Upper extremity deep vein thrombosis (UEDVT) accounts for approximately 5 to 10 percent of all cases of DVT with incidence increasing due to higher frequency of intravenous catheter use.¹ Veins considered to be "deep" classically have a corresponding named artery. In the upper extremity the deep veins include the paired radial veins, paired ulnar veins, paired brachial veins, axillary vein, and subclavian vein. The most common site of UEDVT involves the axillary and subclavian veins; however, the more distal brachial vein may also be involved. Additionally, many also consider the internal jugular veins to be included in the deep veins given their proximity to the central venous system. UEDVT can occur in primary and secondary forms with the symptom severity and treatment options varying between the two types.

Primary UEDVT is less common than secondary UEDVT and most typically is effort-induced, known as Paget-Schroetter syndrome (PSS).² PSS is a venous form of thoracic outlet syndrome (vTOS) which classically occurs in the dominant arm of young athletes. The pathophysiology involves compression of the neurovascular bundle exiting the thoracic outlet. Compression is caused by repetitive motion of the upper extremity which, in the setting of anatomic abnormalities, such as hypertrophied scalene muscles, congenital presence of cervical ribs, and subclavius ligaments, place these individuals at a higher risk of UEDVT. The subclavian vein is most commonly involved due to its anatomical location adjacent to the first rib which often causes compression. Repetitive motion also results in venous microtrauma and subsequent perivenous fibrosis which leads to activation of the coagulation cascade. In chronic cases, venous webs can form.

Secondary UEDVT occurs due to thrombosis as a result of indwelling devices such as a central venous catheters (CVC), pacemaker or defibrillator leads, and tunneled central access lines. Catheter-associated UEDVT is the most common etiology comprising 93% of all UEDVT in one retrospective analysis of 373 patients with the presence of a CVC increasing the risk of developing UEDVT by up to 14-fold.^3-4 The incidence of catheter-associated UEDVT appears to be increasing, likely a result of increased awareness and detection, with overall rates of 14-18% in those with a CVC; however, numbers have been as high as 23% in those undergoing routine screening after pacemaker lead implantation.^5-6 Intravenous catheters cause endothelial trauma triggering a pro-inflammatory and pro-thrombotic response resulting in clot formation. Additionally, the synthetic material used to construct many central venous catheters may induce fibrin sheath formation along the outer lumen of the catheter which can occur within as early as 24 hours of insertion.⁷ Other factors including inherited or acquired thrombophilia and malignancy further increase the risk of developing UEDVT in the setting of intravascular devices.⁸

The severity of symptoms in UEDVT parallels the degree of venous obstruction. Common symptoms include unilateral upper extremity pain, swelling, and arm fatigue. If the more proximal superior vena cava (SVC) is involved, facial plethora and chest wall edema may be noted. Prominent superficial collateral veins may appear on the shoulder and anterior chest wall, known as Urschel's sign. With increasing venous outflow obstruction, arterial compromise can occur leading to limb threatening phlegmasia cerulea dolens.

The diagnosis of UEDVT is made by correlating individual history and typical clinical findings with appropriate radiographic imaging. The most commonly use imaging modality in the diagnosis of UEDVT is venous duplex ultrasonography. Duplex ultrasound typically shows loss of compressibility of the vein and lack of color Doppler flow within the venous lumen. Spectral analysis may show reduced or absent respiratory phasicity suggestive of proximal obstruction. Although direct visualization of the proximal subclavian vein can be difficult due to shadowing from the clavicle, duplex ultrasonography has a sensitivity and specificity approaching 100%.⁹ Computed tomography (CT) and magnetic resonance imaging (MRI) can be helpful if Duplex ultrasonography is indeterminate, however must be protocoled specifically to image the venous phase. Additionally, CT or MRI may be useful in imaging anatomy to assess the proximal extent of DVT, and to assess for the possibility of compression of vascular structures.

There are several clinically relevant complications resulting from UEDVT. Compared to lower extremity DVT, UEDVT has a lower risk of embolism to the pulmonary vasculature. Clinically apparent pulmonary embolism (PE) occurs in 5-8% of patients of UEDVT with a mortality of 0.7%.^1,10 Subclinical PE is far more common being seen in upwards of 36% of patients.¹¹ The post-thrombotic syndrome which combines debilitating upper extremity pain and swelling has been seen in up to 13% of patients.¹² In those with central venous catheters, UEDVT may result in the inability to draw from or infuse into the catheter as well as an important long term complication of loss of venous accessibility which may have implications for treatment options.

The management of UEDVT depends largely on the etiology; however, in the absence of a contraindication, the cornerstone of treatment is anticoagulation. Treatment should be aimed at obtaining early venous recanalization and attempts to restore vein patency. In primary UEDVT, prompt anticoagulation should be initiated with consideration for more advanced therapeutics including catheter directed thrombolytics (CDT). A retrospective study of 30 patients with UEDVT, 97% of patient treated with CDT showed at least 50% reduction in clot burden at the risk of 9% major bleeding.¹³ Anticoagulation should be continued for at least 3 months with either low molecular weight heparin (LMWH), vitamin K antagonists, or direct oral anticoagulants (DOACs). LMWH is the preferred method of anticoagulation in malignancy associated UEDVT with therapy continuing beyond 3 months until cure or remission is achieved. Subsequent rheolytic or mechanical thrombectomy is often utilized to improve venous outflow. The most recent updates to the American College of Chest Physicians (ACCP) guidelines recommend anticoagulant therapy alone over thrombolysis. However, thrombolysis can be considered in patients in whom there are severe symptoms, extent of thrombus from subclavian to axillary vein, symptoms <14 days, good performance status, life expectancy >1 year, and low risk for bleeding.¹⁴ Angioplasty with stent placement at the costoclavicular junction is not advised prior to surgical decompression due to high rates of stent fraction and reocclusion.¹⁵ Cases of vTOS with anatomic compression should be referred to high volume centers specializing in thoracic outlet decompression. Surgical decompression involves resection of the first rib and costoclavicular ligament, anterior scalenectomy, and venolysis. The timing of surgical decompression is controversial; most advocate for surgical evaluation within 3 months of CDT, with some proponents recommending evaluation and treatment during first hospitalization.

In cases of catheter-associated UEDVT, recommendations from the ACCP are to remove the offending catheter only if the catheter is no longer needed or no longer working. Overlap of therapeutic anticoagulation prior to removal of a catheter associated with thrombosis has not been validated in the literature, although is often advocated. This should be followed by a minimum of 3 months of anticoagulation. If the CVC is not removed, anticoagulation should continue as long as the CVC remains in place and continue for 3 months after its removal.¹⁴ CDT can be considered for those in whom there are severe symptoms and require the continued use of the CVC.

The use of superior vena cava filters should only be considered in rare cases in those patients with contraindications for anticoagulant and pulmonary embolism. Given the substantially lower risk of clinically significant pulmonary embolism, as discussed above, the potential benefit must outweigh the significant risks of filter placement, including filter dislocation and development of the superior vena cava syndrome due to thrombus occlusion of the filter. In a review of the literature including 21 publications including 209 cases, there was 2% risk of pericardial tamponade and 1% risk of aortic perforation after the placement of a superior vena cava filter.¹⁰

In conclusion, the incidence of UEDVT appears to be increasing with greater awareness and use of central venous catheters with subclinical DVT likely more common than previously understood. Symptoms can vary widely from complete lack of symptoms to limb threatening phlegmasia cerulea dolens. Clinical suspicion should arise in those with the development of unilateral edema or pain, particularly in young athletes, or those with central venous catheters. In the absence of contraindications, anticoagulation should be initiated with consideration for catheter-directed thrombolysis in those with severe symptoms or those with venous thoracic outlet syndrome prior to evaluation for surgical decompression. Catheter-associated UEDVT does not necessitate removal of the central venous catheter if it continues to function properly and it is still needed. Anticoagulation should be initiated for as long as the catheter is in place and continued for 3 months after removal. Superior vena cava filters have little application in the therapy for UEDVT with the risk outweighing the benefit in the majority of cases.

References

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3. Lee JA, Zierler BK, Zierler RE. The risk factors and clinical outcomes of upper extremity deep vein thrombosis. Vasc Endovascular Surg 2012;46:139-44.
4. Winters JP, Callas PW, Cushman M, Repp AB, Zakai NA. Central venous catheters and upper extremity deep vein thrombosis in medical inpatients: the Medical Inpatients and Thrombosis (MITH) Study. J Thromb Haemost 2015;13:2155-60.
5. Verso M, Agnelli G. Venous thromboembolism associated with long-term use of central venous catheters in cancer patients. J Clin Oncol 2003;21:3665-75.
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7. Baskin JL, Pui CH, Reiss U, et al. Management of occlusion and thrombosis associated with long-term indwelling central venous catheters. Lancet 2009;374:159-69.
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10. Owens CA, Bui JT, Knuttinen MG, Gaba RC, Carrillo TC. Pulmonary embolism from upper extremity deep vein thrombosis and the role of superior vena cava filters: a review of the literature. J Vasc Interv Radiol 2010;21:779-87.
11. Prandoni P, Polistena P, Bernardi E, et al. Upper-extremity deep vein thrombosis. Risk factors, diagnosis, and complications. Arch Intern Med 1997;157:57-62.
12. Slovut DP, Dean SM, Jaff MR, Schneider PA. Comprehensive Review of Vascular and Endovascular Medicine. Minneapolis, MN: Cardiotext; 2012:291.
13. Vik A, Holme PA, Singh K, et al. Catheter-directed thrombolysis for treatment of deep venous thrombosis in the upper extremities. Cardiovasc Intervent Radiol 2009;32:980-7.
14. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 2016;149:315-52.
15. Lee JT, Karwowski JK, Harris EJ, Haukoos JS, Olcott C. Long-term thrombotic recurrence after nonoperative management of Paget-Schroetter syndrome. J Vasc Surg 2006;43:1236-43.

Keywords: Heparin, Low-Molecular-Weight, Anticoagulants, Axillary Vein, Subclavian Vein, Central Venous Catheters, Superior Vena Cava Syndrome, Vena Cava, Superior, Clavicle, Thoracic Wall, Fibrin, Cardiac Tamponade, Life Expectancy, Athletes, Pulmonary Embolism, Postthrombotic Syndrome, Thoracic Outlet Syndrome, Thrombectomy, Angioplasty, Tomography, X-Ray Computed, Pacemaker, Artificial, Thrombophilia, Lower Extremity, Magnetic Resonance Imaging, Stents, Neoplasms, Defibrillators, Decompression, Surgical, Tomography, Ligaments, Vitamin K

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