DVT: A New Era in Anticoagulant Therapy
Inhibition of Factor XIa as a New Approach
to Anticoagulation
William A. Schumacher, Joseph M. Luettgen, Mimi L. Quan, Dietmar A. Seiffert
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Abstract—The dose-limiting issue with available anticoagulant therapies is bleeding. Is there an approach that could
provide antithrombotic protection with reduced bleeding? One hypothesis is that targeting proteases upstream from the
common pathway provides a reduction in thrombin sufficient to impede occlusive thrombosis yet allows enough
thrombin generation to support hemostasis. The impairment of intrinsic coagulation by selective inhibition of factor XI
(FXI) leaves the extrinsic and common pathways of coagulation intact, making FXI a drug target. This concept is
supported by the observation that human deficiency in FXI results in a mild bleeding disorder compared with other
coagulation factor deficiencies, and that elevated levels of FXI are a risk factor for thromboembolic disease. Moreover,
FXI knockout mice have reduced thrombosis with little effect on hemostasis. The results from genetic models have been
supported by studies using neutralizing antibodies, peptide inhibitors, and small-molecule inhibitors. These agents
impede thrombosis without affecting bleeding time in a variety of experimental animals, including primates. Together,
these data strongly support FXIa inhibition as a viable method to increase the ratio of benefit to risk in an
antithrombotic drug. (Arterioscler Thromb Vasc Biol. 2010;30:388-392.)
Key Words: intrinsic pathway 䡲 coagulation 䡲 factor XI 䡲 thrombosis
inhibition of blood coagulation FXIa as a novel mechanism
for preventing and treating thromboembolic diseases.
The Need for Improved
Anticoagulant Therapy
Hemostasis is an adaptive process that maintains blood in a
fluid state and preserves vasculature integrity. Thrombosis is
a maladaptive process of vascular occlusion and remains a
primary cause of cardiovascular morbidity and mortality.
Antithrombotic therapy is effective for the prevention and
treatment of thromboembolic disease. However, the established oral anticoagulant warfarin has numerous limitations,
including lack of reversibility, a steep dose response, food
and multiple drug-drug interactions, need for monitoring, and
a narrow therapeutic index. The availability of newer oral
anticoagulants, such as direct and selective inhibitors of
factor Xa (FXa) and thrombin, has overcome many of these
liabilities; however, dose-dependent bleeding continues to be
observed.1,2 An overlap of antithrombotic benefit and a
disruption of hemostasis are not unexpected given that both
processes involve interactions between the vessel wall, platelets, blood coagulation, and fibrinolysis. Improving the risk to
benefit ratio remains a viable goal for antithrombotic drug
Role of FXIa in Blood Coagulation
Blood coagulation is the coordinated activation of plasma
proteases, their cofactors, and platelets. The end product is
the protease thrombin, which cleaves fibrinogen to generate a
fibrin clot. This cascade has been classically divided into the
intrinsic (contact-activated), extrinsic (tissue factor [TF]–activated), and common (prothrombin and thrombin production) pathways, as recently reviewed3–5 and shown in the
Figure. The most important physiological activator of blood
coagulation is TF, which is expressed in the vessel wall, and,
under pathological conditions, in circulating monocytes and
microparticles. The TF-FVIIa complex catalyzes the formation of FXa, which in turn cleaves prothrombin to generate
thrombin. The activation of the intrinsic cascade remains an
area of active research. In the classic model, FXIIa, formed
by contact activation (collagen, RNA, and polyphosphates6),
catalyzes the formation of FXIa, which leads to the sequential
activations of FIX and FX. However, thrombin and TF-FVIIa
also activate intrinsic coagulation proteases, resulting in
pathways that are closely linked to optimize thrombin
generation.
Platelets play an important role in the final common
pathway of blood coagulation by providing a surface for the
See accompanying article on page 369
discovery. This requires selecting a molecular target that
defines a difference between hemostasis and thrombosis.
Selecting such a target derives from the detailed study of
human physiology and animal models. A good example is the
Received November 16, 2009; accepted December 23, 2009.
From Department of Thrombosis Biology (W.A.S., J.M.L., and D.A.S.), Bristol-Myers Squibb, Pennington, NJ; and Department of Cardiovascular
Discovery Chemistry (M.L.Q.), Bristol-Myers Squibb, Pennington, NJ.
Correspondence to Dietmar A. Seiffert, MD, Bristol-Myers Squibb, Hopewell Biology Drug Discovery, 311 Pennington–Rocky Hill Rd, Pennington,
NJ 08534. E-mail [email protected]
© 2010 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org
388
DOI: 10.1161/ATVBAHA.109.197178
Schumacher et al
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Figure. Classic pathways of blood coagulation include the extrinsic pathway, whereby TF and FVIIa activate FX; and the intrinsic
pathway, whereby FIXa and FVIIIa activate FX. In the common final
pathway, FXa and FVa activate prothrombin to form thrombin.
However, this segregation of pathways is blurred by the fact that
FXI can be activated by FXIIa or thrombin and that TF–factor VIIa
activates FIX.
formation of FXa (tenase complex) and thrombin (prothrombinase complex). Platelets are also activated by thrombin, and
they may support the formation of FXIa. The overlapping
activation of coagulation and platelets thereby supports
thrombosis and hemostasis, while locally regulated fibrinolysis helps resolve both processes.
Target Validation
The utility of FXIa as a therapeutic target has been revealed
by in vitro models of coagulation, human physiology, and
animal models of thrombosis and hemostasis. The animal
models have included mice deficient in FXI and in vivo
studies conducted with FXI or FXIa inhibitors or mechanisms
that reduce FXI or FXIa formation. Each of these lines of
evidence is reviewed in the subsequent sections.
FXIa Inhibition Assessed In Vitro
FXIa enhances both the formation and the stability of clots in
vitro. FXIa amplifies thrombin generation when coagulation
is initiated by low levels of TF or thrombin.7 The activation
of coagulation by high levels of TF in the prothrombin time
(PT) is not affected by FXIa inhibition, whereas contact
activation in the activated partial thromboplastin time (aPTT) is
affected. In this manner, FXIa inhibition limits the amplification
of thrombin formation by the intrinsic cascade, while exerting a
limited effect on the initiation of coagulation by TF.
FXI-dependent amplification of thrombin formation also
leads to activation of the thrombin-activatable fibrinolysis
inhibitor, which renders clots less sensitive to fibrinolysis.8 In
this manner, an FXIa inhibitor might indirectly enhance clot
dissolution.
FXI in Human Physiology
Bleeding Disorder of Hemophilia C
The strongest human data supporting FXIa as a therapeutic
target address its relative safety. A deficiency in FXI (hemophilia C) results in a more benign bleeding phenotype
FXIa Inhibitors
389
compared with a deficiency in either FVIII (hemophilia A) or
FIX (hemophilia B), as described in recent reviews.9 –11
Hemophilia A and B are recessive X-linked bleeding disorders and show a strong correlation between coagulant level
and the severity of bleeding, which can be life threatening and
disabling. Blood loss tends to be spontaneous and occurs
frequently in joints and muscles, although hematuria, skin
bruising, and postoperative bleeding are also observed.
Unlike hemophilia A and B, hemophilia C is present in
both sexes. Most cases involve Ashkenazi Jews12 and result
from either of 2 mutations in the FXI gene, an E117X and an
F283L substitution. However, greater than 180 mutations
have been described in lesser frequency. FXI deficiency also
arises from acquired inhibitors that neutralize its activity; in
these cases, patients may not respond well to FXI replacement therapy. Bleeding in those with hemophilia C is rarely
spontaneous; it tends to occur in response to surgery or
trauma, and especially in tissues that are prone to fibrinolysis
(the urinary track or oral cavity). There is often a poor
correlation between bleeding and coagulant level; however, a
prolonged aPTT often supports the diagnosis of a deficiency.
Severe FXI deficiency in women does not necessarily affect
pregnancy or delivery, even though excessive bleeding during
menstruation may be observed.
Bleeding associated with FXI deficiency is typically corrected by FXI replacement therapy with recombinant clotting
factor. Fibrinolysis inhibitors and desmopressin13 or recombinant FVIIa14 may provide hemostatic support, although
these are not FXI-selective treatments.
Severe FXI deficiency as an inherited coagulation disorder is
rare in the general population (approximately 1:106), except as
previously mentioned for Ashkenazi Jews (1:450). The deficiency has also been repeatedly described in Holstein cows15,16;
as in humans, the bleeding phenotype is highly variable.
Unlike other clotting factors, hemostasis is not impaired
with severe FXII deficiency, even during major surgical
procedures.17 Bleeding related to severe coagulation factor
deficiency is tolerable for FXIII,18 less tolerable for FV,19 and
severe for FX.20 Near-complete reductions in FVII21 and FII22
are not observed in humans, suggesting that their absence is
not physiologically tolerated.
FXI in Thromboembolic Disease
Although the bleeding phenotype of human FXI deficiency
has been well characterized, the potential cardiovascular
benefit associated with the phenotype is less well understood.
Data from limited studies do not support FXIa deficiency as
providing protection against myocardial ischemia,23 but they
do suggest benefit in ischemic stroke.24 These studies are
hampered by the relative infrequency of and narrow patient
population associated with FXI deficiency and the lack of
clinical outcome evaluation. Evidence is stronger for FXI as
a biomarker, with increased levels reported as a risk factor for
venous thromboembolism25–27 and myocardial ischemia or
stroke.27,28 It remains unclear whether elevated FXI levels are
causal for or just correlated with cardiovascular risk. Data
supporting FXI as an antithrombotic target have been best
documented in animal studies, the first of which described the
targeted deletion of FXI in mice.29
390
Arterioscler Thromb Vasc Biol
March 2010
Genetic Manipulation of FXI in Mice
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FXI-null mice are healthy, and their reproduction follows the
expected mendelian ratios without impaired fecundity.29 In
contrast, targeted deletion of coagulation factors in the
common pathway (FX, FII, and FV)19,22,30 and extrinsic
pathway (FVII and TF)3 is lethal prenatally or perinatally in
mice as a result of bleeding in most cases.
Early studies demonstrated that FXI-null mice were protected against oxidative iron chloride (FeCl3)–induced carotid
artery thrombosis, and that infusion of human FXI reversed
this protection.31 This established a cause-effect relationship
between FXI deficiency and reduced thrombosis. Impaired
thrombosis was subsequently observed in the vena cava32 and
mesenteric arterioles33 of FXI-null mice in response to FeCl3
injury. In comparing FIX- with FXI-null mice, similar efficacy was observed in FeCl3-associated carotid artery thrombosis; tail bleeding times were prolonged to a greater extent
with FIX compared with FXI deletion.34 In fact, there was no
detectable effect on bleeding time in FXI-null mice, even
when comparing aspirin-treated FXI-null mice with wild-type
mice.34 FXII-null mice are also protected in FeCl3-associated
arterial thrombosis, with no demonstrable effect on bleeding
time.33 The bleeding profile in null mice is fairly consistent
with human deficiencies in FXI and FXII.
The involvement of FXI in murine thrombosis is not
limited to FeCl3 injury models. Thrombus formation in
FXI-null mice was also reduced in response to laser injury of
arterioles in the cremaster muscle.35 These experiments involving continuous monitoring of thrombosis revealed reduced thrombus stability in the knockout mice along with
decreased deposition of fibrin and especially platelets. FXI
deletion was also effective in preserving carotid artery blood
flow in response to compression injury.33
Genetically modified mice provide the opportunity to
examine combined deficiencies in more than 1 coagulation
component. Activated protein C impairs coagulation by
inactivating FVa and FVIIIa. Deletion of protein C in mice
leads to fibrin deposition in multiple tissues and perinatal
lethality. Mice deficient in both protein C and FXI were
partially protected in that they did not die until much later in
life.36 These data further validate FXI as a therapeutic target
in a model in which fibrin formation is activated in a
physiological manner.
Overall, studies with FXI-null mice are consistent with the
tolerable hemostatic defect of hemophilia C. They also
strongly support FXI as a therapeutic target for preventing
occlusive thrombosis in response to severe vessel injury. The
question of whether efficacy could be obtained with a more
proportionate and incomplete inhibition of FXI or FXIa
requires the evaluation of selective pharmacological tools.
Experimental FXIa Inhibitors
Most inhibitor approaches have directly targeted FXI or FXIa
with an antibody, a peptide inhibitor, or a small-molecule
inhibitor. The disruption of FXI production or FXIa activation offers another approach.
Inhibiting FXI Activation or Production
To the extent that thrombin derived from TF-FVIIa contributes to FXI activation, indirect FXIa inhibition could be
obtained, disrupting these downstream proteases. The inhibition of FXIIa could also affect FXI activation; however,
testing this approach has thus far been limited to FXIIdeficient mice.33 Potent FXIIa inhibition (inhibition constant,
0.067 nmol/L) was observed with an insect-derived serine
protease inhibitor, but this protein was only 10-fold selective
over FXa.37
The inhibition of FXI biosynthesis was obtained with an
antisense oligonucleotide, which produced near-complete
inhibition of hepatic FXI mRNA.38 Oligonucleotide treatment
strongly inhibited FeCl3 venous thrombosis without affecting
tail bleeding time. Another direct approach is the use of FXI
neutralizing antibodies, which would allow preexisting FXIa
to remain active.
Neutralizing Antibodies
FXI neutralizing antibodies were evaluated in a nonterminal
baboon model in which a graft of varying materials was
inserted in an arteriovenous shunt to induce a nonocclusive
thrombus. The first study39 used a polyclonal antibody
administered at a dose that produced a 3.2-fold aPTT prolongation without affecting the PT. Heparin at a dose that
increased the aPTT by 3.8-fold was tested as a reference
agent. Both the FXI antibody and heparin elicited strong and
comparable inhibition of platelet accumulation on grafts
constructed of dacron, polytetrafluoroethylene, and polytetrafluoroethylene coated with TF. The initial accumulation of
platelets was affected to a lesser extent by these treatments.
Template bleeding times were unaffected by FXI antibody,
but were increased 1.4-fold by heparin. Subsequent baboon
studies used an FXI monoclonal antibody that maximally
inhibited plasma FXI activity.40 This antibody partially limited thrombus accumulation on collagen-coated grafts. It also
preserved flow in smaller-diameter grafts that were prone to
occlusive thrombosis; this effect was not observed with
aspirin.
Other studies with neutralizing antibodies have been conducted in rabbits. A monoclonal antibody against FXI or FXIa
reduced thrombus formation in balloon-injured iliac arteries.41
There was no effect on PT or platelet aggregation, whereas the
aPTT was prolonged 2.4-fold. In another in vivo study,42
TF-activated clots containing radiolabeled fibrin, and either a
control or a polyclonal FXI antibody, were injected into jugular
vein segments. The FXI antibody increased clot lysis whether it
was incorporated into the clot or administered systemically.
Peptide and Small-Molecule Inhibitors
A series of potent ketoarginine-based peptidomimetics was
reported by Daiichi Sankyo Co. These are irreversible inhibitors of FXIa and form a covalent bond to the catalytic serine
of the enzyme.43 The most potent compound produced 50%
inhibition of FXIa at 6 nmol/L (IC50), doubled the aPTT at
2.4 ␮mol/L, and showed good selectivity over FVIIa, FXa,
and thrombin. Intravenous infusion of this compound was
efficacious in a rat model of venous thrombosis. Its antithrombotic activity was comparable to that of heparin. A
pyridyl analog with an FXIa IC50 of 12 nmol/L was evaluated
in a rat mesenteric bleeding model; at a 4-fold efficacious
dose, it did not alter bleeding time. Modifications to reduce
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the peptidic character and molecular weight of these inhibitors led to compounds with reduced FXIa affinity; however,
the results of in vivo experiments with these compounds were
not reported.44
Clavatadine A, a natural product isolated from a marine
sponge, was also reported to be an irreversible inhibitor of
FXIa, with an IC50 of 1300 nmol/L.45 This compound had no
effect on FIXa at a 170-fold greater concentration. In vivo
data for clavatadine were not described in this study.
Several small-molecule inhibitors have also been reported.
A racemic boronate was reported to have an FXIa IC50 of
1400 nmol/L, with 30- and 8-fold selectivity over FXa and
thrombin, respectively.46 A potent time-dependent irreversible inhibitor of FXIa with an IC50 of 2.8 nmol/L, and that
doubled the aPTT at 2.2 ␮mol/L, was reported by BristolMyers Squibb, Pennington, NJ.47 The efficacy in FeCl2
models of arterial and venous thrombosis was observed in
rats dosed intravenously, whereas the cuticle, mesenteric, or
renal bleeding time was unchanged compared with vehicle
controls. This compound did not prolong the PT, and it was
not effective in a model of venous thrombosis induced by TF
injection.
Potential Issues
Selective disruption of intrinsic coagulation is mostly untested in clinical medicine and may exert physiological
effects beyond thrombosis and hemostasis. For example, the
phenotype observed in a cross of mice with plasminogen and
FXI deletions suggests a role for FXIa in tissue inflammation.48 Although we have drawn much from genetic models,
these may be problematic aside from species differences.
Lifelong FXI deficiency may differ from pharmacological
disruption of FXI function by triggering physiological adaptation. FXI deficiency in heterozygous humans can result in
increased bleeding; therefore, the target may not be devoid of
a safety issue. It is also obvious that preclinical models
contain, at best, certain components of human disease,
making it difficult to predict the extent of FXI or FXIa
inhibition required for clinical efficacy. The therapeutic
targeting of FIXa has progressed to early-phase clinical
studies.49,50 In contrast, the testing of FXI or FXIa inhibition
is in the preclinical stage.
Summary and Conclusions
Therapies targeting FXI disrupt intrinsic coagulation without
affecting either the extrinsic (TF) or common (FXa or
thrombin) pathways of blood coagulation. The hypothesis
that this approach could inhibit thrombosis while preserving
hemostasis is supported by several lines of evidence. In
humans, FXI deficiency is a tolerable bleeding disorder
(hemophilia C), and elevated levels of FXIa are a risk factor
for thrombotic disease and may predispose to ischemic
stroke. FXI-null mice have reduced thrombosis without
impaired hemostasis. Studies with inhibitors of FXI or FXIa
have shown antithrombotic efficacy with minimal effects on
bleeding time in rats, rabbits, and primates. Thus, the blocking of FXI function is a promising path to making agents
having an increased ratio of efficacy to bleeding available to
patients.
FXIa Inhibitors
391
Disclosures
All authors are employed by Bristol-Myers Squibb Company.
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Inhibition of Factor XIa as a New Approach to Anticoagulation
William A. Schumacher, Joseph M. Luettgen, Mimi L. Quan and Dietmar A. Seiffert
Arterioscler Thromb Vasc Biol. 2010;30:388-392; originally published online February 5, 2010;
doi: 10.1161/ATVBAHA.109.197178
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