Upper extremity deep vein thrombosis – The venous thromboembolism Cinderella?

When referring to venous thromboembolism (VTE), one tends to think of lower limb deep vein thrombosis (DVT) and pulmonary embolism (PE). A rarer and poorly understood form of DVT occurs in the upper extremity (UEDVT). With UEDVT being a cause of significant morbidity and mortality and its prevalence said to be increasing at a concerning rate, ¹ should the scientific community be paying more attention to the VTE Cinderella?

Historically rare with an annual incidence of 2 per 100,000 persons, ² the medical inpatients and thrombosis study reports UEDVT to now complicate approximately 14 per 100,000 hospital admissions. ¹ Whether this is a true representation of the changing epidemiology of UEDVT is unclear due to the study’s low statistical power. What we can be certain of, however, is that secondary UEDVT is becoming increasingly prevalent, ¹ which cannot be ignored.

UEDVT is classified as primary (namely idiopathic, Paget-Schroetter syndrome or thoracic outlet obstruction secondary to a first rib) or, more frequently, secondary to central and peripheral venous catheter insertion, pacemaker insertion or malignancy. Anatomically, UEDVT most commonly involves the subclavian (18–67%) or axillary (5–25%) vein. ³

Unlike previously reported, UEDVT is far from being a benign self-limiting condition. ³ Post-thrombotic syndrome (PTS) complicates up to 44% of UEDVT, ⁴ with patients suffering ipsilateral upper limb swelling, pain and, in severe cases, ulceration. Symptomatic PE occurs in up to 33% of patients, and UEDVT recurs in as many as 8% of patients per year. ⁵ Despite the reduction in patients' quality of life through loss of work productivity and symptom chronicity, UEDVT has generated relatively little research attention.

Reference to UEDVT is sparse in current VTE guidelines. Likewise, a pre-test clinical probability algorithm combining symptoms, diagnostic biochemical markers and imaging is lacking. The National Institute of Health and Care Excellence makes no reference to UEDVT in their VTE guidelines and quality standards. ⁶ The British Journal of Haematology (BJH) ⁷ and the American College of Chest Physicians (ACCP) ⁸ however have. This in part may reflect the lack of robust evidence in the form of randomised controlled trials to base recommendations upon. Although, surely any attempt to standardise clinical practice and promote patient safety is better than none?

The ACCP advocate the use of compression ultrasound for the initial investigation of UEDVT. In cases where a high index of clinical suspicion for UEDVT remains despite a negative ultrasound scan, contrast venography is recommended. ⁸ The BJH, on the other hand, states no preference regarding which of the two imaging modalities is used. ⁷ This is despite compression ultrasound and contrast venography differing in terms of patient safety and accessibility, with the former being non-invasive and inexpensive. The discrepancy in recommendation may reflect the contrasting level of supporting evidence used, with the BJH ascribing it as level 1B evidence compared to 2C evidence used by the ACCP. Given that both guidelines were published in the same year, one would assume that both societies had access to the same available data. We are therefore left with the uncertainty of whether the difference in specificity and sensitivity of compression ultrasound and venography is of any clinical significance in diagnosing UEDVT.

The paucity of high-quality randomised controlled trials also hinders the management of UEDVT. Anticoagulation, whether it is heparin of a non-specified form or fondaparinux, followed by warfarin, is the preferred treatment.^7,8 Duration of anticoagulation is arbitrary with the BJH stating no optimal duration, ⁷ and the ACCP stating it to be aetiology dependent (continuation of anticoagulation for as long as the central venous catheter remains in situ, otherwise discontinue after three months). ⁸ Considering that a significant proportion of patients go on to develop secondary complications and the guidelines on anticoagulation are seemingly vague, is there not a defined role for catheter-directed thrombolysis?

Small retrospective studies suggest a superiority of catheter-directed thrombolysis over anticoagulation alone. ⁹ Vik et al. ⁹ reported greater than 50% (grade 2) clot lysis with catheter-directed thrombolysis in 97% of patients with UEDVT. Although these results are promising, the use of thrombolysis is controversial, with its safety needing to be considered. Vik et al. ⁹ reported 9% of patients developed a major haemorrhage post thrombolysis. It is this safety risk which limits the use of catheter-directed thrombolysis in UEDVT. It is worth noting, however, that these data are derived from a heterogeneous population inclusive of both primary and secondary UEDVT. The contrasting aetiology of primary and secondary UEDVT means that the treatment, and therefore the expected outcomes, may potentially differ.

The ACCP suggests restricting the use of thrombolysis to anatomically complex UEDVT, primary thrombosis and patients with severe symptoms. ⁸ Thrombolysis with or without rib resection has been the management for Paget–Schroetter syndrome and thoracic-outlet obstruction advocated by many interventionalists.^3,10 Even this is now subject to controversy with some vascular surgeons recommending conservative management in Paget–Schroetter syndrome, and the need for thoracic decompression in all patients being uncertain. ¹⁰ So the question remains, how does one treat UEDVT?

Given the lack of high-quality evidence to support a diagnostic and management algorithm, it is unsurprising that an “UEDVT guideline” does not exist. Current recommendations from the ACCP and BJH have, until now, been invaluable in guiding clinicians. However, the VTE Cinderella can no longer be ignored. UEDVT is a disease of increasing incidence with significant morbidity if left untreated. Guidance in effectively investigating and managing this increasingly important disease entity is needed.

Arguably, primary UEDVT remains, and may continue to be, relatively rare. It is the evidence that central and peripheral venous catheters increase the risk of UEDVT up to 14-fold that warrants concern, particularly when they are so frequently used. ¹ We therefore feel that there is a need for high-quality guidance in the management of UEDVT. Likewise, clinicians need to abide by the principle of non-maleficence. Whilst primary UEDVT cannot be prevented, secondary UEDVT certainly can by regulating the use of venous catheters. The implementation of hospital guidelines on line insertion may be influential in averting the increasing incidence of secondary UEDVT.