Continuing Education Activity

May-Thurner syndrome (MTS), described in 1957 by Dr. May and Dr. Thurner, as a left common iliac vein (LCIV) thrombosis secondary to compression by an overriding right common iliac artery (RCIA). There have been reports of right-sided MTS. While LCIV compression is common, MTS is largely an underdiagnosed cause of iliofemoral deep vein thrombosis. This activity reviews the role of the healthcare team in the diagnosis and treatment of this condition.

Objectives:

• Identify the etiology of May-Thurner syndrome medical conditions and emergencies.
• Outline the appropriate evaluation of May-Thurner syndrome.
• Review the treatment and management options available for May-Thurner syndrome.
• Describe interprofessional team strategies for improving care coordination and communication to advance May-Thurner syndrome and improve outcomes.

Introduction

May-Thurner syndrome (MTS) is described as compression of the left iliofemoral vein by the right common iliac artery against the vertebral body. It is also called Cockett syndrome or iliac vein compression syndrome. Rudolph Virchow, in 1851, first reported the increased incidence of the right common iliac artery compressing the left iliofemoral vein in the cadavers of patients with left iliofemoral thrombosis. However, it was not until 1957 when May and Thurner reported the presence of intraluminal fibrous bands in the left iliofemoral vein secondary to compression from the right common iliac artery in 22% of the 430 cadavers they dissected and called this finding MTS. Cockett and Thomas were the first to report these findings in living patients. Although, clinically, MTS is not a common cause of deep vein thrombosis (DVT), cadaveric and radiographic studies have reported a high incidence of compression of the left iliofemoral vein by the right common iliac artery.[1] In this activity, we will discuss the incidence and pathophysiology of MTS and how to diagnose and treat this seemingly rare yet clinically silent syndrome. 

Etiology

May-Thurner syndrome is caused by compression of the left iliofemoral vein by the right common iliac artery, just after it originates from the abdominal aorta and before the iliofemoral junction. The chronic pressure from the overriding artery compresses the vein against the bony structures, usually the lower lumbar vertebrae, leading to the formation of 'venous spurs.' Although MTS primarily results in the thrombosis of the left iliofemoral veins, rarely 'right' sided MTS has also been reported.[2][3] Initially, venous spurs/ stenosis secondary to MTS was thought to be present since birth. However, May and Thurner postulated that chronic irritation of the endothelium by the pulsation of the overlying artery leads to the formation of intraluminal 'spurs,' which promoted clot formation.[4] This theory was further strengthened by Negus et al., who demonstrated the existence of fibrous bands between the anterior and posterior walls of the iliofemoral artery.[5] Cockett et al. further postulated that the band formation might be an irreversible process, as repositioning of the artery did not lead to the recanalization of the veins in their study.[6][2]

Epidemiology

Overall, May-Thurner syndrome is estimated to cause 2% to 5% of all DVT.[1][7] However, many retrospective cadaveric and radiographic studies have estimated the prevalence to be much higher. Multiple autopsy studies on unselected patients showed MTS prevalence to be between 14% to 32%.[1] The radiological studies, which specifically chose patients with left lower extremity DVT, reported MTS incidence in such patients to be between 22% to 76%.[1] A systematic review of the literature reported MTS incidence in women to be two times higher compared to men. It also reported that while men had a higher degree of pain and swelling in the left leg, the women tended to be younger and are more likely to present with a pulmonary embolism in addition to lower extremity DVT.[8] A lot of uncertainty exists over the exact prevalence of MTS, and clinical manifestations of MTS do not happen in all patients. 

Pathophysiology

The chronic pulsatile stimulation from the overlying common iliac artery irritates the endothelium of the left iliofemoral vein, which leads to the formation of bands, which are often referred to as spurs. Most patients are clinically asymptomatic as either venous collaterals develop to maintain the continuity of the blood flow, or the obstruction is not critical. Only in the presence of transient risk factors like surgery, pregnancy, or post-partum can it precipitate a DVT.

History and Physical

May-Thurner syndrome develops through three stages, starting with (1) asymptomatic left CIV compression, leading to (2) the formation of a venous spur, and finally resulting in (3) left lower extremity DVT.[9] Most patients live with MTS without ever having a DVT. They may develop left lower extremity venous hypertension without ever noticing it. Rarely, they may develop phlegmasia cerulea dolens.[10] Subtle signs and symptoms like left lower extremity tightness, which resolves after sleeping overnight, mild swelling, hyperpigmentation, telangiectasias, or venous ulceration, can be secondary to MTS. However, none of these signs are specific to MTS. 

MTS is known to occur more commonly in the second and third decades of life. Young women are more commonly affected compared to men. Due to the proximity with the lower lumbar vertebrae, MTS should be suspected in patients with left lower extremity DVT.[1][7] Although MTS is an anatomical variant present since birth, the presence of transient risk factors like pregnancy or postpartum, prolonged immobilization, post-surgery, or secondary to oral contraceptive pills is needed to precipitate a DVT.[1] A high index of suspicion is needed, especially when a young woman presents with the left lower extremity DVT in the setting of the aforementioned transient risk factors. The hypercoagulability workup is negative.[7]  

Evaluation

May-Thurner syndrome is best diagnosed with the use of imaging. Various modalities for imaging are discussed here[11]:

1. Ultrasound (US) Doppler: This is the most common technique used in the emergency department to diagnose a DVT. However, technical difficulties in assessing the inferior vena cava (IVC) and iliac vein may limit their utility. In addition to this, it is very challenging to diagnose iliac vein compression on a US Doppler. The high velocity of blood in the common iliac vein may indicate iliac vein compression; however, this exam depends on technical expertise.[12]

2. CT venography: It has a higher sensitivity and specificity to detect iliac vein compression nearing 95%. It is also useful in ruling out other causes of iliac vein compression, like lymphadenopathy, hematoma, and cellulitis.[13] However, a common pitfall with CT venography is that it cannot account for the patient's volume status and hence can overestimate the degree of compression in a dehydrated patient.[9]

3. Magnetic Resonance venography (MRV): MRI/MRV has been proposed as an alternative to diagnose MTS. However, a single MRV may not be sufficient to diagnose MTS due to variability of LCI compression over time and may also be limited by cost.[14]

4. Venography with intravascular US (IVUS): This is the gold standard to diagnose MTS. IVUS provides a real-time evaluation of the vessel lumen, the accurate size of the luminal diameter, and provides information regarding the structural changes in the vessel wall.[15] In addition to this, IVUS can also provide information regarding the chronicity of the thrombus, which could help decide management (for example: to perform thrombolysis of acute clot burden or not). IVUS can also localize guidewires during challenging recanalizations in a patient with multiple venous collaterals and assist in accurate placement of stents.[11] The biggest advantage of IVUS is that contrast is not needed in venous studies, which reduces the chances of contrast-related nephropathy and allergies. 

Treatment / Management

All patients with acute thrombosis undergo catheter-directed thrombolysis, after which the endovascular stent is placed. Berger et al. were the first to report the safety and efficacy of vascular stenting in MTS.[16] Multiple studies have shown that vascular angioplasty is not good enough for MTS.[17][18] The guidelines of the Society of Interventional Radiology and the Society of Vascular Surgery recommend iliac venous stenting in the setting of external iliac vein compression.[19][20] Catheter-directed thrombolysis increases the risk of bleeding. 

Absolute contraindications to catheter-directed pharmacologic thrombolysis include

• Active internal bleeding
• Cerebral infarction
• Neurological and eye procedures 
• Head trauma within three months
• Presence of an intracranial tumor, aneurysm, or vascular malformation

Relative contraindications include

• Major trauma, surgery, or obstetrical delivery within 10 days
• Uncontrolled hypertension (systolic greater than 180 mmHg or diastolic greater than 110 mmHg)
• Gastrointestinal bleeding within 3 months
• Pregnancy
• An infected venous thrombus
• Severe renal or liver disease
• Hemorrhagic diabetic retinopathy
• Bleeding diathesis 

Open surgical thrombectomy, especially in the setting of MTS, is losing favor. This is shown by the fact that surgical thrombectomy was done for only 4.1% of all patients with MTS related DVT compared to 75% of all patients before 2000.[8] The operative dissection, morbidity from surgery and anesthesia, and poor surgical outcomes go against surgical dissection.[21] Surgical resection is mostly reserved for patients who fail endovascular procedures. In the rare patients with an occluded left iliac vein who fails an endovascular procedure, a saphenofemoral crossover bypass, cross pelvic venous bypass (the Palmae Dale procedure), femoro-femoral prosthetic bypass, femoro-caval bypass, ilio-ilial prosthetic bypass, and aortic elevation can be pursued.[7]

Anticoagulation forms an important part of the management of patients with MTS who present with iliofemoral DVT. A delay in starting anticoagulation is associated with an increased risk of life-threatening pulmonary embolism (PE). Low molecular weight heparin or fondaparinux is preferred over unfractionated heparin to reduce the risk of bleeding and heparin-induced thrombocytopenia. Major societies still recommend vitamin-K antagonist (VKA), warfarin for anticoagulation in patients with iliofemoral thrombosis.[22] Factor Xa inhibitors have also been approved for DVT management; however, lack of good prospective data prevented their use in patients with iliofemoral thrombosis.[23][24][25]

Recently, a multicenter randomized trial demonstrated the safety of rivaroxaban in patients with iliofemoral vein thrombosis.[25] In this study, approximately 50% of patients were diagnosed with MTS. Although the difference in major bleeding events could not reach statistical significance, the risk of bleeding was quite low in the rivaroxaban group compared to the warfarin group (2.9% versus 9.4%, HR, 0.31; 95% CI, 0.03–2.96; p = 0.31).[25] Another prospective registry-based study led by Sebastian et al. also reported similar efficacy for patients who received catheter-directed thrombolysis and stent placement followed by anticoagulation with rivaroxaban.[26] Anticoagulation alone is not enough in patients with thrombosis of the iliofemoral vein secondary to MTS. The results from the CaVenT trial and subgroup analysis of the ATTRACT trial showed conclusively that catheter-directed thrombolysis with anticoagulation is superior to anticoagulation alone.[27][28] 

Differential Diagnosis

The top three main causes of iliac vein compression other than MTS are the following.

• Malignancy or lymphadenopathy
• Hematoma
• Cellulitis

Other than these, any other anatomical condition compressing the iliofemoral vein must be considered in the differential.

• Uterine enlargement from fibroids, cancer, or pregnancy, and also pelvic masses
• Aortoiliac aneurysm
• Retroperitoneal fibrosis
• Osteophyte

Along with these, alternate causes of thrombosis must be considered in any young patient presenting with a blood clot. All patients who present with thrombosis must undergo age-appropriate cancer screening. 

Prognosis

May-Thurner syndrome remains undetectable or clinically silent in the majority of patients. Multiple cadaveric studies on unselected subjects have shown a much higher prevalence than the actual thrombosis events reported in the alive patients. However, in patients with left-sided iliofemoral thrombosis, the prevalence of MTS has been consistently reported to be quite high. Post-thrombotic syndrome (PTS) is a common complication of MTS.

Complications

Post-thrombotic syndrome is a common complication of PTS, which adds to the morbidity of the patients. Comerota et al. demonstrated that residual thrombosis after catheter-based thrombolysis is positively associated with the development of PTS.[29] A residual thrombus and recurrent DVT are the strongest predictors for PTS in a patient with any kind of DVT.[30] The same principles also apply for iliofemoral DVT. Thrombolysis (mechanical or pharmacological) may reduce the risk of PTS.[29][31] Patients with PTS can benefit from knee or thigh-high compression stocking, applying a pressure of 30 to 40 mmHg.[7] A delay in anticoagulation for the DVT increases the risk of life-threatening pulmonary embolism. Anticoagulation is associated with bleeding risks. 

Deterrence and Patient Education

May-Thurner syndrome is more prevalent than thought; however, most patients do not exhibit the signs or symptoms of MTS. The most common presentation is iliofemoral DVT, which should always raise the suspicion for MTS or iliofemoral compression syndrome. Healthcare teams must maintain a high index of suspicion for MTS in patients presenting with left-sided iliofemoral vein thrombosis. Patients must be made aware of the signs and symptoms of DVT and PE so that they can return to seek care at the onset of symptoms. They must also be taught about the post-thrombotic syndrome and given adequate counseling on how to wear the compression stockings. All patients should also be educated regarding the risk of bleeding with DOAC's, warfarin, and parenteral agents and how to seek care in case of uncontrolled or extensive bleeding. 

Pearls and Other Issues

A few pearls regarding May-Thurner syndrome:

• Although MTS accounts for only 2% to 5% of all patients presenting with DVT, multiple autopsy studies have shown that the actual prevalence is as high as 14% to 32% in the general population.
• Despite the high prevalence, MTS remains clinically silent in most patients.
• Iliofemoral DVT is the most common presentation of MTS.
• Young women are at a higher risk of developing DVT compared to men. 
• A transient risk factor is usually present in patients with MTS, which precipitates the thrombotic event. 
• MTS has been associated with patent foramen ovale and cryptogenic stroke. 
• Prompt anticoagulation with low-molecular-weight heparin or fondaparinux is needed to prevent PE.
• Although most societies recommend warfarin for long-term anticoagulation, recent studies show that rivaroxaban is equally effective and has a lower risk of major bleeding (although this has not reached statistical significance in clinical studies).
• Venogram with IVUS is the gold standard in diagnosing MTS. In addition to diagnosis, it also helps in the treatment of DVT secondary to MTS.
• Catheter-directed thrombolysis, followed by stent placement, is the treatment of choice. 
• Surgical resection of thrombus is falling out of favor. It is reserved for patients in whom endovascular treatment fails.
• Anticoagulation alone is not sufficient to treat patients with DVT secondary to MTS. It should be combined with catheter-directed thrombolysis. 
• Post-thrombotic syndrome is the most common adverse event after developing iliofemoral DVT. Residual thrombus after thrombolysis and stent placement is positively associated with the risk of developing PTS.

Enhancing Healthcare Team Outcomes

The diagnosis of May-Thurner syndrome or iliofemoral compression syndrome requires a high index of suspicion. All clinicians, starting from the emergency department team (where most patients with DVT usually present) or those in the primary care office, must be aware of this condition. A dedicated team of radiologists and vascular surgeons, support staff (nurses, anesthesiologists, etc.) is needed to provide acute care to such patients. Also, post thrombolysis and stent placement, a dedicated team must follow up with patients to help in rehabilitation and early detection of post-thrombotic syndrome. The risk of anticoagulation must be discussed with the patient by a vascular surgeon or a hematologist. Pharmacists review prescriptions, check for interactions, and counsel patients about their use and side effects. This interprofessional collaboration and information sharing will improve patient outcomes. [Level 5]

The treatment modalities discussed in this article have undergone phase II and phase III trials with level I evidence as described above.