Special article

Journal of the Intensive Care Society

2016, Vol. 17(2) 160–167
! The Intensive Care Society 2015
Catheter-related thrombosis: Reprints and permissions:
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A practical approach journalsPermissions.nav
DOI: 10.1177/1751143715618683
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Caroline Wall1, John Moore2 and Jecko Thachil1

Abstract
Catheter-related thrombosis is a relatively common complication of central venous catheter insertion. Central venous
catheter use is ubiquitous in the critical care setting and often in patients with multiple risk factors for venous thrombo-
embolism. With a trend towards increased use of peripherally inserted central catheters, the incidence of catheter-
related thrombosis is likely to increase further. Despite the scale of the problem, there is a paucity of evidence-based
guidelines concerning the management of patients with catheter-related thrombosis, particularly in critically unwell
patients. This has led to heterogeneity in clinical practice. In this review, we describe the risk factors for developing
catheter-related thrombosis and provide practical advice for clinicians on how to recognise, diagnose and treat this
common problem.

Keywords
Catheter-related thrombosis, venous thromboembolism, central venous catheter, peripherally inserted central catheter,
anticoagulation

location of insertion and (b) the type of CVC are

Introduction
Indwelling central venous catheters (CVCs) are ubi-
quitous in the critical care setting. Thrombotic com-
plications can occur with CVC use with reported rates
varying from around 5% for symptomatic events1 to
an overall rate of 14–18%.2 Despite being relatively
common, there is heterogeneity in clinic practice when
it comes to the management of catheter related throm-
bosis (CRT). There are limited evidence-based guide-
lines for the best diagnostic approach and preventive
measures for CRT, particularly in critically unwell
patients. This review aims to provide clinicians with
a pragmatic approach to dealing with CRT.
Risk factors
There are several risk factors for the development of
CRT. They can, broadly speaking, be categorised as
risks relating to the line itself, the insertion process
and patient factors (see Table 1). It is useful to
remember, in this context, how these factors relate
to Virchow’s triad of endothelial damage, stasis and
hypercoagulability, described as the components
involved in thrombus formation (Figure 1).
Prevention is better than treatment when it comes
to CRT. Some of the risk factors for CRT such as (a)
modifiable and careful consideration of these can
minimise the risk for thrombosis. The International
Society of Thrombosis and Haemostasis guidelines
recommend that where possible, CVCs should be
inserted on the right side, in the jugular vein with
the tip located at the junction of the superior vena
cava and the right atrium to minimise the risk of
thrombosis.3,4
Table 2 summarises the types of CVCs most fre-
quently encountered in clinical practice. Tunnelled
lines are infrequently inserted during acute admissions;
however, they are encountered routinely in patients
admitted from other departments such as haematol-
ogy, oncology and renal departments. Within the crit-
ical care setting, temporary, non-tunnelled lines are
most frequently inserted due to their ease of insertion,
multiple lumens, and ability to monitor central-venous
1
Department of Haematology, Manchester Royal Infirmary, Manchester,
UK
2
Department of Critical Care, Manchester Royal Infirmary, Manchester,
UK
Corresponding author:
Caroline Wall, Department of Haematology, Manchester Royal
Infirmary, Oxford Road, Manchester M13 9WL, UK.
Email: carolinewall@doctors.org.uk
Wall et al. 161

Table 1. Risk factors for the development of CRTs.

Factor Variable Effect on risk of CRT

Patient factors Hypercoagulable states including malignancy, sepsis, critical Increased

illness, renal failure, previous VTE, use of certain drugs
(e.g. thalidomide), possibly inherited thrombophillias
Catheter type PICC Increased (additional risk with increased
diameter/number of ports)
Closed-ended or open ended catheter No difference
Increased lumen diameter Increased
Insertion Tip located above the junction between the SVC and atrium Increased
Left sided Increased
Femoral Increased
Use of US guidance No difference
Multiple insertion attempts Increased
CRT: catheter-related thrombosis; VTE: venous thromboembolism; PICC: peripherally inserted central catheter; SVC: superior vena cava syndrome.

Endothelial Damage
Catheter insertion

Thrombosis

Hypercoagulable
Stasis state
Presence of catheter itself Sepsis
Infusion fluid: chemotherapy, Malignancy
viscous drugs, TPN etc. Inflammation
Lack of limb movement Thrombophillia

Figure 1. Postulated mechanisms by which the presence of a CVC may contribute to the development of thrombosis.

pressure. More recently, there has been a trend towards
the use of PICC lines in patients with changing access
needs following the acute phase of their illness or as an
alternative to CVCs. Recent studies in critical care have
suggested that they are associated with lower compli-
cation rates than previously thought, particularly
relating to catheter-related blood stream infections
(CRBSI).5,6 A small retrospective report on the use
of power injectable PICCs (ultra-resistant polyureth-
ane devices allowing high-pressure infusions) in the
critical care setting, reported excellent CRBSI rates
and lower than expected symptomatic CRT rates. Of
89 power-PICC insertions, there were no CRBSIs and
two cases of symptomatic CRT (routine screening did
not occur). The authors claim that low complication
rates were due to robust insertion protocols, including
ultrasound guidance to ensure appropriate vein diam-
eter and the use of intra-cavitatory ECG monitoring to
ensure correct position.6 However, PICCs are generally
considered to be associated with higher rates of CRT
than other devices and it is not unreasonable to suspect
that patients admitted to critical care may be
162
Table 2. Summary of commonly encountered CVCs.
Venous Common
catheter brands Lumens Duration
Non-tunnelled NA 2–4 Temporary: 1–3 weeks
Tunnelled HickmanÕ 1–3 Semi-permanent
BroviacÕ >30 days
GroshongÕ
Implanted port Port-a-cathÕ 1 Semi-permanent
>30 days
Peripherally NA 1–3 Intermediate >7 days
inserted cen-
tral catheter
(PICC)
particularly at risk.7,8 One non-randomised, prospect-
ive trial found higher rates of thrombosis in patients
discharged from critical care with PICC lines than
CVCs, with rates of CRT of 7.7/1000 vs. 4.4/1000 cath-
eter days respectively.8 With increased interest in the
idea of PICC lines being a potential alternative to CVC
insertion, one study aimed to prospectively evaluate
outcomes in patients receiving triple-lumen PICCs.
At interim analysis, this study was terminated due to
unacceptably high CRT rates; 20% of the study group
developed symptomatic CRTs, rising to 58% including
asymptomatic cases.9 This would further suggest that
increasing lumen diameter increases the risk of CRT in
PICCs and perhaps supports the use of CVCs if more
than two lumens are required. It is clear that high-
quality RCTs are required to definitively establish the
relative risks of PICC and CVC insertion with modern
devices and care bundles.10 If in the interim clinicians
do opt for PICC use, it is necessary to consider modi-
fiable risks including the catheter-to-vein ratio, prag-
matically aiming to use the smallest diameter catheter
lumen in the largest diameter vein feasible and be
mindful of potential thrombosis.6,7,9,11,12
Sepsis is of course commonly encountered in crit-
ical care patients and is widely recognised as a risk
factor for venous thromboembolism (VTE). In rela-
tion to CRT there is evidence to suggest this relation-
ship endures. The presence of a CVC-related infection
increases the risk of symptomatic CRT, with the high-
est rates seen systemic rather than localised infec-
tion.13 It may be argued that the presence of
catheter-related infection should prompt screening
for CRT with ultrasound, even in the absence of
other clinical features.13
Clinical symptoms
The majority of CRTs (two-thirds) are asymptomatic
which can make identification difficult; a high index
of suspicion is therefore required. The clinical features
may be fairly self-evident such as arm or neck swelling
and discomfort or venous distension. In some cases,
patients may experience atypical symptoms such as
Journal of the Intensive Care Society 17(2)
General indications
Critical care
Long-term uses: chemotherapy, parenteral
nutrition, etc.
Infrequent but long-term requirements
Paediatrics
Outpatient chemotherapy, intermediate-
term access for sampling, antibiotics,
etc.
Table 3. Possible presentations of CRT.
Asymptomatic (majority)
Swelling of head/neck/limb
Localised pain/numbness
Jaw or shoulder pain
Headaches/sensation of head fullness
Superficial venous distension
Inflammation/phlebitis
Erythema of limb
Difficulty with infusion or aspiration
Incidental finding on CT
CT: computed tomography; CRT: catheter-related thrombosis.
jaw or shoulder pain (see Table 3).14,15 CRT may
also be suspected following difficulty with infusion
or aspiration. It can be difficult to ascertain whether
this is due to mechanical obstruction including mal-
position, fibrin sheath formation, an intraluminal
clot, mural thrombosis, the rare ‘pinch off’ syndrome
(compression between the first rib and lateral clav-
icle), or indeed a venous thrombus. Figure 2 provides
a schematic image of possible thrombotic complica-
tions associated with CVCs.
Is CRT the cause of symptoms?
Whilst it may be common practice in many centres to
simply remove CVCs that are malfunctioning, diffi-
culty with line aspiration or infusion may be second-
ary to CRT and a high index of clinical suspicion is
required. It is also useful to consider other causes of
line occlusion as some are amenable to simple meas-
ures. This is particularly relevant to patients with ‘pre-
cious lines’ such as those with difficult access
. Check the tubing for mechanical obstruction such
as a kinked line, an overtight suture or tip abuttal
to vessel wall and inspect for a malpositioned
port.14 Repositioning manoeuvres include raising
the ipsilateral arm, having the patient sit or
stand, or rolling the patient onto one side may be
helpful in these cases.
Wall et al.
Mural thrombosis
Intraluminal clot
Figure 2. Schematic image of thrombotic events that may be associated with central venous catheters.
. It is worth reviewing preparations administered
through the line. Lipid emulsions, such as parenteral
nutrition, may leave a residue causing obstruction.
These blockages may be amenable to instilling the
line with a 70% ethanol solution, although no large
studies have been conducted into this practice.16 A
medicines review can also yield clues as to the cause
of obstruction as incompatible medications may
precipitate within the lumen.17
. Occlusion by catheter thrombosis is the next consid-
eration if no other cause is identified. In the case of
an intraluminal clot or fibrin sheath formation (see
Figure 2), lumen patency may be restored by instill-
ing the line with a thrombolytic agent such urokin-
ase which is commonly used in the UK and Europe.
Urokinase 10,000 units/ml is reconstituted with 3 ml
of 0.9% normal saline or water for injection. Each
lumen of the occluded catheter is instilled with 5000
units of urokinase and left for 2 h.18 An alternative
thrombolytic agent to urokinase is alteplase, which
has been shown in the cardiovascular thrombolytic
to open occluded lines trial (COOL) to have a good
efficacy and safety profile. Following the adminis-
tration of 2 mg alteplase with a dwell time of
120 min, 78% patency was achieved with one dose,
rising to 87% after a second.19 Whilst the trial data
on local thrombolytic therapy are not extracted
from critically unwell patients, the doses of
thrombolytic agents are small and for the majority
of patients are unlikely to cause harm. It would
however be prudent to review potential risks on an
individual basis.
Complications
The consequences of CRT are not insubstantial; com-
plications can include pulmonary embolism (PE) in 10–
15%, loss of venous access in 10%, infection, post
thrombotic syndrome (PTS) and delays in treatment.2
. PE: whilst thankfully rarely fatal, PEs are the most
serious complication.2
163
Venous thrombosis
Fibrin sheath
. PTS: a chronic complication of VTE that manifests
as oedema, chronic pain, a sensation of limb heavi-
ness, and in the worse cases ulceration. It is thought
that patients with large, proximal VTEs which fail
to completely resolve are at the highest risk of
developing PTS.
. Future lines: there is consensus on the criteria for
line removal when CRT develops; however, there is
no evidence to guide when it is considered reason-
able to insert a new CVC. Clinicians must therefore
assess the risks of further thrombosis against the
urgency for central access.
Diagnostic approach
A ‘linogram’ (contrast study) may theoretically be
used to confirm internal line kinking or the presence
of an intraluminal occlusion, but it is not commonly
performed. In practice, trial of a thrombolytic agent
empirically may be used which is particularly useful in
‘precious’ lines that cannot be easily replaced.14
Duplex ultrasound is the initial imaging modality
of choice if a CRT is suspected clinically or if lumen
patency is not restored with simple measures.20 It is
non-invasive and particularly reliable for assessing
thrombi in anatomically accessible veins including
the jugular, axillary, distal subclavian and arm
veins. In the more proximal veins, sited inside the
thorax, clearly duplex ultrasound is less sensitive.
If clinical suspicion of CRT is high despite a nega-
tive Duplex scan, then contrast venography may be
considered as it is the ‘gold standard’ investigation but
does confer risks associated with contrast and radi-
ation exposure.14,21
It is worth noting that the use of the D-dimer assay
has not been validated for use in patients with sus-
pected CRT and is therefore not recommended for use
in this context.18,22
Treatment
Factors to consider when treating CRT include
164
Catheter-related
thrombosis
CVC to remain CVC removal
Heparin or LMWH 3-5 High risk
days embolisation: 3-5
days heparin/LMWH
prior to line removal
Min 3 months LMWH
or warfarin then Min. 6 weeks
LMWH prophylaxis warfarin/LMWH
until line removed
Figure 3. Proposed treatment algorithm for patients with
confirmed CRT.
CVC: central venous catheter; LMWH: low-molecular weight
heparin.
. assessment of ongoing need for central access,
. the functional status of the line,
. the presence of an underlying prothrombotic state
and
. review of any contraindications to anticoagulation.
Systemic anticoagulation
There is limited good quality data available for the
systemic anticoagulation in CRT, particularly relating
to critical care patients. Recommendations are there-
fore largely extrapolated from data for lower limb
DVTs and small, non-randomised studies on CRT
(of which a significant number are conducted on
patients with malignancies).3 Figure 3 provides a pro-
posed treatment algorithm for the treatment of CRT.
Consensus opinion for the treatment of CRT is for
systemic anticoagulation for a minimum of three
months.3,13,23 In patients with malignancy, treatment
dose low-molecular weight heparin (LMWH) is rec-
ommended due to its superiority over vitamin K
antagonists (VKAs) in preventing recurrent throm-
bosis.23–25 In critical care patients who frequently
have unpredictable pharmacodynamics and are on
multiple medications, this also confers the advantage
of having fewer potential drug interactions which can
be a problem with VKAs like warfarin. In patients
with a rapidly changing clinical picture, such as
developing acute kidney injury, LMWH may require
monitoring with anti-Xa levels. In patients with exten-
sive CRT and particularly high bleeding risk, the use
of unfractionated heparin may also be considered due
to its short half-life and ease of reversal.
If the catheter remains in situ beyond completion
of three months anticoagulation, prophylaxis is
Journal of the Intensive Care Society 17(2)
recommended until line removal.23 In patients with-
out malignancy, VKAs may be commenced following
an initial period of LMWH.
The duration of anticoagulation following line
removal in patients without other ongoing thrombotic
risk factors is again controversial due to a lack of
good quality data. Some physicians continue to antic-
oagulate for three months whilst others shorten the
duration. The decision making process should include
thorough consideration of other potential risks for
thrombosis, the size of the clot and the extent to
which it occludes the vessel. Duration of six weeks’
anticoagulation may be appropriate if there are no
risk factors and the clot is small and non-
occlusive.14,23
There are no trials yet published using non-vitamin
K antagonist oral anticoagulants (NOACs), although
in the absence of malignancy, there is probably no
reason to exclude their use for CRT. Trials are under-
way with the use NOACs in cancer patients with
VTE.
Line removal
The current recommendations3,23 state that if the
CVC is still required and functioning well, it does
not have to be removed provided it
. is well positioned
. is non-infected
. demonstrates good resolution of symptoms on
surveillance.
The line should be removed if not all the criteria
are met, if anticoagulation is contraindicated, if the
thrombosis is life or limb threatening or if symptoms
are not resolving.
The thrombocytopaenic patient
When CRTs develop in the context of thrombocyto-
paenia, there is often concern regarding the best
management in view of increased bleeding risk. A
risk–benefit analysis needs to be carried out on an
individual basis and requires regular review. The
first three months following thrombosis infer the
greatest risk of recurrent thrombosis; therefore,
every attempt should be made to provide safe antic-
oagulation during this period. Current practice is to
modify treatment based on the severity of thrombo-
cytopaenia which must be monitored closely. Table 4
provides an overview based on current UK guide-
lines.26,27 Owing to its short half-life, intravenous
unfractionated heparin can also be considered in
patients with PE or extensive thrombosis in the pres-
ence of significant bleeding risk.18 The use of support-
ive platelet transfusion is addressed infrequently in the
literature; however, recent BSCH guidelines for the
management of cancer-related venous thrombosis
Wall et al.
Table 4. Treatment options in patients with CRT based on degree of thrombocytopaenia.
Platelet count Treatment options
>50  109 Full dose therapeutic anticoagulation taking into account additional
bleeding risk factors e.g. renal failure
25–50  109 50% dose LMWH Regular monitoring
<25  109 No anticoagulation
LMWH: low-molecular weight heparin.
suggest that platelet support may be used to allow full
dose anticoagulation if at high risk of recurrence.27
Temporary IVC filter insertion may also be con-
sidered if anticoagulation is contraindicated.27
Patients who develop thrombocytopaenia follow-
ing anticoagulation with heparin should be reviewed
to exclude heparin induced thrombocytopaenia
(HIT).
Prophylaxis
Current guidelines, based on the evidence available,
do not recommend anticoagulation for the routine
prevention of CRTs,7,25,28,29 although it is expected
that the vast majority of critical care patients will
receive LMWH prophylaxis as standard care.
Previously, low-dose warfarin (1 mg/day) had been
used for patients with indwelling catheters and malig-
nancy30 but subsequent trials disproved its benefit.31
The largest contemporary trial, WARP (Warfarin
thromboprophylaxis in cancer patients with CVCs)
compared the use of adjusted dose warfarin (INR
1.5–2.0), low-dose warfarin (1 mg/day) and no antic-
oagulation in the prevention of CRT in cancer
patients.32 The data from this trial did find a benefit
in CRT reduction in the dose adjusted arm but this
was offset by increased bleeding risk. There was no
significant benefit in taking low-dose warfarin.
In 2011, a Cochrane review analysed the available
data on prophylaxis with UFH and LMWH in the
prevention of CRT. It concluded that despite no
increase in bleeding risk, there was also no benefit in
the reduction of symptomatic thrombosis.33
There is ongoing debate in respect to maintaining
line patency with local measures. Following The
National Patient Safety Agency (NPSA) report in
2008, which highlighted potential dangers associated
with heparin flushes, the use of saline-only flush solu-
tions was recommended.34 This led to a dramatic fall
in the use of heparin flushes in critical care, with some
centres questioning if this has resulted in increased
thrombotic complications and reduced catheter life-
span. Tully et al. performed an observational study
of 445 arterial lines flushed with either saline or hep-
arin solutions and found significantly decreased rates
of line occlusion with increased catheter lifespan in
the heparin group.35 Whilst there is insufficient evi-
dence to recommend the practice of flushing lines with
heparin to maintain line patency at this time,28,36,37
165
Bishop et al.28, Baglin et al.26
Murray et al.18
Watson et al.27
it is an area that requires further evaluation with ade-
quately powered, blinded randomised controlled trial.
Problem areas in relation to CRT
The increasing use of CVCs, and particularly increas-
ing PICCs usage, will likely increase the incidence of
CRT. Although most cases are easily treated, there
are still some dilemmas when it comes to CRT.
These include
. Patients with thrombocytopenia – is not anticoa-
gulating safe?
. Choice of catheters – there is ongoing debate on the
relative risks of PICC and CVCs in regards to
thrombosis and infection
. More data on sepsis/thrombosis relationship
. Absence of epidemiological data for complications
Probably the biggest issue in relation to CRT man-
agement is lack of best evidence.
Conclusions
CRTs are a relatively common occurrence with the
potential for significant morbidity. Given that the
majority of cases occur asymptomatically, a high
index of suspicion is required for diagnosis. The
non-invasive nature and sensitivity of venous duplex
scanning lends this imaging technique to be the ima-
ging modality of choice in the majority of patients. To
date, there is insufficient evidence to support prophy-
lactic anticoagulation in the prevention of CRT; how-
ever, careful consideration of modifiable risk factors
prior to line insertion can reduce risk. Where feasible,
CVCs should be inserted in the right jugular vein with
the tip at the cavoatrial junction and despite the
increasing usage of PICCs, acknowledgment of their
propensity to increase CRT risk needs to be
addressed. Providing that a line is still required, func-
tioning, in the correct position and there is no
evidence of infection, current recommendations
advise against removal. Except in the lowest risk
groups, three months systemic anticoagulation is gen-
erally recommended. In patients with malignancy,
LMWH is the preferred anticoagulant, with warfarin
being an alternative in patients without malignancy
once their critical illness has resolved. The most per-
tinent issue to be derived from this report is the lack
166
of good quality evidence on CRT in the critical care
population. We are currently extrapolating data from
the management of DVTs and small studies of CRT
in patients with co-existing malignancy. Adequately
powered RCTs are required to definitively establish
how best to managed CRT in the critical care arena.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of
this article.
Funding
The authors received no financial support for the research,
authorship, and/or publication of this article.
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