized ratio, this falls into the category of common knowledge. INR of 2–3. Her leg remained swollen and her acute symptoms of venous claudication did not resolve. Her symptoms limited her activity. She could no longer participate as a member of the track team and had difficulty with sustained walking. She lost her athletic scholarship and, because of family finances, could not remain in college. As a result of family responsibilities, she accepted employment that paid minimum wage. Failure to eliminate thrombus and restore normal venous drainage irrevocably changed the life of this young woman. This is one of the many cases that illustrate the need to alter management of patients with iliofemoral DVT (IFDVT), incorporating a treatment

strategy of thrombus removal. Evaluation and reporting of the morbidity of the natural history of IFDVT treated with anticoagulation alone call attention to the morbidity of obstruction of the main venous drainage from the lower extremity. Currently, randomized trials and clinical observations have demonstrated the benefit of eliminating iliofemoral thrombus and preventing recurrent thrombosis with effective therapeutic anticoagulation. Many, if not most, patients with IFDVT continue to be managed with anticoagulation alone. This young woman underwent a full physiologic and anatomic evaluation which demonstrated occlusion of her left common femoral, external iliac, and common iliac veins. She underwent a common femoral vein (CFV) endovenectomy followed by recanalization of the external iliac and common iliac veins which then provided unobstructed venous drainage from the profunda to the inferior vena cava. Postoperatively, the

Jobst Vascular Center, The Toledo Hospital, Toledo, USA Corresponding author: Anthony J Comerota, Jobst Vascular Center, 2109 Hughes Dr Suite 400, Toledo, OH 43606, USA. Email: [email protected]

60 patient’s edema was significantly improved and her venous claudication eliminated.

Therapeutic strategies for acute DVT The therapeutic goals in the modern era of DVT management are to prevent clot propagation, prevent pulmonary embolism (PE), avoid recurrent thrombosis, and reduce the risk of postthrombotic morbidity. The management of DVT traditionally had been viewed as an ‘‘acute’’ condition with an initial period of high risk for PE followed by a steadily diminishing risk over time that ultimately permits discontinuation of anticoagulant therapy. In recent years, there is an improved appreciation of the long-term impact of DVT in terms of risk for recurrence, particularly in those with unprovoked venous thromboembolism (VTE). Additionally, patients with postthrombotic venous disease are now thought to have a ‘‘chronic’’ condition. Conventional anticoagulant therapy aimed to prevent clot propagation, PE, and recurrent VTE has been largely ineffective in preventing postthrombotic syndrome (PTS) in patients with IFDVT. It is recognized that manifestations of PTS result from a combination of valvular incompetence and residual venous obstruction.1–3 However, obstruction is particularly severe and clinically important in patients with IFDVT. Until 2008 national and international guidelines for the treatment of patients with acute DVT recommended anticoagulation alone. However, the 8th American College of Chest Physicians consensus conference on antithrombotic and thrombolytic therapy4 and the 2011 American Heart Association scientific statement on the management of IFDVT5 recognized IFDVT as a unique venous thrombotic condition suggesting interventional strategies for thrombus removal for thrombus that include surgical and catheter-based techniques.

PTS PTS consists of the signs and symptoms that occur as long-term complications of DVT resulting from vein lumen obstruction in venous valvular incompetence. Oftentimes the most severe PTS occurs in patients with both obstruction and valvular incompetence. The symptoms and signs of PTS include chronic aching, swelling, fatigue, heaviness, edema, hyperpigmentation, and/or subcutaneous fibrosis in the affected limb. In severe cases, patients may experience venous claudication and venous leg ulcers, both of which limit ambulation and the ability to work and perform activities of daily life. Consequently, PTS reduces health related quality of life (QoL). In fact, in a recent large prospective cohort study, the presence and severity of PTS were

Phlebology 30(1S) the leading determinants of QoL two years after an initial or extremity DVT.6,7 Patients with IFDVT appear to be a clinically unique subset of patients with acute venous thrombosis in that they tend to develop severe PTS, in 50% or more patients, when treated with anticoagulation alone.8,9 A prospective observational study of anticoagulation for acute DVT demonstrated that IFDVT was the most powerful predictor of severe PTS.10 Labropoulos et al.11 measured resting and hyperemic venous pressures in patients with PTS. They found that patients who were treated for IFDVT (anticoagulation alone) had the highest resting and hyperemic venous pressures. This confirmed previous observations that IFDVT patients treated by anticoagulation alone had ambulatory venous hypertension, with 40% demonstrating venous claudication and up to 15% developing venous ulceration within five years.11,12 Essentially all of these patients will have reduction in their QoL. The morbidity of PTS escalates with ipsilateral recurrence, and IFDVT is associated with the highest risk of recurrence. A metaanalysis of outcomes after treatment for acute DVT demonstrated that recurrence occurs more commonly in patients with a large burden of thrombus.12

Pathophysiology of PTS The pathophysiology of postthrombotic venous disease is ambulatory venous hypertension, which is defined as elevated venous pressure during exercise. Ambulatory venous pressure is linearly linked to the pathophysiologic changes observed with chronic venous disease, such as swelling, pigmentation, and lipodermatosclerosis. Venous hypertension stimulates leukocyte adhesion, activation, and migration, which then further initiates a cascade of cellular and humeral events leading to pain, swelling, skin discoloration, and ultimate ulceration associated with postthrombotic venous disease. The anatomic components contributing to ambulatory venous hypertension are venous valvular incompetence and luminal obstruction. The most severe postthrombotic morbidity is associated with the highest venous pressures, which occur in patients with both valvular incompetence and luminal venous obstruction.13,14 Although valvular function can be reliably assessed with ultrasound by quantifying valve closure times, routine noninvasive techniques are not yet available to assess the relative contribution of venous obstruction to the pathologic venous hemodynamics leading to postthrombotic morbidity. Unfortunately, noninvasive physiologic techniques underestimate venous obstruction as a contributing factor to the pathophysiology of chronic venous disease. Based upon the above background information and our understanding of the pathophysiology of PTS, it

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Figure 1. (a) Patient with extensive iliofemoral and infrainguinal DVT presenting with painful phlegmasia cerulea dolens. (b) Pretreatment phlebogram demonstrates extensive proximal thrombus and distal thrombus. (c) Successful lysis followed by stenting of a residual common iliac vein stenosis restored unobstructed venous drainage from the lower extremity with rapid symptom resolution. (d) Follow-up photo 12 months after treatment shows normal lower extremity without postthrombotic morbidity.

would appear that treatment strategies directed at thrombus removal from the iliofemoral venous segment should successfully reduce the incidence and severity of PTS.

Strategies of thrombus removal to reduce PTS There is a large body of evidence supporting the rationale for a strategy of thrombus removal, especially in patients with IFDVT. When a strategy of thrombus removal is successful, venous patency is restored, valve function is maintained, QoL is improved, and the risk of recurrence is reduced. Qvarfordt et al.13 measured compartment pressures in patients with acute IFDVT before and after operative venous thrombectomy. Compartment pressures (surrogate for venous pressures) were pathologically elevated upon presentation and normalized following venous thrombectomy. These important observations documented significant physiologic benefit of thrombus elimination by restoring unobstructed venous outflow to the lower extremity which formed the basis for future randomized trials. The Scandinavian investigators randomized patients with IFDVT to operative venous thrombectomy plus

arterio-venous fistula and anticoagulation to anticoagulation alone. This multicenter randomized trial demonstrated that patients who underwent venous thrombectomy experienced improved iliac vein patency (p < 0.05), lower venous pressures (p < 0.05), less edema (p < 0.05), and fewer postthrombotic symptoms (p < 0.05) than did patients receiving anticoagulation alone. They also observed that patients who underwent venous thrombectomy were more likely to retain venous valve function in their femoropopliteal segment than those treated with anticoagulation alone. A growing body of evidence suggest that catheter-directed thrombolysis (CDT) is of benefit especially in patients with IFDVT.15,16 A case-controlled study demonstrated significantly improved QoL in patients treated with CDT for IFDVT versus anticoagulation alone.15 The QoL benefit associated with CDT directly correlated with the volume of thrombus removed.17 The more residual thrombus at the completion of CDT, the worse the QoL. This also correlated with objective measures of PTS. The greater the degree of lysis the fewer symptoms of PTS observed.18 The recently published CaVenT trial reported sixmonth and two-year outcomes after additional CDT plus anticoagulation versus anticoagulation alone

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Figure 1. Continued.

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Figure 2. (a) to (c) Preoperative venogram demonstrates extensive venous obstruction from the midthigh to the vena cava in a patient incapacitated following iliofemoral and femoropoliteal deep vein thrombosis (DVT) seven months earlier. (d) A longitudinal venotomy often incorporates the distal external iliac vein (EIV) to the proximal femoral vein. Fibrotic transformation of occlusive thrombus is observed, with a remaining core of old thrombus. (e) Postendovenectomy, the distal external iliac vein (EIV) and the common femoral vein (CFV) are cleared of obstruction, with the dissection extending into the orifice(s) of the profunda venous system. (f) Following the removal of the sheath, closure of the patch venoplasty is completed. The proximal and saphenous veins were resected. Picture shows common femoral vein (CFV) patch extending onto the profunda femoris vein (PFV). (g) Intraoperative venogram following balloon dilation and stenting shows unobstructed drainage from the common femoral vein (CFV) to the inferior vena cava (IVC).

for IFDVT.16 These investigators randomized 209 patients. Their primary endpoint was iliofemoral patency at six months and PTS at two years. CDT was performed using the drip technique. The mean

duration of thrombolysis was 2.4 days. Forty-eight percent (48%) of the patients had complete lysis, 41% had partial, and 11% unsuccessful lysis. Patients receiving CDT had a mean clot resolution of 82%. Patients

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Figure 2. Continued.

treated with CDT had significantly improved iliofemoral venous patency at six months (p ¼ 0.012) and less PTS at two years (p ¼ 0.047). The authors reported that the lower thrombus scores at completion of CDT were associated with increased patency (p < 0.04) and that patency of the iliofemoral venous system directly correlated with the reduction in PTS (p < 0.001). Major bleeding complications occurred in 3.3% of patients who underwent CDT and were usually confined to the puncture site. Only one IVC filter was used and no symptomatic PE was observed. An example of the benefit of a strategy of thrombus removal is demonstrated by the patient summarized in Figure 1. The patient presented with a painful, swollen, phlegmasia cerulea dolens after five days of treatment with LMWH (Figure 1(a)). Ascending phlebogram from the popliteal approach demonstrates extensive iliofemoral venous obstruction (Figure 1(b)). Catheter-directed pharmacomechanical thrombolysis restored patency to the iliofemoral venous system exposing a residual iliac vein stenosis. This was successfully stented restoring unobstructed venous drainage to the vena cava (Figure 1(c)). Twelve months posttreatment the patient’s follow-up examination demonstrated

a normal appearing leg, unobstructed venous drainage, and functional valves (Figure 1(d)). The patient was asymptomatic. The above results demonstrate the significant benefit of strategies of thrombus removal. The largest randomized study to date, the ATTRACT trial, sponsored by the National Institutes of Health, has completed patient entry of 692 patients.19 Patients with iliofemoral and femoropopliteal DVT were stratified at entry into the study, to catheter-based techniques of thrombolysis versus anticoagulation alone. The primary endpoint is PTS at 24 months. The ATTRACT trial will evaluate the relative benefits of pharmacomechanical techniques versus the CDT drip technique and will include a careful cost analysis. These results will not be available until 2016.

Management of PTS due to iliofemoral venous obstruction The most severe postthrombotic morbidity occurs in patients with chronic obstruction of the iliofemoral venous segment which includes the CFV. Patients presenting with postthrombotic iliac vein obstruction can

Comerota be successfully managed with angioplasty and stenting alone. However, if the chronic occlusive disease includes the CFV, treatment is more challenging and cannot be accomplished with percutaneous techniques alone. Relative obstruction of the CFV can persist even after percutaneous intervention leading to incomplete drainage of the femoral profunda femoris venous systems, mitigating the benefit of iliac vein recanalization, and increasing the risk for rethrombosis. Although stenting across the inguinal ligament can be performed, there is a higher risk of stent occlusion in postthrombotic patients. Patients who have successful elimination of CFV obstruction with recanalization of the obstructed iliac venous system in order to restore unobstructed venous drainage from the profunda femoris vein to the vena cava have significant reduction in postthrombotic morbidity with a commensurate improvement in their QoL.20 The technique of endovenectomy of the CFV and interoperative iliac vein recanalization for chronic postthrombotic iliofemoral venous occlusion has been published.21 To date, 20 patients have undergone this procedure with favorable results. The initial five patients who were followed for more than six months were analyzed and the results published. The Venous Clinical Severity Score (VCSS), the Villalta score, and the VEINES Quality of Life (VEINES-QOL)/Sym questionnaire all significantly improved for these patients. Figure 2 demonstrates a typical preoperative ascending venogram of a patient incapacitated with postthrombotic morbidity due to iliofemoral venous obstruction. The venogram shows occlusion of the common femoral and iliac veins. The operative photograph (Figure 2(b)) shows the intraluminal contents of the CFV following venotomy. Figure 2(c) shows the lumen of the CFV following endovenectomy and Figure 2(d) shows the patched CFV after venotomy closure, with the patch extending onto the profunda femoris vein after resection of the obstructed proximal segment of the femoral vein. The completion venogram demonstrates unobstructed venous drainage to the vena cava. The patient was walking 2 miles per day within 10 weeks of the operation and her pain and edema resolved.

Summary IFDVT represents a unique subset of patients presenting with a large thrombus burden. Strategies of thrombus removal, when successful, restore unobstructed venous drainage, can preserve valve function, avoid severe postthrombotic morbidity, and reduce recurrence. Patients treated with anticoagulation alone who suffer severe postthrombotic morbidity due to proximal

65 venous obstruction now have options for elimination of the collagenous obstruction in their CFV with recanalization of their occluded iliofemoral venous segment. Restoration of venous outflow significantly reduces postthrombotic morbidity and improves QoL. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest None declared.

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