John F Eidt, MD
Joseph L Mills, Sr, MD
Kathryn A Collins, MD, PhD, FACS
INTRODUCTION — Spontaneous thrombosis of the veins draining the upper extremity was postulated by Sir James Paget in 1875 as a cause of acute pain and swelling of the arm [1,2], but Von Schroetter, in 1884, was the first to relate the clinical syndrome to thrombotic occlusion of the axillary and subclavian veins . Spontaneous thrombosis of upper extremity veins, subsequently termed the Paget-Schroetter syndrome, is relatively rare . However, the inclusive category of axillosubclavian vein thrombosis (ASVT) from all causes is more common than previously appreciated, probably due to the increasing use of indwelling subclavian vein catheters for venous access in patients with cancer and other chronic medical problems. In two series, upper extremity venous thrombosis accounted for 4 to 11 percent of all cases of venous thromboembolism [5,6].
The Paget-Schroetter syndrome and catheter-induced ASVT will be considered separately, because they affect significantly different patient populations, appear to have different clinical outcomes, and have widely differing goals of therapy . The Paget-Schroetter syndrome will be reviewed here; catheter-induced ASVT is discussed elsewhere. (See “Catheter-induced upper extremity venous thrombosis”.)
ETIOLOGY — Paget-Schroetter syndrome is also referred to as “spontaneous” ASVT, highlighting its often dramatic, unexpected presentation in otherwise healthy young individuals. In the 1960s the term “effort” thrombosis was coined , acknowledging an initial impression that the syndrome often occurred in physically active individuals after unusually strenuous use of the arm and shoulder [9,10].
Anatomic predisposition — It has become evident over the course of subsequent investigations that there is usually an underlying compressive anomaly at the thoracic outlet in patients who develop spontaneous ASVT [11,12]. This is frequently due to compression of the vein either between the first rib and a hypertrophied scalene or subclavius tendon or between these tendons themselves (figure 1). Compression between the clavicle and a cervical rib as well as partial occlusion of the vein by a congenital web have also been reported [13,14]. (See “Brachial plexus syndromes”, section on ‘Thoracic outlet syndrome’.)
The abnormalities of the thoracic outlet are often bilateral and predispose to eventual thrombosis of both venous systems [11,15,16]. In addition, chronic compression of the vein can cause perivenous fibrosis, which may result in partial venous obstruction despite surgical correction of the compressing lesion .
Hypercoagulable state — In addition to anatomic abnormalities, a hypercoagulable state may contribute to ASVT . This issue was addressed in a report comparing 35 patients with spontaneous ASVT to 121 patients with spontaneous lower extremity deep vein thrombosis . The overall prevalence of a hypercoagulable state (including hyperhomocysteinemia) in the patients with upper extremity disease was similar to controls (15 versus 12 percent), but much lower than in patients with lower extremity thrombosis (56 percent).
Some studies suggested higher rates of thrombophilia in patients with recurrent ASVT [18-20]; however, compressive injury of the subclavian vein appears to be the most critical factor in the development of the condition. The presence of an underlying prothrombotic state may have prognostic implications. In one study, 90 percent of postoperative complications were associated with some form of thrombophilia . (See “Evaluation of the patient with established venous thrombosis”, section on ‘Screening for inherited thrombophilia’.)
CLINICAL PRESENTATION — The majority of patients present with unilateral dull, aching pain in the shoulder or axilla and swelling of the arm and hand. These symptoms tend to worsen with vigorous use of the arm and improve with rest and elevation. Local trauma or, more frequently, strenuous use of the arm can be recalled by approximately one-half of patients, and symptoms generally are noted within 24 hours of the unusually strenuous activity.
Physical examination generally shows a mild to moderate amount of unilateral nonpitting edema. Mild cyanosis of the hand and fingers and dilation of subcutaneous collateral veins over the upper arm and chest, which can be dramatic, are occasionally noted.
DIAGNOSTIC EVALUATION — The goal of the diagnostic evaluation is to determine objectively whether thrombosis of the subclavian vein is present. The importance of documenting a suspected thrombosis of the upper extremity was illustrated by a report in which only 27 of 58 patients with suspected upper extremity deep vein thrombosis had a positive venogram .
Venography — Traditionally, arm vein venography has been used to diagnose abnormalities of the subclavian vein . While this provides the best definition of abnormal venous anatomy, it requires cannulation of a peripheral vein of the arm. In some patients, the amount of edema makes this difficult. In these individuals, digital subtraction techniques can allow venography with a smaller amount of contrast material that is easier to infuse into smaller veins .
Noninvasive studies — Noninvasive studies have received significant attention in the diagnosis of both spontaneous and catheter-induced ASVT. While these techniques are helpful in making the diagnosis, they often do not provide adequate data for planning surgical intervention. However, their noninvasive nature makes them suitable for screening purposes (remembering their limitations in sensitivity and, to a lesser extent, specificity) and for making the diagnosis in patients in whom surgical intervention is not contemplated.
- Real-time B-mode ultrasound, duplex ultrasound, and color Doppler ultrasound imaging have been used most extensively, with noncompressibility of the vein being the criterion for the diagnosis of thrombosis [21,24-28]. Color Doppler can diagnose upper extremity thrombosis with a sensitivity of 70 to 100 percent and a specificity of 93 percent [21,28,29].
The types of subclavian vein thrombi not routinely visualized by ultrasound are usually nonocclusive mural thrombi or those located in the proximal subclavian or innominate veins, which are generally shadowed by the clavicle and sternum [27,30]. These types of thrombi are common in catheter-related ASVT, but unusual with the Paget-Schroetter syndrome.
- Magnetic resonance imaging is very specific in its ability to image subclavian vein thrombi, but its sensitivity (80 percent for thrombi that completely occlude the vein, zero percent for partially occlusive thrombi) is too low for this modality to be useful as a screening study . The use of contrast-enhanced magnetic resonance venography (MRV) and three dimensional image reconstruction may improve the sensitivity of this modality, but remains experimental .
- Computed tomography can be used to detect subclavian vein thrombi, but it has not been studied sufficiently to allow determination of its sensitivity and specificity .
In summary, ultrasound examination is the screening tool of choice because of its ease of performance, and noncompressibility of the vein should be the criterion for the diagnosis of thrombosis. The chances of a false positive study are very low when this strategy is used; however, negative images are not always correct, and additional modes of imaging should be used if the clinical suspicion for thrombosis is high .
PROGNOSIS — Embolic complications occur in as many as 36 percent of patients with Paget-Schroetter syndrome . These complications can probably be prevented by standard anticoagulant therapy, although this hypothesis has not been rigorously studied. Since the Paget-Schroetter syndrome generally affects young, otherwise healthy individuals with an active lifestyle and long life expectancy, there is general consensus that the major goal of therapy is to minimize the likelihood of significant symptoms of venous insufficiency. Venous insufficiency can result in occupational disability, especially for those individuals whose livelihood depends on their ability to perform vigorous physical activity. Even in patients whose vocation does not involve vigorous use of the arms, such symptoms can limit avocational activities and adversely impact on quality of life.
Classically, many, if not most, patients with this disorder were thought to have protracted or progressive pain and swelling of the arm caused by the obstruction to venous outflow in the setting of inadequate collateral circulation [11,12,34-39]. The clinical outcome of conservative therapy was evaluated in a series of 54 patients, nearly all of whom were treated with warfarin . Symptomatic progression was unusual. After a mean follow-up of five years, almost one-half of the patients were essentially asymptomatic, 13 percent had severe or disabling symptoms, and 22 percent had severe obstruction to venous flow on ultrasound evaluation. Pulmonary embolism was documented in 26 percent but was symptomatic in only one-third. Among patients treated with thrombolysis (without subsequent surgery), 76 percent were asymptomatic after a mean follow-up of 55 months .
These findings suggest that the long-term risk of venous insufficiency in warfarin-treated patients with Paget-Schroetter syndrome may not be as high as previously thought. However, because the population at risk is generally young, and because symptoms can be debilitating, we recommend the following approach to therapy.
TREATMENT — While there is no one universally accepted way to approach the patient with Paget-Schroetter syndrome, there is general acceptance of the need for some form of therapy to minimize long-term symptoms of venous insufficiency and to protect against pulmonary embolization.
Therapeutic options — Therapy for Paget-Schroetter syndrome can be divided into four basic categories:
- Anticoagulant therapy
- Fibrinolytic therapy
- Surgical therapy
- Combinations of any or all of the above
The best therapeutic approach to a patient with Paget-Schroetter syndrome is not known with certainty, primarily because of the lack of prospective, controlled trials of treatment. Recommendations are made by extrapolating from a host of small, uncontrolled studies or observational series, and the difficulties inherent in this approach have been summarized as follows: “Perhaps the strongest conclusion that can be drawn from this review is that there are no firm data on which clinical decisions can be based” . There is probably a place for each of the above options in the treatment of the full spectrum of patients presenting with subclavian vein thrombosis.
Because symptoms are caused by persistent venous obstruction and inadequate development of collateral flow, various therapeutic modalities have been proposed to remove the thrombus and restore patency of the vessel. These include local (catheter-directed) or systemic fibrinolytic therapy coupled with anticoagulation and/or surgery [11,12,26,38,42].
In what is probably the best report published to date, this combined approach was prospectively applied (to a greater or lesser degree) to 76 patients . Of the 46 patients who had patent veins on long-term follow-up, 87 percent had no or minimal symptoms. While this was better than in patients who either did not receive therapy or reoccluded the vein after treatment, a significant proportion of the patients with reocclusion (64 percent in the author’s preliminary report ) also were asymptomatic. This series seems to validate the hypothesis that eliminating venous obstruction minimizes the likelihood of severe symptoms of venous insufficiency.
However, this study could also be interpreted to show that many patients do well even in the face of persistent venous occlusion (presumably because of the development of adequate collateral circulation). This interpretation is supported by the findings of the 54 patient cohort described above who were treated with only anticoagulant therapy; almost half of the patients became asymptomatic, and only 13 percent had severe or disabling symptoms .
Recommendations — Although strong supporting data are not available for any approach, the following is the one that we generally use:
- We agree with the presumption that the patient will probably do better with a patent than an occluded vein. This philosophy, however, must also consider the patient’s lifestyle requirements, concomitant illnesses, financial resources, and the resources and expertise of the local medical community, especially in the areas of interventional radiology and vascular surgery.
- To achieve long-term venous patency, a patient may need to undergo initial venography, hospitalization for catheter-directed fibrinolytic therapy, several weeks of anticoagulant therapy, and repeat venography [43-45]. This may be followed by surgical correction of underlying venous compression, more anticoagulation, another venogram, balloon dilation of any underlying residual venous stenosis, and more anticoagulation until the vein has recovered from the effects of angioplasty (and perhaps longer if an underlying hypercoagulable state is identified).
- There is no way to determine just how far along this therapeutic road a patient must travel to achieve long-term venous patency, or if the goal is achievable even with a maximal therapeutic approach. Consequently, this approach requires a dedicated patient with adequate financial resources, and patients need to be counseled about the degree of commitment prior to developing a long-term therapeutic plan.
Aggressive approach — In patients for whom the maximal chance of unrestricted use of the arms is of paramount importance, we initially recommend the algorithm listed in the figure (figure 2), consisting of venographic definition of the anatomic extent of the thrombus, followed by catheter-directed fibrinolytic therapy using tissue-type plasminogen activator (tPA). In our experience, even thrombi that have been symptomatic for up to two weeks have a reasonable chance of lysis with catheter-directed infusion of a thrombolytic agent directly into the thrombus.
After lysis of the thrombus, the urge to dilate or stent any residual obstruction should be resisted. Most obstructive lesions are external to the vein and not affected by balloon dilation. Stents placed in the most common area of obstruction — the costoclavicular portion of the subclavian vein — are subjected to repetitive compression and subsequent fracture, especially if placed without resection of the first rib or otherwise removing the external compressive lesion at the level of the thoracic outlet (figure 1) [11,46-48]. Stent use was found to be an independent risk factor for re-thrombosis .
Patients with residual stenosis observed on postthrombolytic venography should be considered for surgical exploration and revision (often including first rib resection). This can reasonably be performed within the subsequent 24 to 48 hours, during which time anticoagulation should be maintained. This recommendation is based upon good outcomes reported in series of over 200 upper limbs treated in this manner [43,44,49]. The contralateral arm should also be studied venographically, and considered for surgical revision if stenoses are present.
Conservative approach — As noted above, not all patients with residual stenoses pursue a uniformly poor course, and a more conservative initial management strategy can be undertaken, especially in patients at high operative risk or those who are reluctant to undergo surgery . Such patients should undergo anticoagulation for another six to eight weeks, after which the patient’s clinical status is reviewed and another venogram is considered.
If residual stenosis is present on repeat venogram, its hemodynamic significance (and, hence, its contribution to the risk of recurrent thrombosis) is estimated by the degree of filling seen in collateral veins (figure 2):
- If no collaterals fill, the stenosis is unlikely to be hemodynamically significant or to pose a significant risk of recurrent thrombosis. Warfarin is tapered, and the patient returns two weeks later for a detailed evaluation of hematologic risk factors for recurrent thrombosis. If none is found, the patient is simply followed clinically for symptoms of recurrence. (See “Evaluation of the patient with established venous thrombosis”, section on ‘Screening for inherited thrombophilia’.)
- If there is significant filling of collateral vessels, the residual stenosis might pose a risk (which is not quantifiable) for recurrent thrombosis. In this case, no firm therapeutic recommendations can be made, although attempts at repeat dilation, long-term anticoagulation, and even no further treatment have been chosen by our patients.
In patients for whom a risk of venous insufficiency is acceptable, making the diagnosis with duplex ultrasound (if possible) followed by anticoagulant therapy for three months is a reasonable option. In such patients, it is probably reasonable to perform contralateral venography (again, while on warfarin) to define anatomic abnormalities that might pose a risk of subsequent thrombosis.
If symptoms of venous insufficiency are found to be unacceptable on follow-up, consideration of first rib resection with or without venous bypass surgery offers a chance at reducing the severity of the symptoms .
SUMMARY — There is no “one size fits all” approach to the treatment of spontaneous upper extremity venous thrombosis. Treatment requires a team of specialists with experience and resources to do all that is warranted in any individual case. Such teams are rare outside tertiary referral centers. The approach to a specific patient should be made by the multidisciplinary team during the patient’s initial hospitalization to insure that all components of therapy are mutually compatible. Early diagnosis and referral to a center with such a team are the cornerstones of management [29,51].
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