Epidemiology, diagnosis, prevention and treatment of catheter-related thrombosis in children and adults

Accepted Manuscript Epidemiology, diagnosis, prevention and treatment of catheterrelated thrombosis in children and adults

Lisa Baumann Kreuziger, Julie Jaffrey, Marc Carrier PII: DOI: Reference:

S0049-3848(17)30405-X doi: 10.1016/j.thromres.2017.07.002 TR 6721

To appear in:

Thrombosis Research

Received date: Revised date: Accepted date:

1 April 2017 9 June 2017 3 July 2017

Please cite this article as: Lisa Baumann Kreuziger, Julie Jaffrey, Marc Carrier , Epidemiology, diagnosis, prevention and treatment of catheter-related thrombosis in children and adults, Thrombosis Research (2017), doi: 10.1016/j.thromres.2017.07.002

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ACCEPTED MANUSCRIPT Epidemiology, diagnosis, prevention and treatment of catheter-related thrombosis in children and adults

Running head: catheter-related thrombosis

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Key words: catheter-related thrombosis, upper extremity deep-vein thrombosis, anticoagulation

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Lisa Baumann Kreuziger, MD, MS BloodCenter of Wisconsin 8733 Watertown Plank Road Milwaukee, WI 53226 Assistant Professor of Medicine, Hematology Medical College of Wisconsin Department of Medicine, Division of Hematology [email protected]

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Authors:

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Julie Jaffrey, MD Assistant Professor of Clinical Pediatrics, Hematology Children's Center for Cancer and Blood Diseases Children's Hospital Los Angeles
 4650 Sunset Blvd. Mailstop #54 Los Angeles, CA 90027 [email protected]

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Marc Carrier, MD Associate Professor of Medicine, Hematology The Ottawa Hospital, General Campus 501 Smyth Road, Box 201A Ottawa, Ontario, Canada. K1H 8L6 [email protected] Corresponding author: Lisa M. Baumann Kreuziger, MD, MS BloodCenter of Wisconsin 8733 Watertown Plank Road Milwaukee, WI 53226 [email protected]

The authors have no conflicts of interest to report 1

ACCEPTED MANUSCRIPT

ABSTRACT In this narrative review, the epidemiology, diagnosis, prevention strategies, and management of catheter-related thrombosis are outlined. Central venous catheters have significantly improved

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the quality of life of patients requiring chemotherapy, parenteral nutrition, and chronic

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transfusions. Catheter-related thrombosis (CRT) complicates between 1-5% of inserted

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catheters, with incidence varying between patient population, catheter type, and vein cannulated. Strategies to prevent CRT, including anticoagulation and locking solutions, have largely been

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ineffective. Using clinical decision tools and D-dimer testing can limit radiographic testing for

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patients with suspected CRT. Although most patients with CRT are treated with anticoagulation, the most effective type and duration of treatment have not been established for adults or children.

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Many unanswered questions remain concerning risk stratification, prevention, and management

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of CRT. National and international collaborative research networks could be harnessed to

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perform these much needed studies.

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ACCEPTED MANUSCRIPT INTRODUCTION The use of indwelling central venous catheters (CVCs) has significantly enhanced the management of patients requiring parenteral treatment.1,2 CVCs facilitate chemotherapy, transfusions, antibiotics, and parenteral nutrition delivery. Furthermore, they allow readily

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available venous access for laboratory testing and have been shown to improve patients’ quality

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of life and reduce health care costs by allowing patients to receive parenteral therapy at home.3

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As a consequence, over 5 million of CVCs are inserted yearly in the United States and their use

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is constantly increasing.1

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All CVCs are designed to have their catheter tip dwelling at the junction of the superior vena cava and the right atrium within the central venous system.4 CVCs can be classified as tunneled

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or non-tunneled catheters, peripherally inserted central catheter (PICC), implanted ports and

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dialysis catheters.4 Different types of CVCs have distinctive features including varying numbers of lumens (single, double or triple) or the addition of valves which prevent reflux of blood back

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into the lumen of the catheter. The data comparing the risks and benefits of the different types of

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CVCs is scarce. Clinicians need to use the smallest-diameter catheter that will fulfill the patient’s need (e.g. multiple lumens might be required for chemotherapy infusion in cancer patients) and

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ensure that the CVC is removed when it is no longer used to minimize the risk of any associated complications.

All CVCs share similar complications. Thrombosis associated with CVC can be divided into different types: 1) fibrin sheath along the length of the CVC; 2) catheter lumen occlusion; 3) Ball-valve-thrombosis impeding aspirations while infusion remains possible; and 4) mural

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ACCEPTED MANUSCRIPT thrombosis leading to deep vein thrombosis (DVT)5 or catheter-related thrombosis (CRT). CRT is a relatively common complication of CVCs which can lead to pulmonary embolism (PE), recurrent DVT, post-thrombotic syndrome (PTS) and sepsis.6 Vessel injury caused by the catheter insertion, venous stasis caused by indwelling catheter, on-going movement of the

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catheter within the vein, and cancer-related hypercoagulability all contribute to the development

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of mural thrombus leading to an occlusive CRT7 in this patient population.8 The diagnosis of

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CRT can have important consequences for patients and confront clinicians with important clinical management dilemmas including the decision to keep or remove the CVCs, type of

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treatment, and duration of anticoagulation. In this narrative review, we will summarize the

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epidemiology of CRT including its associated risk factors and review the medical literature on the prevention and management of this important complication in adult and pediatric

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populations. PubMed and MEDLINE were searched using catheter and thrombosis with

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epidemiology, prevention, diagnosis, treatment, anticoagulation, and appropriate synonyms to

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EPIDEMIOLOGY

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ensure relevant information was included.

Most CRTs occur in the upper extremities where most CVCs are inserted. Overall, CRT

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represents approximately 70% of all upper extremity DVTs and 10% of all venous thromboembolism (VTE).9 The rates of CRT complications vary significantly in the medical literature depending on the study design (retrospective vs. prospective), patient selection (cancer vs. non-cancer patients), type and location of CVC, duration of follow up, and diagnostic modality (ultrasonography (US) vs. venography). For example, the incidence of symptomatic CRT following PICC line insertion is higher among cancer patients compared to patients without

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ACCEPTED MANUSCRIPT cancer.10 The mean duration from catheter insertion to a CRT diagnosis is ten days and a large majority of CRTs will occur with the initial 100 days following the insertion.3,10

Given the recent improvement in the insertion techniques of CVCs (e.g. US-guided insertions,

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vascular access team, etc.) and the evolution in catheter material (i.e. less thrombogenic), the

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overall risk of CRT has been decreasing over time.11,12 While earlier studies in the 1980s-1990s

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reported rates as high as 66%, more recent studies have demonstrated that approximately 16 to 18% patients with CVCs have evidence of CRT when screened with US or venography.8,13,14

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Furthermore, only 1 to 5% of patients will develop a symptomatic CRT.10,15,16 Patients with

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symptomatic CRT will present with variable clinical pictures from minimal symptoms despite

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extensive DVT to superior vena cava syndrome.

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Peripherally inserted central catheter (PICC)

PICC lines are an effective, easy and readily available modality to obtain extended intravenous

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access. Given their widespread use, they now account for up to 80% of all CRT among cancer

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patients.17 PICCs have been reported to increase the risk of symptomatic CRT 2.6-fold when compared to other CVCs.18 This finding might be attributable to longer dwelling time, on-going

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movement of the catheter within the vein, and greater catheter-to-arm vein diameter.5 However, a recently published cohort study of 656 patients with PICCs reported a cumulative rate of CRT of only 1.52% (95% CI, .0.8-2.8%) corresponding to an incidence of 0.2 per 1000 catheter days.19 Standardization in the insertion techniques by a dedicated vascular access team accountable for oversight of the insertion, care, and maintenance of CVCs seems to be beneficial.

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ACCEPTED MANUSCRIPT Indwelling infusion port The cumulative rate of symptomatic CRT associated with indwelling infusion port has been reported to be between 2 and 13%.20-24 The fluctuation in the reported cumulative incidence reflects the heterogeneity between the study (different tumor types, histologies, rate of

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prophylaxis, etc.). The cumulative rate of CRT increases over time among patients with

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implanted ports.20 This suggests that the longer a port remains in situ, the more likely for a

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symptomatic CRT to occur. Hence, international practice guidelines recommend that CVCs be

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removed as soon as they are no longer required.25,26

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Complications of catheter-related thrombosis

Although CRT can lead to PE, recurrent DVT and PTS, these complications are relatively

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uncommon.5 Older studies in the 1990s reported that PE could be detected in up to 10% of

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patients with symptomatic CRT.27 However, a recently published systematic review including 4000 patients with CVCs did not report any symptomatic PE complications.18 Similarly, a review

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of 252 patients with CRT did not report any symptomatic PE during the follow-up period.26 PTS

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is rare in patients with CRT. Whereas the frequency of post-thrombotic syndrome after upper extremity DVT ranges from 7 to 46% especially if patients have residual axillo-subclavian

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thrombosis, CRT seems to be associated with a decreased risk of this complication.28 The management of CRT may also influence the risk of PTS complications. In a cohort study including 112 patients with CRT, only patients managed without anticoagulation and line removal did not have resolution of the presenting symptoms.29 Therefore adequate anticoagulation management might minimize the risk of this complication. More importantly, CRT can lead to loss of CVC function which can result in delay of administration of the

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ACCEPTED MANUSCRIPT parenteral treatment (e.g. chemotherapy). A diagnosis of CRT will also need to be treated with therapeutic doses of anticoagulation potentially exposing these patients to major bleeding complications. Lastly, delay in CRT diagnosis can lead to superior vena cava syndrome and chronic venous stenosis which can be catastrophic for patients requiring long-term venous

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access.

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RISK FACTORS

A number of studies have assessed the different risk factors for CRT. However, many of these

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studies have important limitations including a retrospective design, small sample size, and

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heterogeneity across the study outcome definitions and procedures. Therefore, the risk factors associated with CRT are still unclear. Risk stratification of patients with CVC according to their

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underlying risk of CRT would be a very helpful tool for clinicians to help them decide which

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CVC patients may potentially benefit from pharmacologic prophylaxis and keep a low threshold for CRT diagnosis in the high-risk patients. The derivation and validation of such a clinical

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decision rule would need to prospectively assess the importance of intrinsic factors [e.g. type of

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central venous catheters (PICC vs. implanted port), side of catheter placement, lumen size, tip location, etc.] and extrinsic risk factors (e.g. previous venous thromboembolism, obesity,

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immobility, etc.) on the risk of CRT in cancer patients with CVC.

Risk factors can be divided into those that are intrinsic to the CVC (or its insertion) and those extrinsic or related to patient’s characteristics (Table 1). The largest systematic review and metaanalysis on this topic have shown that the type of CVC (PICC > implanted ports), its location (e.g. junction of the superior vena cava and the right atrium) and the insertion site (femoral >

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ACCEPTED MANUSCRIPT subclavian > jugular) are important intrinsic predictors of CRT.3 Other possible risk factors include CVC diameter and left-sided insertions.26 The most important extrinsic predictor of CRT is the prior history of venous thromboembolism (OR: 2.0; 95% CI: 1.1 to 3.9).3 The risk factors associated with CRT are also likely to be dependent on the type of CVC. A number of risk

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factors (e.g. side of implanted port insertion, tumor types, metastatic disease, etc.) have been

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evaluated to predict CRTs with implanted ports among cancer patients.20,30-34 However, the

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presence of metastatic disease seems to be the most important and consistent risk factor among all studies. A subsequent randomized trial of subclavian, jugular and femoral vein CVC

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placement in the intensive care unit revealed a decreased risk of CRT when placed in the

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subclavian vein compared to femoral vein (HR 3.4 95% CI 1.2-9.3).35 Jugular and subclavian vein placement of catheters yielded similar number of CRT. When combined with infectious

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complications, subclavian vein placement of CVC in the ICU yielded superior outcomes, but was

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associated with an increased risk of pneumothorax.35 Inherited thrombophilias may be an important predictor of CRT. A systematic review and meta-analysis has reported that factor V

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Leiden and prothrombin gene mutation were associated with an increased risk of CRT [OR 4.6

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(95% CI: 2.6 to 8.1) and 4.9 (95% CI: 1.7 to 14.3), respectively].36 Data on other inherited thrombophilia is lacking. Acquired thrombophilia (e.g. elevated FVIII, D-dimers, etc.) were also

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recently shown to be potential predictors of CRT.37-39 Although the accuracy of identified CRT risk

factors is uncertain, it is reasonable to minimize them if possible and educate high-risk patients about signs and symptoms of CRT.

DIAGNOSIS

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ACCEPTED MANUSCRIPT Signs and symptoms of CRT cannot distinguish between a fibrin sheath within the catheter, superficial vein thrombosis, and DVT of the arm and neck.40 Catheter dysfunction has been reported in 14-36% of patients within the first two years of CVC implantation, of which 60% are due to thrombosis.41 Pain and tenderness along the vein occurs due to a local inflammatory

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reaction to the thrombus. The amount of upper extremity edema depends upon the number of

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veins affected, location of the effected veins, and amount of collateral venous flow.

Historically, contrast venography was the gold standard radiologic test for diagnosis of upper

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extremity DVT and CRT. Due to the invasive nature of venography and the need for radiation,

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clinical prediction rules and alternative diagnostic imaging have been tested. The Constans score combines four items (Table 2) and a score of two or more corresponds to an incidence of upper-

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extremity DVT of greater than 20%.42 In validation cohorts, 50% of patients could be classified

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as unlikely to have an upper extremity DVT using the Constans score.42 The Constans score includes the presence of a catheter as a risk factor for upper extremity DVT, but a CRT-specific

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prediction rule has not been developed.

Although compression US is widely used, its sensitivity and specificity has wide variation and

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averages 91% and 93%, respectively.43 Kleinjan and colleagues studied a diagnostic algorithm that sequentially used the Constans score, D-dimer testing, and US.44 They found that in 21% of patients, upper-extremity thrombosis could be ruled out with an unlikely Constans score and Ddimer testing. Upper extremity DVT was diagnosed in 25% of patients and superficial vein thrombosis in 13%. Only one patient with a normal diagnostic evaluation developed an upper extremity DVT during the 3-month follow-up, corresponding to a failure rate of 0.4%. The

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ACCEPTED MANUSCRIPT efficacy of this algorithm was significantly less in patients with central venous catheters or pacemakers, however, as US could only be withheld in 4% of patients.38 In inpatients and patients with active cancer, the diagnostic algorithm prevented imaging in 5% and 11%, respectively. 38 A recent study evaluated an expanded Constans score (1 point for presence of

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superficial vein dilatation, arm swelling > 1.5 cm compared with the other arm, estrogen use or

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skin color difference, and -1 point in the case of an intravenous injection or peripheral venous

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catheter in the past 5 days; score ≤2 as upper extremity DVT unlikely).45 Unfortunately, the expanded score did not increase the efficacy of the algorithm and thus is not recommended. The

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use of age-adjusted D-dimers increased the number of patients in whom imaging could be

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avoided by 4%, similar results as studies of PE.46 Subgroup analysis of CRT were not reported. Further refinement of the Constans score and diagnostic algorithm would be needed to allow the

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algorithm to be more discriminatory in patients with indwelling catheters.

PREVENTION

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Anticoagulation has been tested in many studies to prevent CRT. In a systematic review and

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meta-analysis of seven interventional studies in patients requiring parenteral nutrition, intravenous heparin treatment did not prevent CRT compared to saline.47 A 2014 Cochrane

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systematic review of anticoagulation for the prevention of CRT in patients with cancer reported 12 randomized control trials containing 2564 adults.48 Use of prophylactic heparin compared to no heparin was associated with a statistically significant reduction in symptomatic upper extremity thrombosis (RR 0.48, 95% CI 0.27-0.86). An effect on mortality, major bleeding, minor bleeding, or thrombocytopenia was not found. Different regimens of low-dose vitamin-K antagonists (VKAs) have been studied including one mg of warfarin daily or adjusted dose to

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ACCEPTED MANUSCRIPT achieve an INR (international normalized ratio) less than two. Low-dose VKAs reduced the risk of asymptomatic thrombosis (RR 0.43; 95% CI 0.30 to 0.6) but did not show an effect on symptomatic DVT. Prophylactic heparin had a higher risk of thrombocytopenia in comparison to low-dose VKA. The cost and burden of anticoagulation would need to be balanced with the risk

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reduction of thrombosis in patients with CRT. The 2012 ISTH guideline for treatment and

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prevention of CRT and 2012 CHEST guidelines do not recommend routine anticoagulant

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prophylaxis in cancer patients with CVCs.26,49

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Local therapies to the catheter (i.e. locks) have been attempted to decrease the risk of CRT and

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dysfunction. A randomized placebo-controlled trial in adults with cancer evaluated the efficacy of urokinase to prevent catheter-related infections and thrombosis.50 Patients received urokinase

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25,000 units via a slow IV infusion and lock over 30 minutes three times a week. A significant

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reduction in CRT was seen in patients treated with urokinase compared to placebo (1.3% vs 9%, respectively; RR 0.14; 95% CI 0.02-0.82) without any major bleeding complications. Due to the

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limited number of studies, though, routine prophylaxis with thrombolytic therapy in cancer

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patients cannot be recommended. The 2016 Cochrane review of anticoagulant and antiplatelet therapy for prevention of catheter-related complications in hemodialysis patients reported no

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difference in catheter-related dysfunction when comparing heparin to alternative locking solutions (RR 0.96, 95% CI 0.74-1.26) or no therapy (RR 0.9, 95% CI 0.1-8.3).51 CRT outcomes were not assessed. A systematic review and meta-analysis of low (<5,000 Unit/mL) versus high dose (>5,000 units/mL) summarized five randomized controlled trials and three single armed studies of patients with hemodialysis catheters.52 High-dose heparin was associated with an increased risk of bleeding (RR=3.29, 95% CI 2.19-4.94), but no difference in catheter

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ACCEPTED MANUSCRIPT dysfunction (RR 1.07 95% CI 0.75-1.53) or CRT (RR0.68 95% SI 0.28-1.65). Given the lowquality evidence currently in the literature, the benefit of locking solutions on CRT remains unclear.

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Correct location and insertion method may reduce the risk of CRT (See Risk Factors above). Due

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to these risk factors, the 2012 ISTH catheter-associated thrombosis guidelines suggest placement

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of catheters in the right internal jugular vein with the catheter tip located at the junction of the superior vena cava and the right atrium.26 Subsequent randomized studies have shown similar

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rates of CRT between subclavian and internal jugular placement of catheters;35 thus, the catheter

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location that limits complications including thrombosis remains debated.

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TREATMENT

Catheter-removal

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Variation in clinical practice exists as to how CRT is treated.53 A retrospective review of 112

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oncology patients with CRT reported a combination of treatment modalities including anticoagulation, catheter replacement, and catheter removal.54 Four patients who had their

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catheter replaced did not have resolution of their symptoms until catheter removal. The 39 patients treated with anticoagulation alone were spared catheter removal.54 A prospective pilot study of 74 patients with CRT treated with anticoagulation for three months reported no episodes of recurrent VTE or need to remove the catheter due to catheter malfunction or thrombosis extension.55 Current CHEST guidelines recommend that catheters should be removed only if non-functional or not needed.49

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Anticoagulation Type and duration of anticoagulation for CRT varies significantly in the literature and there are no randomized trials to guide anticoagulant choice or duration. A recent systematic review

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reported the outcomes of patients with CRT treated with anticoagulation (Table 3).53 Four studies

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reported unfractionated heparin (UFH) transitioned to VKA treatment,27,56-58 three studies used

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low molecular weight heparin (LMWH) transitioned to VKA,55,59,60 three studies used LMWH alone, 61-63 one study reported VKA treatment only,64 and 5 studies reported combined

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therapy.59,65-68 Anticoagulation duration was limited as 8 days of treatment to over six months of

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therapy. Recurrent DVT was reported in 7% of patients with upper extremity thrombosis treated with anticoagulation and 2.8% experienced pulmonary embolism. Major hemorrhage was

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reported in 2.8% of patients in studies identifying CRT alone and 4.9% of patients with upper

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extremity DVT and CRT. The incidence of post-thrombotic syndrome varied between 0-75% due to a wide variation in definition of PTS. A subsequent analysis from the RIETE registry

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reported that 67% of patients with isolated CRT and 49% of patients with CRT and pulmonary

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embolism were treated with LMWH.69 Sixty four percent of patients (358/558) had cancer which likely influenced choice of anticoagulant. Median duration of LMWH was 4.7 months (range 54-

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201) and did not differ between patients with and without pulmonary embolism. A recent prospective cohort study of patients with upper extremity DVT, of which 66 patients had CRT, reported a 2-year cumulative incidence of VTE of 3.5% (95% CI 1.5-8) with no difference in recurrence between spontaneous upper extremity thrombosis and CRT.70

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ACCEPTED MANUSCRIPT The direct oral anticoagulants (DOACs) have been approved for treatment of VTE. Randomized trials leading to approval of dabigatran,71 rivaroxaban,72 apixaban,73 and edoxaban74 excluded patients with upper extremity DVT. A retrospective review of cancer patients with CRT treated with rivaroxaban showed a low incidence of line removal due to dysfunction (3/83 3.6%). The

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incidence of recurrent VTE was similar to other studies at 3.6%. Two major bleeds and one

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clinically relevant non-major bleed was also noted.75 A prospective pilot study of rivaroxaban for

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treatment CRT has been reported in abstract form.76 No catheters required removal due to thrombosis. At three month follow-up, recurrent thrombosis occurred in one patient (incidence of

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1.43%) and nine patients had 11 bleeding events (6 major and 5 clinically relevant non-major

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bleeds). Additional cohort studies and comparative trials are needed for DOAC therapy in cancer

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patients with CRT.

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ISTH 2012 and CHEST guidelines recommend anticoagulant therapy for CRT and suggest use of LMWH.26,49 VKAs can also be used due to lack of comparative studies between

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anticoagulants.26 Consensus guidelines have a weak recommendation for anticoagulation for 3

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months after catheter removal in patients with upper extremity CRT, but these recommendations are extrapolated from data on provoked lower extremity thrombosis, retrospective case series and

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two prospective cohort studies. 26,47

Thrombolysis Limited information regarding the safety and efficacy of thrombolysis in patients with CRT has been published. Five studies reported combined outcomes for CRT and upper extremity DVT.7781

In studies of patients with upper extremity DVT, recurrent thrombosis occurred in 10.9%

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ACCEPTED MANUSCRIPT (6/55) patients.77-81 In studies of CRT only, thrombolytic therapy in addition to anticoagulation showed that 53% of patients had initial clot resolution,61,82 but recurrence of the clot within the vein occurred frequently despite the use of anticoagulation.82 Due to the limited data, consensus guidelines recommend thrombolytic therapy only if the thrombotic risks outweigh the bleeding

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risk of treatment (e.g. poorly tolerated superior vena cava syndrome despite anticoagulation).26

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PEDIATRICS

When compared to adults, the overall incidence of thrombosis in children is low. Due to

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improved care of acutely ill children and the increased placement of CVCs, however, the rate of

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VTE in children is increasing. Children show a bimodal age distribution, with a peak incidence in those >1 year of age and another peak during adolescence.83,84 Hospitalized children have the

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highest rate of VTE. Review of the Pediatric Health Information System database from 2001-

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2007 revealed an increase in hospital-acquired VTE by 70%.85 Children with hospital-acquired

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VTE have increased mortality and increased hospital length of stay.

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The most common risk factor associated with pediatric VTE is the presence of a CVC. 83,86,87 CVCs are being placed in children at increasing rates, especially the placement of PICCs.88 This

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is most likely due to PICCs ease of placement, which often can be at the bedside without need for sedation.

The incidence of pediatric CRT ranges from 2-81%,89 and recurrent VTE occurs in 6.5% of children.90 This wide variation in incidence is due to differences in patient subpopulations studied (cancer vs. dialysis patients), type of CVC used (PICC vs. tunneled line), diagnostic

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ACCEPTED MANUSCRIPT imaging modality (US vs. venography), and use of screening imaging. Asymptomatic VTE diagnosed by screening ultrasound or venography are of unclear clinical significance. The incidence of asymptomatic CRT ranges from 5-50%, and most asymptomatic thrombi are detectable within four days of catheterization.91,92 Infants have the highest incidence of CRT.86,93

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The Dutch pediatric VTE registry revealed that 93% of children under 1 year of age had a CRT,

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compared to 35% in adolescents.86 A retrospective analysis of hospital associated-VTE similarly

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young adults who most often experienced non-CRT.83

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found that infants and young children predominantly had CRT, compared with adolescents and

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Studies evaluating CVC-specific risk factors for pediatric thrombosis, such as the type of CVC, size or catheter material, or insertion technique have yielded conflicting results. A prospective

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study by Revel-Vilk et al. evaluated pediatric cancer patients with upper extremity CVCs

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(Hickmans, indwelling infusion port, or PICCs) and found an increased occurrence of VTE with PICCs (5.3%) compared to non-PICCs (1.9%). 94 A retrospective analysis of a Pediatric

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Oncology Group acute lymphoblastic leukemia (ALL) study also noted an increased VTE risk

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with external CVCs versus indwelling infusion ports.95 On the other hand, a study which included children with various diagnoses, found no difference in CRT rate between PICCs versus

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centrally placed catheters. 96 This study reported an increased CRT rate in children with femoral and subclavian CVCs (versus brachial and jugular),96 in contrast to the study in cancer patients in which did not find a correlation between the vein cannulated and risk of thrombosis.94 A single institution study of infants with a tunneled CVC, PICC, or percutaneous catheter, found that CVCs placed in the femoral vein, compared to the subclavian or jugular and multi-lumen CVCs, had the highest risk of CRT.97 The PARKAA study evaluated CRT in children with ALL and

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ACCEPTED MANUSCRIPT upper extremity CVCs. They found an increased CRT in CVCs placed on the left side, in the subclavian vein (versus jugular), and via percutaneous technique (versus cut-down). 98 In children with cancer and an indwelling infusion port , an increased risk of CRT was seen also seen with left sided placement, 99 Revel-Vilk and colleagues found no difference when

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comparing side of insertion.94 Lastly, increased CRT risk has been reported in patients with a

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CVC with repeated occlusions or infection.100

Most children with CRT have serious underlying medical conditions. Those with congenital

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heart disease (CHD) and cancer have the highest risk for developing CVC-related VTE. VTE has

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been seen in up to 11% of children after cardiac surgeries.101 Children with CHD <31 days old, with baseline oxygen saturation <85%, previous thrombosis, heart transplant, need for ECMO,

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prolonged insertion of their CVC, and prolonged time in the ICU are at highest risk for

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thrombosis.101 Providers must consider the risk of embolic stroke in children with large right-toleft shunts. Similar to adults, cancer increases the risk of VTE due to the cancer itself, but

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children with ALL have an additional thrombosis risk due to treatment with L-asparaginase and

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steroids, particularly prednisone.102,103 Depending on the type of cancer and study design, the reported VTE incidence ranges from 1-37%.102 CRT is also seen in other hematological diseases

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such as sickle cell disease due to chronic activation of the coagulation system and hemophilia due to long-term indwelling catheters.104 Approximately 10% of children with sickle cell disease will experience a CRT.105 Increased risk of CRT has also been reported in patients with inflammatory bowel disease, short bowel syndrome requiring total-parental nutrition, and endstage renal disease requiring dialysis.89

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ACCEPTED MANUSCRIPT Inherited and acquired thrombophilias are also risk factors for pediatric VTE. Young et al. showed that children with inherited thrombophilias or deficiencies of protein C, protein S and antithrombin have a higher risk of VTE.106 A systematic review and meta-analysis of thrombophilia and CRT revealed the presence of an inherited or acquired thrombophilia

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increases the risk of CRT, especially protein C deficiency, elevated factor VIII activity, and

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factor V Leiden mutation.39

Successful measures to prevent CRT have not been established in children. Four randomized

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controlled trials have evaluated pharmacological prophylaxis, although most were underpowered

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and unable to determine efficacy. Three trials studied children with cancer and CVCs treated with LMWH, antithrombin, or low dose warfarin in comparison to a control group.107-109 These

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studies showed prophylactic anticoagulation was safe, but efficacy was unclear. This was

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potentially due to the use of screening US or venography to detect CRT, fluctuating drug levels, small study numbers, or not targeting the highest-risk population.The fourth trial established

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prophylactic anticoagulation efficacy for pediatric trauma patients to prevent all types of VTE

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(not only CRT), but this trial was performed in a single center with a limited patient population.110 In addition, a single institution study evaluated the safety of prophylactic

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anticoagulation to prevent CRT. This study was conducted in 89 high-risk adolescents, in which only 2 (4%) had a bleeding event and no patients developed a non-catheter related VTE.111 Therefore, due to the paucity of data for CRT prevention in children, additional trials are needed before generalized anticoagulant prophylaxis can be recommended. In order to address this need in a high-risk population, the Children’s Oncology Group is currently enrolling newly diagnosed

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ACCEPTED MANUSCRIPT patients with ALL in a phase III randomized controlled trial to evaluate the safety and efficacy of apixaban to prevent thrombosis during induction therapy (NCT02369653).

Anticoagulation is the standard care for treatment of children diagnosed with VTE including

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CRT. Dosing and length of treatment for children are extrapolated from adult studies.112

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Anticoagulation can be more difficult to manage in neonates and children compared to adults due

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to their developing coagulation system.113,114 Children are most commonly treated with unfractionated heparin, LMWHs and VKAs. Due to developmentally low levels of anti-thrombin

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at birth, treatment of infants less than 6 months of age with unfractionated or LMWH is difficult.

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Pediatric studies of parental DTIs (argatroban and bivalirudin) and fondaparinux have

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for pediatric VTE remain ongoing.

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established dosing in children. 115-117 Trials evaluating the safety and efficacy of DOAC therapy

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Unanswered questions and future directions

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Despite the amount of literature published to date regarding CRT, many questions remain. Although risk scores for thrombosis in patients with cancer have been developed, the scoring

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systems are not specific for CRT. Appropriate risk stratification tools for patients with CVC are needed to target highest-risk patients for prophylaxis strategies. Although most patients with CRT are treated with anticoagulation, the most effective type and duration of treatment have not been established for adults or children. National and international collaborative research networks could be harnessed to perform these much needed studies.

19

ACCEPTED MANUSCRIPT Acknowledgements None

References

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119. Vu K, Luong NV, Hubbard J, et al. A retrospective study of venous thromboembolism in acute leukemia patients treated at the University of Texas MD Anderson Cancer Center. Cancer Med. 2015;4(1):27-35.

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Table 1. Suggested risk factors for catheter-related thrombosis Intrinsic catheter-related factors CVC types (PICCs > other CVCs > imported ports) Tip location (proximal to SVC > SVC and RA junction) CVC diameters (triple > double > single lumen) Insertion site: (femoral > subclavian > jugular) Side of insertion (Left > right) Time elapse since insertion (less than 10 days > Less than 100 days > later) Multiple attempts at CVC insertion Extrinsic patient-related factors Tumor type Metastatic disease Chemotherapy Previous venous thromboembolism Known thrombophilia (Factor V Leiden; Prothrombin Gene Mutation) CVC: central venous catheters; PICC: peripherally inserted central catheter; RA: right atrium; SVC: superior vena cava.

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Table 2. Constans Clinical Decision Tool for upper extremity thrombosis. Scores ≥2 indicate a likely upper extremity thrombosis Item Score Central venous catheter or pacemaker present +1 Localized pain +1 Unilateral edema +1 Other diagnosis as or more likely -1

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ACCEPTED MANUSCRIPT Table 3. Anticoagulant therapy for adults with catheter-related thrombosis in studies when duration of anticoagulation was reported Author

Adults (n)

Aburahma57

45

Baumann Kreuziger69

558

33 (73%)

DVT Recurrence n (%)

PE n (%)

Major hemorrhage n (%)

≥ 3 mo Mean 142-236

8 (1.4%)

9 (1.6%)

22 (3.9%)

224

< 6 mo (51%) > 6 mo (35%) Censored (14%) 3 mo

Frizzelli56

83

Gloviczki58

23

6 (2.6%)

Kahn66

24

4 CRT (36%)

36

55

0 (0%)

74

0 (0%)

0 (0%) at 7 days

3% CRT

29

Monreal 199427

86

Monreal 200667

98

Savage59

46

Vu119

80

PT

23 (5.6%)

2 (3.6%) CRT

0 (0%)

Massoure65

8 (27.5%)

6 (1.5%)

2 (2%)

30 (13.4%)

3 mo 3 mo (29%) 6 mo (6%) Other (65%) <1 mo (21%); 1-3 mo (45%) 3-6 mo (10%) >6 mo (24%) At least 8 d

CE

66

AC

Lazo-Langner

70

<3 mo (16%) > 3mo (74%) Median 5 mo (range 0-49 mo) mean 4.7 mo (range 3-6 mo)

ED

Karabay60

IP

Flinterman64

7 (1.7%)

3 (3%)

US

409

4 (4%)

AN

Farge118

Range 1-62 mo Median 124 d Average 5 mo

CR

99

T

d

68

Kovacs

AC Duration (% of patients)

M

Delluc

PTS n (%)

0 (0%)

3 (4%) 2.8%

2 (6.9%)

2 (6.9%)

1 (3.4%)

0 (0%)

2 (2.3%)

At least 3 mo

4 (3.8%)

4 (3.8%)

4 (3.8%)

At least 12 weeks < 1 mo (75%) > 6 mo (25%)

1 (2.2%)

0 (0%)

1 (2.2%)

22 (15.8%)

5 (3.6%)

AC=anticoagulation; n – number of adult patients included in the analysis. PTS= Post thrombotic syndrome; hr=hours, d=days, wk= weeks, mo=months, y=year; fu=follow up; NR= Not Reported. UFH=unfractionated heparin, LMWH= low molecular weight heparin; VKA=vitamin K antagonist,

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ACCEPTED MANUSCRIPT Highlights

CE

PT

ED

M

AN

US

CR

IP

T

Catheter-related thrombosis (CRT) occurs in 1-5% of inserted catheters. The Constans score is a clinical prediction rule for upper extremity thrombosis. The most effective type and duration of therapy for CRT has not been established. Treatment of CRT in children is based upon studies in adults.

AC

   

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