**4. Risk factors for arm vein thrombosis**

Compared to deep vein thrombosis of the legs, local factors play a dominant role in deep arm vein thrombosis. By far the highest risk for thrombosis in this region is caused by foreign material in the lumen of the arm veins, most importantly indwelling central venous catheters and pacemaker leads. The odds ratio for arm vein thrombosis of patients carrying these intravascular devices compared to patients that do not has been reported to be as high as 10 to more than 1000 (Joffe et al*.*, 2004; Blom et al*.*, 2005), Table 1. This large variation in risk may in part be explained by specific features of the central venous catheter, as e.g. catheter type and material, site, technique and level of insertion as reviewed by Van Rooden et al*.*, 2005. Additional factors that have an impact on the risk of thrombosis in patients with central venous catheters include the number of punctures during catheter insertion, the duration of catheterization, the fluid administered, and catheter related infections (Koksoy et al*.*, 1995; Hernandez et al*.*, 1998; Martin et al*.*, 1999). In addition, wrong placement of the catheter tip in the upper half of the superior vena cava, subclavian or innominate veins results in a higher risk of thrombosis (Luciani et al*.*, 2001; Verso et al*.*, 2008). Implanted port a cath systems and pacemaker leads significantly increase the risk of arm vein thrombosis as well (Van Rooden et al*.*, 2004; Goltz et al*.*, 2010). The major pathogenetic mechanism appears to be the thrombogenicity of the foreign material itself. Other possible factors include injury of the vascular wall and disturbances of venous blood flow (Beathard, 2001). Different types of thrombi associated with central venous catheters have been described, ranging from fibrin sleeves that may be embolized following catheter removal, nonocclusive mural thrombi and complete venous obstruction (Brismar et al., 1981; Martin et al. 1999; Beathard, 2001). The second major risk factor for arm vein thrombosis is the presence of active malignant disease. Since chemotherapeutic agents are frequently delivered via central venous catheters, both major risk factors are often present in cancer patients. However, malignant disease carries a significant risk also in the absence of foreign material in the arm veins. The mechanisms by which malignant tumors promote thrombosis in various venous segments include local arrosion or invasion of blood vessels, hypercoagubility of the blood by the expression of tumor antigens, and stasis by tumor compression of venous segments proximal to the site of thrombosis (Sood, 2009; Martinelli et al*.*, 2010). It is the experience of clinicians treating patients with thrombosis that this disease is most aggressive and difficult to treat in tumor patients. Hospitalisation has also been cited as a strong risk factor, which may be explained by the increasing frequency of complex therapeutic regimens requiring central venous lines for various indications (Joffe et al*.*, 2004; Mai & Hunt, 2011). Other major risk factors are listed in Table 1 and include local factors (arm surgery, arm injury and immobilisation of the upper extremities by plaster casts), unusual strenuous arm exercise ("thrombosis par effort"), a family history of venous thromboembolism and inherited forms of thrombophilia, and the use of estrogen containing contraceptive drugs (Martinelli et al*.*, 2004; Joffe et al*.*, 2004; Blom et al*.*, 2005). Although cited frequently, a thoracic outlet syndrome is diagnosed in comparably few cases (Blom et al*.*, 2005). Several unusual risk factors for arm vein thrombosis have been reported in case reports, including backpacking (Schoen et al., 2007), portable computer games (Phipps & Joo, 2008), ambulatory blood pressure monitoring (Marschang et al*.*, 2008), intravenous calcium guconate injection (Chen et al*.*, 2009), and infraclaviculary lipoma (Palamari et al*.*, 2010). Interestingly, two known risk factors for lower extremity deep vein thrombosis, namely age and obesity, do not appear to confer additional risk for upper deep vein thrombosis (Joffe et al*.*, 2004; Mai & Hunt, 2011). Isolated thrombosis of the internal jugular vein may be observed in the context of two

Deep Vein Thrombosis of the Arms 133

of the subclavian vein at the costoclavicular junction. This syndrome is usually precipitated by musculoskeletal compression and / or repetitive microtrauma by strenuous arm exercise (thrombosis par effort) (Constans et al*.*, 2008; Illig & Doyle, 2010). In some cases, a compression of the subclavian vein by muscular hypertophy (anterior scalenus muscle, subclavian muscle) or by the clavicle and the first rib with extreme arm movements (hyperabduction and elevation) may be responsible (thoracic outlet syndrome). Likewise, the syndrome has been linked to certain sport activities, as e.g. weight lifters, baseball pitchers or tennis players (Sheeran et al*.*, 1997; van Stralen et al*.*, 2005). It is observed more frequently in young patients, men (2:1), and in the dominant extremity (Illig & Doyle, 2010). The typical clinical presentation of this syndrome is a sudden onset of the typical symptoms of deep vein thrombosis described above (Illig & Doyle, 2010). Isolated thrombosis of the internal jugular vein is a rare disease which may be due to local (central venous catheters, recent oropharyngeal infections with anaerobic bacteria like fusobacterium necrophorum) or systemic factors (cancer, thrombophilia, ovarian hyperstimulation syndrome) (Sheikh et al*.*, 2002; Gbaguidi et al*.*, 2011). Lemierre´s syndrome, first described in 1910, is a severe condition of septic thrombosis following oropharyngeal infections, mostly due to fuosbacterium necrophorum. This syndrome is also known as human necrobacillosis or post-anginal septicaemia. Besides local symptoms (cervical edema, localized pain, dilated superficial collateral veins, erythrocyanosis, indurated vein), severe systemic complications like septicaemia and septic pulmonary embolism may occur (Vargiami & Zafeiriou, 2010;

When evaluating patients for clinical signs of deep arm vein thrombosis, it is important to bear in mind possible alternative diagnoses. These include e.g. superficial thrombophebitis, paravasates after peripheral infusions, lymphedema, cellulitis, haematoma, venous

As in thrombosis of the lower extremities, there are no reliable clinical symptoms to diagnose deep arm vein thrombosis. Therefore, diagnostic test are necessary to diagnose or rule out upper extremity thrombosis. Contrast venography is the gold standard diagnostic method, allowing an unparalleled overview of all arm veins with high resolution (Fig 2). However, venography is invasive, inconvenient for the patient and suffers from moderate inter-observer agreement rates (between 71 and 83%) in upper extremity deep vein thrombosis (Baarslag et al*.*, 2003). Furthermore, possible complications as contrast agent mediated kidney damage, allergic reactions and even venography-induced thrombosis can

Ultrasound has several advantages compared to invasive methods and has become the diagnostic method of choice in lower extremity deep vein thrombosis (Kearon et al*.*, 1998; Goodacre et al*.*, 2006). The main strengths of ultrasound are its non-invasive nature, general availability, as well as the lack of radiation and contrast material. However, ultrasound suffers generally from some disadvantages, including observer variability and usually lack of standardized documentation. In arm vein thrombosis, an additional obstacle is the portion of the subclavian vein behind the clavicle, impeding compression manoeuvres in this clinically important region. In addition, the brachiocephalic veins and the superior vena

compression and traumatic injuries (Kommareddy et al*.*, 2002; Bernardi et al*.*, 2006).

Gbaguidi et al*.*, 2011).

**6. Diagnostic procedures** 

occur (Bernardi et al*.*, 2006).

distinct clinical entities, namely after recent oropharyngeal infections with anaerobic bacteria (fusobacterium necrophorum) and in the ovarian hyperstimulation syndrome (Gbaguidi et al*.*, 2011). For the latter syndrome, the increased risk of thrombosis has been explained by the drainage of excessive estrogen concentrations in the peritoneal fluid via the thoracic and right lymphatic duct into the confluence region of the large neck veins (Bauersachs et al*.*, 2007).


\*heterozygous mutation. VTE venous thromboembolism

Table 1. Major risk factors for arm vein thrombosis with odds ratios adjusted for age and sex.

### **5. Clinical presentation**

The presence of typical symptoms (swelling of the upper extremity, localized pain, and superficial collaterals) will raise the suspicion of the clinician to consider deep vein thrombosis of the arms. The most frequent symptom is edema of the upper extremity, which has been reported in 80% of cases by Joffe and coworkers . In addition, about 40% of patients report localized pain or aching discomfort in the involved extremity (Joffe et al*.*, 2004). Other symptoms include reddish-blue discoloration, a sensation of heat or heaviness in the respective arm, or dilated superficial collateral veins on the upper arm, shoulder girdle, neck, and anterior chest wall (Prandoni et al*.*, 1997a; Kommareddy et al*.*, 2002; Bernardi et al*.*, 2006). In at least 5% of cases, deep vein thrombosis of the arms will be completely asymptomatic (Mai & Hunt, 2011). In some cases, patients will become symptomatic only after the occurrence of complications, like dyspnea in the case of pulmonary embolism, or rarely venous gangrene (Kaufman et al*.*, 1998). In dialysis patients, arm vein thrombosis may become symptomatic only by catheter dysfunction, like the inability to draw blood, increased dialysis pressure or arm swelling after dialysis (Hernandez et al*.*, 1998).

In addition, classical syndromes have been described which share some but not all of their symptoms with the clinical picture described above. Superior vena cava syndrome has been described as a complication especially of catheter related arm vein thrombosis, but may also be caused by other mechanisms, e.g. venous compression by chest tumors (Lepper et al*.*, 2011). It comprises usually bilateral edema of the face, neck, and upper extremities, together with cyanosis, plethora, and dilated subcutaneous vessels. Paget von Schroetter´s syndrome, which was first described at the end of the 19th century, is defined as a primary thrombosis

distinct clinical entities, namely after recent oropharyngeal infections with anaerobic bacteria (fusobacterium necrophorum) and in the ovarian hyperstimulation syndrome (Gbaguidi et al*.*, 2011). For the latter syndrome, the increased risk of thrombosis has been explained by the drainage of excessive estrogen concentrations in the peritoneal fluid via the thoracic and right lymphatic duct into the confluence region of the large neck veins (Bauersachs et al*.*, 2007).

Central venous catheter 1136 153 - 8448 Blom et al. 2005

Active cancer 18.1 9.4 – 35.1 Blom et al. 2005 Arm surgery 13.1 2.1 – 80.6 Blom et al. 2005 Plaster cast 7.0 1.7 – 29.5 Blom et al. 2005 Factor V Leiden\* 6.2 2.5 – 15.7 Martinelli et al. 2004 Prothrombin G20210A\* 5.0 2.0 – 12.2 Martinelli et al. 2004 Protein C, Protein S 4.9 1.1 – 22.0 Martinelli et al. 2004 Family history of VTE 2.8 1.6 – 4.9 Blom et al. 2005 Arm injury 2.1 0.7 – 6.2 Blom et al. 2005 Oral contraceptives 2.0 1.1 -3.8 Blom et al. 2005 Unusual arm exercise 1.5 1.0 – 2.1 Blom et al. 2005

Table 1. Major risk factors for arm vein thrombosis with odds ratios adjusted for age and sex.

The presence of typical symptoms (swelling of the upper extremity, localized pain, and superficial collaterals) will raise the suspicion of the clinician to consider deep vein thrombosis of the arms. The most frequent symptom is edema of the upper extremity, which has been reported in 80% of cases by Joffe and coworkers . In addition, about 40% of patients report localized pain or aching discomfort in the involved extremity (Joffe et al*.*, 2004). Other symptoms include reddish-blue discoloration, a sensation of heat or heaviness in the respective arm, or dilated superficial collateral veins on the upper arm, shoulder girdle, neck, and anterior chest wall (Prandoni et al*.*, 1997a; Kommareddy et al*.*, 2002; Bernardi et al*.*, 2006). In at least 5% of cases, deep vein thrombosis of the arms will be completely asymptomatic (Mai & Hunt, 2011). In some cases, patients will become symptomatic only after the occurrence of complications, like dyspnea in the case of pulmonary embolism, or rarely venous gangrene (Kaufman et al*.*, 1998). In dialysis patients, arm vein thrombosis may become symptomatic only by catheter dysfunction, like the inability to draw blood,

increased dialysis pressure or arm swelling after dialysis (Hernandez et al*.*, 1998).

In addition, classical syndromes have been described which share some but not all of their symptoms with the clinical picture described above. Superior vena cava syndrome has been described as a complication especially of catheter related arm vein thrombosis, but may also be caused by other mechanisms, e.g. venous compression by chest tumors (Lepper et al*.*, 2011). It comprises usually bilateral edema of the face, neck, and upper extremities, together with cyanosis, plethora, and dilated subcutaneous vessels. Paget von Schroetter´s syndrome, which was first described at the end of the 19th century, is defined as a primary thrombosis

**95 % Confidence** 

**interval Reference** 

9.7 7.8 – 12.2 Joffe et al. 2004

**Risk factor Odds** 

\*heterozygous mutation. VTE venous thromboembolism

**5. Clinical presentation** 

**ratio** 

of the subclavian vein at the costoclavicular junction. This syndrome is usually precipitated by musculoskeletal compression and / or repetitive microtrauma by strenuous arm exercise (thrombosis par effort) (Constans et al*.*, 2008; Illig & Doyle, 2010). In some cases, a compression of the subclavian vein by muscular hypertophy (anterior scalenus muscle, subclavian muscle) or by the clavicle and the first rib with extreme arm movements (hyperabduction and elevation) may be responsible (thoracic outlet syndrome). Likewise, the syndrome has been linked to certain sport activities, as e.g. weight lifters, baseball pitchers or tennis players (Sheeran et al*.*, 1997; van Stralen et al*.*, 2005). It is observed more frequently in young patients, men (2:1), and in the dominant extremity (Illig & Doyle, 2010). The typical clinical presentation of this syndrome is a sudden onset of the typical symptoms of deep vein thrombosis described above (Illig & Doyle, 2010). Isolated thrombosis of the internal jugular vein is a rare disease which may be due to local (central venous catheters, recent oropharyngeal infections with anaerobic bacteria like fusobacterium necrophorum) or systemic factors (cancer, thrombophilia, ovarian hyperstimulation syndrome) (Sheikh et al*.*, 2002; Gbaguidi et al*.*, 2011). Lemierre´s syndrome, first described in 1910, is a severe condition of septic thrombosis following oropharyngeal infections, mostly due to fuosbacterium necrophorum. This syndrome is also known as human necrobacillosis or post-anginal septicaemia. Besides local symptoms (cervical edema, localized pain, dilated superficial collateral veins, erythrocyanosis, indurated vein), severe systemic complications like septicaemia and septic pulmonary embolism may occur (Vargiami & Zafeiriou, 2010; Gbaguidi et al*.*, 2011).

When evaluating patients for clinical signs of deep arm vein thrombosis, it is important to bear in mind possible alternative diagnoses. These include e.g. superficial thrombophebitis, paravasates after peripheral infusions, lymphedema, cellulitis, haematoma, venous compression and traumatic injuries (Kommareddy et al*.*, 2002; Bernardi et al*.*, 2006).
