correspondence

Safety of prothrombin complex concentrate in healthy subjects

Prothrombin complex concentrate (PCC) is recommended

as first-line treatment for vitamin K antagonist (VKA)associated major bleeding. Different PCC formulations contain non-activated vitamin K-dependent coagulation factors
plus varying amounts of coagulation inhibitors. Three-factor PCC contains factor II, IX and X, but little or no factor VII, which is, conversely, contained in significant
amounts in 4-factor PCC. PCC is effective in reversing
VKA activity as it instantly replaces the deficient zymogens
in VKA-anticoagulated patients, restoring the physiological
haemostatic response to injury. However, the use of PCC
in emergency situations has been associated with thrombotic events (Dentali et al, 2011; Milling et al, 2016). It is
unclear whether the risk of thrombosis is caused by the
PCC itself or by the concomitant withdrawal of anticoagu-

lants in patients with an underlying condition that requires

anticoagulation. A pooled analysis of two recent randomized trials enrolling patients with acute VKA-associated
bleeding or scheduled with urgent invasive procedures
found that 2
6% of 191 patients enrolled in the 4-factor
PCC arm had a thrombotic event within 7 d from infusion, rising to 7
3% at 60 d (Milling et al, 2016). Rates
were similar in the comparator group receiving fresh frozen plasma (Milling et al, 2016). A prior meta-analysis of
27 studies evaluated the safety of reversal with PCC in
1,032 patients with VKA-associated bleeding or the need
for urgent invasive procedure: 12 events occurred within
4 d from PCC infusion [1
4%; 95% confidence interval
(95%CI):0
82
1] (Dentali et al, 2011). The risk of thrombosis was numerically higher with 4-factor PCC than with

Table I. Characteristics of the included studies evaluating PCC infusion in healthy subjects

Study reference

Subjects, n

Age (years);
male sex

Anticoagulation before
PCC infusion

22 (2050);
6 (100)
31 (6
6); 20 (83)

Rivaroxaban 15 mg bid
for 2
5 d
Edoxaban 180 mg
single-dose
Edoxaban 60 mg
single-dose
Apixaban 10 mg bid
for 3
5 d
Apixaban 10 mg bid
for 3
5 d
Edoxaban 60 mg
single-dose

4F-PCC Cofact

Rivaroxaban 20 mg
bid for 4
5 d
Rivaroxaban 20 mg
bid for 2
5 d
Dabigatran 150 mg
bid for 2
5 d
None

3F-PCC Profilnine
4F-PCC Beriplex P/N
4F-PCC Cofact

Barco et al (2016)

Brown et al (2015)

24

Cheung et al (2015)

Perlstein et al (2014)

15

33 (7); n.a.

Zahir et al (2015)

93

30
6; 64 (68
8)

Levi et al (2014)

23

Eerenberg et al
(2011)

12

42 (11
5); 5 (42)
43
3 (8
3); 7 (64)
24 (4); 12 (100)

Ostermann et al
(2007)
Total

26 (7); 6 (100)

15

41 (13); 8 (53)

n = 194

2243 (means);
128 (72)

n
n
n
n
n

=
=
=
=
=

41 (Rivaroxaban)
42 (Apixaban)
6 (Dabigatran)
130 (Edoxaban)
15 (none)

PCC type

3F-PCC Bebulin

4F-PCC Cofact
4F-PCC Cofact
4F-PCC Beriplex P/N
4F-PCC Beriplex P/N

PCC dose
(iu/kg)

PCC
infusions, n

37
5
25
50
25
50
25
37
5
25
50

6
6
11
10
12
12
6
6
15
15
27
28
30
12
11
6

50
25
10
50
50

6
4F-PCC Beriplex P/N
n = 177 (4F-PCC)
n = 57 (3F-PCC)

50
n
n
n
n

=
=
=
=

15
130 (50 iu)
12 (37
5 iu)
62 (25 iu)
30 (10 iu)

n = 234

Age expressed as mean (SD) or median (range). Proportion of males expressed as n (%).
PCC, prothrombin complex concentrate; 4F, four-factor; 3F, three-factor; iu, international unit; bid, twice daily; n.a., not available.

2016 John Wiley & Sons Ltd, British Journal of Haematology

doi: 10.1111/bjh.13974

Correspondence
3-factor PCC (1
8%; 95%CI:1
03
0 vs. 0
7%; 95%CI:0
0
2
4) (Dentali et al, 2011).
We aimed to systematically review the literature to estimate the proportion of thrombotic events following PCC
infusion in healthy subjects, given that these individuals do
not have any underlying condition requiring anticoagulation
and, therefore, thrombotic events would be caused by the
PCC itself.
MEDLINE (via PubMed) and EMBASE (via Ovid) were
searched up to 25 October 2015 without language restriction (search strategy available upon request). The search
was supplemented by reviewing additional articles from the
reference lists of retrieved studies, and by hand searching.
Prospective interventional studies enrolling more than 5
adult healthy subjects who received PCC were considered
eligible. Thrombotic events were defined according to criteria adopted by the authors of the prior meta-analysis
(Dentali et al, 2011) and included deep vein thrombosis or
pulmonary embolism, myocardial infarction or acute coronary syndrome, ischaemic stroke, transient ischaemic attack
or arterial thrombosis of a limb. Studies were included in
the meta-analysis if safety outcomes regarding potential
thrombotic adverse events were reported and if the mean
follow-up after PCC infusions was longer than 7 d, as the
infused coagulation factors have half-lives ranging from 6
to 72 h. A two-step selection process was applied in parallel and data regarding study population, intervention, outcomes and type of study were then abstracted. The
weighted mean proportion of thrombotic events (number
of thrombotic events/number of PCC infusions) is presented together with Wilson score 95%CI.
Our literature search identified 5,142 papers (1,336
from MEDLINE and 3,806 from EMBASE). Fourteen studies
were evaluated in full text for eligibility and 8 were
included (Table I) (Ostermann et al, 2007; Eerenberg
et al, 2011; Levi et al, 2014; Perlstein et al, 2014; Brown
et al, 2015; Cheung et al, 2015; Zahir et al, 2015; Barco et al,
2016), of which one is available as conference abstract
only (Perlstein et al, 2014). The main goal of these studies
was to test the haemostatic changes induced by PCC infusion in healthy subjects previously exposed (Eerenberg
et al, 2011; Levi et al, 2014; Perlstein et al, 2014; Brown
et al, 2015; Cheung et al, 2015; Zahir et al, 2015; Barco
et al, 2016) or not (Ostermann et al, 2007) to oral anticoagulants. Safety outcomes on thrombotic complications
after PCC administration were recorded. We identified a
total of 234 infusions in 194 subjects. No thrombotic
events were documented (0
0%; 95%CI:01
6). Due to the
lack of events, we did not investigate any subgroup of
subjects.
Overall, PCC increased thrombin generation (Eerenberg
et al, 2011; Levi et al, 2014; Perlstein et al, 2014; Brown
et al, 2015; Cheung et al, 2015; Zahir et al, 2015; Barco et al,
2016), but seemed to be associated with a very low risk of

thrombotic complications in healthy subjects. The upper

limit of the 95%CI still exceeds the point estimate of the
prior meta-analysis [overall 1
4%; (95%CI:0
82
1)] (Dentali et al, 2011), but is lower than the 2
6% 7-d rate
observed in two randomized controlled trials studying 4factor PCC (Milling et al, 2016). In our analysis, subjects
were relatively young, with no personal (and often familial) history of thrombosis, and no relevant co-morbidities.
Patients on anticoagulants, apart from having an underlying condition for which the anticoagulants are prescribed,
are usually older, have more co-morbidities leading to a
higher baseline risk of thrombosis and present transient
risk factors associated with acute bleeding or invasive procedures. On the other hand, the PCC dose used in most
of these studies was higher than the dose required for
reversal of VKAs (median 25 iu/kg, range 15
550
5 iu/kg),
although the thrombotic risk after PCC might not be proportional to PCC dosage as one would expect (Milling
et al, 2016).
PCC administration in healthy subjects leads to a negligible risk of thrombotic events and appears to be safe for
research purposes. This suggests that the increased thrombosis risk after emergency PCC infusion in acute patients is due
to the withdrawal of anticoagulation and underlying prothrombotic conditions. Further studies need to dissect
whether specific factors are boosting the potential PCC-associated thrombogenicity.

Author contributions:
S. Barco: concept and study design; collection, analysis
and interpretation of data, writing of the manuscript. C.
Picchi and A. Trinchero: collection and interpretation of
data, critical revision of the manuscript and final
approval. S. Middeldorp: critical revision of the manuscript and final approval. M. Coppens: analysis and interpretation of data, critical revision of the manuscript and
final approval.
Stefano Barco1,2
Chiara Picchi3
Alice Trinchero1
Saskia Middeldorp2
Michiel Coppens2
1

Centre for Thrombosis and Haemostasis, University Medical Centre of

the Johannes Gutenberg University, Mainz, Germany, 2Department of

Vascular Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands and 3Oncology Unit, Istituto di
Cura Citta di Pavia, Gruppo San Donato, University and Research
Hospital, Pavia, Italy.
E-mail: stefano.barco@unimedizin-mainz.de

Keywords: anticoagulants, prothrombin complex

thrombosis, reversal, meta-analysis, bleeding disorders

concentrate,

2016 John Wiley & Sons Ltd, British Journal of Haematology

Correspondence

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