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 as Cockett syndrome or iliac vein compression syndrome. Rudolph Virchow, in 1851, first reported the increased incidence of right common iliac artery compressing the left iliofemoral vein in the cadavers of patients with left iliofemoral thrombosis. However, it was not till 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 as MTS. Cockett and Thomas were the first to report these findings in living patients. Although, the 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.
MTS 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]
Overall, MTS is estimated to be the cause of 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 the prevalence of MTS to be between 14% to 32%.[1] The radiological studies, which specifically chose patients with left lower extremity DVT, reported the incidence of MTS in such patients to be between 22% to 76%.[1] A systematic review of the literature reported the incidence of MTS 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.
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, a DVT is precipitated.
MTS 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 that is 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, and the hypercoagulability workup is negative.[7]
MTS 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 be an indicator of iliac vein compression; however, this exam is dependent 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 volume status of the patient 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 in deciding 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 in venous studies, contrast is not needed, which reduces the chances of contrast related nephropathy and allergies.
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 by 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
Relative contraindications include
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), femorofemoral prosthetic bypass, femorocaval bypass, ilioilial 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 the management of DVT; 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 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]
The top three main causes of iliac vein compression other than MTS are the following.
Other than these any other anatomical condition compressing the iliofemoral vein must be considered in the differential
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.
MTS remains undetectable or clinically silent in the majority of patients. Multiple cadaveric studies on unselected subjects have shown a much higher prevalence compared to 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.
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.
MTS 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.
A few pearls regarding MTS
The diagnosis of MTS or iliofemoral compression syndrome requires a high index of suspicion. All physicians, starting from the team in the emergency department (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, along with support staff (nurses, anesthesiologists, etc.) are needed to provide acute care to such patients. Also, post thrombolysis and stent placement, a dedicated team is required to 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.
The treatment modalities discussed in this article have undergone phase II and phase III trials with level I evidence as described above.
[1] | Harbin MM,Lutsey PL, May-Thurner syndrome: History of understanding and need for defining population prevalence. Journal of thrombosis and haemostasis : JTH. 2019 Dec 10; [PubMed PMID: 31821707] |
[2] | Burke RM,Rayan SS,Kasirajan K,Chaikof EL,Milner R, Unusual case of right-sided May-Thurner syndrome and review of its management. Vascular. 2006 Jan-Feb; [PubMed PMID: 16849024] |
[3] | Abboud G,Midulla M,Lions C,El Ngheoui Z,Gengler L,Martinelli T,Beregi JP, [PubMed PMID: 19629587] |
[4] | MAY R,THURNER J, The cause of the predominantly sinistral occurrence of thrombosis of the pelvic veins. Angiology. 1957 Oct; [PubMed PMID: 13478912] |
[5] | Negus D,Fletcher EW,Cockett FB,Thomas ML, Compression and band formation at the mouth of the left common iliac vein. The British journal of surgery. 1968 May; [PubMed PMID: 5648014] |
[6] | Cockett FB,Thomas ML, The iliac compression syndrome. The British journal of surgery. 1965 Oct; [PubMed PMID: 5828716] |
[7] | Mousa AY,AbuRahma AF, May-Thurner syndrome: update and review. Annals of vascular surgery. 2013 Oct; [PubMed PMID: 23850314] |
[8] | Kaltenmeier CT,Erben Y,Indes J,Lee A,Dardik A,Sarac T,Ochoa Chaar CI, Systematic review of May-Thurner syndrome with emphasis on gender differences. Journal of vascular surgery. Venous and lymphatic disorders. 2018 May; [PubMed PMID: 29290600] |
[9] | Ibrahim W,Al Safran Z,Hasan H,Zeid WA, Endovascular management of may-thurner syndrome. Annals of vascular diseases. 2012; [PubMed PMID: 23555515] |
[10] | Brinegar KN,Sheth RA,Khademhosseini A,Bautista J,Oklu R, Iliac vein compression syndrome: Clinical, imaging and pathologic findings. World journal of radiology. 2015 Nov 28; [PubMed PMID: 26644823] |
[11] | Knuttinen MG,Naidu S,Oklu R,Kriegshauser S,Eversman W,Rotellini L,Thorpe PE, May-Thurner: diagnosis and endovascular management. Cardiovascular diagnosis and therapy. 2017 Dec; [PubMed PMID: 29399519] |
[12] | Metzger PB,Rossi FH,Kambara AM,Izukawa NM,Saleh MH,Pinto IM,Amorim JE,Thorpe PE, Criteria for detecting significant chronic iliac venous obstructions with duplex ultrasound. Journal of vascular surgery. Venous and lymphatic disorders. 2016 Jan; [PubMed PMID: 26946891] |
[13] | Wu WL,Tzeng WS,Wu RH,Tsai WL,Chen MC,Lin PC,Tsai IC, Comprehensive MDCT evaluation of patients with suspected May-Thurner syndrome. AJR. American journal of roentgenology. 2012 Nov; [PubMed PMID: 23096209] |
[14] | McDermott S,Oliveira G,Ergül E,Brazeau N,Wicky S,Oklu R, May-Thurner syndrome: can it be diagnosed by a single MR venography study? Diagnostic and interventional radiology (Ankara, Turkey). 2013 Jan-Feb; [PubMed PMID: 22801870] |
[15] | Forauer AR,Gemmete JJ,Dasika NL,Cho KJ,Williams DM, Intravascular ultrasound in the diagnosis and treatment of iliac vein compression (May-Thurner) syndrome. Journal of vascular and interventional radiology : JVIR. 2002 May; [PubMed PMID: 11997362] |
[16] | Berger A,Jaffe JW,York TN, Iliac compression syndrome treated with stent placement. Journal of vascular surgery. 1995 Mar; [PubMed PMID: 7877235] |
[17] | Park JY,Ahn JH,Jeon YS,Cho SG,Kim JY,Hong KC, Iliac vein stenting as a durable option for residual stenosis after catheter-directed thrombolysis and angioplasty of iliofemoral deep vein thrombosis secondary to May-Thurner syndrome. Phlebology. 2014 Aug; [PubMed PMID: 23761876] |
[18] | Nazarian GK,Bjarnason H,Dietz CA Jr,Bernadas CA,Hunter DW, Iliofemoral venous stenoses: effectiveness of treatment with metallic endovascular stents. Radiology. 1996 Jul; [PubMed PMID: 8657909] |
[19] | Vedantham S,Millward SF,Cardella JF,Hofmann LV,Razavi MK,Grassi CJ,Sacks D,Kinney TB, Society of Interventional Radiology position statement: treatment of acute iliofemoral deep vein thrombosis with use of adjunctive catheter-directed intrathrombus thrombolysis. Journal of vascular and interventional radiology : JVIR. 2006 Apr; [PubMed PMID: 16614142] |
[20] | Neglén P,Hollis KC,Olivier J,Raju S, Stenting of the venous outflow in chronic venous disease: long-term stent-related outcome, clinical, and hemodynamic result. Journal of vascular surgery. 2007 Nov; [PubMed PMID: 17980284] |
[21] | Hartung O,Benmiloud F,Barthelemy P,Dubuc M,Boufi M,Alimi YS, Late results of surgical venous thrombectomy with iliocaval stenting. Journal of vascular surgery. 2008 Feb; [PubMed PMID: 18241761] |
[22] | Meissner MH,Gloviczki P,Comerota AJ,Dalsing MC,Eklof BG,Gillespie DL,Lohr JM,McLafferty RB,Murad MH,Padberg F,Pappas P,Raffetto JD,Wakefield TW, Early thrombus removal strategies for acute deep venous thrombosis: clinical practice guidelines of the Society for Vascular Surgery and the American Venous Forum. Journal of vascular surgery. 2012 May; [PubMed PMID: 22469503] |
[23] | Koitabashi N,Niwamae N,Taguchi T,Ohyama Y,Takama N,Kurabayashi M, Remarkable regression of massive deep vein thrombosis in response to intensive oral rivaroxaban treatment. Thrombosis journal. 2015; [PubMed PMID: 25788868] |
[24] | Nakashima N,Sueta D,Kanemaru Y,Takashio S,Yamamoto E,Hanatani S,Kanazawa H,Izumiya Y,Kojima S,Kaikita K,Hokimoto S,Tsujita K, Successful treatment of deep vein thrombosis caused by iliac vein compression syndrome with a single-dose direct oral anti-coagulant. Thrombosis journal. 2017; [PubMed PMID: 28163657] |
[25] | Kang JM,Park KH,Ahn S,Cho S,Han A,Lee T,Jung IM,Kim JY,Min SK, Rivaroxaban after Thrombolysis in Acute Iliofemoral Venous Thrombosis: A Randomized, Open-labeled, Multicenter Trial. Scientific reports. 2019 Dec 30; [PubMed PMID: 31889152] |
[26] | Sebastian T,Hakki LO,Spirk D,Baumann FA,Périard D,Banyai M,Spescha RS,Kucher N,Engelberger RP, Rivaroxaban or vitamin-K antagonists following early endovascular thrombus removal and stent placement for acute iliofemoral deep vein thrombosis. Thrombosis research. 2018 Dec; [PubMed PMID: 30391776] |
[27] | Enden T,Haig Y,Kløw NE,Slagsvold CE,Sandvik L,Ghanima W,Hafsahl G,Holme PA,Holmen LO,Njaastad AM,Sandbæk G,Sandset PM, 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 (London, England). 2012 Jan 7; [PubMed PMID: 22172244] |
[28] | Comerota AJ,Kearon C,Gu CS,Julian JA,Goldhaber SZ,Kahn SR,Jaff MR,Razavi MK,Kindzelski AL,Bashir R,Patel P,Sharafuddin M,Sichlau MJ,Saad WE,Assi Z,Hofmann LV,Kennedy M,Vedantham S, Endovascular Thrombus Removal for Acute Iliofemoral Deep Vein Thrombosis. Circulation. 2019 Feb 26; [PubMed PMID: 30586751] |
[29] | Comerota AJ,Grewal N,Martinez JT,Chen JT,Disalle R,Andrews L,Sepanski D,Assi Z, Postthrombotic morbidity correlates with residual thrombus following catheter-directed thrombolysis for iliofemoral deep vein thrombosis. Journal of vascular surgery. 2012 Mar; [PubMed PMID: 22277690] |
[30] | Prandoni P,Villalta S,Bagatella P,Rossi L,Marchiori A,Piccioli A,Bernardi E,Girolami B,Simioni P,Girolami A, The clinical course of deep-vein thrombosis. Prospective long-term follow-up of 528 symptomatic patients. Haematologica. 1997 Jul-Aug; [PubMed PMID: 9299855] |
[31] | Casey ET,Murad MH,Zumaeta-Garcia M,Elamin MB,Shi Q,Erwin PJ,Montori VM,Gloviczki P,Meissner M, Treatment of acute iliofemoral deep vein thrombosis. Journal of vascular surgery. 2012 May; [PubMed PMID: 22440631] |