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Upper extremity deep venous thrombosis: interventional management
Upper Extremity Deep Venous Thrombosis: Interventional Management Albert A. Nemcek, Jr, MD
Upper extremity deep venous thrombosis, previously thought to be a relatively innocuous disorder in comparison to lower extremity deep venous thrombosis, has recently begun to receive the attention it merits. Its optimal management remains controversial despite the development of several new techniques and devices which allow more rapid removal of thrombus and treatment of underlying venous stenotic disease. The following article provides a framework to discuss its treatment, with the emphasis on endovascular management. © 2004 Elsevier Inc. All rights reserved.
ntil recently, upper extremity venous thrombosis received scant attention in the literature as compared with its lower extremity counterpart. This is not too surprising, since upper extremity venous thrombosis is encountered much less often: most series estimate that it accounts for only 4 to 5% of all cases of deep venous thrombosis (DVT).1-3 This situation has begun to change, however, and most recent reports imply that the incidence of upper extremity venous thrombosis is on the rise. In large part this appears related to the increasing frequency with which indwelling central venous catheters and devices are being utilized for such indications as oncologic therapy, transvenous cardiac pacing, dialysis, nutritional support, and long-term antibiotic administration. Upper extremity venous thrombosis has also commanded greater attention with the realization that it may carry a greater risk of acute and chronic clinical sequelae than initially appreciated.
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Predisposing Factors and Pathophysiology Upper extremity venous thrombosis may be categorized into primary and secondary types, an important stratification to bear in mind when evaluating reports of treatment strategies and clinical outcomes.4-6 Primary cases can be idiopathic or related to Paget-Schroetter syndrome. The latter is related to axillarysubclavian venous compression produced by provocative arm movements involving hyperabduction and extension, a relationship making the term “effort thrombosis” an appropriate alternate term. The subclavian vein in particular is subject to extrinsic compression in the thoracic outlet (or thoracic inlet, in reference to the venous system) by muscular, tendinous, and/or bony structures; sites of compression include the costoFrom the Northwestern University Medical School, Northwestern Memorial Hospital Department of Radiology, Chicago, IL. Address reprint requests to Albert A. Nemcek, Jr, MD, Associate Professor of Radiology, Northwestern University Medical School, Northwestern Memorial Hospital Department of Radiology, Chicago, Illinois. © 2004 Elsevier Inc. All rights reserved. 1089-2516/04/0702-0007$30.00/0 doi:10.1053/j.tvir.2004.05.003
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clavicular space and interscalene triangle. Such compression can occur commonly and can be severe even in normal, asymptomatic individuals.7,8 The development of symptoms and of fixed venous pathology also require repetitive compression via strenuous physical exertion such as exercise or occupational activities. Repetitive compression likely leads to venous intimal damage and inflammation which in turn predisposes to thrombosis; cases of Paget-Schroetter syndrome also commonly show fibrotic thickening surrounding the involved subclavian vein.9 Patients with effort thrombosis tend to be young, otherwise healthy, and physically active. In one study the mean age of patients was 28.8 years, with about 60% occurring in males, and with a distinct antecedent history of repetitive upper extremity activity in nearly 80%.10 In Sze’s review of the literature, 61% of patients were male, 65% of pathology was right sided (probably reflecting dominance of the right extremity), and the mean age at onset of symptoms was 34 years.7 Cases of primary upper extremity DVT without an identifiable trigger or underlying mechanical disorder are considered idiopathic. However, many may later be found to be related to underlying malignancy. One study found that approximately one-fourth of patients presenting with idiopathic upper extremity DVT were diagnosed with cancer within 1 year of follow-up (most fairly early).11 Secondary cases are much more common than primary cases. These are often related to indwelling intravenous devices: in Marinella’s series of 90 patients with upper extremity venous thrombosis, for example, a central venous catheter was present in 72%.1 Secondary cases can also be related to central venous compression by neoplasms, to direct trauma, or to hypercoagulable states.3,4 In some cases of upper extremity thrombosis, multiple predisposing causes may be present. Indeed, in Prandoni’s series, hypercoagulable disorders were found in 26% of cases, including many with other identified etiologies. This percentage is similar to that in patients presenting with lower extremity DVT and argues that patients presenting with upper extremity DVT should be screened for such disorders.2 Patients with secondary thrombosis are often older, and more often systemically ill, than patients with primary upper extremity venous thrombosis.1 With respect to indwelling venous devices, multiple factors may account for a predisposition to thrombosis. These include endothelial injury at the time of device insertion or as a result of chronic contact of the device and venous wall, perivascular bleeding with venous compression, slowing or turbulence of flow as a result of luminal compromise by the device itself and any deposition of fibrin around the device, or damage to the vein as a result of infusion of medications.9,11 In the latter case, inappropriately peripheral locations of the tips of infusion catheters may be a contributing cause. The exact incidence of thrombosis related to venous catheterization is difficult to as-
Techniques in Vascular and Interventional Radiology, Vol 7, No 2 (June), 2004: pp 86-90
certain because of variability in patient populations, catheters, and definitions in reported series, but it has been suggested that clinically silent thrombosis related to central venous catheterization occurs in at least 30% and as high as 60% of cases, and that a residual venous stenosis may develop in 30 to 40% of cases.9,12-14 Symptomatic upper extremity venous thrombosis, on the other hand, probably occurs in 3 to 4% or less of patients with central venous catheters.1,13,14 Larger catheters, infected catheters, and miscellaneous other factors have been associated with a higher risk of catheter-related upper extremity thrombosis.2,12 Note also that not all patients present with thrombus; many patients develop stenoses slowly over time, allowing collateral veins to form and keeping the patient asymptomatic until an acute event or stress (eg, increased flow related to an ipsilateral dialysis fistula) makes the stenosis clinically evident.15
Diagnostic Tests Ipsilateral upper extremity edema is the most common sign of upper extremity venous thrombosis. Other signs and symptoms which should prompt consideration of this diagnosis include upper extremity pain or cyanosis, facial or neck swelling, functional impairment of the affected arm, or development of distended venous collaterals in the shoulder girdle and neck.2,10,12 Catheter dysfunction may be present in cases associated with central venous catheterization. Headache and signs of pulmonary embolism are less common manifestations; however, it should be recognized that signs of pulmonary embolism may occur before or in the absence of other signs of upper extremity venous thrombosis.2 In cases of effort thrombosis, an antecedent history of sustained or repetitive physical activity involving abduction and external rotation of the involved arm can often be elicited.10 As the signs and symptoms may be nonspecific, and as they may be produced by venous stenosis or compression without thrombus formation, objective confirmation of the diagnosis should typically precede any significant treatment decisions. In one series, for example, less than 50% of those who underwent venography for suspected upper extremity DVT had the diagnosis confirmed.2 A variety of diagnostic tests may be used in the evaluation of patients with suspected or proven upper extremity venous thrombosis. Compression ultrasonography and color-flow Doppler imaging have been used effectively to diagnose upper extremity DVT.2,10 However, tests based on sonographic techniques are subject to interference with optimal vein evaluation by adjacent bony structures, the lung, or associated catheters. As a result, venography may be needed before a decision regarding therapy is made. Contrast venography remains a highly reliable and accurate test for upper extremity and central thoracic venous thrombosis. While hand vein injections may give satisfactory depiction of venous occlusion and associated venous collaterals, detailed assessment of the central veins and associated thrombi, venous webs, or venous stenoses is best performed with contrast injection into large, medially located upper arm veins, or even with central catheterization and injection directly into the subclavian or brachiocephalic veins.2,4,10 In cases of effort thrombosis, evaluation should also include positional venography, in which the arm is abducted and externally rotated to assess the presence and severity of subclavian venous compression and/or INTERVENTIONAL MANAGEMENT OF UPPER EXTREMITY DVT
compression of venous collaterals in the thoracic inlet.10 It should once again be noted, however, that venous compression in this region is common in normal, asymptomatic individuals and cannot be considered in isolation as an indicator for more aggressive therapies such as surgical decompression. Recently, great strides have been made in vascular imaging utilizing both computed tomography (CT) and magnetic resonance imaging (MRI). In many cases the depiction of upper extremity veins and venous abnormalities rivals that of contrast venography, with the additional advantage conferred by these cross-sectional techniques of detailed depiction of perivascular anatomy and of three-dimensional image reconstruction and manipulation.7,8,16 The impact of such tests on therapeutic decision-making remains to be determined. However, they do seem in particular to provide insight into the structural relations of thoracic outlet syndrome and, with further investigation, may prove helpful in pre- and posttherapeutic evaluation in these disorders.
Prognosis While some reports have considered upper extremity deep venous thrombosis a relatively innocuous disorder, a number of investigators have suggested that it is a serious disorder resembling, in many ways, lower extremity deep venous thrombosis and requiring a similar degree of diagnostic vigilance and prompt treatment.2,5 Evaluation of clinical outcomes of upper extremity venous thrombosis focus primarily on the risks of postphlebitic syndrome and of pulmonary embolism. A third sequel, not as often cited but often highly devastating in its consequences, is the loss of future vascular access which results from venous obliteration by chronic occlusion.5 Postphlebitic syndrome consists of residual swelling, pain, limitation of motion, or easy fatigability of the involved extremity. Such symptoms are probably more common in cases of primary upper extremity thrombosis and can be especially disabling in cases relating to occupational or athletic activities, leading to loss of productivity or the quality of life.4,7 The incidence of such symptoms varies greatly among published reports and likely attests to variation in case selection and therapy. In one series of spontaneous axillary-subclavian venous thrombosis, 54 patients responded to a questionnaire relating to postphlebitic symptoms.17 In this group, most of whom were treated with anticoagulation and none of whom received thrombolytic therapy, nearly half the patients were asymptomatic or had negligible symptoms. However, 13% rated symptoms as severe or intolerable. Review of the literature in this same report gave rates of overall postphlebitic sequelae of 21 to 73% and of severe sequelae of 0 to 55%. Another review of the literature by Becker and coworkers estimated the rate of long-term morbidity to be 34%.13 It has been estimated that up to 75% of patients with subclavian vein thrombosis treated conservatively have permanent upper extremity disability.7 While early reports suggested that upper extremity DVT is a relatively unimportant source for pulmonary emboli (PE), Becker’s 1991 review, for example, suggests a 5 to 10% rate of pulmonary emboli, considerably lower than the estimated 50% rate from proximal DVT of the lower extremity.13 Other reports, many more recent, suggest that this complication may be more common. Various series report pulmonary emboli in 11 to 36% of cases, including a small number of fatalities.2,17-19 There
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may also be a difference in the risk between primary upper extremity DVT and secondary, particularly those related to central catheters. Monreal and colleagues looked at 30 consecutive patients with proven upper extremity DVT, all but one of whom (a patient who died with massive pulmonary embolism) had ventilation/perfusion lung scans at the time of admission to the hospital.19 In 9 of 10 patients with primary upper extremity DVT, lung scans were normal, with indeterminate findings in the tenth patient. The remaining 20 patients had upper extremity DVT related to venous catheterization; of these, 5 patients (25%) either had proven pulmonary emboli or most likely had pulmonary emboli. Similarly, in Linblad’s article there were no cases of pulmonary emboli in a group of 73 patients with primary upper extremity DVT, but five cases presented in a group of 47 patients with the secondary form.18
Interventions The appropriate management of both primary and secondary upper extremity venous thrombosis is highly controversial, and algorithms for such management continue to evolve as our understanding of these disorders grows. Before discussing therapy for upper extremity thrombosis once it occurs, methods for prevention of its occurrence bear mention. The use of prophylactic low-dose anticoagulation, for example, is gaining favor in patients with chronic indwelling catheters.3,12,13 Standard therapy for thrombosis once it occurs consists of anticoagulation, elevation of the affected limb, and, if applicable, removal of the offending intravenous device. Indeed, anticoagulation alone results in symptomatic improvement in 50% or more of patients.4,9,12,13 However, anticoagulation does not remove existent thrombus and may not prevent other postthrombotic sequelae; further, the clinical improvement noted following anticoagulation may, in many cases, be related more to development of collateral veins than resolution of thrombus.4 While removal of catheters or other devices seems reasonable, it is not practical in many instances because of continued need for venous access and the risks of catheter insertion at another site.12 Evidence suggests that an attempt can be made to treat patients with upper extremity venous thrombosis while leaving the catheter in place. In one study of anticoagulation in children, seven of nine patients treated with anticoagulation without catheter removal responded well to therapy, allowing their venous access to be retained.20 Similarly, Seigel and coworkers treated 38 patients with thrombolytic therapy while leaving catheters in place, utilizing adjunctive balloon angioplasty to macerate thrombus-resistant agents alone or to treat residual stenoses and found they were able to achieve symptomatic relief and catheter salvage in 33 patients (87%).14 The use of local, catheter-directed thrombolytic therapy in the treatment of symptomatic upper extremity venous thrombosis has been adopted enthusiastically by many practitioners, particularly in the initial therapy of primary upper extremity deep venous thrombosis. Thrombolytic therapy appears to be more effective than anticoagulation in producing early resolution of symptoms and carries the theoretical advantage of restoring venous patency.7,9,21 Sheeran’s review, for example, suggests that the immediate patency rate after lytic therapy for upper extremity venous thrombosis ranges from 40 to 100%.9 As a cautionary note, however, the benefits of thrombolytic
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therapy have not been tested rigorously in well-designed randomized trials.13,17 In addition, at least one retrospective study comparing systemic (rather than catheter-directed) thrombolysis with anticoagulation in the treatment of a mixed group of primary and secondary upper extremity DVT drew less enthusiastic conclusions. In this study of 95 treated patients (33 with systemic UK and subsequent anticoagulation, 62 with anticoagulation alone) thrombolysis was found to improve venous recanalization rates compared with anticoagulation; the frequency of symptomatic postthrombotic syndrome was similarly low in the two groups, and bleeding complications were significantly higher in the thrombolysis arm. The authors concluded that conservative treatment may be the favored treatment of upper extremity venous thrombosis. However, acknowledging the limitations and potential for selection bias in their study, they also stated that their findings may “initiate a discussion on the indications of thrombolysis rather than give final recommendations on optimal management strategies for these patients.”22 In general, many authors have suggested abandonment of systemic thrombolytic therapy in favor of catheter-directed therapy at the site of thrombosis because of the concern for higher risks of systemic therapy.6 A number of thrombolytic agents have been used for the treatment of upper extremity deep venous thrombosis; there is little evidence to suggest one should be favored over any of the others. For a review of available agents and typical dosing regimens, the reader is referred to the review by Sharafuddin and coworkers.6 Adjunctive mechanical thrombectomy with a variety of devices has been utilized in with thrombolysis to help hasten the “debulking” of upper extremity venous thrombosis; mechanical thrombectomy can also be considered when thrombolysis is contraindicated.6 However, further data are needed to ascertain the efficacy and role of mechanical devices in this setting. Following thrombolytic therapy for primary upper extremity venous thrombosis, an underlying venous stenosis is often encountered. While it is tempting to perform balloon angioplasty on such lesions, it is frequently unsuccessful or lesions recur quickly, as a result of the associated compressive abnormality and perivascular fibrosis.6,7,9,10,21 In Lee’s study, for example, balloon angioplasty in 12 patients with severe venous stenoses failed in each case to produce any visible improvement in the lesion, and in Machleder’s study, 7 of 12 angioplasties performed before surgical decompression of the thoracic outlet resulted in immediate venous occlusion. It has also been suggested that initial failure of angioplasty may worsen long-term results.21 Similarly, intravascular stenting, while often producing initial results which are venographically pleasing, does not appear to be a durable therapy.6,7,9 Current stents are not able to withstand the repetitive compressive forces of the thoracic inlet, and the literature includes multiple examples of fatigue and fracture of both rigid and flexible stents as well as early occlusion of intact stents.10,23,24 Interestingly, stent compression has not only been limited to the classic site of venous compression in the thoracic outlet; Hammer and colleagues reported stent compression in the in two patients treated for benign catheterinduced stenosis of the left brachiocephalic vein; in these cases it was postulated that reduction of the space between the great arteries of the upper thorax and the sternum resulting from pulsation and respiration was responsible.15 Current algorithms for treatment of Paget-Schroetter synALBERT A. NEMCEK, JR.
drome typically include surgical decompression of the thoracic inlet. However, the timing of such decompression and the exact method used remains controversial, particularly with respect to critical stenoses uncovered by thrombolytic therapy.7,10,21,25 In this regard, some advocate early decompression to prevent recurrence of thrombosis, while others advocate anticoagulation with delayed decompression, to allow perivenous inflammation to subside and make surgery easier and safer. Indeed, a recent study by Lee and colleagues, prompted in part by the observation that serious complications can occur as a result of decompressive surgery, suggests that at least some patients with this disorder may be managed more conservatively after initial thrombolytic therapy.10 In this study, patients, most of whom had undergone thrombolytic therapy for effort thrombosis, were treated with anticoagulation for 1 month. At this time they were reexamined, and if they remained asymptomatic with minimal physical findings, they were maintained for two more months on anticoagulation. If they were still asymptomatic, anticoagulation was discontinued, and the patients were allowed to return to full activity. Of 22 patients treated in this manner, 13 eventually required surgery. Indications for surgery included persistent or recurrent symptoms of venous hypertension, positional occlusion of venous collaterals with demonstrated axillary-subclavian venous thrombosis on venography, thrombus extension, or occurrence of pulmonary embolism. Of the nine treated nonoperatively with anticoagulation, eight had minimal symptoms at the end of anticoagulation. One patient had moderate early arm fatigue despite lack of physical findings and despite a patent vein with lack of positional occlusion on upper extremity venography. Thus, with close follow-up and gradual return to physical activity, just over 40% of patients were able to return to baseline status without the need for surgery. The use of endovascular techniques such as angioplasty and stenting for residual hemodynamically significant stenoses following surgical decompression has been suggested.6,7,9,10 However, there are little data at this time to evaluate the long-term outcomes of such postoperative adjuncts in the setting of primary upper extremity DVT. Symptomatic cases of secondary upper extremity DVT associated with underlying stenoses are also generally treated first with thrombolytic therapy. This helps to uncover underlying stenoses and minimize risk for pulmonary embolism during endovascular therapy. In some cases, occlusive disease is so profound that catheterization across the occluded segment proves very difficult. In such instances, careful “sharp” recanalization may allow successful endovascular therapy. As opposed to effort thrombosis, there is mounting evidence that endovascular stenting is an effective adjunct in the treatment of stenoses associated with long-term central venous catheterization, thoracic malignancy, or mediastinal irradiation. Although more long-term prospective data are needed, most reports suggest immediate and dramatic improvement in symptoms following stenting, especially in cases of central stenoses producing SVC syndrome. Note also that in many of these cases, due to underlying short life expectancy, prolonged stent patency is not as relevant.6 Clearly, however, each case must be considered individually: for example, it is probably prudent to avoid stenting for as long as possible in dialysis patients with subclavian vein stenoses, because of longer life expectancy, less convincing evidence of intermediate to long-term patency, and the critical INTERVENTIONAL MANAGEMENT OF UPPER EXTREMITY DVT
need to preserve central venous patency to optimize the function of upper extremity dialysis grafts and fistulas.
Conclusions The optimal algorithm for treatment of upper extremity venous thrombosis remains to be determined. In this regard, as has been emphasized there is a great need for large-scale (and almost by necessity multicenter) controlled studies with careful assessment of outcomes at regular intervals, and with stratification of results according to etiologic categories.13 In all likelihood, the optimal approach will be multidisciplinary and involve both preventive measures and appropriately timed and applied medical, surgical, and interventional therapies. The goals of such therapy should be multiple and include preservation of venous access, prevention of acute thromboembolic complications, and restoration of a functional and asymptomatic premorbid status.
References 1. Marinella MA, Kathula SK, Markert RJ: Spectrum of upper-extremity deep venous thrombosis in a community teaching hospital. Heart Lung 29:113-117, 2000 2. Prandoni P, Polistena P, Bernardi E, et al: Upper-extremity deep vein thrombosis: risk factors, diagnosis, and complications. Arch Intern Med 157:57-62, 1997 3. Kommareddy A, Zaroukian MH, Hassouna HI: Upper extremity deep venous thrombosis. Semin Thromb Hemost 28:89-99, 2002 4. Hirsh J, Hoak J: Management of deep vein thrombosis and pulmonary embolism: a statement for healthcare professionals: from the council on thrombosis (in consultation with the council on cardiovascular radiology), American Heart Association. Circulation 93:22122245, 1996 5. Joffe HV, Goldhaber SZ: Upper-extremity deep vein thrombosis. Circulation 106:1874-1880, 2002 6. Sharafuddin MJ, Sun S, Hoballah JJ: Endovascular management of venous thrombotic diseases of the upper torso and extremities. J Vasc Interv Radiol 13:975-990, 2002 7. Sze DY, Shifrin RY, Semba CP: Current diagnostic and therapeutic strategies for effort vein thrombosis. Tech Vasc Interv Radiol 3:1220, 2000 8. Matsumura JS, Rilling WS, Pearce WH, et al: Helical computed tomography of the normal thoracic outlet. J Vasc Surg 26:776-783, 1997 9. Sheeran SR, Hallisey MJ: Upper extremity thrombolysis. Tech Vasc Interv Radiol 1:183-191, 1998 10. Lee WA, Hill BB, Harris EJ Jr, et al: Surgical intervention is not required for all patients with subclavian vein thrombosis. J Vasc Surg 32:57-67, 2000 11. Girolami A, Prandoni P, Zanon E, et al: Venous thromboses of upper limbs are more frequently associated with occult cancer as compared with those of lower limbs. Blood Coag Fibrinol 10:455-457, 1999 12. Lee AY, Levine MN: Management of venous thromboembolism in cancer patients. Oncology 14:409-426, 2000 13. Becker DM, Philbrick JT, Walker FB IV: Axillary and subclavian venous thrombosis: prognosis and treatment. Arch Intern Med 151: 1934-1943, 1991 14. Seigel EL, Jew AC, Delcore R, et al: Thrombolytic therapy for catheter-related thrombosis. Am J Surg 166:716-719, 1993 15. Hammer F, Becker D, Goffette P, et al: Crushed stents in benign left brachiocephalic vein stenoses. J Vasc Surg 32:392-396, 2000 16. Rilling WS, Nemcek AA Jr, Vogelzang RL, et al: CT angiography in evaluation of thoracic outlet syndrome, in Yao JST, Pearce WH, (eds): Progress in Vascular Surgery. Stamford, Appleton & Lange, 1997, pp 287-297 17. He´ron E, Lozinguez O, Emmerich J, et al: Long-term sequelae of spontaneous axillary-subclavian venous thrombosis. Ann Intern Med 131:510-513, 1999
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18. Linblad B, Tengborn L, Bergqvist D: Deep vein thrombosis of the axillary-subclavian veins: epidemiologic date, effects of different types of treatment and late sequelae. Eur J Vasc Surg 2:161-165, 1988 19. Monreal M, Lafoz E, Ruiz J, et al: Upper-extremity deep venous thrombosis and pulmonary embolism. A prospective study. Chest 99:280-283, 1991 20. Kenney BD, David M, Bensoussan AL: Anticoagulation without catheter removal in children with catheter-related central vein thrombosis. J Pediatr Surg 31:816-818, 1996 21. Machleder HI: Evaluation of a new treatment strategy for PagetSchroetter syndrome: spontaneous thrombosis of the axillary-subclavian vein. J Vasc Surg 17:305-317, 1993
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22. Sabeti S, Schillinger M, Mlekusch W, et al: Treatment of subclavianaxillary vein thrombosis: long-term outcome of anticoagulation versus systemic thrombolysis. Thromb Res 108:279-285, 2003 23. Rhodes AI, Gibson M, Al-Katoubi M: Mechanical disruption of a Wallstent in the subclavian vein between clavicle and first rib. J Interveent Radiol 12:151-153, 1997 24. Meier GH, Pollak JS, Rosenblatt M, et al: Initial experience with stents in exertional axillary-subclavian vein thrombosis. J Vasc Surg 24:974-983, 1996 25. Rutherford RB: Primary subclavian-axillary vein thrombosis: the relative roles of thrombolysis, percutaneous angioplasty, stents, and surgery. Semin Vasc Surg 11:91-95, 1998
ALBERT A. NEMCEK, JR.
Upper extremity deep venous thrombosis, previously thought to be a relatively innocuous disorder in comparison to lower extremity deep venous thrombosis, has recently begun to receive the attention it merits. Its optimal management remains controversial despite the development of several new techniques and devices which allow more rapid removal of thrombus and treatment of underlying venous stenotic disease. The following article provides a framework to discuss its treatment, with the emphasis on endovascular management. © 2004 Elsevier Inc. All rights reserved.
ntil recently, upper extremity venous thrombosis received scant attention in the literature as compared with its lower extremity counterpart. This is not too surprising, since upper extremity venous thrombosis is encountered much less often: most series estimate that it accounts for only 4 to 5% of all cases of deep venous thrombosis (DVT).1-3 This situation has begun to change, however, and most recent reports imply that the incidence of upper extremity venous thrombosis is on the rise. In large part this appears related to the increasing frequency with which indwelling central venous catheters and devices are being utilized for such indications as oncologic therapy, transvenous cardiac pacing, dialysis, nutritional support, and long-term antibiotic administration. Upper extremity venous thrombosis has also commanded greater attention with the realization that it may carry a greater risk of acute and chronic clinical sequelae than initially appreciated.
U
Predisposing Factors and Pathophysiology Upper extremity venous thrombosis may be categorized into primary and secondary types, an important stratification to bear in mind when evaluating reports of treatment strategies and clinical outcomes.4-6 Primary cases can be idiopathic or related to Paget-Schroetter syndrome. The latter is related to axillarysubclavian venous compression produced by provocative arm movements involving hyperabduction and extension, a relationship making the term “effort thrombosis” an appropriate alternate term. The subclavian vein in particular is subject to extrinsic compression in the thoracic outlet (or thoracic inlet, in reference to the venous system) by muscular, tendinous, and/or bony structures; sites of compression include the costoFrom the Northwestern University Medical School, Northwestern Memorial Hospital Department of Radiology, Chicago, IL. Address reprint requests to Albert A. Nemcek, Jr, MD, Associate Professor of Radiology, Northwestern University Medical School, Northwestern Memorial Hospital Department of Radiology, Chicago, Illinois. © 2004 Elsevier Inc. All rights reserved. 1089-2516/04/0702-0007$30.00/0 doi:10.1053/j.tvir.2004.05.003
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clavicular space and interscalene triangle. Such compression can occur commonly and can be severe even in normal, asymptomatic individuals.7,8 The development of symptoms and of fixed venous pathology also require repetitive compression via strenuous physical exertion such as exercise or occupational activities. Repetitive compression likely leads to venous intimal damage and inflammation which in turn predisposes to thrombosis; cases of Paget-Schroetter syndrome also commonly show fibrotic thickening surrounding the involved subclavian vein.9 Patients with effort thrombosis tend to be young, otherwise healthy, and physically active. In one study the mean age of patients was 28.8 years, with about 60% occurring in males, and with a distinct antecedent history of repetitive upper extremity activity in nearly 80%.10 In Sze’s review of the literature, 61% of patients were male, 65% of pathology was right sided (probably reflecting dominance of the right extremity), and the mean age at onset of symptoms was 34 years.7 Cases of primary upper extremity DVT without an identifiable trigger or underlying mechanical disorder are considered idiopathic. However, many may later be found to be related to underlying malignancy. One study found that approximately one-fourth of patients presenting with idiopathic upper extremity DVT were diagnosed with cancer within 1 year of follow-up (most fairly early).11 Secondary cases are much more common than primary cases. These are often related to indwelling intravenous devices: in Marinella’s series of 90 patients with upper extremity venous thrombosis, for example, a central venous catheter was present in 72%.1 Secondary cases can also be related to central venous compression by neoplasms, to direct trauma, or to hypercoagulable states.3,4 In some cases of upper extremity thrombosis, multiple predisposing causes may be present. Indeed, in Prandoni’s series, hypercoagulable disorders were found in 26% of cases, including many with other identified etiologies. This percentage is similar to that in patients presenting with lower extremity DVT and argues that patients presenting with upper extremity DVT should be screened for such disorders.2 Patients with secondary thrombosis are often older, and more often systemically ill, than patients with primary upper extremity venous thrombosis.1 With respect to indwelling venous devices, multiple factors may account for a predisposition to thrombosis. These include endothelial injury at the time of device insertion or as a result of chronic contact of the device and venous wall, perivascular bleeding with venous compression, slowing or turbulence of flow as a result of luminal compromise by the device itself and any deposition of fibrin around the device, or damage to the vein as a result of infusion of medications.9,11 In the latter case, inappropriately peripheral locations of the tips of infusion catheters may be a contributing cause. The exact incidence of thrombosis related to venous catheterization is difficult to as-
Techniques in Vascular and Interventional Radiology, Vol 7, No 2 (June), 2004: pp 86-90
certain because of variability in patient populations, catheters, and definitions in reported series, but it has been suggested that clinically silent thrombosis related to central venous catheterization occurs in at least 30% and as high as 60% of cases, and that a residual venous stenosis may develop in 30 to 40% of cases.9,12-14 Symptomatic upper extremity venous thrombosis, on the other hand, probably occurs in 3 to 4% or less of patients with central venous catheters.1,13,14 Larger catheters, infected catheters, and miscellaneous other factors have been associated with a higher risk of catheter-related upper extremity thrombosis.2,12 Note also that not all patients present with thrombus; many patients develop stenoses slowly over time, allowing collateral veins to form and keeping the patient asymptomatic until an acute event or stress (eg, increased flow related to an ipsilateral dialysis fistula) makes the stenosis clinically evident.15
Diagnostic Tests Ipsilateral upper extremity edema is the most common sign of upper extremity venous thrombosis. Other signs and symptoms which should prompt consideration of this diagnosis include upper extremity pain or cyanosis, facial or neck swelling, functional impairment of the affected arm, or development of distended venous collaterals in the shoulder girdle and neck.2,10,12 Catheter dysfunction may be present in cases associated with central venous catheterization. Headache and signs of pulmonary embolism are less common manifestations; however, it should be recognized that signs of pulmonary embolism may occur before or in the absence of other signs of upper extremity venous thrombosis.2 In cases of effort thrombosis, an antecedent history of sustained or repetitive physical activity involving abduction and external rotation of the involved arm can often be elicited.10 As the signs and symptoms may be nonspecific, and as they may be produced by venous stenosis or compression without thrombus formation, objective confirmation of the diagnosis should typically precede any significant treatment decisions. In one series, for example, less than 50% of those who underwent venography for suspected upper extremity DVT had the diagnosis confirmed.2 A variety of diagnostic tests may be used in the evaluation of patients with suspected or proven upper extremity venous thrombosis. Compression ultrasonography and color-flow Doppler imaging have been used effectively to diagnose upper extremity DVT.2,10 However, tests based on sonographic techniques are subject to interference with optimal vein evaluation by adjacent bony structures, the lung, or associated catheters. As a result, venography may be needed before a decision regarding therapy is made. Contrast venography remains a highly reliable and accurate test for upper extremity and central thoracic venous thrombosis. While hand vein injections may give satisfactory depiction of venous occlusion and associated venous collaterals, detailed assessment of the central veins and associated thrombi, venous webs, or venous stenoses is best performed with contrast injection into large, medially located upper arm veins, or even with central catheterization and injection directly into the subclavian or brachiocephalic veins.2,4,10 In cases of effort thrombosis, evaluation should also include positional venography, in which the arm is abducted and externally rotated to assess the presence and severity of subclavian venous compression and/or INTERVENTIONAL MANAGEMENT OF UPPER EXTREMITY DVT
compression of venous collaterals in the thoracic inlet.10 It should once again be noted, however, that venous compression in this region is common in normal, asymptomatic individuals and cannot be considered in isolation as an indicator for more aggressive therapies such as surgical decompression. Recently, great strides have been made in vascular imaging utilizing both computed tomography (CT) and magnetic resonance imaging (MRI). In many cases the depiction of upper extremity veins and venous abnormalities rivals that of contrast venography, with the additional advantage conferred by these cross-sectional techniques of detailed depiction of perivascular anatomy and of three-dimensional image reconstruction and manipulation.7,8,16 The impact of such tests on therapeutic decision-making remains to be determined. However, they do seem in particular to provide insight into the structural relations of thoracic outlet syndrome and, with further investigation, may prove helpful in pre- and posttherapeutic evaluation in these disorders.
Prognosis While some reports have considered upper extremity deep venous thrombosis a relatively innocuous disorder, a number of investigators have suggested that it is a serious disorder resembling, in many ways, lower extremity deep venous thrombosis and requiring a similar degree of diagnostic vigilance and prompt treatment.2,5 Evaluation of clinical outcomes of upper extremity venous thrombosis focus primarily on the risks of postphlebitic syndrome and of pulmonary embolism. A third sequel, not as often cited but often highly devastating in its consequences, is the loss of future vascular access which results from venous obliteration by chronic occlusion.5 Postphlebitic syndrome consists of residual swelling, pain, limitation of motion, or easy fatigability of the involved extremity. Such symptoms are probably more common in cases of primary upper extremity thrombosis and can be especially disabling in cases relating to occupational or athletic activities, leading to loss of productivity or the quality of life.4,7 The incidence of such symptoms varies greatly among published reports and likely attests to variation in case selection and therapy. In one series of spontaneous axillary-subclavian venous thrombosis, 54 patients responded to a questionnaire relating to postphlebitic symptoms.17 In this group, most of whom were treated with anticoagulation and none of whom received thrombolytic therapy, nearly half the patients were asymptomatic or had negligible symptoms. However, 13% rated symptoms as severe or intolerable. Review of the literature in this same report gave rates of overall postphlebitic sequelae of 21 to 73% and of severe sequelae of 0 to 55%. Another review of the literature by Becker and coworkers estimated the rate of long-term morbidity to be 34%.13 It has been estimated that up to 75% of patients with subclavian vein thrombosis treated conservatively have permanent upper extremity disability.7 While early reports suggested that upper extremity DVT is a relatively unimportant source for pulmonary emboli (PE), Becker’s 1991 review, for example, suggests a 5 to 10% rate of pulmonary emboli, considerably lower than the estimated 50% rate from proximal DVT of the lower extremity.13 Other reports, many more recent, suggest that this complication may be more common. Various series report pulmonary emboli in 11 to 36% of cases, including a small number of fatalities.2,17-19 There
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may also be a difference in the risk between primary upper extremity DVT and secondary, particularly those related to central catheters. Monreal and colleagues looked at 30 consecutive patients with proven upper extremity DVT, all but one of whom (a patient who died with massive pulmonary embolism) had ventilation/perfusion lung scans at the time of admission to the hospital.19 In 9 of 10 patients with primary upper extremity DVT, lung scans were normal, with indeterminate findings in the tenth patient. The remaining 20 patients had upper extremity DVT related to venous catheterization; of these, 5 patients (25%) either had proven pulmonary emboli or most likely had pulmonary emboli. Similarly, in Linblad’s article there were no cases of pulmonary emboli in a group of 73 patients with primary upper extremity DVT, but five cases presented in a group of 47 patients with the secondary form.18
Interventions The appropriate management of both primary and secondary upper extremity venous thrombosis is highly controversial, and algorithms for such management continue to evolve as our understanding of these disorders grows. Before discussing therapy for upper extremity thrombosis once it occurs, methods for prevention of its occurrence bear mention. The use of prophylactic low-dose anticoagulation, for example, is gaining favor in patients with chronic indwelling catheters.3,12,13 Standard therapy for thrombosis once it occurs consists of anticoagulation, elevation of the affected limb, and, if applicable, removal of the offending intravenous device. Indeed, anticoagulation alone results in symptomatic improvement in 50% or more of patients.4,9,12,13 However, anticoagulation does not remove existent thrombus and may not prevent other postthrombotic sequelae; further, the clinical improvement noted following anticoagulation may, in many cases, be related more to development of collateral veins than resolution of thrombus.4 While removal of catheters or other devices seems reasonable, it is not practical in many instances because of continued need for venous access and the risks of catheter insertion at another site.12 Evidence suggests that an attempt can be made to treat patients with upper extremity venous thrombosis while leaving the catheter in place. In one study of anticoagulation in children, seven of nine patients treated with anticoagulation without catheter removal responded well to therapy, allowing their venous access to be retained.20 Similarly, Seigel and coworkers treated 38 patients with thrombolytic therapy while leaving catheters in place, utilizing adjunctive balloon angioplasty to macerate thrombus-resistant agents alone or to treat residual stenoses and found they were able to achieve symptomatic relief and catheter salvage in 33 patients (87%).14 The use of local, catheter-directed thrombolytic therapy in the treatment of symptomatic upper extremity venous thrombosis has been adopted enthusiastically by many practitioners, particularly in the initial therapy of primary upper extremity deep venous thrombosis. Thrombolytic therapy appears to be more effective than anticoagulation in producing early resolution of symptoms and carries the theoretical advantage of restoring venous patency.7,9,21 Sheeran’s review, for example, suggests that the immediate patency rate after lytic therapy for upper extremity venous thrombosis ranges from 40 to 100%.9 As a cautionary note, however, the benefits of thrombolytic
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therapy have not been tested rigorously in well-designed randomized trials.13,17 In addition, at least one retrospective study comparing systemic (rather than catheter-directed) thrombolysis with anticoagulation in the treatment of a mixed group of primary and secondary upper extremity DVT drew less enthusiastic conclusions. In this study of 95 treated patients (33 with systemic UK and subsequent anticoagulation, 62 with anticoagulation alone) thrombolysis was found to improve venous recanalization rates compared with anticoagulation; the frequency of symptomatic postthrombotic syndrome was similarly low in the two groups, and bleeding complications were significantly higher in the thrombolysis arm. The authors concluded that conservative treatment may be the favored treatment of upper extremity venous thrombosis. However, acknowledging the limitations and potential for selection bias in their study, they also stated that their findings may “initiate a discussion on the indications of thrombolysis rather than give final recommendations on optimal management strategies for these patients.”22 In general, many authors have suggested abandonment of systemic thrombolytic therapy in favor of catheter-directed therapy at the site of thrombosis because of the concern for higher risks of systemic therapy.6 A number of thrombolytic agents have been used for the treatment of upper extremity deep venous thrombosis; there is little evidence to suggest one should be favored over any of the others. For a review of available agents and typical dosing regimens, the reader is referred to the review by Sharafuddin and coworkers.6 Adjunctive mechanical thrombectomy with a variety of devices has been utilized in with thrombolysis to help hasten the “debulking” of upper extremity venous thrombosis; mechanical thrombectomy can also be considered when thrombolysis is contraindicated.6 However, further data are needed to ascertain the efficacy and role of mechanical devices in this setting. Following thrombolytic therapy for primary upper extremity venous thrombosis, an underlying venous stenosis is often encountered. While it is tempting to perform balloon angioplasty on such lesions, it is frequently unsuccessful or lesions recur quickly, as a result of the associated compressive abnormality and perivascular fibrosis.6,7,9,10,21 In Lee’s study, for example, balloon angioplasty in 12 patients with severe venous stenoses failed in each case to produce any visible improvement in the lesion, and in Machleder’s study, 7 of 12 angioplasties performed before surgical decompression of the thoracic outlet resulted in immediate venous occlusion. It has also been suggested that initial failure of angioplasty may worsen long-term results.21 Similarly, intravascular stenting, while often producing initial results which are venographically pleasing, does not appear to be a durable therapy.6,7,9 Current stents are not able to withstand the repetitive compressive forces of the thoracic inlet, and the literature includes multiple examples of fatigue and fracture of both rigid and flexible stents as well as early occlusion of intact stents.10,23,24 Interestingly, stent compression has not only been limited to the classic site of venous compression in the thoracic outlet; Hammer and colleagues reported stent compression in the in two patients treated for benign catheterinduced stenosis of the left brachiocephalic vein; in these cases it was postulated that reduction of the space between the great arteries of the upper thorax and the sternum resulting from pulsation and respiration was responsible.15 Current algorithms for treatment of Paget-Schroetter synALBERT A. NEMCEK, JR.
drome typically include surgical decompression of the thoracic inlet. However, the timing of such decompression and the exact method used remains controversial, particularly with respect to critical stenoses uncovered by thrombolytic therapy.7,10,21,25 In this regard, some advocate early decompression to prevent recurrence of thrombosis, while others advocate anticoagulation with delayed decompression, to allow perivenous inflammation to subside and make surgery easier and safer. Indeed, a recent study by Lee and colleagues, prompted in part by the observation that serious complications can occur as a result of decompressive surgery, suggests that at least some patients with this disorder may be managed more conservatively after initial thrombolytic therapy.10 In this study, patients, most of whom had undergone thrombolytic therapy for effort thrombosis, were treated with anticoagulation for 1 month. At this time they were reexamined, and if they remained asymptomatic with minimal physical findings, they were maintained for two more months on anticoagulation. If they were still asymptomatic, anticoagulation was discontinued, and the patients were allowed to return to full activity. Of 22 patients treated in this manner, 13 eventually required surgery. Indications for surgery included persistent or recurrent symptoms of venous hypertension, positional occlusion of venous collaterals with demonstrated axillary-subclavian venous thrombosis on venography, thrombus extension, or occurrence of pulmonary embolism. Of the nine treated nonoperatively with anticoagulation, eight had minimal symptoms at the end of anticoagulation. One patient had moderate early arm fatigue despite lack of physical findings and despite a patent vein with lack of positional occlusion on upper extremity venography. Thus, with close follow-up and gradual return to physical activity, just over 40% of patients were able to return to baseline status without the need for surgery. The use of endovascular techniques such as angioplasty and stenting for residual hemodynamically significant stenoses following surgical decompression has been suggested.6,7,9,10 However, there are little data at this time to evaluate the long-term outcomes of such postoperative adjuncts in the setting of primary upper extremity DVT. Symptomatic cases of secondary upper extremity DVT associated with underlying stenoses are also generally treated first with thrombolytic therapy. This helps to uncover underlying stenoses and minimize risk for pulmonary embolism during endovascular therapy. In some cases, occlusive disease is so profound that catheterization across the occluded segment proves very difficult. In such instances, careful “sharp” recanalization may allow successful endovascular therapy. As opposed to effort thrombosis, there is mounting evidence that endovascular stenting is an effective adjunct in the treatment of stenoses associated with long-term central venous catheterization, thoracic malignancy, or mediastinal irradiation. Although more long-term prospective data are needed, most reports suggest immediate and dramatic improvement in symptoms following stenting, especially in cases of central stenoses producing SVC syndrome. Note also that in many of these cases, due to underlying short life expectancy, prolonged stent patency is not as relevant.6 Clearly, however, each case must be considered individually: for example, it is probably prudent to avoid stenting for as long as possible in dialysis patients with subclavian vein stenoses, because of longer life expectancy, less convincing evidence of intermediate to long-term patency, and the critical INTERVENTIONAL MANAGEMENT OF UPPER EXTREMITY DVT
need to preserve central venous patency to optimize the function of upper extremity dialysis grafts and fistulas.
Conclusions The optimal algorithm for treatment of upper extremity venous thrombosis remains to be determined. In this regard, as has been emphasized there is a great need for large-scale (and almost by necessity multicenter) controlled studies with careful assessment of outcomes at regular intervals, and with stratification of results according to etiologic categories.13 In all likelihood, the optimal approach will be multidisciplinary and involve both preventive measures and appropriately timed and applied medical, surgical, and interventional therapies. The goals of such therapy should be multiple and include preservation of venous access, prevention of acute thromboembolic complications, and restoration of a functional and asymptomatic premorbid status.
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18. Linblad B, Tengborn L, Bergqvist D: Deep vein thrombosis of the axillary-subclavian veins: epidemiologic date, effects of different types of treatment and late sequelae. Eur J Vasc Surg 2:161-165, 1988 19. Monreal M, Lafoz E, Ruiz J, et al: Upper-extremity deep venous thrombosis and pulmonary embolism. A prospective study. Chest 99:280-283, 1991 20. Kenney BD, David M, Bensoussan AL: Anticoagulation without catheter removal in children with catheter-related central vein thrombosis. J Pediatr Surg 31:816-818, 1996 21. Machleder HI: Evaluation of a new treatment strategy for PagetSchroetter syndrome: spontaneous thrombosis of the axillary-subclavian vein. J Vasc Surg 17:305-317, 1993
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22. Sabeti S, Schillinger M, Mlekusch W, et al: Treatment of subclavianaxillary vein thrombosis: long-term outcome of anticoagulation versus systemic thrombolysis. Thromb Res 108:279-285, 2003 23. Rhodes AI, Gibson M, Al-Katoubi M: Mechanical disruption of a Wallstent in the subclavian vein between clavicle and first rib. J Interveent Radiol 12:151-153, 1997 24. Meier GH, Pollak JS, Rosenblatt M, et al: Initial experience with stents in exertional axillary-subclavian vein thrombosis. J Vasc Surg 24:974-983, 1996 25. Rutherford RB: Primary subclavian-axillary vein thrombosis: the relative roles of thrombolysis, percutaneous angioplasty, stents, and surgery. Semin Vasc Surg 11:91-95, 1998
ALBERT A. NEMCEK, JR.