Vascular Medicine

http://vmj.sagepub.com/ Upper extremity deep venous thrombosis

Michael Czihal and Ulrich Hoffmann Vasc Med 2011 16: 191 originally published online 22 February 2011 DOI: 10.1177/1358863X10395657 The online version of this article can be found at: http://vmj.sagepub.com/content/16/3/191

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Upper extremity deep venous thrombosis

Michael Czihal and Ulrich Hoffmann

Vascular Medicine 16(3) 191202 The Author(s) 2011 Reprints and permission: sagepub. co.uk/journalsPermissions.nav DOI: 10.1177/1358863X10395657 vmj.sagepub.com

Abstract Upper extremity deep venous thrombosis is a serious disease entity which, based on the pathogenesis and in view of the individual patients prognosis, must be divided into a primary and a secondary form. Primary upper extremity deep venous thrombosis is, when related to effort, a rather benign disease with excellent prognosis quoad vitam, carrying only a minor potential of developing disabling post-thrombotic syndrome. If primary upper extremity deep venous thrombosis occurs without any obvious cause, screening for underlying malignancy is recommended. Secondary upper extremity deep venous thrombosis typically occurs in older patients with severe comorbidities, mainly related to indwelling central venous catheters and cancer. As a consequence of the underlying diseases, prognosis of secondary upper extremity deep venous thrombosis is poor. Despite a lack of high-quality validation data, ultrasonography is regarded the first-line imaging technique, since it is a non-invasive method without exposure to radiation. In case of a non-diagnostic result of ultrasonography, other imaging modalities such as magnetic resonance imaging and computed tomography may be applied. Regardless of the etiology, the cornerstone of therapy is anticoagulant treatment with low molecular weight heparin or unfractionated heparin and vitamin K antagonists in order to prevent thrombus progression and pulmonary embolism. Owing to a lack of evidence, the optimal duration of anticoagulant treatment remains unclear. The additional benefit of compression therapy as well as of more aggressive therapeutic approaches such as thrombolysis, angioplasty and surgical decompression of the thoracic outlet needs to be investigated in randomized trials. Keywords cancer; central venous catheter; Paget-von Schroetter syndrome; thoracic outlet syndrome; upper extremity deep venous thrombosis

Introduction
Upper extremity deep venous thrombosis refers to thrombosis of the brachial, subclavian and/or axillary veins and accounts for up to 11% of all cases of deep venous thrombosis.1 Usually, the thrombotic process involves more than one venous segment, with the subclavian vein most frequently affected.25 The internal jugular vein, the brachiocephalic vein and the basilic vein each are additionally involved in 2030% of patients with upper extremity deep venous thrombosis.57 The term upper extremity deep venous thrombosis comprises different disease entities on the basis of pathogenesis, with considerable differences regarding long-term sequelae and mortality.2,8 Primary upper extremity deep venous thrombosis is a rare disease occurring spontaneously, without clinically apparent risk factors (idiopathic thrombosis) or after strenuous exercise (effort thrombosis). While idiopathic thrombosis gives reason for screening for occult cancer, effort thrombosis is frequently related to the thoracic outlet syndrome and typically occurs in young and physically active individuals. The main complication in the latter patients, otherwise healthy, is post-thrombotic syndrome due to impairment of the venous outflow. In contrast to the primary form, secondary upper extremity deep venous thrombosis develops in consequence of obvious

underlying causes, mainly cancer and indwelling central venous catheters. Owing to the increasing use of central venous catheters in patients with cancer or critical illness, the incidence of catheter-related thrombosis has increased in past decades.9 The excessively increased mortality rate in patients with secondary upper extremity deep venous thrombosis is related to underlying diseases.10 Moreover, it has been shown that thrombosis of the arm veins, in particular secondary upper extremity deep venous thrombosis, carries a substantial risk of pulmonary embolism.11,12 In this review article, we address the risk factors and clinical characteristics of primary and secondary upper extremity deep venous thrombosis and discuss the diagnostic

Division of Vascular Medicine, University Hospital Campus City Center, Munich, Germany Corresponding author: Ulrich Hoffmann Division of Vascular Medicine University Hospital Campus City Center Pettenkoferstrasse 8a D-80336 Munich Germany Email: ulrich.hoffmann@med.uni-muenchen.de

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192 options available to date as well as the current strategies in treatment and prophylaxis.

Vascular Medicine 16(3) differences in the prevalence of the particular clotting anomalies between patients with upper extremity deep venous thrombosis and controls, except for the prothrombin G20210A mutation.27,28 Data on the prevalence of antiphospholipid antibodies in upper extremity deep venous thrombosis are inconsistent.23,24,26,28 Recently, elevated levels of several coagulation factors (factor VIII, von Willebrand factor, fibrinogen) were shown to be independently associated with an increased risk of upper extremity deep venous thrombosis, as was blood group non-0 compared to 0.29 On the contrary, hyperhomocysteinemia as well as hemorheological alterations do not seem to contribute to the pathogenesis of thrombosis of the arm veins.26,30

Risk factors and pathogenesis Primary upper extremity deep venous thrombosis
Thrombosis of the arm veins without evident predisposing factors in the patients history is classified as primary upper extremity deep venous thrombosis and accounts for up to one-third of all thromboses involving the upper extremities.2,8,13 Primary upper extremity deep venous thrombosis includes idiopathic thrombosis and effort thrombosis. The latter, according to the first describers, also entitled Pagetvon Schroetter syndrome, typically occurs in the dominant arm after strenuous, repetitive or unusual physical activity, such as weight lifting, rowing or playing tennis.14,15 The affected individuals are usually young and otherwise healthy; the male to female ratio is approximately 2:1.15 The major predisposing factor for effort thrombosis is the thoracic outlet syndrome, which is characterized by external compression of the neurovascular bundle at the thoracic outlet.15,16 Whereas venous thoracic outlet syndrome accounts for only 23% of all cases with thoracic outlet syndrome, it is frequently found in patients with primary upper extremity deep venous thrombosis.17,18 It has been hypothesized that intermittent and positional vein compression during exercise results in repeated microtrauma of the vessel intima with consecutive activation of the coagulation cascade.13 Repeated vessel trauma may also lead to perivascular scar tissue formation with persistent vein compression.8,15,19 In most of these cases, etiology is believed to be compression of the subclavian vein due to congenital narrowing of the space bounded by the clavicle, the first rib, the subclavian muscle tendon and the costoclavicular ligament.15,16 Whereas compression of the subclavian vein by the anterior scalene muscle and constriction of the axillary vein by the pectoralis minor muscle are more unusual causes, cervical ribs in general are not considered to be relevant for the development of venous thoracic outlet syndrome.15,16,20,21 Medical history of subjects with idiopathic upper extremity deep venous thrombosis lacks apparent risk factors or obvious underlying diseases.2,8 However, one small observational study reported on a high rate (25%) of occult malignancies in this subgroup of patients.22 Moreover, albeit the rate is somewhat lower compared to lower extremity deep venous thrombosis, inherited or acquired coagulopathies are found in a substantial number of patients with thrombosis of the arm veins (e.g. upper extremity deep venous thrombosis 34.2% vs lower extremity deep venous thrombosis 55.3% in the German MAISTHRO registry).23 The prevalence of coagulation abnormalities appears to be even higher in patients with idiopathic thrombosis than in those with effort thrombosis or catheter-related thrombosis.23,24 In particular, a higher frequency of upper extremity deep venous thrombosis was observed in heterozygote carriers of the factor V Leiden and prothrombin G20210A mutation and in patients with antithrombin-, protein C- or protein S-deficiency.25,26 However, these findings still are controversially discussed, since other casecontrol studies did not find consistent

Secondary upper extremity deep venous thrombosis

Upper extremity deep venous thrombosis is classified as secondary in the presence of known endogenous or exogenous risk factors. The secondary form accounts for about two-thirds of all cases with upper extremity deep venous thrombosis and usually affects older patients with severe comorbidities.2,8,13 The most important risk factor for upper extremity deep venous thrombosis is the presence of an indwelling central venous catheter.1,25 Owing to the increased use of central venous catheters for administration of medication, blood products and parenteral nutrition as well as for hemodialysis, the incidence of catheter-related thrombosis has increased in past decades, and today a central venous catheter is present in at least every second patient with thrombosis of the arm veins.8,10,31 Dependent on the catheters entry site, the internal jugular vein is also frequently affected. However, whether the subclavian or the internal jugular vein are chosen for vascular access does not seem to affect the risk of thrombosis.9 The risk of developing catheter-related thrombosis rather depends on an individual patients profile and on factors related to the catheter itself. Cancer patients with indwelling central venous catheters are at particular risk, with rates of thrombosis detected by screening venography ranging from 16% to 66%.32,33 In line with these figures, an ultrasonographic screening study in patients with hematological disorders and indwelling central venous catheters reported a cumulative incidence of catheter-related thrombosis of 29%.34 A high frequency of upper extremity deep venous thrombosis (23%) was also observed in patients who underwent implantation of permanent pacemaker leads.35 Inherited coagulation disorders (the factor V Leiden and prothrombin G20210A mutation) seem to result in a threefold increased risk of developing catheter-associated thrombosis.36 Catheter-related factors that have been reported to increase the risk of thrombosis include the type and material of the catheter, position of the catheter tip, catheter infection and a history of prior central venous catheterization (Table 1).9,33,3641 Whether an ultrasound guided-insertion technique reduces the risk of thrombosis, when compared to a landmark-guided technique, is currently not known. Malignancy is the other main risk factor for secondary upper extremity deep venous thrombosis. Even though the thrombotic risk in cancer patients mainly results from indwelling central venous catheters, active malignancy in

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Table 1. Catheter characteristics associated with an increased risk of upper extremity deep venous thrombosis9,33,3641 Left insertion side More than one insertion attempt Catheter tip localized proximal to the atriocaval junction Catheter material (polyethylene, polyvinylchloride > silicon, polyurethane) Number of lumina (triple lumen > double lumen) Prior catheterization at the same puncture site Prolonged catheter dwell time (> 2 weeks) Catheter-related infection/septicemia

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Table 2. Clinical probability score for upper extremity deep venous thrombosis59 Indwelling venous catheter 1 point Localized pain 1 point Unilateral pitting edema 1 point Other diagnosis at least as plausible 1 point 0 low clinical probability (rate of thrombosis: 13%) 1 intermediate clinical probability (rate of thrombosis: 38%) 2 high clinical probability (rate of thrombosis: 69%)

Figure 1. Etiology of upper extremity deep venous thrombosis.

patients without central venous catheters in the MEGA study resulted in an 18-fold increased risk of upper extremity deep venous thrombosis.25 In large cohort studies, 2238% of the patients with thrombosis of the arm veins had cancer.1,10,25,31,42 The thrombotic process is thought to be multifactorial, with endothelial damage caused by indwelling catheters or radiotherapy, venous stasis due to immobilization or direct vein compression by the tumor itself, and cancer-induced inhibition of natural anticoagulants and fibrinolysis as well as release of prothrombotic factors.9,43 Of note, the risk of developing deep venous thrombosis increases in the presence of distant metastases.25,33 It has been suggested that, at least in the presence of an indwelling catheter, ovarian carcinoma and lung adenocarcinoma could carry a particularly increased risk of upper extremity deep venous thrombosis, when compared with other malignant entities.9,39,41 In addition, cancer treatment also affects the risk of venous thromboembolism. This has been shown particularly for the use of antiangiogenesis agents, such as thalidomide or bevacizumab.44 Furthermore, administration of erythropoiesis-stimulating agents is associated with an increased rate of venous thromboembolic events in cancer patients.45 However, specific data on the risk of upper extremity deep venous thrombosis related to cancer treatment are not available.9 Another evident risk factor for thrombosis of the arm veins is upper extremity immobilization by plaster casts or following arm surgery.25 Previous episodes of lower extremity deep venous thrombosis are found in 18% of these cases, and a history of lower extremity deep venous thrombosis or a family history of venous thromboembolism also increase the risk of upper extremity deep venous thrombosis.3,25 The

association between oral contraceptive use and the development of upper extremity deep venous thrombosis is still controversial, but women taking oral contraceptives and carrying the factor V Leiden or prothrombin G20210A mutation appear to be at particular risk.3,25,26,28 On the contrary, obesity and postmenopausal hormone replacement therapy do not seem to increase the risk.25,46 While the general risk of upper extremity deep venous thrombosis related to pregnancy has not been assessed, some case reports raised concerns about thrombosis of the arm veins (and more frequently the internal jugular veins) related to ovarian hyperstimulation syndrome, a serious complication of in vitro fertilization.47 In this group of patients, the site specificity may be explained by excessively elevated estrogen levels in the peritoneal fluid, which is drained via the thoracic and right lymphatic duct into the upper extremity veins with consecutive local activation of the coagulation cascade.48 The main risk factors for upper extremity deep venous thrombosis are summarized in Figure 1.

Clinical presentation Signs and symptoms of upper extremity deep venous thrombosis
Patients suffering from upper extremity deep venous thrombosis most commonly present with edematous swelling of the affected arm and/or upper extremity discomfort or pain.1,3 Other clinical features such as cyanosis, visible collateral veins at the shoulder girdle (Figure 2) or jugular distension are less frequently found.49 Of note, most thrombotic events

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Vascular Medicine 16(3) chial plexus and is characterized by arm pain or paresthesia radiating to the fourth and fifth digit, worsening with hyperabduction of the shoulder.21 Symptoms related to thoracic outlet obstruction with venous compression are rare, typically presenting with position-dependent arm swelling and cyanosis.16,17 A careful medical history and clinical examination are essential for diagnosis of the thoracic outlet syndrome. Several clinical provocative tests such as the military-exercise test (Edens test) and the hyperabduction test (Wrights maneuver) are described in the literature. Edens test is applied for diagnosis of costoclavicular compression: the patient is asked to breathe in and to retract his/ her shoulders, while the examiner draws the patients arm down. Wrights maneuver (retraction of the hyperabducted, externally rotated arm) is useful for the detection of costopectoral compression. However, although frequently used for the evaluation of suspected thoracic outlet obstruction, diagnostic accuracy of provocative maneuvers is unclear as a diagnostic gold standard is missing and, on average, sensitivity (73%) and specificity (53%) are low.17 Moreover, positive results are only indirectly indicated by the onset of neurological symptoms, pulse attenuation or a subclavian artery bruit.17 In the majority of cases with suspected venous thoracic outlet syndrome, subclavian vein compression cannot be directly disclosed. It must be pointed out in this context, that Adsons maneuver appears to be of little value in suspected venous thoracic outlet syndrome, since it aims to detect compression within the interscalene triangle, where only the brachial nerve and the subclavian artery run. In view of these limitations, additional dynamic testing with indirect (pulse volume recording) and direct (ultrasonography, magnetic resonance imaging, contrast venography) assessment of compression of the vascular structures at the thoracic outlet during postural maneuvers may be helpful to further establish the diagnosis of venous thoracic outlet syndrome (Figure 3).16,17 Of note, confirmation

Figure 2. Dilatation of subcutaneous collateral veins in a patient with left-sided upper extremity deep venous thrombosis.

related to indwelling central venous catheters remain completely subclinical and may only be discovered during the diagnostic workup of catheter sepsis, catheter dysfunction with an inability to draw blood from the catheter, or pulmonary embolism.34,50 Low-grade fever may be caused by venous thromboembolism, but can also be the heralding sign of underlying malignancy. Higher fever occurs with catheter sepsis or septic thrombophlebitis.8 Simultaneous occurrence of bilateral upper extremity deep venous thrombosis is a typical feature of cancer-associated venous thromboembolism.10

Signs and symptoms of underlying thoracic outlet syndrome

Underlying thoracic outlet obstruction is mostly asymptomatic prior to effort thrombosis. If clinically apparent, the thoracic outlet syndrome usually (more than 90%) presents with neurological symptoms due to compression of the bra-

Figure 3. Non-occluding thrombus of the right subclavian vein with prominent collateral veins in a patient with effort thrombosis (A). Hyperabduction leads to complete venous compression with a stop in venous blood flow (B).

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Czihal M and Hoffmann U of venous compression does not necessarily imply a clinically relevant syndrome since this phenomenon is also frequently observed in asymptomatic individuals during arm elevation.51

195 patients with effort-related, idiopathic or secondary thrombosis) and the criteria applied for diagnosis of pulmonary embolism (symptomatic event vs routine screening). Most clinical observations reported rates of symptomatic pulmonary embolism between 3% and 12%.1,3,4,8,10,12,31,55 This number is considerably lower compared to the frequency of clinically overt pulmonary embolism in lower extremity deep venous thrombosis, which was between 16% and 29% in large registries.1,10 Prandoni et al. revealed pulmonary embolism using routine perfusion-scintigraphy in as much as 8 of 22 prospectively evaluated patients (36%) with thrombosis of the arm veins.3 In earlier studies using screening scintigraphy, Monreal and co-workers documented pulmonary embolism in 13% and 16% of patients with upper extremity deep venous thrombosis, respectively.11,57 Carriers of central venous catheters suffering from upper extremity deep venous thrombosis appear to be at particular risk of developing pulmonary embolism, whereas in primary thrombosis of the arm veins (particularly in effort thrombosis) pulmonary embolism seems to be a rare complication.11,12 Symptoms of pulmonary embolism include dyspnoea, visceral or pleuritic chest pain, syncope, low-grade fever and sinus tachycardia. Sinus tachycardia may also occur due to obstruction of the superior vena cava, a potentially life-threatening condition going along with facial edema, vertigo, vision disturbances and dyspnoea.1 Fatal pulmonary embolism is an extremely rare event under therapeutic anticoagulation.13,10,31,57

Complications Post-thrombotic syndrome

The post-thrombotic syndrome is a chronic complication of upper extremity deep venous thrombosis, leading to significant functional disability and impaired quality of life, in particular when occurring in the dominant arm.52 There is currently no accepted diagnostic standard available for the diagnosis of this disorder. Depending on the criteria applied, frequencies of post-thrombotic syndrome vary considerably, ranging from 7% to 46%.53 The post-thrombotic syndrome seems to occur less frequently after catheter-associated thrombosis.52 Noteworthy, there is no clear correlation between morphologic and hemodynamic sequelae and development of the post-thrombotic syndrome.5,7,54 Symptoms include edema, persistent pain or heaviness of the affected arm, limb fatigue with exertion, skin discoloration and distended collateral veins in the shoulder region. Severe postthrombotic syndrome resulting in skin ulceration is virtually unknown after upper extremity deep venous thrombosis.5,52,55

Recurrent upper extremity deep venous thrombosis

The 2-year cumulative incidence rates of recurrent venous thromboembolism after a first episode of upper extremity deep venous thrombosis range between 4% and 8%.10,26,42,55 Thus, the overall recurrence rates after deep venous thrombosis of the upper and lower extremities appear to be similar, while patients with idiopathic thrombosis of the arm veins exhibit a significantly lower risk of recurrence when compared to subjects with idiopathic lower extremity deep venous thrombosis.4,10 Upper extremity deep venous thrombosis associated with an indwelling catheter goes along with a decreased risk of recurrent thromboembolic events. On the other hand, once a catheter is removed after a thrombotic event there is a high probability (up to 86%) of recurrent thrombosis at the insertion side of a new catheter.56 Patients with cancer and women could be at higher risk for recurrence.10,42 In a longitudinal study by Martinelli and co-workers, the presence of thrombophilia was not associated with a significant increase in the risk of recurrent thrombosis.26 Another cohort study failed to document an association between the number of recurrent events of upper extremity deep venous thrombosis and the presence of the factor V Leiden or prothrombin G20210A mutation.42

Mortality
A striking difference exists between primary and secondary upper extremity deep venous thrombosis regarding the prognosis quoad vitam. Patients with primary (effortrelated) thrombosis are typically young and otherwise healthy, whereas subjects with secondary thrombosis of the arm veins are frequently of advanced age and/or troubled by chronic medical conditions. Hence, this latter group has a considerably worse outcome, with cancer being the major cause of death.42,58 In the RIETE Registry, the overall 3-month mortality rate of patients with upper extremity deep venous thrombosis was 11%, a percentage significantly higher compared to that of patients with lower extremity deep venous thrombosis, of whom 7% had died within 3 months after diagnosis. The subgroup of patients with known malignancy had a very poor prognosis, with a death rate reaching from 16% in cancer patients with catheter-related thrombosis to 28% in cancer patients without an indwelling central venous catheter (Figure 4).10 Hingorani et al. also observed an excessive mortality rate of 28% after 2 months in their cohort of patients with upper extremity deep venous thrombosis. They found that the presence of a central venous catheter, concomitant lower extremity deep venous thrombosis, not undergoing anticoagulation and the placement of a superior vena cava filter were associated with an increased short-term mortality.31 Other cohort studies reported on mortality rates between 21% and 50% in patients with thrombosis of the arm veins after a mean follow-up of between 2 and 4 years.42,55,58

Pulmonary embolism
The actual incidence of pulmonary embolism resulting from upper extremity deep venous thrombosis is difficult to ascertain, as the studies reporting on this complication differ with regard to their design (retrospective vs prospective), the patient population investigated (percentage of

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Figure 4. Three-month mortality rate of upper extremity deep venous thrombosis according to data from the RIETE-registry.10

Diagnostic strategies Clinical prediction score and D-dimer test

The clinical signs and symptoms of upper extremity deep venous thrombosis are non-specific. Alternative diagnoses include thrombophlebitis, cellulitis, venous congestion due to external vessel compression and lymphatic edema.3 Constans and colleagues proposed a clinical probability score for upper extremity deep venous thrombosis consisting of four items and yielding a sensitivity of 78% and a specificity of 64% (Table 2).59 However, in the group with the low clinical probability still 13% of patients subsequently were diagnosed with thrombosis of the arm veins.59,60 Therefore, objective diagnostic testing to confirm or exclude upper extremity deep venous thrombosis is mandatory.2,3,8,9 Unlike in deep venous thrombosis of the lower limbs, diagnostic algorithms based on clinical probability and subsequent D-dimer or ultrasound testing have not been evaluated in upper extremity deep venous thrombosis. So far, there is only one small study reporting on the diagnostic accuracy of the D-dimer test in patients suspected of having thrombosis of the arm veins. Compared with ultrasonography in 52 patients (23 patients with cancer, 18 patients with an indwelling central venous catheter), the test showed a sensitivity of 100% but a specificity as low as 14%, resulting in positive and negative predictive values of 32% and 100%, respectively.61 Given the high prevalence of cancer and critical illness among in-hospital patients with upper extremity deep venous thrombosis, D-dimer testing in these patients seems to be of limited value for the diagnostic workup. By contrast, a diagnostic algorithm including D-dimer testing may be more efficient in outpatients with suspected primary thrombosis of the arm veins, as most of these patients do not have relevant comorbidities.9,60,61

Ultrasonography
Ultrasonography has replaced other non-invasive methods such as strain-gauge plethysmography, which only indirectly assess venous patency. A complete examination

should include compression sonography (transverse plain) of the internal jugular vein, the brachial and axillary vein, and the subclavian vein distal to the clavicle. The cephalic vein and the basilic vein at their confluence with the deep venous system should also be visualized. Thrombosis is characterized by incomplete compressibility of the venous segment examined. Although the additional diagnostic benefit is questionable,3,60 evaluation of the proximal subclavian veins and the brachiocephalic veins on both sides by pulsed wave- and color Doppler ultrasonography may be helpful to assess venous patency. Examination of these centrally situated venous segments requires a supraclavicular approach and may necessitate the use of a phased array transducer. Unilateral conversion of the normal biphasic flow pattern into a non-pulsatile, continuous flow signal suggests central venous obstruction as an indirect sign of proximal thrombosis of the arm veins (Figure 5).62,63 Once a catheter is removed after catheter-induced thrombosis, it is reasonable to perform another ultrasound to establish a new baseline. A recent systematic review reported a sensitivity of 97% and a specificity of 96% for the diagnosis of upper extremity deep venous thrombosis with compression-ultrasonography.60 However, sufficient high-quality validation data is still missing because of small sample sizes and/or methodological shortcomings of the studies available.3,60,64,65 Despite these limitations, ultrasonography today is regarded the first-line diagnostic imaging procedure in suspected upper extremity deep venous thrombosis, since it is a non-invasive and inexpensive method without exposure to radiation. Interobserver agreement can be considered to be high in experienced centers.3 However, the safety of withholding anticoagulation therapy in symptomatic patients with a negative ultrasonography study still remains uncertain.3,65 There are also no data on the value of diagnostic algorithms including serial sonographic examinations or the combination of pretest probability and a single sonographic study. In case of central venous obstruction or a non-diagnostic ultrasonography in subjects with high clinical suspicion (e.g. in patients with indwelling central venous catheters), additional imaging techniques are required.2,9,60

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Figure 5. Side difference of the venous flow in the distal subclavian vein in a patient with thrombosis of the proximal right subclavian vein. (A) Normal biphasic flow pattern; (B) continuous flow signal.

Other imaging techniques

Only preliminary data are available regarding the diagnostic value of magnetic resonance- and computed tomography venography.60 Potential advantages include the visualization of the central thoracic veins as well as collateral pathways and the confirmation of alternative diagnoses, in particular vein compression caused by local tumor growth.2,8,9 In two cohort studies, magnetic resonance imaging (time-of-flight magnetic resonance venography on a 1-Tesla unit in one study, three-dimensional gadolinium-enhanced magnetic resonance venography on a 1.5-Tesla unit in another study) was compared with other imaging modalities (contrast venography and ultrasonography) in some of the patients investigated. The results were promising, showing a high diagnostic accuracy and even an additional benefit of magnetic resonance venography in determining the thrombus extent.66,67 On the contrary, Baarslag et al. reported a sensitivity and specificity of magnetic resonance venography (1.5-Tesla unit) compared with contrast venography of only 71% and 89% (time-of-flight) and 50% and 80% (threedimensional gadolinium-enhanced magnetic resonance venography), respectively. Furthermore, the authors noted that for several reasons (e.g. pacemaker, claustrophobia) magnetic resonance imaging was not feasible in one-third of the patients.68 Newer studies utilizing advanced magnetic resonance imaging-techniques are lacking. Surprisingly, the value of computed tomography venography for diagnosis of upper extremity deep venous thrombosis so far has not been systematically evaluated. To date, magnetic resonance imaging and computed tomography should be considered as supplemental methods to be applied in case of unequivocal or negative results of ultrasonography despite high clinical suspicion. Further evidence is needed to clearly establish the diagnostic benefit of both imaging modalities. Although still considered the diagnostic reference standard, contrast venography today is only exceptionally performed in suspected upper extremity deep venous thrombosis because of its inherited methodological drawbacks, including

the invasive character and the need for application of iodinated contrast agents and exposure to radiation. The advantages of the method are the ability to visualize the entire deep venous system and to delineate functional vein compression as well as the collateral circulation (Figure 3).8,69

Screening for thrombophilia and occult cancer

According to results from large registries, hypercoaguable states seem to be a rather frequent finding in upper extremity deep venous thrombosis.23 As stated above, there is currently no evidence for an association between the presence of thrombophilic factors and an increased recurrence rate after a first episode of thrombosis of the arm veins.26,42 As the vast majority of thrombotic episodes are causally related to strenuous effort, cancer or indwelling central venous catheters, regular screening for thrombophilia will only rarely affect clinical management. Moreover, as the overall risk of recurrence is low and data regarding the benefit of a prolonged anticoagulation are lacking, there is currently no scientific basis to recommend general screening for thrombophilia in upper extremity deep venous thrombosis.70 From a clinical perspective, screening for the factor V Leiden and prothrombin G20210A mutation and for antithrombin-, protein C- or protein S-deficiency might be advisable in patients with a positive family history of venous thromboembolism and in the small group of patients with otherwise unexplained upper extremity deep venous thrombosis.2,23 Based on the documented benefit of long-term anticoagulation in patients with the antiphospholipid syndrome and venous thromboembolism, screening for lupus anticoagulants and anticardiolipin/anti-2-glycoprotein antibodies may also be considered in selected patients with upper extremity deep venous thrombosis (e.g. subjects with concomitant arterial thrombosis and women with a history of recurrent pregnancy loss).71,72 In view of the potential risk of underlying occult malignancies, patients with unexplained upper extremity deep venous thrombosis should undergo cancer screening.22 Screening should be performed in accordance with the

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198 recommendations for patients with lower extremity deep venous thrombosis, including a detailed medical history and physical examination, routine laboratory analysis, abdominal ultrasound, chest X-ray and completion of the age- and sex-specific screening measures. It should be pointed out that it is unknown whether screening for malignant conditions in patients with venous thromboembolism, aimed to detect early and limited disease stages, will reduce cancer-related mortality and morbidity.73

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Thrombolysis, surgical and interventional methods

Thrombolysis aims to early restore venous patency, primarily to reduce the risk of post-thrombotic syndrome.8 Thrombolysis may theoretically reduce the rate of thromboembolic recurrences or the need for long-term anticoagulation, although there are no data available to support this hypothesis. A large number of mainly retrospective studies have reported encouraging results of thrombolytic therapy alone or in combination with surgical decompression and/ or percutaneous transluminal angioplasty with or without stenting of the subclavian vein for restoration of venous patency in upper extremity deep venous thrombosis.15,76,79 In cases with upper extremity deep venous thrombosis associated with acute thrombotic superior vena cava obstruction, thrombolytic therapy eventually supported by angioplasty and stenting of the superior vena cava may even be life-saving.8 Various protocols with streptokinase, urokinase and recombinant tissue plasminogen activator in different doses and with different methods of administration (intravenous, catheter-directed) have been applied, mostly in patients with primary thrombosis of the arm veins.15,76,79 However, randomized studies comparing thrombolysis with anticoagulation alone for the initial treatment of upper extremity deep venous thrombosis are lacking. Since severe post-thrombotic syndrome is almost never observed after conservative treatment of upper extremity deep venous thrombosis, it remains unclear to what extent patients may benefit from thrombolysis in the long-term.5,52 According to the current guidelines, thrombolytic therapy may be considered in selected patients with acute thrombosis of the arm veins and severe symptoms but low bleeding risk.76 Based on single-center series, some authors recommend a multimodal approach combining thrombolysis, angioplasty with or without stent placement and early or late surgical decompression of the thoracic outlet for the treatment of primary upper extremity deep venous thrombosis.15,79 Surgical decompression usually involves resection of parts of the clavicle and the first rib, supplemented by circumferential venolysis and scalenectomy, if appropriate.8,15,19 As for thrombolysis alone, randomized studies comparing a multimodal therapeutic approach to conservative treatment with anticoagulation alone are lacking and uncertainty exists regarding the long-term benefit.76 According to the guidelines, surgical decompression may be considered in symptomatic patients with failure of medical treatment and confirmation of venous compression at the thoracic outlet.76 Venous bypass grafting is generally not recommended as grafts may frequently fail because of low venous pressure and flow.8,76 Placement of superior vena cava filters may only be considered in patients with contraindications for anticoagulant treatment and pulmonary embolism.76 The potential benefit must be outweighed against the significant risks of filter placement, including filter dislocation and development of the superior vena cava syndrome due to thrombus formation in the filter.2,8

Treatment and prophylaxis Anticoagulant treatment

Although it is generally accepted that, as for patients with lower extremity deep venous thrombosis, patients with (symptomatic) thrombosis of the arm veins require anticoagulant treatment to prevent thrombus propagation and pulmonary embolism, the optimal treatment duration and intensity so far was not determined in randomized controlled trials. Therefore, the management of patients with both primary and secondary thrombosis remains controversial.2 Based on the available data from prospective cohort studies,26,55,74,75 the current guidelines recommend initial treatment with low molecular weight heparin (LMWH) or unfractionated heparin, followed by vitamin K antagonists (target INR: range 2.03.0 for at least 3 months).76 Even in the presence of severe comorbidities, outpatient treatment may be feasible in many patients.70 The necessity to remove a central venous catheter in catheter-related thrombosis depends on the ongoing need for a vascular access. If the device is functional and further required for the patients care, it can be left on site.9,50,75,76 If so, it is recommended to continue anticoagulation as long as the catheter remains in place. Therapeutic anticoagulation should not be shortened to fewer than 3 months after catheter removal.76 The treatment of patients with active malignancy suffering from upper extremity deep venous thrombosis is particularly challenging, as these patients have an increased risk of recurrence but also an increased incidence of major bleeding complications under anticoagulation.10 In patients with venous thromboembolism and cancer, anticoagulation is recommended for at least 36 months.9 Since there are no data for the time period beyond 6 months, indication for treatment continuation thereafter depends on the tumor activity and the individual bleeding risk. On the basis of data on cancer-associated lower extremity deep venous thrombosis, indicating a lower recurrence risk but similar bleeding risk, the use of LMWH may be preferred over vitamin K antagonists also in patients with upper extremity deep venous thrombosis.9,77,78 However, there are no specific data available regarding the use of LMWH or newer anticoagulants for the long-term treatment of upper extremity deep venous thrombosis.76 While there is no evidence to support indefinite anticoagulant therapy for a first unprovoked episode, this treatment regimen may be considered in recurrent upper extremity deep venous thrombosis.9,76

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Czihal M and Hoffmann U A high level of evidence from randomized studies exists for low-dose thrombolytic treatment of catheter-dysfunction due to thrombotic luminal occlusion.9,50 For example, catheter function was restored in 74% of the patients treated with recombinant tissue plasminogen activator (2 mg per 2 ml) compared to 17% of patients in the placebo arm in a study by Ponec et al. The associated bleeding risk was negligible.80 Acknowledgement
The authors declare that they have no conflicts of interest.

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Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

References
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Compression therapy
The effectiveness of compression therapy in order to prevent the post-thrombotic syndrome after thrombosis of the arm veins is unclear and this treatment modality hence is not generally recommended by the current guidelines.52,76 The use of elastic bandages or elastic compression sleeves is suggested only for patients with persistent symptoms of the post-thrombotic syndrome.76

Prevention of upper extremity deep venous thrombosis

Despite data available from several randomized studies, controversies remain regarding the value of thromboprophylaxis in cancer patients with indwelling central venous catheters.9,50 By contrast with results from previous prospective studies, more recent large-scale randomized trials did not show a significant benefit of the prophylactic use of either low-dose warfarin (1 mg once daily) or LMWH in this patient population.8184 In accordance with the results of various meta-analyses, the current guidelines of the American College of Chest Physicians therefore recommend against the use of LMWHs or vitamin K antagonists to prevent upper extremity deep venous thrombosis in cancer patients with indwelling central venous catheters.8588 This recommendation also applies for critically ill patients with indwelling catheters not suffering from cancer, since for this group of patients no clear benefit of anticoagulant prophylaxis was observed in small randomized studies.50

Conclusion
Primary upper extremity deep venous thrombosis occurs either idiopathically or is effort-related. Occult malignancy is a frequent underlying cause of idiopathic thrombosis, whereas effort-related thrombosis (Paget-von Schroetter syndrome) results from venous obstruction at the thoracic outlet. The main causes for secondary upper extremity deep venous thrombosis are central venous catheters and malignancies, with cancer being the major factor for the excessive mortality rate in these patients. Diagnosis of thrombosis of the arm veins is based on imaging methods, primarily ultrasonography. The cornerstone of treatment in all patients with upper extremity deep venous thrombosis is anticoagulation with LMWH and vitamin K antagonists in order to prevent thrombus progression and pulmonary embolism. The benefit of other treatment modalities, such as compression therapy, thrombolysis and surgical decompression, needs to be investigated in randomized trials.

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