Peripherally Inserted Central Catheter-Associated Deep Vein Thrombosis: A Narrative Review

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Peripherally Inserted Central Catheter-associated
Deep Vein Thrombosis: A Narrative Review
Nabil Fallouh, MD, MS,
a
Helen M. McGuirk, MPH,
a,b
Scott A. Flanders, MD,
a
Vineet Chopra, MD, MSc
a,b
a
Department of General Medicine, University of Michigan Health System, Ann Arbor;
b
Patient Safety Enhancement Program, Hospital
Outcomes Program of Excellence and the Center for Clinical Management Research, Ann Arbor VA Medical Center, Ann Arbor, Mich.
ABSTRACT
Although common, little is known about factors associated with peripherally inserted central catheter-related
deep vein thrombosis (PICC-DVT). To better guide clinicians, we performed a comprehensive literature
review to summarize best practices for this condition. A systematic search of the literature for studies
reporting epidemiology, diagnosis, treatment, and prevention of PICC-DVT was conducted. Algorithms for
diagnosis and management were compiled using available evidence. The incidence of PICC-DVT varied
between 2% and 75% according to study population, testing modality and threshold for diagnosis. Studies
evaluating the diagnostic utility of clinical symptoms suggested that these were neither sensitive nor specific
for PICC-DVT; conversely, ultrasonography had excellent sensitivity and specificity and is recommended as
the initial diagnostic test. Although more specific, contrast venography should be reserved for cases with high
clinical probability and negative ultrasound findings. Centrally positioned, otherwise functional and clinically
necessary PICCs need not be removed despite concomitant DVT. Anticoagulation with low-molecular-
weight heparin or warfarin for at least 3 months represents the mainstay of treatment. The role of
pharmacologic prophylaxis and screening for PICC-DVT in the absence of clinical symptoms is unclear at
this time.
Published by Elsevier Inc. !The American Journal of Medicine (2015) -,---
KEYWORDS: Deep vein thrombosis; Diagnosis; DVT; Peripherally inserted central catheter; PICC; Prevention;
Thrombosis; Treatment
Over the past decade, use of peripherally inserted central
catheters (PICCs) to achieve nonpermanent yet durable
venous access has grown dramatically.
1,2
Originally devel-
oped in 1975 for delivering total parenteral nutrition,
3
PICCs today serve roles spanning delivery of short- and
long-term intravenous antibiotics to invasive hemodynamic
monitoring. However, PICCs are also associated with
complications, including upper-extremity deep vein throm-
bosis.
4,5
Peripherally inserted central catheter-related deep
vein thrombosis (PICC-DVT) is important because it
interrupts venous therapy, increases cost of care, and often
leads to sequelae such as phlebitis, vein stenosis, and pul-
monary embolism.
5-10
Despite these facts, little is known about risk factors,
diagnostic strategies, treatment, and prevention of PICC-
DVT. While a recently published meta-analysis reported
that PICCs were associated with a greater risk of throm-
bosis compared with central venous catheters,
11
factors
that may drive this increased risk are not well defined. An
overview incorporating the myriad scientific and technical
aspects of diagnosis, management, and prevention of
PICC-DVT is thus needed. Therefore, we reviewed the
literature and synthesized available data to develop
evidence-based algorithms for evaluation and treatment of
PICC-DVT.
METHODS
With a medical research librarian, we searched MEDLINE
(via PubMed), CINAHL, Embase, and the Cochrane
Funding: No funding was received for this project. VC is supported by
a career development award from the Agency for Healthcare Research and
Quality (1K08HS022835-01).
Conflicts of Interest: None for all authors.
Authorship: All authors had access to the data and a role in writing the
manuscript.
Requests for reprints should be addressed to Vineet Chopra, MD, MSc,
Department of General Medicine, University of Michigan Health System,
2800 Plymouth Road, Building 16, Rm 432W, Ann Arbor, MI 48109.
E-mail address: vineetc@umich.edu
0002-9343/$ -see front matter Published by Elsevier Inc.
http://dx.doi.org/10.1016/j.amjmed.2015.01.027
REVIEW

CENTRAL registry for English-language articles with
the following keywords: “peripherally inserted central
catheter,”“PICC,”“deep vein thrombosis,”and “throm-
bosis”(Appendix). Boolean operators and medical subject
heading terms were used to enhance electronic searches.
Additional studies of interest were identified by hand
searches of bibliographies.
Studies that involved patients
<18 years of age, or that were
case reports, editorials, or con-
ference proceedings were ex-
cluded. The search was last
updated August 1, 2014.
Using the retrieved articles,
we summarized findings to
develop evidence-based algo-
rithms for decision-making in
PICC-DVT. To create such al-
gorithms, we first categorized
studies by patient-, provider-, and
device-related domains according
to a published conceptual model (Figure 1).
12
Two authors
(VC and NF) then developed workflows in each domain to
develop an organizational framework. By determining
which factors were modifiable (and consequently, target-
able), we developed recommendations for testing and
treatment.
RESULTS
A total of 83 articles were included in our review (Figure 2).
Studies are presented as follows: (a) epidemiology and risk
factors; (b) clinical signs and symptoms; (c) diagnosis,
treatment, and prevention of PICC-DVT.
Epidemiology and Risk
Factors for PICC-DVT
The incidence of PICC-DVT var-
ies by patient population. Studies
involving critically ill popula-
tions, those with cancer, and hos-
pitalized patients report higher
rates of PICC-DVT (5%-15%)
than ambulatory populations
(2%-5%).
4,5,11,13,14
Correspond-
ingly, estimates of the frequency
of PICC-DVT often relate to
epiphenomena such as population
studied, method of diagnosis, and
diagnostic testing thresholds.
11
Studies that utilize screening
techniques (eg, testing in the absence of clinical signs or
symptoms) demonstrate a pooled frequency of PICC-DVT
that is substantially greater than studies where testing is
prompted by clinical symptoms (24.2%; 95% confidence
interval [CI], 17.9-50.4 vs 4.3%; 95% CI, 3.4-5.2).
11
In a
recent study, screening for PICC-DVT was associated with
thrombosis in 75% of devices, with the majority of these
being asymptomatic.
15
Patient-related Risk Factors. Several patient-specific
characteristics influence the risk of PICC-DVT. For
instance, prior venous thromboembolism is associated with
greater risk of PICC-DVT.
7,16,17
Critically ill patients and
those with a cancer diagnosis are also at a substantially
greater risk of PICC-DVT.
4,18,19
Additionally, higher rates of
PICC-DVT have been reported in patients with end-stage
renal disease, potentially due to the prothrombotic state
associated with this condition.
20
Inherited thrombophilias
such as protein C or protein S deficiency also fall into this
category.
21
Specific comorbidities (eg, diabetes mellitus,
obesity, and chronic obstructive pulmonary disease) may be
associated with greater risk of PICC-DVT according to a
number of observational studies.
4,14,20,22,23
Notably, surgery
with a PICC in situ is an important factor associated with this
outcome and should be avoided whenever clinically feasible.
7
Device-related Risk Factors. Blood flow in peripheral
veins is hampered by PICC placement; the caliber of the
catheter and degree of cross-sectional area occupied by
the PICC correlates with reduction in venous flow.
24
In a retrospective cohort study of 966 unique PICC place-
ments, 5- and 6-French PICCs were more likely to develop
PICC-DVT compared with 4-French PICCs (hazard
ratio [HR] 3.56; 95% CI, 1.31-9.66, and HR 2.21; 95% CI,
Figure 1 Conceptual model For PICC-DVT. A conceptual
model, adapted from a prior submission,
16
displaying patient-,
provider-, and device-related characteristics associated with
PICC-DVT. COPD ¼chronic obstructive pulmonary disease;
ICU ¼intensive care unit; PICC ¼peripherally inserted central
catheter; VTE ¼venous thromboembolism.
CLINICAL SIGNIFICANCE
!Despite increasing recognition, little is
known about patient-, provider-, and
device-specific risk factors associated
with peripherally inserted central
catheter-related deep vein thrombosis
(PICC-DVT).
!Novel algorithms utilizing these data to
guide clinicians in diagnosis and treat-
ment of PICC-DVT are presented.
2 The American Journal of Medicine, Vol -, No -,-2015

1.04-4.70, respectively).
25
Thus, greater PICC gauge is an
important, modifiable device-related risk factor for PICC-
DVT.
7,16,25,26
Some studies suggest that power-capable PICCs
(specialized devices that can withstand high pressures
associated with contrast injection machines) might be
associated with greater risk of PICC-DVT.
27
However,
recent data challenge this finding.
16
Additionally, the
nature of the infusate administered through the PICC may
influence thrombotic risk and confound this association.
For instance, administration of antibiotics such as van-
comycin, ceftriaxone, and metronidazole are associated
with increased rates of PICC-DVT.
5,20
In a study of
neurosurgical intensive care unit patients, infusion of
mannitol and vasopressors through the PICC was asso-
ciated with PICC-DVT.
28
The use of erythropoietin-
stimulating agents or infusion of specificchemothera-
peutic agents (eg, fluorouracil and capecitabine) may
also increase the risk of PICC-DVT.
29,30
Collectively,
extremes of pH (#5or$9), osmolarity, and concentra-
tion of infusates (alone or in combination) may predis-
pose to intimal damage, inflammation, and subsequent
thrombosis.
31
Of note, whether the pH of an intermittently
delivered medication influences risk of thrombosis or
phlebitis has been called into question recently.
32-34
In a study involving cancer patients, catheter dysfunc-
tion (eg, inability to flush the PICC or infuse therapeutics)
was noted to herald or accompany DVT in 25% of pa-
tients.
35
However, formation of fibrin sheaths composed of
platelets, collagen, and smooth muscle elements may also
impair PICC performance, as would precipitation of crys-
tals or minerals from infusions and extraluminal factors
such as coiling or kinking.
36-38
Thus, although problematic
from a clinical perspective, dysfunction is not a reliable
predictor of PICC-DVT.
39
In a randomized trial of 326 patients, Ong et al
40
reported a lower rate of phlebitis and infection associ-
ated with proximal-valved PICCs than distal-valved de-
vices. However, other studies, including a recent
randomized controlled trial, failed to identify any clinical
advantage to valved, compared with nonvalved
PICCs.
41,42
Antimicrobial-coated or anti-thrombotic
catheters, although promising, are yet to prove effective in
preventing PICC-related thrombosis.
43
Figure 2 Study flow diagram.
Fallouh et al Peripherally Inserted Central Catheter-associated Deep Vein Thrombosis 3

Provider-related Risk Factors. To minimize thrombosis,
insertion into appropriately sized veins and localization of
the catheter tip at the cavoatrial junction are vital.
44-46
The
rationale for the latter recommendation relates to blood
velocity in these regions compared with other sites. PICC
tips that lie outside of the superior vena cava are more
likely to develop thrombosis; conversely, placement of the
PICC tip at the cavoatrial junction substantially reduces
such risk.
5,11,18,47
Early findings of novel technology to
improve positioning of PICC tips (eg, electromagnetic and
electrocardiogram-based PICC-tip systems) suggest
reduced thromboses with use of these modalities.
48-50
Vein and arm of insertion may be an important factor
associated with PICC-DVT.
20,51
In their study, Liem et al
14
reported that PICCs placed in the basilic vein were associ-
ated with twice the risk of DVT compared with nonbasilic
vein placements (3.1% vs 1.5%, P¼.05).
14
While PICCs
placed in the left arm may be associated with greater risk of
thrombosis (perhaps due to insertion challenges leading to
endothelial damage),
20
Sperry et al
52
examined 798
consecutively placed PICCs and found that laterality was
not associated with symptomatic DVT. Thus, available ev-
idence does not support preferential insertion of the PICC in
one arm over the other; patient preferences should influence
this decision.
53
Rather than avoidance of a specific vein or
arm, ascertainment of an appropriate catheter-to-vein ratio
and avoidance of smaller forearm veins are important to
prevent PICC-DVT.
24,54,55
A summary of publications relevant to patient-, provider-,
and device-related factors associated with PICC-DVT is
presented in Table 1.
Clinical Signs and Symptoms of PICC-DVT
When symptomatic, PICC-DVT often presents with signs of
impaired venous outflow (eg, arm pain, swelling, or
distention of the veins in the arm, neck, and chest). Mani-
festations related to superficial thrombophlebitis may also
be observed.
56,57
Characterized by erythema, redness, and
warmth along the vein of entry, thrombophlebitis may
become painful or infected (eg, septic thrombophlebitis) so
as to necessitate PICC removal.
58
Although less frequent than embolization from deep
veins of the leg,
9,57,59
PICC-associated pulmonary embo-
lism is more common in those that are critically ill or
afflicted with cancer.
11
In studies involving critically ill
patients, pulmonary embolism accounts for 13%-20% of all
thrombotic events related to PICCs.
8,28-30
Interestingly,
unlike the lower extremities, the frequency of post-
thrombotic syndrome following upper-extremity DVT is
highly variable, potentially due to the differences in venous
pressure between the limbs. Therefore, whether PICC-DVT
increases risk of postthrombotic syndrome is unclear at this
time.
30,60,61
It is important to emphasize that most PICC- and
catheter-related DVTs are often clinically silent,
62
and
diagnosis is hampered by low specificity.
56,63
While a risk
score to assess probability of catheter-related DVT has been
proposed, the mere presence of an indwelling venous
catheter moves the probability of DVT from low to inter-
mediate.
64
An unmet need for a clinical risk prediction tool
that offers high specificity for PICC-DVT thus exists.
Diagnosis of PICC-DVT
Owing to noninvasiveness, radiation, and contrast-free
properties, compression ultrasonography is the initial mo-
dality for diagnosis of PICC-DVT. Ultrasound confirmation
of PICC-DVT is often based on (a) the presence of visible
thrombus in the vein, (b) noncompressibility of the affected
vein, or (c) absence of venous flow on Doppler or color
ultrasound.
63,65
Early systematic reviews reported sensi-
tivity and specificity of ultrasound for catheter-associated
DVT of 56%-100% and 94%-100%, respectively.
66
Of
note, because compression of the veins to confirm thrombus
requires access to the segment involved, sensitivity and
specificity of ultrasound diminish with proximal involve-
ment (eg, brachiocephalic, subclavian, or innominate
veins).
67,68
However, a systematic review of 17 studies and
793 patients concluded that ultrasonography is an acceptable
alternative to venography given summary sensitivity and
specificity estimates of 97% and 96%, respectively.
63
Contrast venography is an invasive and a more techni-
cally challenging procedure that should be reserved for
cases where ultrasound is not confirmatory but alternative
diagnoses are unlikely. While venography performed by
computed tomography or magnetic resonance imaging has
emerged as a less invasive alternative, the diagnostic accu-
racy of these modalities in upper-extremity or catheter-
related thrombosis is unclear.
68,69
No studies have directly
compared these with ultrasound for catheter or PICC
thrombosis.
Compared with lower-extremity DVT, plasma bio-
markers have a limited role in diagnosis of catheter
DVT.
70-72
In a Swiss study of 52 consecutive patients, D-
dimer was highly sensitive (100%) but not specific (14%) in
patients with suspected arm DVT.
73
The diagnostic utility of
D-dimer is also weakened by the coexistence of conditions
such as cancer or infection, both of which confound
PICC use and D-dimer elevation. Novel biomarkers not
affected by these factors (eg, P-selectin) may be of greater
utility.
74
For example, Ramacciotti et al
75
found that the
combination of soluble P-selectin and Wells score was the
strongest predictor of catheter DVT among a number of
candidate markers. More evidence regarding such markers
in upper-extremity DVT is needed.
Integrating the available evidence, an algorithmic approach
for diagnosis of PICC-DVT is presented in Figure 3.
Treatment and Management
Treatment and management of PICC-DVT centers on 3
principles: 1) therapeutic systemic anticoagulation; 2)
4 The American Journal of Medicine, Vol -, No -,-2015

Table 1 Epidemiology, Risk Factors and Evidence for Catheter-Associated Thrombosis
Risk Factor
Study/Citation
(First Author) n Design/Population
Results/Effect Size
(95% Confidence
Interval) Comments
Patient-related
Surgery $1 h Evans, 2010
7
1728 Prospective cohort study of
hospitalized patients at a
single health system
OR 1.66 (0.91-3.01) Avoiding PICC insertion in
those undergoing elective
surgery may prevent
thrombosis
Wilson, 2012
28
431 Retrospective cohort study of
critically ill neurological
intensive care unit patients
OR 3.26 (1.48-7.17) Neurological ICU patients who
underwent surgery for 1 h
or more had higher risk of
PICC-DVT
COPD Aw, 2012
4
340 Retrospective cohort of patients
with cancer who received PICCs
for outpatient chemotherapy
OR 2.67 (0.65-11) Following adjustment, COPD
remained associated with
higher risk of PICC-DVT
Diabetes
mellitus
Yi, 2013
22
81 Prospective cohort of
hospitalized patients with
cancer and PICCs who
underwent screening Doppler
sonography every 3 d for the
first month
OR 3.01 (1.01-9.5) Diabetes mellitus was
associated with higher risk
of PICC-related thrombosis
Aw, 2012
4
340 Retrospective cohort of patients
with cancer who received PICCs
for outpatient chemotherapy
OR 3.18 (1.06-9.53) Diabetes increased the risk of
developing PICC-DVT in
patients receiving
chemotherapy
Prior CVCs Lee, 2006
35
444 Prospective cohort of patients
with cancer undergoing CVC
insertion for outpatient
chemotherapy
OR 3.8 (1.4-10.4) History of prior CVC use/
insertion was associated
with higher risk of
thrombosis
History of DVT Lobo, 2009
17
777 Retrospective cohort of patients
who required PICCs during
their hospitalization
OR 10.83 (4.89-23.95) Avoiding PICCs in patients
who have prior history of
DVT may prevent
thrombosis
Evans, 2010
7
1728 Prospective cohort study at a
single health system of
hospitalized patients
OR 9.92 (5.08-21.25) Patients with a history of DVT
are at increased risk for
developing PICC-DVT
Wilson, 2012
28
431 Retrospective cohort study of
critically ill neurosurgical
intensive care unit patients
OR 6.66 (2.38-18.62) A history of venous
thromboembolism was
associated with the
development of PICC-
related large vein
thrombosis
Renal failure Marnejon,
2012
20
400 Case-control study of consecutive
patients post PICC insertion at
a single hospital
OR 2.095
P¼.010
Patients with renal failure
were at greater risk of
thrombosis following
adjustment for other
confounders
Malignancy or
metastatic
cancer
Verso, 2008
18
310 Retrospective analysis of
thrombosis risk factors from a
randomized controlled trial
targeting outpatient
chemotherapy
OR 9.36 (1.53-57.05) Along with prior history of
DVT, active malignancy
and, particularly,
metastatic cancer are
factors that were most
associated with increased
risk of catheter-related
thrombosis
Fallouh et al Peripherally Inserted Central Catheter-associated Deep Vein Thrombosis 5

Table 1 Continued
Risk Factor
Study/Citation
(First Author) n Design/Population
Results/Effect Size
(95% Confidence
Interval) Comments
Liem, 2012
14
690 Retrospective cohort study
comparing patients with PICC-
related symptomatic
thrombosis to those without
thrombosis
OR 4.1 (1.9-8.9) Concurrent or recent
malignancy was associated
with the development of
DVT in patients with PICCs
Tran, 2010
19
498 Retrospective single-center
analysis of patients with
hematological malignancies
with PICCs and symptomatic
UEDVT
7.8% High incidence of DVT
associated with PICCs in
patients receiving
myelosuppressive
chemotherapy; central IJ
PICCs were associated with
low incidence of
thrombosis
Chopra, 2013
11
64 Systematic review and meta-
analysis of 64 studies
including 29,503 patients
OR 2.24 (1.01-4.99) In patients with a
malignancy, PICCs were
associated with a higher
risk of DVT as compared
with CVCs
Recent trauma Marnejon,
2012
20
400 Case-control study of consecutive
patients post PICC insertion at
a single hospital
OR 2.76
P¼.011
History of trauma was
associated with higher risk
of thrombosis
Chest
radiotherapy
Verso, 2008
18
310 Retrospective analysis of
thrombosis risk factors from a
randomized controlled trial
targeting outpatient
chemotherapy
OR 7.01 (1.42-34.66) Prior chest radiotherapy was
highly associated with
increased risk of
thrombosis
Paretic arm Wilson, 2012
28
431 Retrospective cohort study of
critically ill neurosurgical
intensive care unit patients
OR 9.85 (4.42-21.95) Providers should avoid
placing PICCs in paretic
arms
Critically ill and
hospitalized
Chopra, 2013
11
64 Systematic review and meta-
analysis of 64 studies
including 29,503 patients
OR 4.04 (2.17-7.07) Critically ill patients with
PICCs are more likely to
develop DVT than those
who receive acute CVCs
High BMI Moran, 2014
23
1444 Case control analysis of adult
inpatients who underwent PICC
placement at a single hospital
BMI >30
OR 1.98 (1.09-3.61)
Providers should pay
attention to patients with
PICCs and a BMI >30 in
order to reduce the risk of
PICC-associated
complications
Device-related
Larger catheter
diameter
Evans, 2010
7
1728 Prospective cohort study at a
single health system of
hospitalized patients
Double-lumen 5-Fr vs
single-lumen
OR 7.54 (1.61->100)
Smaller catheters and
correspondingly, catheters
with a lower number of
lumens were associated
with lower risk of
thrombosis
Triple-lumen 6-Fr vs
single-lumen
OR 19.5 (3.54->100)
Evans, 2013
10
5018 Prospective observational study
at a Level I trauma and tertiary
referral hospital for 3 years
with smaller-diameter PICCs
used more during the third
year of the study
Double-lumen 5 Fr vs
single-lumen 4Fr
OR 2.24 (1.16-4.31)
Clinicians should select the
smallest-diameter PICC
necessary for the patient’s
care to reduce risk of
thrombosis from PICCs
Triple-lumen 6 Fr vs
single-lumen 4 Fr
OR 6.35 (2.78, 14.52)
6 The American Journal of Medicine, Vol -, No -,-2015

Table 1 Continued
Risk Factor
Study/Citation
(First Author) n Design/Population
Results/Effect Size
(95% Confidence
Interval) Comments
Liem, 2012
14
690 Retrospective cohort study
comparing patients with PICC-
related symptomatic
thrombosis to those who did
not develop thrombosis
OR 3.9 (1.1-13.9) Catheters with a large
diameter ($5 Fr) were
associated with the
development of UEDVT
compared with smaller size
devices
Nifong, 2011
24
N/A Experimental study that used
fluid mechanics to calculate
relative flow rates as a
function of the ratio of the
catheter to vein diameters
Linear relationship
between the relative
flow rate and the
catheter to cylinder
diameter ratio
was found with a
correlation of
r
2
¼0.90
PICCs may substantially
decrease venous flow rates
by as much as 93%
PowerPICCs Baxi, 2013
27
1652 Retrospective cohort of patients
who received PICCs during
their hospitalization at a
single medical center
OR 2.3 (1.08-4.91) PowerPICCs were associated
with both venous
thrombosis and central
line-associated
bloodstream infection
Catheter-
associated
infection
Ahn, 2013
29
237 Retrospective cohort study of
patients with cancer at a single
medical center
OR 2.46 (1.03-5.86) Higher rate of PICC-DVT
observed when catheters
were infected compared
with those that were not.
Del Principe,
2013
106
71 Prospective cohort study of
patients with acute myeloid
leukemia; sepsis associated
with PICC-DVT
HR 4.12 Patients with sepsis had
higher rates of catheter
thrombosis than those
without this condition.
Number of
lumens
O’Brien, 2013
25
1328 Quasi experiment (pre-post)
study in a Canadian teaching
hospital. Intervention
consisted of screening all PICC
orders and placing only single-
lumen PICCs unless more
lumens were warranted
Rates of thrombosis
was reduced from
1.22% with double
lumen catheters to
0% with single
lumen catheters
A hospital-wide effort to
decrease the insertion of
multi-lumen PICCs without
an appropriate rationale for
the same can decrease
overall rates of PICC-DVT
Vancomycin
infusion
Marnejon,
2012
20
400 Case-control study of consecutive
patients post PICC insertion at
a single medical center
OR 3.44
P¼.001
Because vancomycin has a
low pH, endothelial
irritation and thrombosis is
possible, although this is
controversial and likely also
influenced by duration of
treatment
Amphotericin B
infusion
Chemaly, 2002
5
2063 34-month retrospective chart
review of patients who had a
PICC placed at the Cleveland
Clinic Foundation
OR 10.0 (2.04e49.05) Association of UEDVT with
antifungal AmB likely
relates to thrombogenicity
from irritation of the
venous intima
Chemotherapy Yi, 2013
22
81 Prospective cohort of
hospitalized patients with
cancer and PICCs who
underwent Doppler sonography
every 3 days for the first month
OR 2.77 (1.01-9.5) Chemotherapy was associated
with higher risk of PICC-
related thrombosis
Mannitol
infusion
Wilson, 2012
28
431 Retrospective cohort study of
critically ill neurosurgical
intensive care unit patients
OR 3.27 (1.27-8.43) Mannitol use in critically ill
neurosurgical patients was
associated with increased
risk of thrombosis
Fallouh et al Peripherally Inserted Central Catheter-associated Deep Vein Thrombosis 7

Table 1 Continued
Risk Factor
Study/Citation
(First Author) n Design/Population
Results/Effect Size
(95% Confidence
Interval) Comments
ESA
administration
Ahn, 2013
29
237 Retrospective cohort study of
patients with cancer at a single
medical center
OR 10.7 (2.3-50.0) Concomitant administration
of ESAs while a PICC is in
situ was the strongest
predictor of thrombosis
Catheter
dysfunction
Lee, 2006
35
444 Prospective cohort of patients
with cancer undergoing CVCs
insertion for outpatient
chemotherapy
OR 14.7 (5.5-40) Catheter blockage is
significantly associated
with catheter-related
thrombosis
Spontaneous
dislodgement
Qiu, 2014
44
510 Prospective cohort of oncology
patients with PICCs followed
until catheter removal or
spontaneous dislodgment
RR 17.46 (8.29-36.82) Catheter-related thrombosis
was observed to be strongly
associated with
spontaneous dislodgement
of PICCs
Provider-related
Decision to
screen
Itkin, 2014
15
332 Prospective randomized,
controlled trial in a single
center comparing 2 types of
PICCs and symptomatic vs
nonsymptomatic screening
Symptomatic: 4.3%
and 3.6%
Asymptomatic PICC-DVT is far
more common than
symptomatic DVT. At-risk
patients may need to be
screened regularly in order
to detect this event
Asymptomatic: 65.2%
and 69.1%
Chopra, 2013
11
64 Systematic review and meta-
analysis. 533 citations, 64
studies with 29,503 patients
Asymptomatic
screening:
OR 3.22 (1.67-6.18)
PICC-DVT might be more
prevalent than clinically
perceived and more evident
when screened for than
when clinically recognized
Symptomatic testing:
OR 2.37 (1.18-4.76)
Site other than
cavoatrial
junction/
noncentral
PICC tip
Lobo, 2009
17
777 Retrospective cohort of patients
who required PICCs during
hospitalization
OR 2.61 (1.28-5.35) Verifying the cavoatrial
junction placement of
PICCs is protective against
PICC-DVT
US guidance
during
insertion
Gong, 2012
54
180 Prospective cohort of patients
with cancer who were divided
to receive PICC using
ultrasound or traditional
method
Thrombosis upon
removal of the
catheter was noted
in 7.5% of the
traditionally placed
PICCs vs 0% of the
US guided
PICCs placed using the
ultrasound were less likely
to have thrombotic
complications
Basilic vein
placement
Marnejon,
2012
20
400 Case-control study of consecutive
patients post PICC insertion at
a single hospital
OR 2.95 Providers should avoid basilic
vein PICCs placement
Bonizzoli,
2011
13
239 Prospective cohort of patients
admitted to a teaching
hospital’s intensive care unit in
Florence, Italy who were (i)
discharged with CVCs (during
the first 4 mo) or PICCs (during
the last 4 mo) and (ii) serially
underwent Doppler studies
OR 2.18 (1.122-4.244)
if placed in left
basilic vein
Found a higher risk of DVT
development related to sex
(female) and site access
(left basilic vein)
Liem, 2012
14
690 Retrospective cohort study
comparing the characteristics
of patients with PICC-related
symptomatic thrombosis to the
ones of patients who did not
develop thrombosis
Basilic 3.1%
Non-basilic 1.5%
Basilic vein PICCs were
associated with a higher
incidence of UEDVT,
however, there is no
significant evidence that
cephalic veins should be
used for PICCs
8 The American Journal of Medicine, Vol -, No -,-2015

removal of PICCs that are no longer necessary; and 3)
thrombolysis or interventional procedures.
Systemic Anticoagulation. No randomized controlled trials
of systemic anticoagulation for PICC-DVT exist. Available
recommendations are thus extrapolated from lower-
extremity DVT and studies of recurrent venous thrombo-
embolism in patients with cancer.
9,76,77
Weight-based low-molecular-weight heparin (eg,
fondaparinux or enoxaparin) is recommended over
intravenous unfractionated heparin infusion as the initial
therapeutic strategy for PICC-DVT in patients with can-
cer.
76,78,79
Warfarin dosed to achieve an international
normalized ratio of 2-3 is acceptable for noncancer pa-
tients or those who cannot receive low-molecular-weight
heparins due to medical or cost constraints. At mini-
mum, 3 months of anticoagulation are recommended
(Grade 2B evidence). Should the affected PICC be clini-
cally needed beyond 3 months, prolonging systemic
anticoagulation to match the duration of catheter use is
Table 1 Continued
Risk Factor
Study/Citation
(First Author) n Design/Population
Results/Effect Size
(95% Confidence
Interval) Comments
Cephalic vein
placement
Allen, 2000
51
119 Retrospective study on patients
who had (i) normal findings
during initial venography, (ii)
PICC placement, and (iii)
underwent repeated
venography
Cephalic 57%
Basilic 14%
Brachial 10%
Relatively high rate of venous
thrombosis associated with
PICCs placed in the cephalic
vein
BMI ¼body mass index; COPD ¼chronic obstructive pulmonary disease; CVC ¼central venous catheter; DVT ¼deep vein thrombosis;
ESA ¼erythropoiesis-stimulating agents; Fr ¼French; IJ ¼internal jugular; OR ¼odds ratio; PICC ¼peripherally inserted central catheter; UEDVT ¼upper-
extremity deep vein thrombosis; US ¼ultrasonography.
Figure 3 Algorithmic, evidence-based approach to diagnosis of PICC-DVT. The flowchart shows an algorithmic, evidence-based
approach to diagnosis of PICC-DVT. CT ¼computed tomography; MRI ¼magnetic resonance imaging; PICC-DVT ¼peripher-
ally inserted central catheter-deep venous thrombosis; US ¼ultrasonography.
Fallouh et al Peripherally Inserted Central Catheter-associated Deep Vein Thrombosis 9

recommended (Grade 1C evidence).
76
However, limited
data regarding risks and benefits of prolonged anti-
coagulation are currently available.
PICC Removal. Because PICCs remain a nidus for prop-
agation of clot, removal should be considered when
thrombosis is detected. In this context, 2 questions should be
answered: 1) is the PICC still clinically necessary? and if so,
2) is it still well positioned (eg, at the cavoatrial junction)
and functional? Existing guidelines do not advocate routine
removal of PICCs provided the answer to these questions is
affirmative (Grade 2C evidence).
76
However, PICC removal
may be unavoidable in settings where anticoagulation is
contraindicated or if bloodstream infection coexists.
Persistent symptoms such as arm pain or swelling despite
several days of anticoagulation may also warrant catheter
removal.
80
Thrombolysis and Interventional Procedures. Few
studies have compared thrombolytic or endovascular treat-
ments with anticoagulation alone for catheter-related DVT,
let alone PICC-DVT. However, observational data suggest
improvement in upper-extremity venous patency with early
institution of thrombolytic therapy and anticoagulation,
albeit with an increased risk of bleeding.
81-84
Catheter-
directed therapy has replaced systemic thrombolytic
therapy in upper-extremity DVT.
85-87
Current guidelines
recommend that thrombolysis be reserved for patients who
present with severe symptoms (eg, phlegmasia or functional
impairment of the limb); extensive thrombus burden in the
subclavian or axillary veins; symptoms for 14 days; good
functional status; life expectancy of at least 1 year; and low
risk of bleeding.
76
Endovascular modalities including thrombectomy and
angioplasty reduce the risk of postthrombotic syndrome in
the lower extremities, but their role in treating PICC-DVT is
unclear.
88,89
Observational studies of endovascular therapies
for catheter-related DVT suggest promise of early recana-
lization.
85,90
Although in use,
91
long-term safety and effi-
cacy data for superior vena cava filters in upper-extremity
DVT are not available
92
; thus, use in PICC-DVT cannot be
recommended at this time.
76
An algorithmic approach for managing PICC-DVT that
synthesizes the available evidence is presented in Figure 4.
Prevention of PICC-DVT
Prevention of PICC-DVT should center on patient-, pro-
vider-, and device-related characteristics. Consideration of
vascular access devices that are associated with lower risk of
thrombosis is therefore a pragmatic and proactive
approach.
19,34,93,94
Similarly, use of ultrasound to ensure
appropriate catheter-to-vein ratio, verification of tip posi-
tion, and early removal of PICCs are but a few provider
Figure 4 Flowchart showing an algorithmic, evidence-based approach to treatment of PICC-DVT. CrCl ¼creatinine clearance;
LMWH ¼low-molecular-weight heparin; IVUH ¼intravenous unfractionated heparin; PICC ¼peripherally inserted central catheter;
PICC-DVT ¼peripherally inserted central catheter-deep venous thrombosis.
10 The American Journal of Medicine, Vol -, No -,-2015

Table 2 Diagnosis, Treatment, and Prevention of Catheter-Associated Thrombosis
Method Used
Study/Citation
(First Author) N Design/Population
Sensitivity/Specificity
(95% Confidence Interval) Comments
Diagnosis
US and contrast
venography
Di Nisio,
2010
63
17 articles
793
patients
Retrospective systematic
review assessing
diagnostic accuracy of
tests for clinically
suspected UEDVT and
to evaluate replacement
of venography up to
June 2009
Compression US: 97% (90%-100%)/
96% (87%-100%)
Compression US may be
an acceptable
alternative to
venography
Doppler US: 84% (72%-97%)/94%
(86%-100%)
Doppler US with compression: 91%
(85%-97%)/93% (80%-100%)
Phleborheography: 85%
(72%-99%)/87% (71%-100%)
Color Doppler does not seem
to improve the accuracy
of UEDVT diagnosis
Mustafa,
2002
66
6 articles
170
patients
Prospective review of
duplex US for
diagnosis of UEDVT
from 1980-2000
56%-100%/94%-100% Doppler evaluation alone is
less sensitive and less
specificthanreal-time
imaging or duplex UEDVT
diagnosis. US for
clinically suspected
UEDVT needs further
study
Baarslag,
2002
67
126 Prospective study of
duplex US compared
with venography at
one teaching hospital
Duplex US: 82% (70%-93%)/82%
(72%-92%)
Duplex US may be used
for initial diagnosis
50% of isolated flow abnormalities
were thrombosis-related
Contrast venography
should be performed in
patients with isolated
flow abnormalities
Kim, 2003
69
18 Prospective study
following patients
who underwent CT
and MR venography
Spearmen rank correlation
coefficient:
Reader 1: Rs¼0.58 (P<.01)
Reader 2: Rs¼0.56 (P<.01)
CT and MR venography
are correlated; CT
venography accurately
depicted benign venous
obstruction; more
studies are needed
Plasma
biomarkers
Merminod,
2006
73
52 Preliminary data on
D-dimer testing in
clinically suspected
UEDVT
100% (78%-100%)/14% (4%-29%)
PPV: 32% (19%-47%)
NPV: 100% (47%-100%)
There is doubt that D-
dimer can be used as a
diagnostic test for
UEDVT; further study is
needed
Ramacciotti,
2011
75
178 Prospective study to
evaluate diagnosis
of DVT with a
combination of soluble
P-sel, D-dimer and
clinical Wells score
P-sel: 28%/96% P-sel in combination with
Wells score could be
useful in DVT diagnosis
P-sel þWells score:
Establish diagnosis of DVT
33%/95%, PPV: 100%
Rule-out DVT 99%/33%, NPV: 96%
D-dimer: 98%/29%
PPV: 40%, NPV: 80%
P-sel þD-dimer: 43%/81%
PPV: 58%, NPV: 81%
Rectenwald,
2005
74
73 Prospective study to
evaluate diagnosis of
DVT with a combination
of D-dimer, soluble
P-sel, and total
microparticles
73%/81% Plasma biomarkers,
specifically P-sel, can be
developed to achieve
moderate sensitivity and
specificity to diagnose
DVT
Treatment
Systemic
anticoagulation
Akl, 2008
78
and Akl,
2014
104
Review and systematic
meta analysis of
heparin (UFH or
LMWH) and warfarin
on DVT treatment
Heparin RR 0.43 (0.18-1.06) Heparin (UFH or LMWH)
was the only therapy
associated with a
reduction of
symptomatic DVT
Mortality RR 0.74 (0.40-1.36)
Infection RR 0.91 (0.36-2.28)
Major bleeding RR 0.68 (0.10-4.78)
Thrombocytopenia RR 0.85
(0.49-1.46)
Fallouh et al Peripherally Inserted Central Catheter-associated Deep Vein Thrombosis 11

Table 2 Continued
Method Used
Study/Citation
(First Author) N Design/Population
Sensitivity/Specificity
(95% Confidence Interval) Comments
Warfarin RR 0.62 (0.30-1.27)
Thrombolysis
and other
interventions
Sabeti, 2002
82
95 Prospective study of
inpatients with
subclavian-axillary
vein thrombosis
treated either with
thrombolysis and
subsequent oral
anticoagulation, or
with anticoagulation
only
60% reduced risk for a thrombosis
(0.2 to 0.9)
Systemic thrombolysis
was useful in treating
subclavian-axillary vein
thrombosis as
compared with
anticoagulation alone;
high rate of
complications during
thrombolysis may
exceed the harm of
thrombosis
Horne, 2000
81
18 Small prospective study
of patients diagnosed
with lower-extremity
thrombosis treated
with intraclot
administration of
urokinase substitute,
rtPA
Venous patency achieved in 10
of the 18 patients with
axillary-subclavian thrombosis
after 1 or 2 treatments
No observation of
uncontrolled bleeding,
however, more studies
are needed to evaluate
use of rtPA
Maleux,
2010
85
68 Retrospective case review
of patients with active
cancer and without
cancer between 1997
and 2009 who
underwent CDT
91% (P¼.68) CDT may be a feasible and
effective intervention
for catheter-related
thrombosis in patients
without cancer
Enden, 2009
88
103 Multicenter randomized
controlled trial where
patients with ilia-
femoral patency
received either
additional CDT or
standard treatment
alone
Iliofemoral patency: RR 28.2%
(9.7%-46.7%)
Additional CDT may
increase iliofemoral
patency; lysis or
angioplasty did not
correlate significantly
with 6-month patency
Venous obstruction: RR 29.1%
(20.0%-38.0%)
Prevention
Patient-,
provider-, and
device-related
characteristics
Pikwer, 2012
94
12 Review of studies
comparing
complications of
CVCs or PICCs
Catheter tip malposition 9.3%
(CVC) vs 3.4% (PICC)
Risks of tip malposition,
thrombophlebitis, and
catheter dysfunction
are more common in
CVCs as compared with
PICCs
Thrombophlebitis 78 vs 7.5 per
10,000 indwelling days
Catheter dysfunction 78 vs
14 per 10,000 indwelling days
Institution-wide
limits to PICC
gauge
Evans, 2013
10
5018 Prospective
observational study
at a level I trauma
and tertiary referral
hospital for 3 years
with smaller-diameter
PICCs were more used
during the 3
rd
year of
the study
Double-lumen 5-Fr vs
single-lumen 4-Fr
OR 2.24 (1.16-4.31)
The use of significantly
(P<.0001) more
single-lumen PICCs in
2010 (compared with
2008-2009) was a
major contributor to
the decrease in PICC-
associated DVTs
O’Brien,
2013
25
1328 Quasi experiment (pre-
post) in a Canadian
teaching hospital
consisted of
screening all PICC
orders by a nurse and
Triple-lumen 6-Fr vs
single-lumen 4-Fr
OR 6.35 (2.78-14.52)
A significant increase in
the use of single-lumen
and smaller PICCs was
associated with a
significant decrease in
PICC-DVT
Triple-lumen 6-Fr vs
single-lumen 4-Fr
OR 6.35 (2.78-14.52)
12 The American Journal of Medicine, Vol -, No -,-2015

practices that may reduce thrombosis risk.
17,45,49,95
Such
efforts may occur at an institutional level by removing
PICCs of greater gauge or multiple lumens, both of which
have been shown to effectively reduce cost and DVT
rates.
10,25
Early studies of thromboprophylaxis suggested small
reductions in rates of catheter thrombosis.
96-99
However,
newer studies have rendered the matter controversial, at
best.
16,100-103
In a Cochrane review, Akl et al
104
included 12
randomized trials of 3611 cancer patients and found that
prophylaxis with heparin was not associated with reduction
in symptomatic DVT compared with placebo (relative risk
[RR] 0.4; 95% CI, 0.2-1.1). Similarly, anticoagulation with
low-dose warfarin did not reduce symptomatic or asymp-
tomatic DVT (RR 0.6; 95% CI, 0.3-1.3).
78
However, a
recent update to this review reported a statistically signifi-
cant reduction of symptomatic DVT with heparin and
asymptomatic DVT with warfarin.
104
However, given the
risk of important adverse events, existing guidelines do not
recommend routine use of pharmacologic prophylaxis to
prevent catheter thrombosis.
76
Notably, 2 recent studies
involving PICCs have suggested that prophylaxis may
prevent PICC-DVT.
23,105
Thus, further PICC-specific
studies in this area appear necessary. While some studies
have reported that antiplatelet agents such as aspirin and
clopidogrel may reduce PICC-DVT,
29
limited large-scale
data exist at this time. Screening ultrasonography in pa-
tients with PICCs has not been shown to be beneficial to
date. Given the uncertainty regarding the clinical signifi-
cance of asymptomatic thrombi and the natural history of
these events, well-designed studies are also needed in this
area.
Table 2 summarizes 16 studies relevant to diagnosis,
treatment, and prevention of PICC-DVT.
Limitations
Despite a systematic approach, this review has some limi-
tations. First, the existing PICC-DVT literature comprises
many observational studies. As such, the quality of the
available evidence and inherent risk for bias must be care-
fully considered. Second, while the algorithms we propose
Table 2 Continued
Method Used
Study/Citation
(First Author) N Design/Population
Sensitivity/Specificity
(95% Confidence Interval) Comments
placing only single-
lumen PICCs unless
more lumens are
indicated
Evans, 2013
10
5018 Prospective
observational study
at a Level I trauma
and tertiary referral
hospital for 3 years
with smaller-diameter
PICCs were more used
during the third year
of the study
Double-lumen 5-Fr vs
single-lumen 4-Fr
OR 2.24 (1.16- 4.31)
A significant increase in
the use of single-
lumen, smaller gauge
PICCs was associated
with a significant
decrease in PICC-DVT
Triple-lumen 6-Fr vs
single-lumen 4-Fr
OR 6.35 (2.78, 14.52)
Use of
antiplatelet
agents
Ahn, 2013
29
237 Retrospective cohort
study of patients
with cancer at a
Dallas medical center
OR 10.7 (2.3-50.0) Use of antiplatelet agents
seems to have a
protective effect
against UEDVT
US screening
high-risk
patients
Bonizzoli,
2011
13
239 Prospective cohort of
patients admitted to
a teaching hospital’s
intensive care unit in
Florence, Italy who
were discharged with
CVCs (during the first
4 mo) or PICCs
(during the last 4
mo) and serially
underwent Doppler
studies
80% of PICC-DVTs
occurred 2 weeks
after intensive care
unit discharge
Screening during this
2-week period may be of
clinical value for
prevention of PICC-DVT
CDT ¼catheter-directed thrombolysis; CT ¼computer tomography; CVC ¼central venous catheter; LMWH ¼low molecular weight heparin;
MR ¼magnetic resonance; NPV ¼negative predictive value; PICC ¼peripherally inserted central catheter; PPV ¼positive predictive value;
P-sel ¼P-selectin; RR ¼relative risk; rtPA ¼recombinant tissue plasminogen activator; UEDVT ¼upper extremity deep vein thrombosis;
UFH ¼unfractionated heparin; US ¼ultrasonography.
Fallouh et al Peripherally Inserted Central Catheter-associated Deep Vein Thrombosis 13

are evidence based, these should be viewed as informative
until better data are available. Third, because many studies
do not report the association between catheter-dwell time
and risk of PICC-DVT, recommendations regarding an
“optimal”window of PICC use cannot be defined. However,
early removal of nonessential PICCs is an important aspect
in preventing thrombosis and should be encouraged when-
ever possible.
CONCLUSIONS
This review summarizes the state of the art with respect to
diagnosis, treatment, and prevention of PICC-DVT. Despite
substantial progress in our understanding of this condition,
many questions remain to be answered. Given the clinical
consequences (pain, interruption of venous therapy, risk of
infection, and pulmonary embolism), potential for chronic
debility (venous outflow obstruction, central vein stenosis,
postthrombotic syndrome), and challenges associated with
treatment and diagnosis of this state, further research would
be welcomed. In the interim, a mindful approach that weighs
the pros and cons of PICC use may be our most effective
approach: an ounce of prevention may thus be our greatest
ally in thwarting PICC-DVT.
ACKNOWLEDGMENT
The authors thank Whitney Townsend, medical research
librarian, for her assistance with the literature search.
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APPENDIX
PubMed Clinical Queries
(Etiology/Broad[filter] OR risk) AND ((PICC OR “periph-
erally inserted central catheter”OR peripherally inserted
central catheter) AND (DVT OR “deep vein thrombosis”
OR deep vein thrombosis))
Scopus
TITLE-ABS-KEY((etiology OR risk
*
) AND ((picc OR
“peripherally inserted central catheter”OR peripherally
inserted central catheter) AND (dvt OR “deep vein throm-
bosis”OR deep vein thrombosis OR thromboembolism
*
OR
thrombus OR thrombosis)))
CINAHL
(etiology OR risk) AND (picc OR “peripherally inserted
central catheter”OR peripherally inserted central catheter)
AND (dvt OR “deep vein thrombosis”OR deep vein
thrombosis OR thromboembolism
*
OR thrombus OR
thrombosis)
16 The American Journal of Medicine, Vol -, No -,-2015

Embase
(‘etiology’/exp OR etiology OR risk
*
) AND (picc OR
‘peripherally inserted central catheter’/exp OR ‘peripherally
inserted central catheter’OR (peripherally AND inserted
AND central AND (‘catheter’/exp OR catheter))) AND (dvt
OR ‘deep vein thrombosis’/exp OR ‘deep vein thrombosis’
OR ((deep AND (‘vein’/exp OR vein)) AND (‘thrombosis’/
exp OR thrombosis)) OR thromboembolism
*
OR
‘thrombus’/exp OR thrombus OR ‘thrombosis’/exp OR
thrombosis)
CCRT
((etiology OR risk
*
) AND ((picc OR “peripherally inserted
central catheter”OR peripherally inserted central catheter)
AND (dvt OR “deep vein thrombosis”OR deep vein throm-
bosis OR thromboembolism
*
OR thrombus OR thrombosis)))
Fallouh et al Peripherally Inserted Central Catheter-associated Deep Vein Thrombosis 17