Significance

Deep vein thrombosis (DVT) is a potentially life-threatening condition that affects more than 300,000 individuals in the U.S. annually.¹ Thrombosis of an iliofemoral vein accounts for ~25% of all lower extremity DVTs and is associated with an increased risk of pulmonary embolism (PE), limb malperfusion, and post-thrombotic syndrome (PTS) when compared to DVT that occurs below the knee.^2-4

Predisposing Conditions

Iliofemoral DVT typically affects patients with an anatomic predisposition to venous stasis. In a retrospective study of 56 patients presenting with acute iliofemoral DVT, 45 (84%) patients had evidence of iliac vein compression on CT venography.⁵ The most well described scenario involves compression of the left iliac vein between the right iliac artery and a vertebral body (May-Thurner syndrome). However, extrinsic compression of an iliac vein can occur in either leg and through a variety of mechanisms, including pelvic malignancy or trauma.

In addition to an anatomic predisposition to venous stasis, the majority of patients with iliofemoral DVT have at least one additional risk factor for venous thrombosis.⁶ Endothelial injury and hypercoagulability, along with stasis, comprise Virchow's triad of thrombogenesis. Common examples include the postoperative state, prolonged immobility (e.g., travel, hospitalization), malignancy, pregnancy, and inherited hypercoagulable conditions.

Clinical Manifestations

Patients with acute DVT commonly present with lower extremity pain and swelling. Physical exam may reveal a palpable cord, ipsilateral edema, erythema, or venous distension. Rarely, patients with DVT may present with evidence of arterial insufficiency due to massive iliofemoral DVT. Known as phlegmasia cerulea dolens, this life-threatening condition occurs as a consequence of severe venous obstruction. As swelling progresses, compartment syndrome and arterial compromise can lead to venous gangrene.⁷ Prompt venous recanalization via catheter-directed thrombolysis and thrombectomy is indicated to prevent limb loss, circulatory collapse, and death.

Long-term complications of DVT include persistent lower extremity edema, venous claudication, hyperpigmentation, and ulceration – known collectively as PTS. Mediated by venous hypertension and valve incompetence arising from persistent iliofemoral obstruction, these sequelae affect up to 50% of patients following an incident iliofemoral DVT and are associated with a reduced quality of life and increased health care expenses.^6,8-10 In a retrospective study of 26,958 patients with DVT or PE, the development of PTS was associated with a 32% increase in annualized total health care costs, due in large part to outpatient resource utilization and the management of venous ulcers.¹¹

Diagnosis

Many patients who present with lower extremity pain and swelling do not have DVT. Stratifying patients according to their pretest likelihood of having this disease is, therefore, a fundamental element of a cost-effective approach to diagnosis. The Wells score includes nine variables to determine whether a patient has a low, moderate, or high probability of having a DVT. In patients with a low or moderate pretest probability of having a DVT, a negative D-dimer effectively rules out the diagnosis. Current guidelines favor D-dimer testing in these populations, although ultrasound may be used when comorbid conditions confound the interpretation of a positive result. In patients with high probability of DVT, a venous ultrasound of the affected limb should be performed.¹² While venography remains the gold standard for diagnosis of DVT, ultrasound offers an efficient, noninvasive modality that is more practical in most clinical settings. The sensitivity and specificity of venous ultrasound for detecting proximal DVT approaches 95%.^13,14

Management

The initial management of an iliofemoral DVT should be aimed at preventing thrombus propagation and lowering the risk of embolic complications. In the absence of contraindications, all patients should be treated with therapeutic anticoagulation at the time of diagnosis. A delay in initiation of anticoagulation has been associated with an increased risk of life-threatening PE.¹⁵ Current guidelines recommend the initial use of a low-molecular weight heparin (e.g., enoxaparin, dalteparin) or fondaparinux, rather than unfractionated heparin, in patients with proximal DVT who are being initiated on warfarin. More recently, factor Xa inhibitors (e.g., rivaroxaban and apixiban) have been approved as potential anticoagulants for use in treatment of DVT. The duration of therapy should be based on attendant risk factors and whether there is a history of previous DVT. Patients with unprovoked or recurrent iliofemoral DVTs should be treated indefinitely in the absence of bleeding complications. In patients with an incident proximal DVT and a reversible risk factor, current guidelines recommend three months of anticoagulation (Table 1).¹²

Table 1: Duration of Anticoagulation Therapy for Patients With Proximal DVT: Summary of the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

First unprovoked proximal DVT	If low-to-moderate bleeding risk, indefinite therapy. If high bleeding risk, 3 months.
Second unprovoked proximal DVT	If low-to-moderate bleeding risk, indefinite therapy. If high bleeding risk, 3 months.
Proximal DVT in the setting of active malignancy	Extended therapy with reassessment of risk at periodic intervals (e.g. annually).
Proximal DVT provoked by surgery	3 months
Proximal DVT provoked by nonsurgical transient risk factor	3 months

More than 30% of patients with symptomatic, iliofemoral DVT will have residual thrombus following a three-month course of anticoagulation.¹⁶ Residual thrombus is a strong risk factor for recurrent DVT, which occurs nearly three times as often following iliofemoral thrombosis as compared to a distal DVT.¹⁷ Residual thrombus and recurrent DVT are, in turn, strong predictors of subsequent PTS.¹⁸ Despite the use of anticoagulation and adjunctive therapies such as compression stockings, over 50% of patients with iliofemoral DVT will go on to develop PTS.^8,19 Observational data suggests that the risk of PTS may be reduced through removal of thrombus by either thrombolytic therapy or mechanical thrombectomy.⁹

Invasive Therapies

Invasive therapies such as catheter-directed thrombolysis (CDT) and inferior vena cava (IVC) filter placement are currently reserved for patients with vascular compromise or with a contraindication to anticoagulation, respectively. Patients presenting with an iliofemoral DVT associated with severe swelling and vascular compromise of the affected extremity should be considered for CDT in an effort to restore perfusion to the affected limb and avoid limb ischemia. Limited data suggest that CDT is a safe and effective means of restoring venous return and arterial blood flow in these patients, provided they have had symptoms for less than 14 days and are not at high risk of bleeding.⁷

IVC filter placement is recommended in patients with contraindications to anticoagulation therapy who present with iliofemoral thrombosis.¹² The routine use of IVC filters in patients with DVT treated with anticoagulation, however, is not recommended. Several studies investigating the use of IVC filters in patients with acute DVT have failed to show a benefit with regard to symptomatic PE or mortality, with some data suggesting that IVC filter placement is associated with a higher risk of recurrent DVT, especially if the IVC filter is not subsequently removed.^20,21

CDT and Adjunctive Angioplasty

The use of CDT to treat iliofemoral DVT and mitigate the risk of PTS is currently being investigated. In observational studies, CDT has been associated with a significant reduction in risk of post thrombotic syndrome and venous obstruction at one year.²² Furthermore, when compared to therapy with anticoagulation alone, patients with iliofemoral DVT successfully treated with CDT have reported fewer long-term physical limitations and improved health-related quality of life.²³

Two prospective trials comparing CDT to standard treatment with compression and anticoagulation are currently underway. The Catheter Versus Anticoagulation (CAVA) trial is a multicenter study in which patients with acute iliofemoral DVT are randomized to ultrasound-enhanced CDT and standard therapy or standard therapy alone. Ultrasound has been shown to positively augment delivery of lytic enzymes into thrombus and to accelerate thrombolysis in patients with upper and lower extremity DVT^24,25 The CAVA trial aims to enroll 180 patients to assess a primary endpoint of PTS at 12 months.

The Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter-Directed Thrombolysis (ATTRACT) trial recently completed enrollment of 692 patients. This study aims to compare medical management with standard anticoagulation to CDT (using a pharmacomechanical device) in addition to standard anticoagulation in patients with illiofemoral and femoropopliteal DVTs to determine the effect of these interventions on rates of PTS at 24 months. The study completed enrollment in 2014 and results are expected in 2017.

Percutaneous mechanical thrombectomy (PMT) offers an important mechanical adjunct to thrombolytic therapy. When used in isolation, PMT is associated with an increased risk of embolic complications, including pulmonary embolism.^26,27 However, this risk can be mitigated with the concomitant use of CDT and the incorporation of thrombo-aspiration catheter technology.^27,28 In addition to pharmacologic and mechanical removal of a thrombus, catheter-directed therapies can be used to detect and modify venous stenosis through angioplasty and stent implantation. Studies have shown reduced rates of recurrent DVT and improved five-year patency in patients with iliofemoral DVT treated with endovenous stenting.^29,30 The ATTRACT trial allows for balloon angioplasty and stenting in patients with identified obstructive lesions.

Conclusions

In summary, iliofemoral vein thromboses account for up to 25% of all DVTs and are associated with an increased risk of embolic and post-thrombotic complications when compared to more distal DVTs.^2-4 Despite treatment with anticoagulation and compression, over 50% of patients with iliofemoral DVT will develop PTS, a burdensome condition characterized by venous claudication, edema, skin damage, and ulceration.⁹ PTS occurs as a consequence of a unresolved thrombus that predisposes patients to recurrent DVT, valve incompetence, and venous hypertension.^31,32 Early thrombus removal via thrombolysis or thrombectomy offers a means of restoring venous patency and preserving valve function. These therapies have been associated with less post-thrombotic morbidity in patients with iliofemoral DVT but are currently reserved for patients with evidence of arterial insufficiency as a result of venous obstruction.³³ Whether catheter-based approaches to thrombolysis and thrombectomy offer a safe, effective adjunct to standard therapy remains uncertain. Current trials exploring the efficacy of CDT in reducing rates of PTS in patients with iliofemoral DVT will yield important insights into the optimal treatment of this disease. In the meantime, a prompt diagnosis and initiation of anticoagulation and compression remain the mainstays of therapy for the majority of patients with iliofemoral DVT.

References

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Keywords: Angioplasty, Angioplasty, Balloon, Laser-Assisted, Anticoagulants, Compartment Syndromes, Constriction, Pathologic, Dalteparin, Edema, Enoxaparin, Erythema, Factor Xa Inhibitors, Fibrin Fibrinogen Degradation Products, Gangrene, Health Care Costs, Heparin, Heparin, Low-Molecular-Weight, Hospitalization, Hyperpigmentation, Hypertension, Iliac Artery, Iliac Vein, May-Thurner Syndrome, Molecular Weight, Morpholines, Outpatients, Pain, Phlebography, Polysaccharides, Postthrombotic Syndrome, Pregnancy, Prospective Studies, Pulmonary Embolism, Quality of Life, Retrospective Studies, Risk Factors, Stents, Thiophenes, Thrombectomy, Thrombolytic Therapy, Thrombophilia, Thrombosis, Tomography, X-Ray Computed, Varicose Ulcer, Vena Cava, Inferior, Venous Thrombosis, Warfarin

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