Continuing Education Activity

Subclavian vein thrombosis (SCVT) is a condition where a blood clot forms in the subclavian vein. SCVT can occur from multiple etiologies and is a potentially life-threatening pathology if not treated promptly. SCVT occurs due to either a primary etiology or a secondary etiology. Primary thrombosis is further delineated as effort-induced (Paget-Schroetter syndrome) or idiopathic (frequently associated with undiagnosed malignancy). Secondary subclavian vein thrombosis is associated with catheters or lines in the vein. While primary thrombosis is rare, the incidence of secondary thrombosis continues to rise due to complex cardiac devices and long-term central venous catheter (CVC) placement in cancer patients. This activity outlines the evaluation and management of subclavian vein thrombosis and highlights the role of an interprofessional team in the care of patients with this condition.

Objectives:

• Identify the etiology and epidemiology of subclavian vein thrombosis.
• Describe the appropriate history, physical, and evaluation of subclavian vein thrombosis.
• Outline the treatment and management options available for subclavian vein thrombosis.
• Summarize interprofessional team strategies for improving care coordination and communication to advance the treatment of subclavian vein thrombosis and improve outcomes.

Introduction

Subclavian vein thrombosis (SCVT) is a condition where a blood clot forms in the subclavian vein. SCVT can occur from multiple etiologies and is a potentially life-threatening pathology if not treated promptly. SCVT occurs due to either a primary etiology or a secondary etiology. Primary thrombosis is further delineated as effort-induced (Paget-Schroetter syndrome) or idiopathic (frequently associated with undiagnosed malignancy). Secondary subclavian vein thrombosis is associated with catheters or lines in the vein. While primary thrombosis is rare, the incidence of secondary thrombosis continues to rise due to complex cardiac devices and long-term central venous catheter (CVC) placement in cancer patients.[1] SCVT has high rates of acute mortality and long-term disability without proper and timely treatment. Early diagnosis and treatment are essential in preventing fatal acute complications, such as pulmonary embolism and long-term morbidity related to venous inflow restriction.

The most widely recognized etiology for subclavian artery thrombosis is atherosclerosis; other uncommon etiologies are congenital deformities, fibro-muscular dysplasia, neurofibromatosis, autoimmune vasculitis-like Takayasu, radiation exposure, neurofibromatosis, and mechanical causes including injury or compression disorders.[2]

The UEDVT is classified into two major primary and secondary categories. The secondary UEDVT is more common. Among the primary UEDVT subtypes, effort-related thrombosis or Paget-Schroetter syndrome is the most common. Typically, it is reported in otherwise healthy male patients with a history of vigorous upper extremity exercises, including but not limited to weight lifting and pitching a baseball. Moreover, repetitive physical activities, including painting, were associated with UEDVTs. The latter association was more common in venous thoracic outlet syndrome (VTOS). VTOS or effort thrombosis results in the subclavian vein compression in the following anatomic borders; 1. the intersection of the clavicle and first rib with the subclavian muscle and the costoclavicular ligament anteromedially and 2. the anterior scalene muscle posterolateral.[3]

The idiopathic UEDVT, as implied by its nomenclature, lacks an apparent underlying risk factor. Moreover, the abnormal results in thrombophilia measures in patients with idiopathic UEDVT are less often predicted compared to the lower extremity deep vein thrombosis (LEDVTs). It should be noted that positive thrombophilia test results in patients with UEDVTs are more predicted in idiopathic patients than in patients with effort-related or catheter-associated UEDVT.[4]

Catheter-associated-DVT accounts for the majority of secondary UEDVTs. Secondary UEDVTs are mostly related to indwelling catheters, either central venous catheters, chemo ports, pacemakers, or defibrillators.

Specific cancer types, including ovarian and lung adenocarcinoma, and higher cancer stages, specifically metastatic ones, increase the risk of cancer-associated thrombosis in indwelling catheters. The significance of cancer-related thromboembolism in patients primarily diagnosed as idiopathic UEDVT is the potential for subsequent cancer diagnosis. Accordingly, in up to 25% of those initially diagnosed as idiopathic UEDVT, further cancer diagnosis with mainly lung adenocarcinoma and lymphoma is predicted.[5][6]

Etiology

Causes of Primary SCVT

• Effort-induced thrombosis (Paget von Schroetter syndrome)[7][8]
• Idiopathic (frequently associated with undiagnosed malignancy)

Causes of Secondary SCVT

• Mechanical trauma
  • Chronic CVC placement
  • Pacemaker leads
  • Clavicle fracture
  • Hemodialysis catheters
• Long term feeds
• Prone position in surgery
• Antithrombin III deficiency
• Factor V Leiden mutation
• Protein C deficiency
• Protein S deficiency
• Surgery
• Superior vena cava syndrome
• underlying malignancies with the following mechanisms; a. cancer-associated thrombosis, b. venous compression, and c. tumoral infiltration[5]
• Ovarian hyperstimulation syndrome
• Lung cancer malignancy (rare) - more common with Pancoast tumor[1][9][10][11][12][13][14][15]
• Catheter-related risk factors include:
  1. Subclavian venipuncture
  2. Technically difficult or left-sided catheter placement
  3. Location of the catheter tip away from the right atrium and caval junction
  4. Prior central venous catheterization
  5. Catheters with larger lumens
  6. Peripherally-inserted central catheters compare to the chemo ports
  7. Underlying conditions, including chest radiation therapy, bolus chemotherapy, and total parenteral nutrition

Epidemiology

The incidence of upper extremity deep vein thrombosis has been reported as high as ten percent of all cases of deep venous thrombosis and 28% of catheter-related thrombosis.[12] However, effort-induced primary thrombosis is rare, occurring in 2 patients per 100,000 per year. Generally, effort-induced primary thrombosis occurs in young, healthy, and athletic patients. The male: female ratio is approximately 2:1.[8] 

While idiopathic thrombosis is associated with inherited thrombophilia, the precise incidence is unknown due to a lack of data. Interestingly, 25% to 30% of patients with unexplained upper extremity thrombosis will have an underlying malignancy. On the other hand, UEDVT was reported in up to two-thirds of cancer patients with central venous catheters.[16] There have been contradictory studies regarding if oral contraceptives can increase the risk for SCVT.[16][17][18]

The incidence of secondary subclavian thrombosis increases with advanced cardiac devices and chronic central venous catheters. Catheter-associated thrombosis is the cause of 93% of upper extremity thrombosis. The incidence is higher with peripherally inserted catheters as compared to centrally inserted. The inappropriate position of the catheter tip can also contribute to increased thrombotic events.[4][19][20]

Pathophysiology

Primary Thrombosis Etiology (Paget–von Schrötter syndrome)

Primary thrombosis is usually seen in healthy, young individuals. It is also referred to as spontaneous axillary subclavian vein thrombosis (ASVT) due to its unexpected presentation. Recent studies have shown that the syndrome can affect all ages. In the past, the syndrome was known as effort-induced thrombosis. Effort-induced thrombosis was used to describe the disease as unexpected thrombosis occurring after strenuous or repetitive use of the upper extremity on the affected side.[21]

The pathophysiology of the disease is attributed to many factors. First, it is important to understand the anatomy of the structures of the thoracic outlet and the venous system. The clavicle is superior to the thoracic border of the subclavian vein, and the first rib is inferior to the subclavian vein. The anterior scalene muscle is located laterally to the vein and the medial costoclavicular ligament. The subclavian vein passes through the thoracic outlet before reaching the internal jugular vein. Changes in slight anatomy can cause compression of the vein. When the arm abducts, the subclavian vein is compressed between the clavicle and the first rib. This results in the perfect setup for Virchow’s triad- endothelial cell damage, inflammation, scarring, hypercoagulability, and blood stasis.[7][8]

The costoclavicular ligament is more commonly seen inserted laterally in patients with thrombosis resulting in subclavian vein compression. Repetitive movements in the area that includes the subclavius and anterior scalene muscles also contribute to venous compression and injury. Other anatomical changes that can increase the risk of thrombosis are the abnormal insertion of the first rib, congenital fiber-muscular bands, or narrowing of the costoclavicular space. In addition, any hematologic pathologies that coexist can contribute to thromboses, such as factor V Leiden mutation, protein C deficiency, or anti-thrombin III. Idiopathic primary thrombosis is frequently linked to an occult malignancy or coagulation abnormality.[12][16]

Catheter-induced Subclavian Vein Thrombosis

Placing pacemakers and central catheters will alter the venous blood flow and create turbulence in the vein. This will start the cascade of platelet aggregation, the release of procoagulants, and, ultimately, fibrin deposition. A thrombus forms that will reduce the size of the vein, ultimately leading to total vessel occlusion. In patients with risk factors for thrombus, such as cancer, immobility, and hemophilic disorders, this will be an additional contributing factor.[4][19]

History and Physical

Patients with SCVT will present with complaints of upper extremity or neck discomfort or pain. They may describe it as a "feeling of vague fullness" and possible swelling in the affected upper extremity. Patients with primary effort-induced SCVT can present as typically healthy, teenage to 40 years old, males more often than females. History may reveal recent strenuous or repetitive extremity movements, whereas idiopathic SCVT has no strenuous activity history. A patient's complaints and findings in secondary SCVT are similar, but a catheter or device lead or history of trauma will be present. The loss of function of the catheter is also frequently noted.[12][20][22][23]

Physical findings will reveal supraclavicular fullness, a palpable mass, changes in extremity color, and Urschel's sign (dilation of the collateral veins in the anterior chest wall). The severity of symptoms depends on the degree of venous obstruction. Early in the disease process, patients will complain of mild discomfort. As the process evolves, more prominent signs and symptoms will appear.[24][25][26][27]

Evaluation

An active, healthy individual who presents with a new onset of upper extremity swelling should be considered for SCVT.[1] Ultrasound is the preferred diagnostic tool, with a specificity of 96% and a sensitivity of 97%. The diagnosis can be made with computed tomography, magnetic resonance imaging (MRI), and direct venography when the diagnosis is uncertain, but there are disadvantages. Disadvantages of these other diagnostic modalities include expense, radiation exposure, use of intravenous contrast, and delay in diagnosis. Workup for hypercoagulable states should be reserved for patients with idiopathic primary SCVT.[28][29][30][31]

Treatment / Management

The primary treatment for SCVT is anticoagulation. Within the first 14 days of primary SCVT, pharmacologic or mechanical thrombolysis yield excellent results. Anticoagulation with low molecular weight heparin (LMWH), warfarin, or direct oral anticoagulants (DOAC) for 3-6 months is recommended. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines recommends LMWH or fondaparinux to manage UEDVT, which should be continued for at least five days, followed by vitamin K antagonists. The latter should be continued for at least three months.[32] Patients with effort-induced SCVT and recurring symptoms will likely benefit from surgery by surgical decompression of the thoracic outlet or resection of the first rib and associated muscles and ligaments, depending on the anatomy. Angioplasty and vessel stenting can also manage thrombosis, but it is more invasive and typically reserved for recurrent events.[33][34]

In managing cancer-associated thromboembolism and upper extremity involvement, extended LMWH monotherapy, compared to vitamin K antagonists, is preferred.[32]

Compression therapy with either sleeves or bandages is not recommended during acute UEDVT. However, it might be considered in the management of PTS.[32]

Idiopathic primary SCVT without evidence of malignancy is treated with anticoagulation for 3 to 6 months. SCVT associated with malignancy is treated with LMWH until the malignancy is cured or in remission.

Management of catheter-related SCVT varies. If the catheter can be removed, and there is a low risk of embolization and no prothrombotic risk, the catheter should be removed.[1][26] Then there is no need for anticoagulation therapy. Anticoagulant therapy should be initiated if there is a high risk of embolization. Once the long-term catheter is complete, the catheter must be removed, and anticoagulant treatment must continue for at least six weeks after removal.[30][33] If thrombosis occurs, the catheter is required for therapy and is still functional. Anticoagulation should be initiated immediately and continued for at least three months after removing the chronic catheter.[34][35] There is no consensus on the benefits of the use of compression sleeves.[36][37][38]

Catheter-assisted therapy in managing patients with UEDVT is recommended for those with the following eligibility criteria; 1. recent onset, 2. presence of severe symptoms, 3. low risk for bleeding complications, and 4. good functional status.[3]

Differential Diagnosis

Differential diagnoses of subclavian vein thrombosis include:

• Superior vena cava syndrome
• Lymphatic obstruction
• Cellulitis
• Thoracic outlet obstruction
• Pancoast tumor
• Necrotizing fasciitis
• Superficial thrombophlebitis

Treatment Planning

A sequential approach integrating risk stratification and biomarkers could be a valuable strategy when managing upper extremity thrombosis. Based on the model employed for lower extremity DVT, the Diagnostic Algorithm in suspected upper extremity Deep Vein Thrombosis (ARMOUR) study explored an algorithm that commenced with risk stratification using the Constans rule, followed by D-dimer testing and compression ultrasonography to more accurately rule in or rule out patients with upper extremity DVT. The evaluation of the Constans rule in a cohort of 406 patients with varying risks of upper extremity thrombosis demonstrated good performance in identifying individuals at low risk of events. This approach enabled around 20% of the cohort to avoid ultrasound imaging. However, in a different study including a high-risk patient population such as elderly patients over 75, hospitalized patients, those with malignancy, or those with upper extremity catheters/devices, the algorithm did not perform as well in differentiating a subset of patients where imaging could be withheld. Therefore, this strategy may be more advantageous for patients with low risk for venous thromboembolism.

Prognosis

Prognosis varies based on risk factors for thrombosis and the percentage of vein occlusion. If untreated, residual venous obstruction in patients with Paget-Schroetter is present in 78%, with persistent symptoms. Disability occurs due to thrombosis in 41% to 91% of cases. If treated appropriately with conservative measures or surgical intervention, the prognosis of effort-induced SCVT is excellent.[39]

The prognosis of idiopathic SCVT depends on the presence or absence of malignancy or thrombophilia. Cancer patients with SCVT have rates of complication as high as 50%. Complications of pulmonary embolism are about 9.2%, superior vena cava syndrome is 14.9%, and post-thrombotic syndrome is 26.4%. The risk of thromboembolism following idiopathic UEDVT is lower than the secondary type.[40] The 12-month mortality associated with SCVT and malignancy is reported as high as 40% secondary to the underlying disease (malignancy, multi-system disease) rather than direct complications of SCVT.[39]

Complications

• Pulmonary embolism
• Post-thrombotic syndrome secondary to venous outflow obstruction and valvar insufficiency
• Range from mild edema to incapacitating venous stasis leading to ulcer or gangrene
• Septic thrombophlebitis
• Embolism
• Superior vena cava
• Loss of access due to occlusion[41]

Deterrence and Patient Education

There is no consensus regarding prophylactic anticoagulation. More recent studies have shown little benefit for prophylactic treatment; however, using low molecular weight heparin in selected groups of patients may be worthwhile. Misplacement of the catheter tip in the superior vena cava should be identified and corrected. Left-sided catheter insertion should be avoided if possible. Patients should be educated on risk factors that may increase the risk of thromboses, such as smoking, pregnancy, and obesity, to name a few.[42][43]

Pearls and Other Issues

If SCVT is diagnosed, anticoagulation must be started immediately. Doppler ultrasound is the first choice of diagnostic modality. If a patient has cancer, the patient must be treated with anticoagulation while being treated for active cancer. If the physical exam suggests a thrombus in a patient with risk factors and the patient is complaining of chest pain, the patient should be started on anticoagulation immediately if the testing modality is delayed due to the risk of pulmonary embolism. If chronic catheters are required, and SCVT is diagnosed, then anticoagulation must be continued for at least 3 to 6 months with close follow-up depending on the individual underlying risk factors.

Enhancing Healthcare Team Outcomes

If SCVT is suspected, it must be treated promptly to prevent dire consequences, such as pulmonary embolism or complete occlusion of the vessel. This is based on a good and detailed history and physical exam that can lead to decreased mortality.

A strong interprofessional healthcare team should manage SCVT, including primary and emergency department clinicians, hematology, oncology, interventional radiology, and vascular surgery. These clinicians must operate cohesively from their disciplines to ensure proper measures are enacted to guide the patient's case; none of these practitioners should operate "in a silo." Nurses and pharmacists should also be part of the team, particularly where anticoagulation is concerned. Nurses can answer patient questions, administer medication, and serve as the liaison point for the various clinicians on the case. Pharmacists will verify the appropriateness of dosing, recommend particular anticoagulants based on the patient's profile, monitor for adverse events, answer patient questions about their drug regimen, and perform medication reconciliation. Collaboration, coordination, and open communication within the interprofessional team in the care of these patients will lead to better outcomes. [Level 5]