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University of Groningen
Optimal dosing strategy for prothrombin complex concentrateKhorsand, Nakisa
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CHaPter 1Introduction
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10
General introduction
HISTOry OF VITAMIN K ANTAGONISTS
The mysterious ability of blood to clot has intrigued people over millennia.
The fascinating story of the discovery of vitamin K antagonists to manipulate
this clotting begins on the Canadian prairies in 1920s. The story ran as
follows:1 Previously healthy cattle in these areas died of internal bleeding
with no obvious cause. Given that livestock was one of the most important
industries in these areas combined with The Great Depression, this was a
disaster for the farmers. As there was an apparent lack of a recognizable
pathological disorder responsible for the haemorrhage, the diet of the
livestock was questioned. The cattle and sheep had grazed on sweet
clover hay (Melilotus alba and Melilotus officinalis) and the incidence of
bleeding occurred most frequently when the climate, and therefore the
hay, in these areas was damp. Damp hay became infected by moulds such as
Penicillium nigricans and Penicillium jensi, which appeared to be integral
in the disease process occurring in the cattle. As Duxbury and Poller point
out in their review article on warfarin,2 such hay would normally have been
discarded if it spoiled in storage, but in the financial hardship of the 1920s
few farmers could afford to buy supplementary fodder for their cattle and
thus the mouldy hay was used for feed. The resultant haemorrhagic disease
was called ‘sweet clover disease’ in 1922.
In 1929, Roderick observed that the affected cattle were deficient in a
clotting factor, prothrombin.3 At the same time, Dam was investigating a
severe bleeding condition with similar depletion of prothrombin in hens that
were maintained on sterol-depleted diets.4 This work led to the discovery
of vitamin K, for which Dam received the Nobel Prize for Medicine in 1943.
Another story is very informative:5 Ten years after the original outbreak of
sweet clover disease, a young Wisconsin farmer, Ed Carlson, angry about
losing his cows from internal bleeding, drove 200 miles with a dead cow in
the back of his truck to the local agricultural experimental station.
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11
Chapter 1
As the investigator Karl Link was the only person left working late, Carlson
entered Link’s office handing him a milk can of unclotted blood. Link
experimented with the blood that evening and, as Duxbury and Poller
comment, ‘The can of uncoagulated blood lying on the floor of Link’s
laboratory was to change the course of history, and little did Link know
what the long-term implications would be’.2 Link and colleagues got to
work on finding the active substance from the spoiled hay causing the
internal bleed. In 1940, they published the purification and synthesis of
dicumarol (3,3-methylenebis-9 [4-hydroxycoumarin]), the active component
in the spoiled sweet clover.6 This agent, referred to as “coumarin”, was
promptly made available for clinical studies and already one year later first
experiences on the effectiveness in deep vein thrombosis as well as its
hemorrhagic complications were published.7-9 At that time, the most potent
synthesized coumarin, warfarin, was successfully used to fight rats.10
The first clinical study with administration of coumarins in thromboembolic
conditions is reported in 1948.11 Not much later, president Eisenhower
was treated with warfarin following a heart attack.12 By that time, it was
empirically known that vitamin K reversed the bleeding problem caused
by coumarins as these agents were also called ‘vitamin K antagonists’.
However, it took another 2 decades until in 1974 the vitamin K cycle was
proposed.13, 14 After 30 years the complicating biochemical relation between
vitamin K, vitamin k-epoxide, and the role of vitamin K antagonists was
clarified by identification of VKORC1 in Nature in 2004.15, 16
It is rare for any drug introduced more than 50 years ago to remain
unsurpassed today, yet millions of patients are still being treated with
vitamin K antagonists.17 In 1985, a goal was set to develop new oral
anticoagulants to replace vitamin K antagonists.18 However, due to many
challenges facing the scientists, novel oral anticoagulants did not enter the
market until the 21st century.19-21
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12
General introduction
General hemostasis
In case of vessel damage, the body reacts fast to prevent blood loss. This
process, ‘hemostasis’ or ‘coagulation’, involves platelets, coagulation factors
and several other proteins, all working closely together with the vessel wall
in a complicated and precisely balanced process (figure 1).22 Briefly, when the
vessel wall is damaged, tissue factor (TF) is released. This initiates activation
of factor VII in blood with formation of TF-factor VIIa-complex. This complex
enables the conversion of factor X into Xa. After its activation, factor Xa
facilitates the formation of small amounts of thrombin, which is necessary
to activate platelets and cofactor V and VIII. Activated factor X together with
activated factor V configures the prothrombinase complex. This complex
converts prothrombin (factor II) to thrombin (factor IIa). Thrombin initiates
many pathways. For hemostasis, the most important one is the configuration
of fibrinogen into a fibrin and subsequently into fibrinclot.
Figure 1: Coagulation pathway adopted from Borissoff et al, NEJM 2011.22
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13
Chapter 1
Vitamin K antagonists
Most coagulation factors are synthesized in the liver. Some of these factors
need vitamin K as a co-enzyme for their formation.23 These factors are
coagulation factors II (prothrombin), VII, IX, X, and coagulation inhibiting
factors Protein C and S.
For this process, vitamin K is oxidized into vitamin K epoxide. As vitamin K
is very limitedly available in tissues, the epoxide must rapidly be reduced
again to vitamin K. An enzyme called ‘vitamin K epoxide reductase complex’
(VKOr) is needed to facilitate this step.16
Vitamin K antagonists (earlier referred to as coumarins) block the VKOr
enzyme and prevent the regeneration of reduced vitamin K.23 Therefore, the
synthesis of coagulation factors cannot be completed; subsequently these
factors cannot take part in the coagulation cascade. As this blockage only
affects the new formation of the clotting factors, the effect of vitamin K
antagonists is delayed for 72 to 96 hours after the start of treatment.
To date, different vitamin K antagonist agents are known of which warfarin,
acenocoumarol, and phenprocoumon are the most widely used. In the
United States of America and the United Kingdom only warfarin is used,
whereas in the Netherlands only acenocoumarol and phenprocoumon are
available. The most important differences of these drugs are summarized
in table 1.
The effectiveness of vitamin K antagonists has been established by well-
designed clinical trials.17, 29 They are applied for the primary and secondary
prevention of venous thromboembolism, for the prevention of systemic
embolism in patients with prosthetic heart valves or atrial fibrillation and for
the prevention of stroke, recurrent infarction or death after acute coronary
syndrome. For the prevention of stroke in patients with atrial fibrillation,
vitamin K antagonists showed a 64% reduction of stroke risk compared to
placebo and 37% risk reduction compared to antiplatelet therapy.30
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14
General introduction
table 1: Differences in VKA drugs
Onset period Half-life time Wash out period
Metabolism27-29
Warfarin 36-72 hours 40 hours 4-5 days CyP2C9 mainly, also CyP1A2 and CyP3A4
acenocoumarol 36-48 hours 11 hours 48 hours CyP2C9 mainly, also CyP2C19
Phenprocoumon 48-72 hours 160 hours 1-2 weeks CyP2C9 (less than acenocoumarol), also
CyP3A4 and urinary
and gut excretion
Vitamin K antagonists all have a narrow therapeutic range as the effective
dose is close to the minimum and maximum safe dose. Deviating from the
effective dose to under-treatment increases the risk of thrombosis and to
over-treatment the risk of bleeding.24 However, finding the right dose is
difficult because of the large inter- and intra-individual differences in dosage
requirement for optimal efficacy. The inter- and intra-individual variability
thereby the range in required dosages can, at least in part, be explained by
factors such as age, gender, co-morbidity, vitamin K intake, co-medication,
and genetic variation in its main metabolizing enzyme, cytochrome P450
isoform CyP2C9.25, 26 This means that the anticoagulant effect in patients on
vitamin K antagonists needs to be measured regularly and that doses need
to be adjusted accordingly.
The level of anticoagulation is historically monitored by a coagulation test
that measures the prothrombin time (PT). However, because laboratories
used different reagents for this test, PT results between different
laboratories were not comparable. Therefore, a standardized expression of
the level of anticoagulation, the International Normalized ratio (INr) has
been adopted.31-33 For this, the International Sensitivity Index (ISI) is used,
which indicates the level of tissue factor in the PT-reagent. When the ISI
and PT are known, INr is calculated using a formula:
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15
Chapter 1
The INr, being a ratio, has no units. The normal INr is 1. When using VKA,
elevated INrs from 2 to 3,5 are desired. Higher INr intensities are associated
with higher incidences of bleeding complications, whereas lower intensities
are associated with more thromboembolic events.24, 34
Complications of vitamin K antagonists
As its toxicity was discovered before the active therapeutic component
itself, it is of no surprise that vitamin K antagonists are among the most
toxic drugs in current medicine. In fact, these drugs are one of the main
reason for drug-related hospital admissions.35, 36
Despite many thrombosis services and anticoagulation clinics world-wide
and rapid INr controls for individual vitamin K antagonist dosage regimens,
major bleeding complications are still common practice. Intracranial bleeds
are the most feared complication as these bleeds are most often fatal. Other
frequently seen major bleeds include gastrointestinal, intra-peritoneal,
intraocular and muscle bleeds.
Numerous studies have shown that the incidence of vitamin K antagonist-
associated major bleeding is 0.4-7.2% per year.37-39 This wide range is
considered to be the result of the many patient-related factors that can
alter the pharmacokinetics and pharmacodynamics of vitamin K antagonists.
In addition, earlier studies often had different definitions of major
bleed. More recent studies have been more consistent and usually define
major bleed as proposed by the International Society of Thrombosis and
Haemostasis.40 According to this, a major bleed is defined as a fatal bleed,
and/or a symptomatic bleed in a critical area or organ, such as intracranial,
intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or
intramuscular with compartment syndrome, and/or bleeding that causes
a fall in hemoglobin level of 20 g L-1 (1.24 mmol L-1) or more, or leading to
transfusion of two or more units of whole blood or red blood cells.
In recent years, several well-designed studies have been conducted due to
the discovery of novel oral anticoagulants and their effectiveness compared
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16
General introduction
to the well-established vitamin K antagonists. Throughout these studies,
knowledge has increased about incidences of major, intracranial and fatal
bleeds in the studied populations. In table 2 these incidences are shown.
table 2: incidences of different VKA-associated bleeds obtained from novel oral anticoagulant studies
Gastrointestinal Major Intracranial Fatal
reLY19 1.02%/year 3.36%/year 0.74%/year -
rocket-aF20 2.2%/year 3.4%/year 0.7%/year 0.5%/year
aristotle21 0.86%/year 3.09%/year 0.80%/year -
re-Cover41 2.8% 1.9% 0.24% 0.08%
einstein42 - 1.2%* 0.3%* -
* per treatment period resulting in lower percentages than other studies
treatment of vitamin K antagonist-associated bleeds
Management of vitamin K antagonist-associated bleeds depends mainly on
the severity of the bleed and is still a common clinical challenge.
In addition to hemodynamic stabilization, and possible surgical, endoscopic
or other interventional control, the anticoagulant effect of vitamin K
antagonist must be reversed.17 This can be accomplished by withholding
vitamin K antagonist therapy. In this case, it takes 3 to 5 days, depending on
the vitamin K antagonist (table 1), before the vitamin K cycle is restored and
the vitamin K antagonist effect is diminished. In case a more rapid reversal
is needed, vitamin K can be replaced by its administration. This allows
the liver to directly start producing normally carboxylized clotting factors.
By administering vitamin K, the vitamin K antagonist effect is diminished
within 24 hours. However, for a longer-term correction of the coagulopathy,
daily administration of vitamin K is necessary.
For an urgent, direct reversal of vitamin K antagonists, the depleted vitamin
K dependent clotting factors as described above, should be administered.
This could either be done by infusion of fresh frozen plasma in which clotting
factors are present or by transfusion of prothrombin complex concentrates,
which contain clotting factors II, IX and X and a variable amount of factor
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17
Chapter 1
VII (see below). Prothrombin complex concentrates usage is associated with
several benefits when compared to fresh frozen plasma, of which the lower
volume of prothrombin complex concentrate43 and the rapid correction
of the INr resulting to better clinical outcome44 are the most important
ones. Currently, the American College of Chest Physicians (ACCP) guidelines
recommend the use of prothrombin complex concentrates rather than
plasma for reversal of VKA-induced coagulopathy in patients with a vitamin
K antagonist-associated major bleeding.45
Prothrombin Complex Concentrate
Prothrombin Complex Concentrates are human plasma-derived products
containing clotting factors II, IX, X, and VII. In addition to these so-called
4 factor concentrates, 3 factor concentrates are available that contain
far less factor VII. Furthermore, all prothrombin complex concentrates
contain variable amounts of natural anticoagulant proteins C and S, and
anti-thrombin. Different prothrombin complex concentrates are available
worldwide. These agents and their content, related to 100 units of factor IX
are summarized in table 3. In the Netherlands only 4 factor PCCs are used.
The safety of prothrombin complex concentrates has been subject to
research for several decades as well. A recent meta-analysis reported the
incidence of thromboembolic events to be +1,8% in patients after receiving
four-factor prothrombin complex concentrates.47 It is also believed that
the thrombogeneity of prothrombin complex concentrates increases with
higher doses.48
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18
General introduction
tabl
e 3:
Pro
thro
mbi
n co
mpl
ex c
once
ntra
tes
and
thei
r co
nten
t re
late
d to
100
IU o
f fa
ctor
IX a
dopt
ed f
rom
Wor
ld F
eder
atio
n of
Hem
o-ph
ilia
regi
ster
of
clot
ting
fac
tor
conc
entr
ates
46 a
nd t
he a
vaila
ble
Sum
mar
y of
Pro
duct
Cha
ract
eris
tics
(SP
C)
Bran
d na
me
Man
ufac
ture
r3
or 4
fac
tor
Fact
or II
Fa
ctor
VII
Fact
or IX
Fa
ctor
XO
ther
Beri
plex
CSL
Behr
ing,
Ger
man
y
4F12
868
100
152
Prot
ein
C, h
epar
in,
anti
thro
mbi
n an
d
albu
min
Cofa
ctSa
nqui
n,
Net
herl
ands
4F56
-140
28-8
010
056
-140
Prot
ein
S an
d C
and
anti
thro
mbi
n
Kask
adil
LFB,
Fra
nce
4F14
840
100
160
Hep
arin
Oct
aple
xO
ctap
harm
a,
Aust
ria
& F
ranc
e
4F44
-152
36-9
610
050
Prot
ein
C &
S an
d
hepa
rin,
low
acti
vate
d fa
ctor
VII
PPSB
-Ht
Nic
hiya
kuN
ichi
yaku
, Ja
pan
4F10
010
010
010
0Pr
otei
n C
Profi
linG
rifo
ls,
USA
3F14
8Lo
w10
064
-
PtX-
VFCS
L Bi
opla
sma,
Aust
ralia
3F10
0-
100
100
-
Um
anKe
drio
n, It
aly
3F10
0-
100
80An
tith
rom
bin
and
hepa
rin
-
19
Chapter 1
The efficacy of prothrombin complex concentrate is well-established. Also,
its safety has been subject to many trials. However, its safety and efficacy
have never been investigated in relation to the optimal dose. Ideally, optimal
dose of prothrombin complex concentrate is the minimum effective dose as
its thrombogeneity is supposed to increase with the dosage. Furthermore,
the optimal, minimum effective dose is cost-effective as this low dosage
should not lead to any other additional interventions.
In this thesis we aimed to find the optimal prothrombin complex concentrate
dose while addressing its effectiveness, safety and costs.
SCOPE OF THE THESIS
In this thesis, we address the use of prothrombin complex concentrates in
emergency reversal of vitamin K antagonists. In this, we focus on finding
the optimal cost-effective and safe prothrombin complex concentrate dose
strategy in vitamin K antagonist taking population who need prothrombin
complex concentrate for acute reversal of vitamin K antagonists.
In chapter 2, by means of a pilot, we explored the feasibility of a simple,
low fixed dose prothrombin complex concentrate treatment strategy.
In chapter 3, we prospectively enrolled consecutive patients with a major
vitamin K antagonist associated bleed who were either treated by the
earlier mentioned low fixed dose or a more widely used variable, INR and
weight dependent, prothrombin complex concentrate dosing strategy.
Subsequently, as we found the fixed dose to be non-inferior to the variable
dosing strategy in terms of clinical outcome, an important question from
both a clinical and costing point of view rose about whether additional
interventions were needed in the fixed dose cohort to reach the non-
inferior outcome. We studied this by performing a cost-study which is
reported in chapter 4.
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20
General introduction
A review of the literature is performed in chapter 5 to assess the currently
used prothrombin complex concentrate strategies for emergency vitamin
K antagonist reversal and to present their efficacy in terms of target INR
achievement and clinical outcome.
Finally, in chapter 6, patients, who survived the vitamin K antagonist
related major bleed in the study described in chapter 3, were followed
to determine their long term outcome in terms of incidences of (fatal)
thromboembolism, recurrent (fatal) bleed and mortality. In addition, we
characterized patients who either continued or discontinued the vitamin K
antagonist therapy.
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21
Chapter 1
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General introduction
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