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    http://vmj.sagepub.com/Vascular Medicine

    http://vmj.sagepub.com/content/16/3/191The online version of this article can be found at:

    DOI: 10.1177/1358863X10395657

    2011 16: 191 originally published online 22 February 2011Vasc MedMichael Czihal and Ulrich Hoffmann

    Upper extremity deep venous thrombosis

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    Vascular Medicine

    16(3) 191202

    The Author(s) 2011

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    DOI: 10.1177/1358863X10395657

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    Division of Vascular Medicine, University Hospital Campus City

    Center, Munich, Germany

    Correspondingauthor:Ulrich Hoffmann

    Division of Vascular Medicine

    University Hospital Campus City Center

    Pettenkoferstrasse 8a

    D-80336 Munich

    Germany

    Email: [email protected]

    Upper extremity deep venous thrombosis

    Michael Czihal and Ulrich Hoffmann

    Abstract

    Upper extremity deep venous thrombosis is a serious disease entity which, based on the pathogenesis and in view ofthe individual patients prognosis, must be divided into a primary and a secondary form. Primary upper extremity deepvenous thrombosis is, when related to effort, a rather benign disease with excellent prognosis quoad vitam, carrying onlya minor potential of developing disabling post-thrombotic syndrome. If primary upper extremity deep venous thrombo-sis occurs without any obvious cause, screening for underlying malignancy is recommended. Secondary upper extremitydeep 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 extremitydeep venous thrombosis is poor. Despite a lack of high-quality validation data, ultrasonography is regarded the rst-lineimaging technique, since it is a non-invasive method without exposure to radiation. In case of a non-diagnostic result ofultrasonography, 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 orunfractionated 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 benet ofcompression therapy as well as of more aggressive therapeutic approaches such as thrombolysis, angioplasty and surgicaldecompression 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 throm-

    bosis of the brachial, subclavian and/or axillary veins and

    accounts for up to 11% of all cases of deep venous throm-

    bosis.1 Usually, the thrombotic process involves more than

    one venous segment, with the subclavian vein most fre-

    quently affected.25 The internal jugular vein, the brachio-

    cephalic 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 com-

    prises different disease entities on the basis of pathogene-

    sis, with considerable differences regarding long-term

    sequelae and mortality.2,8 Primary upper extremity deep

    venous thrombosis is a rare disease occurring spontane-

    ously, 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 syn-drome 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 par-

    ticular 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 clin-

    ical characteristics of primary and secondary upper extrem-

    ity deep venous thrombosis and discuss the diagnostic

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    192 VascularMedicine16(3)

    options available to date as well as the current strategies in

    treatment and prophylaxis.

    Risk factors and pathogenesis

    PrimaryupperextremitydeepvenousthrombosisThrombosis 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 extremi-

    ties.2,8,13 Primary upper extremity deep venous thrombosis

    includes idiopathic thrombosis and effort thrombosis. The

    latter, according to the first describers, also entitled Paget-

    von 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

    Themajor predisposing factor for effort thrombosis is the tho-

    racic outlet syndrome, which is characterized by external

    compression of the neurovascular bundle at the thoracic out-

    let.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 exer-

    cise 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 gen-

    eral 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 extrem-

    ity deep venous thrombosis lacks apparent risk factors or

    obvious underlying diseases.2,8 However, one small obser-

    vational study reported on a high rate (25%) of occult malig-nancies 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 throm-

    bosis was observed in heterozygote carriers of the factor VLeiden 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

    differences in the prevalence of the particular clotting anom-

    alies between patients with upper extremity deep venous

    thrombosis and controls, except for the prothrombin

    G20210A mutation.27,28 Data on the prevalence of antiphos-

    pholipid antibodies in upper extremity deep venous throm-

    bosis are inconsistent.23,24,26,28 Recently, elevated levels of

    several coagulation factors (factor VIII, von Willebrand fac-tor, 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 hemor-

    heological alterations do not seem to contribute to the

    pathogenesis of thrombosis of the arm veins.26,30

    Secondaryupperextremitydeepvenousthrombosis

    Upper extremity deep venous thrombosis is classified as

    secondary in the presence of known endogenous or exoge-

    nous risk factors. The secondary form accounts for abouttwo-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 inter-

    nal jugular vein is also frequently affected. However,

    whether the subclavian or the internal jugular vein are cho-

    sen for vascular access does not seem to affect the risk of

    thrombosis.9 The risk of developing catheter-related throm-

    bosis rather depends on an individual patients profile and on

    factors related to the catheter itself. Cancer patients with ind-

    welling central venous catheters are at particular risk, with

    rates of thrombosis detected by screening venography rang-

    ing from 16% to 66%.32,33 In line with these figures, an ultra-

    sonographic 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 venousthrombosis (23%) was also observed in patients who under-

    went 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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    CzihalMandHoffmannU 193

    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 radio-

    therapy, venous stasis due to immobilization or direct vein

    compression by the tumor itself, and cancer-induced inhibi-

    tion 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 pres-

    ence of distant metastases.25,33 It has been suggested that, at

    least in the presence of an indwelling catheter, ovarian carci-

    noma 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 addi-

    tion, cancer treatment also affects the risk of venous throm-

    boembolism. This has been shown particularly for the use of

    antiangiogenesis agents, such as thalidomide or bevacizu-

    mab.44 Furthermore, administration of erythropoiesis-stimu-

    lating agents is associated with an increased rate of venous

    thromboembolic events in cancer patients.45 However, spe-

    cific data on the risk of upper extremity deep venous throm-

    bosis 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 extrem-ity 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 develop-

    ment of upper extremity deep venous thrombosis is still con-

    troversial, 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 con-

    trary, obesity and postmenopausal hormone replacement

    therapy do not seem to increase the risk.25,46 While the gen-

    eral 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 fre-

    quently the internal jugular veins) related to ovarian hyper-

    stimulation 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 andright 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

    Signsandsymptomsofupperextremitydeepvenousthrombosis

    Patients suffering from upper extremity deep venous throm-

    bosis most commonly present with edematous swelling ofthe 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

    Table 1. Catheter characteristics associated with an increased

    risk of upper extremity deep venous thrombosis9,33,3641

    Left insertion sideMore than one insertion attemptCatheter tip localized proximal to the atriocaval junctionCatheter material (polyethylene, polyvinylchloride > silicon,polyurethane)Number of lumina (triple lumen > double lumen)Prior catheterization at the same puncture siteProlonged catheter dwell time (> 2 weeks)Catheter-related infection/septicemia

    Table 2. Clinical probability score for upper extremity deep

    venous thrombosis59

    Indwelling venous catheter 1 pointLocalized pain 1 pointUnilateral pitting edema 1 pointOther 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.

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    related to indwelling central venous catheters remain com-pletely 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 pulmo-

    nary 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 typ-

    ical feature of cancer-associated venous thromboembolism.10

    Signsandsymptomsofunderlyingthoracic

    outletsyndromeUnderlying thoracic outlet obstruction is mostly asympto-

    matic 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-

    chial plexus and is characterized by arm pain or paresthesia

    radiating to the fourth and fifth digit, worsening with hyper-

    abduction of the shoulder.21 Symptoms related to thoracic

    outlet obstruction with venous compression are rare, typi-

    cally presenting with position-dependent arm swelling and

    cyanosis.16,17 A careful medical history and clinical examina-

    tion are essential for diagnosis of the thoracic outlet syn-drome. 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 com-

    pression: 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 costo-

    pectoral 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, sensi-tivity (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 can-

    not be directly disclosed. It must be pointed out in this con-

    text, 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 (ultra-

    sonography, magnetic resonance imaging, contrast venog-

    raphy) assessment of compression of the vascular structures

    at the thoracic outlet during postural maneuvers may be

    helpful to further establish the diagnosis of venous tho-

    racic outlet syndrome (Figure 3).16,17 Of note, confirmation

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

    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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    CzihalMandHoffmannU 195

    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

    Complications

    Post-thromboticsyndrome

    The post-thrombotic syndrome is a chronic complication of

    upper extremity deep venous thrombosis, leading to signifi-

    cant functional disability and impaired quality of life, in par-

    ticular 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 correlationbetween morphologic and hemodynamic sequelae and devel-

    opment 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 dis-

    tended collateral veins in the shoulder region. Severe post-

    thrombotic syndrome resulting in skin ulceration is virtually

    unknown after upper extremity deep venous thrombosis.5,52,55

    Recurrentupperextremitydeepvenousthrombosis

    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 throm-

    bosis of the upper and lower extremities appear to be simi-

    lar, 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 throm-

    bosis 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 cathe-

    ter.56 Patients with cancer and women could be at higherrisk 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 recur-

    rent 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

    Pulmonaryembolism

    The actual incidence of pulmonary embolism resulting

    from upper extremity deep venous thrombosis is difficult toascertain, as the studies reporting on this complication dif-

    fer with regard to their design (retrospective vs prospec-

    tive), the patient population investigated (percentage of

    patients with effort-related, idiopathic or secondary throm-

    bosis) and the criteria applied for diagnosis of pulmonary

    embolism (symptomatic event vs routine screening). Most

    clinical observations reported rates of symptomatic pulmo-

    nary 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 extremitydeep 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 docu-

    mented pulmonary embolism in 13% and 16% of patients

    with upper extremity deep venous thrombosis, respec-

    tively.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 (parti-cularly 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 supe-

    rior 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

    Mortality

    A striking difference exists between primary and secondary

    upper extremity deep venous thrombosis regarding the

    prognosis quoad vitam. Patients with primary (effort-

    related) 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 signifi-

    cantly higher compared to that of patients with lower

    extremity deep venous thrombosis, of whom 7% haddied 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 with-

    out 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 antico-

    agulation 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

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    Diagnostic strategies

    ClinicalpredictionscoreandD-dimertest

    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 consi-

    sting 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 subse-

    quently 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 sub-

    sequent D-dimer or ultrasound testing have not been evalu-

    ated 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 ultrasonogra-

    phy in 52 patients (23 patients with cancer, 18 patients with

    an indwelling central venous catheter), the test showed asensitivity of 100% but a specificity as low as 14%, result-

    ing 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 meth-

    ods 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 ben-

    efit is questionable,3,60 evaluation of the proximal subcla-

    vian 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 cen-

    trally 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 extrem-

    ity deep venous thrombosis with compression-ultrasonog-

    raphy.60 However, sufficient high-quality validation data is

    still missing because of small sample sizes and/or methodo-logical 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-inva-

    sive 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 combina-

    tion 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

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

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    Otherimagingtechniques

    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 mag-

    netic resonance venography in determining the thrombus

    extent.66,67 On the contrary, Baarslag et al. reported a sensi-

    tivity 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% (three-

    dimensional gadolinium-enhanced magnetic resonance

    venography), respectively. Furthermore, the authors notedthat 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 stand-

    ard, contrast venography today is only exceptionally per-

    formed in suspected upper extremity deep venous thrombosis

    because of its inherited methodological drawbacks, including

    the invasive character and the need for application of iodi-

    nated contrast agents and exposure to radiation. The advan-

    tages 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

    Screeningforthrombophiliaandoccultcancer

    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 stren-

    uous effort, cancer or indwelling central venous catheters,

    regular screening for thrombophilia will only rarely affect

    clinical management. Moreover, as the overall risk of recur-

    rence 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 pro-thrombin 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 thromboem-

    bolism, screening for lupus anticoagulants and anticardioli-

    pin/anti-2-glycoprotein antibodies may also be considered

    in selected patients with upper extremity deep venous throm-

    bosis (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 malig-

    nancies, patients with unexplained upper extremity deep

    venous thrombosis should undergo cancer screening.22

    Screening should be performed in accordance with the

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

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    198 VascularMedicine16(3)

    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 malig-

    nant conditions in patients with venous thromboembolism,aimed to detect early and limited disease stages, will reduce

    cancer-related mortality and morbidity.73

    Treatment and prophylaxis

    Anticoagulanttreatment

    Although it is generally accepted that, as for patients with

    lower extremity deep venous thrombosis, patients with

    (symptomatic) thrombosis of the arm veins require antico-

    agulant treatment to prevent thrombus propagation and pul-

    monary embolism, the optimal treatment duration andintensity so far was not determined in randomized control-

    led trials. Therefore, the management of patients with both

    primary and secondary thrombosis remains controversial.2

    Based on the available data from prospective cohort stud-

    ies,26,55,74,75 the current guidelines recommend initial treat-

    ment 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 anticoagula-

    tion 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 anticoag-

    ulation.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 beyond6 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 pati-

    ents 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 antico-

    agulant therapy for a first unprovoked episode, this treat-ment regimen may be considered in recurrent upper

    extremity deep venous thrombosis.9,76

    Thrombolysis,surgicalandinterventionalmethods

    Thrombolysis aims to early restore venous patency, prima-

    rily to reduce the risk of post-thrombotic syndrome.8

    Thrombolysis may theoretically reduce the rate of throm-

    boembolic recurrences or the need for long-term anticoagu-

    lation, although there are no data available to support thishypothesis. 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 indifferent doses and with different methods of administra-

    tion (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 treat-

    ment of upper extremity deep venous thrombosis are lack-

    ing. 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 thrombo-

    sis 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, angi-

    oplasty with or without stent placement and early or late

    surgical decompression of the thoracic outlet for the treat-

    ment of primary upper extremity deep venous thrombo-

    sis.15,79 Surgical decompression usually involves resection

    of parts of the clavicle and the first rib, supplemented by

    circumferential venolysis and scalenectomy, if appropri-

    ate.8,15,19 As for thrombolysis alone, randomized studies

    comparing a multimodal therapeutic approach to conser-

    vative treatment with anticoagulation alone are lackingand uncertainty exists regarding the long-term benefit.76

    According to the guidelines, surgical decompression may

    be considered in symptomatic patients with failure of med-

    ical 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 con-

    sidered 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 ofthe superior vena cava syndrome due to thrombus forma-

    tion in the filter.2,8

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    CzihalMandHoffmannU 199

    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, cathe-

    ter 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

    Compressiontherapy

    The effectiveness of compression therapy in order to pre-

    vent 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

    PreventionofupperextremitydeepvenousthrombosisDespite data available from several randomized studies,

    controversies remain regarding the value of thrombopro-

    phylaxis in cancer patients with indwelling central venous

    catheters.9,50 By contrast with results from previous pro-

    spective 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 recom-

    mend against the use of LMWHs or vitamin K antagonists

    to prevent upper extremity deep venous thrombosis in can-

    cer 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 malig-

    nancies, with cancer being the major factor for the exces-

    sive 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, suchas compression therapy, thrombolysis and surgical decom-

    pression, needs to be investigated in randomized trials.

    Acknowledgement

    The authors declare that they have no conflicts of interest.

    Funding

    This research received no specific grant from any funding agency

    in the public, commercial, or not-for-profit sectors.

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