Upper extremity deep vein thrombosis (UEDVT); Does end stage renal disease (ESRD) triggers UEDVT?

Received: August 26, 2020; Accepted: October 19, 2020; Published: October 22, 2020 A 50 years old man, presented to the Emergency department, with progressive left arm swelling, which started few days ago. He was a known case of ESRD (secondary to lupus nephritis), on dialysis for the past five years. He had a right sided subclavian catheter, for dialysis. He had no surgical interventions or injuries, to his left upper extremity. He was apyrexial, hemodynamically stable, with significant edema and erythema over his left upper extremity. There were no signs of limb ischemia. Ultrasound followed by venography of the involved extremity, revealed venous thrombosis of limb veins, which extended to the left subclavian and internal jugular vein. The patient was successfully treated with anticoagulation therapy, in an outpatient setting. There were no further episodes of venous thromboembolism (VTE), at 6 months follow up. There has been no similar case reports in published literature (Figure 1).


Introduction
Up to 10% of all deep vein thrombosis (DVT) are related to upper extremities, with an incidence of, 3 per 100,000 in the general population [1][2][3]. The incidence of UEDVT is less than the lower extremity DVT, possibly due to following factors [4][5][6].
• Lesser venous valves in the upper extremity.
• bedridden patients generally have more arm than leg movements, • less hydrostatic pressure in the arms, • fibrinolytic activity is more, in the vascular endothelium of the arms, • Absence of a complex network of veins, as seen in the calf muscles.
The incidence of thrombosis in the upper extremity is maximal, in the subclavian vein (18-67%), followed by axillary(5-25%) and the brachial (4-11%), with marked predilection for the left side, probably as a result of anatomical reasons [7]. UEDVT involves more than one segment of the vein, at a time. Venous catheters are mostly implicated with UEDVT [8]. Larger the size of the inserted venous catheter, higher is thought to be the chance of clot formation [9]. Other factors are also thought to play an important role, but the information regarding the whole spectrum of UEDVT is still lagging [10].
We wanted to explore, the pathophysiology, incidence, diagnostic techniques and management of UEDVT, in general population & specifically within the ESRD patients ( Figure 2).
The search strategy has been described below: Pathophysiolog "Virchow's Triad" is a multifactorial phenomenon, that leads to thrombosis [11]. Venous stasis, vascular injury and hyper coagulability are the three factors, which work singly or together, to generate a thrombus [12]. DVT starts within the venous valves, of the deep veins of the leg. Venous thrombi tend to form in the sinuses, adjacent to venous valves [13,14].
Venous stasis decreases oxygen tension, which increases hematocrit [15]. This leads to expression of some procoagulants (e.g p-selectin), which attracts tissue factor and downgrades certain anticoagulant proteins (like thrombomodulin), which are expressed on venous valves [16]. The risk of thrombus formation increases proportionately, as the ratio between the procoagulants and anticoagulant factors is disturbed [17].
In some patients, genetic variants lead to higher levels of certain procoagulant factors (VII, VIII, IX and prothrombin), which increases the risk of thrombus formation. Malignancy can exert a constrictive effect on veins, leading to stasis. It also sheds procoagulants, such as tissue factor on membrane particles that forms a thrombus [18].
Advancing age is associated with increased frequency of illness, prolonged immobility, co-morbid medical conditions and an increased level of procoagulant [19]. Paget Schroetter disease is characterised by UEDVT, induced by vigorous effort of the involved extremity, clavicular impingement and a sequelae of thoracic outlet syndrome [20].
ESRD is associated with increased procoagulants, like cystatin C, interleukin-6, tumor necrosis factor, intercellular adhesion molecule-1, fibrinogen and factor VIII. Anticoagulants, like protein C, protein S and anti-thrombin are comparatively decreased. The risk for thrombosis in patients with ESRD is further increased, as a result of platelet activation, occurring within the extracorporeal hemodialysis device. These factors lead to increase the risk of thrombosis in these patients, independent of the other conventional risk factors. Systemic lupus erythematosis (SLE), which leads to lupus nephritis and consequentially ESRD, is an additional factor, that can also enhance the risk of thrombosis in these patients [21].

Classification
Coon and Willis classified UEDVT, into two divisions; traumatic, which may be internal (caused by central venous cannulation) or external (like fracture, stress) and spontaneous (associated with cancer or idiopathic) [22].

Clinical presentation
UEDVT can be asymptomatic. The typical presentation is, the presence of arm discomfort, edema, discolouration and dilated venous collaterals [24]. The level of suspicion increases in the presence of risk factors, like indwelling catheters and vigorous arm exercise (Figure 3).

Diagnosis
The diagnostic work up of DVT of the lower extremities is well established, however, the same is not true, in relation to UEDVT. A systematic review, throws light on the diagnostic values of various methods [25]. Ultrasonography (USG) is probably the first choice for investigating UEDVT and venography is used, when there is disparity between USG and clinical findings. It is also not known, whether the validated recurrent thrombosis "risk prediction models" for lower limb DVT (like the Vienna prediction model), which use a combination of clinical and diagnostic criteria, can be applied to patients with UEDVT [26,27].

Anticoagulant therapy
Anticoagulation is the mainstay of treatment, with the goal of re-canalising the thrombosed vein, preventing progression to pulmonary embolism (PE) and recurrence of thrombosis [28,29]. The recommendations for lower extremity DVT are applied to UEDVT.  Low Molecular Weight Heparin (LMWH) is preferred over unfractionated heparin (UFH), for treatment of thrombotic events. The predictability of their anti thrombotic effect, better compliance and absence of thrombocytopenia, favours them over heparin [30][31][32][33][34][35]. LMWH are overlapped with Vitamin K antagonists (like warfarin), to achieve an International Normalised Ratio (INR), in a range of 2.5-3.0.
Direct Oral Anticoagulants (DOACs), like dabigatran are also considered an important modality of treatment. Their safety and efficacy profile is not very clear in ESRD patients, as 80% of their clearance happens in the kidneys. The guidelines by American college of Chest Physicians (ACCP), recommend DOACs for all non-cancer related VTE and LMWH for VTE, associated with cancer [36].
Cohort studies indicate that the optimum duration of anticoagulation is for a period of 3-6 months [37,38]; however, the evidence is moderate. The current guidelines from ACCP recommend 3 months treatment, for unprovoked DVT.
However, multimodal therapy is recommended in patients, who present with massive DVT (massively swollen limb, acrocyanosis, severe pain, ischemia). These patients are more than twice as likely, to develop extension of thrombosis, compared to patients with less extensive DVT (11.2% vs. 5.3%) [39,40].

Systemic Thrombolysis (ST)
Systemic thrombolysis, for fully obstructed segments of veins with DVT, does not have as much therapeutic efficacy, as seen in coronary & cerebral thrombolysis. This is due to inefficient diffusion of the thrombolytic agent in the large venous thrombi, along with low flow conditions [41][42][43]. This approach, as compared to anticoagulation alone, is also associated with a very high risk of bleeding related complications [44][45][46][47][48][49][50].

Catheter Directed Thrombolysis (CDT)
It is a minimally invasive technique, which involves infusing a fibrinolytic agent directly in the thrombus, via a catheter, within the involved vessel. A 3-point scale has been proposed, to define the outcomes of this therapy. Grades 2 and 3, signify at least 50% luminal patency, which is classed as a satisfactory therapeutic outcome [51]. CDT has been compared with combined anticoagulation and compression stockings treatment, in patients with lower extremity DVT. Immediate grade 2 to 3 lysis was observed in 40% of patients post procedure, with almost double the patency rates, in the former group. Absolute risk reduction of 28% (95% CI 9.7-46.7%; P < 0.004) was achieved [52]. This trial claimed superior clot lysis with CDT, with better long-term venous patency rates in patients with lower limb DVT. CDT is only considered selectively for treatment of UEDVT.

Thrombectomy (THB)
THB, is one of the approved therapies, in the management of acute DVT of the lower limbs. The risk of post-thrombotic symptoms were less frequent in the THB group, when compared with anticoagulation group (7% vs. 42%; P < 0.005). The luminal patency rates in the THB group were also better (76% vs. 35%; P < 0.025) [53]. THB applicability is not well established in UEDVT.

Discussion
UEDVT is a fatal disease, which is relatively under diagnosed [54]. Majority of the risk factors, which cause DVT of the lower extremities, also contribute in development of UEDVT. The risk factors also have a synergistic effect [55].
ESRD, increases the risk of DVT, due to imbalance between the pro and anti coagulants factors [56]. The insertion of central venous catheter and creation of arteriovenous fistulas play a significant part, in triggering VTE in an ESRD patient [57].
The prevalence of pulmonary embolism, has been reported at autopsy in patients dying of ESRD [58]. A prospective study conducted in an intensive care unit, found ESRD as a risk factor for DVT (hazard ratio (HR) 3.7, 95% confidence interval (CI) 1.2-11.1) [59]. Lupus nephritis can have a contributory role, in development of VTE in ESRD patients, due to the systemic effect of the disease [60].
In our patient, there was no prior surgical or vascular intervention, in the affected upper extremity. In fact, the contralateral limb had a previous non-functional arteriovenous fistula and a central venous catheter. It is unclear, why the thrombosis occurred in an extremity, where there was seemingly, no vascular stasis or injury. It is likely to be related with the relative hyper-coagulable state, in ESRD patients, with possible synergistic effect from the SLE [61]. PE complicates UEDVT in 36% of cases and is more commonly associated with central venous catheters [62]. Post-thrombotic syndrome, which occurs in up to 50% of patients (within 2 years of DVT), has similar prevalence in UEDVT [63]. The mortality rate in UEDVT patients, range from 10 to 50%, mainly due to the underlying malignancy [64,65].
The 30-day mortality rate exceeds 3% in patients with DVT, who are not anti-coagulated, and this mortality risk increases 10-fold in patients who develop PE.
The current scientific research is unclear, about the use of prophylactic anticoagulants in ESRD patients.

Conclusions
High index of suspicion is required in patients with ESRD, to diagnose UEDVT. Prevention strategies for UEDVT in ESRD patients can be explored further.