Brief Review

Factor XII as a Therapeutic Target in Thromboembolic

and Inflammatory Diseases
Katrin F. Nickel, Andy T. Long, Tobias A. Fuchs, Lynn M. Butler, Thomas Renné

Abstract—Coagulation factor XII (FXII, Hageman factor) is a plasma protease that in its active form (FXIIa) initiates the
procoagulant and proinflammatory contact system. This name arises from FXII’s unique mechanism of activation that
is induced by binding (contact) to negatively charged surfaces. Various substances have the capacity to trigger FXII
contact-activation in vivo including mast cell–derived heparin, misfolded protein aggregates, collagen, nucleic acids,
and polyphosphate. FXII deficiency is not associated with bleeding, and for decades, the factor was considered to be
dispensable for coagulation in vivo. However, despite the fact that humans and animals with deficiency in FXII have
a normal hemostatic capacity, animal models revealed a critical role of FXIIa-driven coagulation in thromboembolic
diseases. In addition to its role in thrombosis, FXIIa contributes to inflammation through the activation of the inflammatory
bradykinin-producing kallikrein-kinin system. Pharmacological inhibition of FXII/FXIIa interferes with thrombosis
and inflammation in animal models. Thus, targeting the FXIIa-driven contact system seems to be a promising and safe
therapeutic anticoagulation treatment strategy, with additional anti-inflammatory effects. Here, we discuss novel functions
of FXIIa in cardiovascular thrombotic and inflammatory disorders.   (Arterioscler Thromb Vasc Biol. 2017;37:13-20.
DOI: 10.1161/ATVBAHA.116.308595.)
Key Words: blood coagulation ◼ factor XII ◼ inflammation ◼ reperfusion injury ◼ therapy ◼ thrombosis

Factor XII–Driven Contact System clotting in the diagnostic coagulation assay activated partial
The factor XII (FXII)–driven plasma contact system is a pro- thromboplastin time. Although deficiency in any of the con-
coagulant and proinflammatory protease cascade. The sys- tact factors, with the exception of C1INH, prolongs the acti-
tem consists of the serine protease zymogens FXII, plasma vated partial thromboplastin time, contact factor deficiency
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prekallikrein (PPK), the nonenzymatic cofactor high molec- is not associated with hemostatic abnormalities in humans
ular weight kininogen, and the serpin C1 esterase inhibitor or in mice.6 In contrast to FXII, FXI deficiency is associ-
(C1INH), the major inhibitor of both activated FXII (FXIIa) ated with trauma-induced bleeding in humans (hemophilia
and plasma kallikrein.1–3 In addition, the FXIIa substrate C), possibly because of FXII-independent activation by the
FXI, although not a classical contact factor, structurally and thrombin-driven feedback loop.7 In contrast to FXI-deficient
functionally belongs to the system.4 FXII binding to nega- humans, FXI-deficient mice do not bleed excessively, sug-
tively charged surfaces induces a conformational change in gesting species-specific functions of the protein in hemosta-
the presence of zinc ions. Minute amounts of formed FXIIa sis.8 Normal bleeding in FXII-deficient individuals led to the
activate PPK to plasma kallikrein by limited proteolysis. PPK premise that the factor has no function for coagulation in vivo.
then reciprocally activates further FXII and also cleaves high This hypothesis was challenged by the discovery that throm-
molecular weight kininogen to release the proinflammatory bosis was defective in FXII-deficient mice, despite the fact
peptide hormone bradykinin (kallikrein-kinin system).1–3 that the animals have a normal hemostatic capacity.9 FXII-
Binding of bradykinin and its metabolite desArg9-bradykinin driven coagulation specifically contributes to thrombosis but
to their G-protein–coupled kinin B2 and B1 receptors, respec- not to hemostasis, indicating that these 2 processes principally
tively, initiates a variety of signaling pathways culminating in differ in mechanism.5 The critical role of FXII in thrombosis
pain, reduced blood pressure, vascular leakage, and neutro- has sparked renewed interest in the contact system pathway
phil chemotaxis.5,6 In addition to the kallikrein-kinin system, in the past decade and several FXII-in vivo contact activators,
contact-activated FXII triggers the intrinsic pathway of coagu- such as platelet polyphosphate,10 nucleic acids (RNA11 and
lation via FXI (Figure 1). DNA12), collagen,13 misfolded protein aggregates,14 and mast
A role of FXII for fibrin formation has been established cell–released heparin15,16 have been identified. Furthermore,
for decades. FXII contact activation is used to initiate plasma FXII can be directly activated through proteolytic activation

Received on: April 9, 2016; final version accepted on: November 1, 2016.
From the Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Germany (K.F.N., A.T.L., T.A.F.,
L.M.B., T.R.); and Division of Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital,
Stockholm, Sweden (K.F.N., T.A.F., L.M.B., T.R.).
Correspondence to Katrin F. Nickel, PhD, Institute of Clinical Chemistry and Laboratory Medicine (N27), University Medical Center Hamburg
Eppendorf, D-20246 Hamburg, Germany, and Division of Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet and
University Hospital, SE-17176 Stockholm, Sweden. E-mail [email protected]
© 2016 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org DOI: 10.1161/ATVBAHA.116.308595

13
 14   Arterioscler Thromb Vasc Biol   January 2017

suggesting a role of FXII in atherothrombosis.21 In a mouse

Nonstandard Abbreviations and Acronyms
model of atherosclerosis (ApoE−/− mice fed with Western-type
AD Alzheimer’s disease diet) targeting FXIIa with corn trypsin inhibitor interfered with
ASO antisense oligonucleotides vessel occlusive clot formation on ultrasound-driven ruptured
C1INH C1 esterase inhibitor atherosclerotic plaques in carotid arteries.22 Similarly, knock-
FXIIa activated factor XII down of FXI expression by an antisense nucleotide-approach
HAE hereditary angioedema reduced thrombus size in the same model.23 FXIIa was localized
HK high molecular weight kininogen in human thrombi removed during carotid endarterectomy24
PE pulmonary embolism and tissue homogenates prepared from human atherosclerotic
PPK plasma prekallikrein
plaques showed FXII activity.21 Deficiency in FXII or FXI, or
combined deficiencies, similarly reduced thrombus formation
tMCAO transient middle cerebral occlusion
on immobilized plaque material in a laminar flow chamber
system, indicating that FXIIa operates via FXI in plaque-
independent of plasma kallikrein by plasmin17 or bacterial driven coagulation.23 Intravital microscopy studies revealed
proteases.18 the mechanism of defective vessel occlusive thrombus forma-
tion associated with FXII deficiency.9,23 Initially, thrombi simi-
Role of FXII in Experimental Thrombotic larly develop in wild-type and FXII-targeted mice, consistent
Disease with the hypothesis that tissue factor mostly, if not exclusively,
FXII deficiency impairs contact-driven plasma clotting; how- drives coagulation at vascular injury sites. However, subse-
ever, defective in vitro clotting is not associated with bleeding quently thrombus propagation is defective in the absence of
abnormalities. This apparent discrepancy motivated us to pro- FXII. Both FXII-deficient and FXIIa-targeted mice have
duce FXII-deficient (F12−/−) mice and to phenotype the animals impaired thrombus propagation and exposed to arterial shear
in a variety of thrombosis models. FXII deficiency provided the developing thrombus sheds microemboli. In contrast, inhi-
potent thromboprotection and infusion of human FXII restored bition of tissue factor–driven coagulation reduced early throm-
thrombus formation in F12−/− mice.9 Deficiency in FXII inter- bus size without increased embolization.23 Together, the data
fered with ferric chloride–induced thrombus formation in the show that FXII-driven coagulation contributes to thrombus
carotid artery19,20 and mesenteric arteriols.9 Thromboprotection propagation by producing fibrin within the developing clot,
seen in F12−/− mice was not restricted to chemical vessel injury. leading to increased thrombus stability. Vice versa, deficiency
Thrombosis was also defective in mechanically9 or Rose Bengal in FXII does not allow for intrinsic pathway-driven fibrin pro-
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laser-injured19 carotid arteries. Carotid arteries are prone for duction, impairs thrombus growth, and protects from vessel
atherosclerosis. FXII and the proteins of the contact system are occlusive clot formation. Consistently, mechanical clot stabil-
enriched in early and unstable human atherosclerotic plaques ity (assessed by thromboelastography) is largely reduced in

Figure 1. Factor XII (FXII)–driven contact system and its roles in diseases. Polyphosphate (polyP), mast cell–derived heparin, collagen,
nucleic acids (DNA and RNA), and misfolded protein aggregates such as amyloid β-protein (Aβ) 42 induce FXII contact-activation in vivo.
Activated FXII (FXIIa) triggers fibrin formation through the factor XI (FXI)–mediated intrinsic coagulation pathway, contributing to athero-
thrombosis, ischemic stroke, venous thromboembolism (VTE) such as deep vein thrombosis (DVT), pulmonary embolism (PE), and can-
cer-driven VTE. FXIIa also activates prekallikrein (PPK) leading to release of bradykinin (BK) by plasma kallikrein (PK)–mediated cleavage
of high molecular weight kininogen (HK). Both FXI and PPK are bound indirectly to cells via HK. BK activates kinin B2 receptors (B2R),
whereas the BK metabolite des-Arg9 BK binds to kinin B1 receptor (B1R), both of which activate proinflammatory signaling cascades that
contribute to increased vascular leak in hereditary and angiotensin-converting enzyme (ACE) inhibitor–induced angioedema (AE), allergic
and anaphylactic reactions, and vascular dysfunction in patients with Alzheimer’s disease. Serpin C1 esterase inhibitor (C1INH) is the
major inhibitor of both activated FXII and PK.
 Nickel et al   Factor XII as a Therapeutic Target   15

the absence of FXII in human and mouse blood. How is FXII mechanisms are not clear, but may relate to thrombus stabil-
activated in thrombosis? Platelets store an inorganic polymer, ity. Similar to atherothrombosis, unstable thrombi are formed
polyphosphate, in their dense granules that is released on in cerebral vessels occluded by the inserted filament in the
activation.25 Platelet-size synthetic polyphosphate activates absence of FXII. In the reperfusion phase that occurs in the
FXII and initiate coagulation in an FXII-dependent manner tMCAO, but not in the permanent occlusion of the middle
in human plasma.26 Using thrombosis and inflammation mod- cerebral artery model, these thrombi are cleared more easily
els in mice, as well as a human disease model, our labora- facilitating restoration of blood flow. FXII functions in cere-
tory has shown that polyphosphate-mediated FXII activation bral thrombosis are not limited to ischemia/reperfusion injury.
drives platelet-driven thrombosis and inflammation in vivo.10 Targeting FXII interferes with trauma-induced thrombosis in
Targeting polyphosphate with recombinant exopolyphospha- microvessels and reduces brain injury.30
tase mutants ablates thrombus formation in ferric chloride– Importance of FXII is not restricted to arterial thrombosis
challenged carotid arteries without increasing bleeding risk and contributes to venous thromboembolism. Mouse models
reproducing the thromboprotective phenotype of F12−/− mice have shown a critical role of FXII in deep vein thrombosis.
in this model.27 Neutralizing polyphosphate interferes with Stasis-driven deep vein thrombosis in the inferior vena cava
carotid artery thrombosis by increasing the embolization rate, (IVC ligation model) is reduced in F12−/− mice.31 Embolization
confirming a central role of the platelet polyphosphate/FXII of venous thrombi can cause pulmonary embolism (PE).
pathway for arterial thrombosis. In sum, the data support a F12−/− mice are protected from PE triggered by the infusion
model of tissue factor–initiated and polyphosphate/FXII- of collagen/epinephrine9 or synthetic and platelet-derived
propagated coagulation in atherothrombosis (Figure 2). polyphosphate into the vena cava.10 Furthermore, malignant
FXII also contributes to cerebrovascular thrombosis. disease is a major and well-established risk factor for venous
F12−/− mice are protected from cerebral ischemia in a model of thromboembolism. Mouse PE models and cancer patient
ischemic stroke (transient middle cerebral occlusion [tMCAO] materials showed that the polyphosphate/FXII pathway drives
induced by an inert filament).28 Brain damage and vessel coagulation in cancer-associated venous thromboembolism.32
occlusive fibrin formation were similarly reduced in FXI- Prostate cancer cells and cancer cell–derived microvesicles
deficient mice, indicating that FXII contributes to ischemic exposed polyphosphate on their plasma membrane, activat-
stroke through the intrinsic coagulation pathway. In contrast, ing FXII and induced FXIIa-driven clotting in patient plasma
FXII deficiency was not protective in a model of permanent and PE in mice.32 The polyphosphate/FXII pathway oper-
occlusion of the middle cerebral artery.29 The underlying ates independently of tissue factor–driven coagulation33 and
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Figure 2. Model of atherothrombosis after atherosclerotic plaque rupture. A, After plaque rupture, tissue factor (TF) is exposed to blood
and triggers fibrin formation. B, Platelets rapidly bind to formed fibrin, become activated, and secrete polyphosphate (polyP) and TF
pathway inhibitor (TFPI) that terminates TF activity. C, PolyP activates factor XII (FXII)–driven coagulation driving fibrin formation within the
forming thrombus that is critical for thrombosis.
 16   Arterioscler Thromb Vasc Biol   January 2017

interference with this pathway allows for safe anticoagulation. were not associated with the incidence for myocardial infarc-
Collectively, these data show that the FXII-driven contact sys- tion or ischemic stroke.44 In contrast, a Dutch study found
tem drives arterial and venous thrombosis in mice. FXII clotting activity associated with decreased risk of myo-
cardial infarction.45 Consistently, low FXIIa/C1INH and kal-
Role of FXII in Human Thrombotic Disease likrein/C1INH complexes were associated with increased risk
Despite accumulating evidence that FXII critically contributes for coronary heart disease and ischemic stroke.46 Other studies
to thrombosis in experimental mouse2 and baboon models,34 a failed to find an association between FXII activity and myo-
role of FXII for human thrombotic disease has remained con- cardial infarction47 or ischemic stroke.48 Possible explanation
troversial.35 Anecdotal reports suggesting that FXII deficiency for the discrepant results may reflect the use of different non-
may predispose to thrombosis date back to the death of the standardized biomarkers, the short half-life of free FXIIa in
index FXII-deficient patient, Mr. John Hageman, who suc- plasma, rapid clearance of FXIIa/C1INH complexes, different
cumbed to an episode of post-traumatic/immobilization-asso- study designs and patient cohorts. In summary, the wealth of
ciated PE.35 In most of these cases, patients with thrombotic the data has remained somehow uncertain indicating a need
events had other inherited or required risk factors such as het- for novel clinical studies and better biomarkers.
erozygous factor V Leiden, antithrombin deficiency, trauma, Data from a large Austrian registry reported an inverted
or pregnancy that might explain the thrombosis development U-shape association of FXII plasma levels (assessed by an
independently of FXII deficiency.36 In addition, antiphospho- activated partial thromboplastin time–based clotting assay)
lipid antibodies, although a thrombotic risk factor, cause a and mortality.49 Mortality in patients with severe FXII defi-
prolonged clotting time in an activated partial thromboplas- ciency (<10%) was similar to those with FXII level in the
tin time–based assay and may suggest false-positive results normal range (100%) and elevated for all reduced levels.
(pseudo-FXII deficiency). Indeed, controlled clinical studies The underlying mechanism remains unclear; however, it may
failed to find an association of FXII deficiency with increased reflect a delicate interplay of thromboprotection and increased
risk of thromboembolic disease.37 Because there is still a lack risk of embolization in individuals with reduced FXII levels.
of clinical data analyzing for potential thromboprotection in
FXII-deficient individuals, we have initiated a registry on FXII and Inflammation
FXII-deficient humans (www.factor12.net) and invite readers Activated FXII triggers the kallikrein-kinin system leading to
to include individuals with inherited severe FXII deficiency. release of bradykinin.6 Bradykinin activates kinin B2 receptor–
Epidemiological studies have found an association mediated signaling cascades that lead to increased intracel-
between plasma FXII/FXIIa levels and arterial thrombosis. lular calcium, formation of nitric oxide and eicosanoids, and
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Plasma FXIIa, measured by FXIIa-specific antibody-based release of tissue-type plasminogen activator. B2 receptors are
ELISA, was elevated in a large cohort (>2400) of middle- constitutively expressed throughout healthy tissues, whereas
aged men with high risk of coronary heart disease. FXIIa B1R is selectively expressed. Bradykinin induces increase in
was independent and positively associated with risk factors microvascular permeability, nitric oxide–mediated vasodila-
for coronary heart disease, such as cholesterol and triglycer- tion, hypotension, and inflammatory reactions such as swelling,
ides, blood pressure, body mass index, fibrinogen concentra- hyperperfusion, and pain.50 Furthermore, bradykinin stimulates
tion, tobacco smoking, and alcohol intake.38 Thus, the contact macrophages to release neutrophil, monocyte, and eosinophil
system of coagulation seems to be activated when coronary chemotactic substances51 and directly stimulates migration of
heart disease risk is increased. Circulating levels of FXIIa are neutrophils.52 Bradykinin is rapidly degraded by kinin-degrad-
increased in patients with ischemic heart disease, compared ing enzymes (kininases) such as angiotensin-converting enzyme
with control subjects.39 Using the same assay, FXIIa was ele- or carboxypeptidases N and M resulting in a short plasma half-
vated in a large cohort of 870 patients with acute coronary life (second-range) of bradykinin in vivo53 (Figure 1).
syndrome at the time of admission and predicted long-term Although defective FXII activity provides thrombopro-
all-cause and cardiac mortality.40 Elevated FXIIa plasma level tection, excessive FXII activity results in hereditary angio-
also predicted recurrent cardiovascular events after acute edema (HAE), a rare life-threatening inherited disorder. HAE
myocardial infarction.41 Free FXIIa is unstable as the protease is caused by excessive bradykinin formation or signaling and
binds to inhibitors in plasma and inhibitor binding mask the characterized by recurrent episodes of acute swelling in multi-
anti-FXIIa antibody epitope that was used in the aforemen- ple organs because of increased vascular permeability.53 HAE
tioned studies. To overcome these preanalytical challenges, types I and II are characterized by deficiency or dysfunctional-
later studies assessed that FXIIa bound to its endogenous ity of C1INH, respectively.53 Patients with a third HAE vari-
inhibitors C1INH or antithrombin as a biomarker for contact ant (HAE type III) have normal levels of a fully functional
activation. FXIIa/C1INH or FXIIa/antithrombin levels were C1INH.54 This variant is associated with single-nucleotide
elevated in plasma of patients with myocardial infarction at polymorphisms in the F12 gene that cause missense mutations
admission.42 Similarly, the Dutch RATIO study involving at position 309 (Thr309Arg and Thr309Lys) in FXII.54 The
>200 young women with myocardial infarction found levels mutations lead to a loss of a single O-linked glycosylation that
of activated contact system proteins associated with arterial facilitates autoactivation of the zymogen. Mutant FXII presents
thrombosis. Although elevated kallikrein/C1INH complexes a gain-of-function variant leading to excess bradykinin forma-
strongly indicated risk of myocardial infarction, FXIIa/ tion in patient plasma and edema in a humanized HAE type
C1INH was elevated in patients with a history of ischemic III mouse model.55 Mutated FXII zymogen also has increased
stroke.43 In the same cohort, however, FXII zymogen levels sensitivity for enzymatic cleavage by plasmin.17 In sum, both
 Nickel et al   Factor XII as a Therapeutic Target   17

excess contact activation and proteolytic activation result in vivo and demonstrated thromboprotective effects with addi-
pathological mutant FXII activation culminating in excess tional anti-inflammatory properties.
bradykinin formation. Similar to increased bradykinin forma- The recombinant FXIIa inhibitor rHA-infestin-4 is based
tion, reduced bradykinin metabolism mostly because of ACE on the fourth domain of the nonclassic Kazal-type serine pro-
inhibitor therapy provides a common cause of angioedema.50 tease inhibitor from the midgut of the insect Triatoma infestans
A growing body of evidence suggests that the contact sys- fused to human albumin to increase its stability.67 Intravenous
tem contributes to Alzheimer’s disease (AD). AD is character- infusion protected mice and rats from ferric chloride–induced
ized by the accumulation of misfolded amyloid β-protein (Aβ) arterial thrombosis and ischemic stroke. Furthermore, rHA-
leading to neuroinflammation.56 Misfolded proteins have the infestin-4–treated mice were protected from lethal PE, ischemic
capacity for activating FXII, and FXIIa levels are elevated in brain injury, thrombus formation on ruptured atherosclerotic
patients with systemic amyloidosis, a vascular disease marked plaques,67 hypotension during acute episodes of anaphylaxis,16
by the accumulation and deposition of misfolded plasma pro- and experimental autoimmune encephalomyelitis.66 One of the
teins.14 Similarly, FXIIa is increased in plasma of AD mouse drawbacks of using rHA-infestin-4 is that it modestly inhibits
models and patients with AD.57 AD presents a prothrombotic plasmin and FXa at high concentrations.71 Additionally, the
state, and anticoagulation therapy has been shown to be bene- insect-derived protein has immunogenic properties.
ficial in patients58 and mouse models.59 Indeed, the Aβ isoform The synthetic peptide H-D-Pro-Phe-Arg-chloromethylketone
Aβ42 promotes FXII-mediated thrombin generation through irreversibly inhibits the amidolytic activity of FXIIa and plasma
the intrinsic coagulation pathway60 and activates the kalli- kallikrein-mediated activation of FXII. Mice pretreated with
krein-kinin system.57 Thus, Aβ produced FXIIa may contrib- the inhibitor were resistant to cerebral infarction in the tMCAO
ute to the procoagulant and inflammatory mechanisms in AD. model28 and were protected from polyphosphate-induced
This cross talk of procoagulant and inflammatory mecha- edema formation10 and hypotension during acute episodes of
nism, a concept described as thromboinflammation,61 also anaphylaxis.16
contributes to the pathophysiology of stroke. Previously, it Targeting FXII/FXIIa by antibodies has been success-
was suggested that the kallikrein-kinin system plays an impor- fully used by various groups. Antibody 15H8 inhibited FXII
tant role in the thromboinflammation process during cerebral activation and reduced platelet-rich thrombus formation in a
ischemia. In addition to FXII, both PPK62 and high molecu- collagen-coated vascular graft in baboons.34 The recombinant
lar weight kininogen63 contribute to microvascular thrombo- fully human FXIIa-neutralizing antibody 3F7 binds into the
sis and blood–brain barrier leakage, edema formation, and FXIIa enzymatic pocket of the protease with high affinity and
inflammation after tMCAO. Significantly fewer macrophages/ interfered with FXIIa-mediated coagulation, abolished throm-
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microglia and neutrophils were present in the brains of PPK- bus formation under flow, and blocked experimental thrombo-
and high molecular weight kininogen–deficient mice when sis in mice and rabbits.20 3F7 provided thromboprotection as
compared with wild-type mice. Consistently, infusion of efficiently as heparin in an extracorporeal membrane oxygen-
C1INH protected mice and rats from intracerebral thrombosis ation cardiopulmonary bypass system in rabbits. However, in
and had antiedematous functions after tMCAO.64 Furthermore, contrast to heparin, 3F7 treatment did not impair hemostatic
genetic and pharmacological targeting of kinin B1 receptors, capacity or increase bleeding. 3F7 also protected mice from
but not of B2 receptors, resulted in smaller infarct size, reduc- prostate cancer–induced lethal PE.32 In addition to its throm-
tion of brain edema and reduced invasion of immune cells in boprotective effects, 3F7 abolished bradykinin generation in
the brain after tMCAO-induced ischemia/reperfusion injury.65 HAE type III patient plasma and blunted edema in a human-
Furthermore, FXII was recently identified as a key regulator ized HAE type III mouse model.55 Humanized antibodies such
of adaptive immune responses in autoimmune diseases of the as 3F7 have minimal immunogenic potential in humans and a
central nervous system such as multiple sclerosis via CD87- long half-life in the circulation.
mediated modulation of dendritic cells.66 Another approach for FXIIa inhibition is based on ASO.
In sum, the dual role of FXII in thrombosis and inflamma- Targeting FXII expression with ASO reduced arterial and
tion makes it an attractive drug target. venous thrombosis in mice72 and attenuated catheter-induced
thrombosis in rabbits70 without increased therapy-associated
Targeting FXII bleeding. Furthermore, anti-FXII ASO treatment protected
Despite the increasing availability of anticoagulants, throm- mice from C1INH deficiency–induced increased vascular per-
botic disease treatment remains challenging. Currently avail- meability.73 Targeting FXII by ASO has a slow onset of action
able coagulation inhibitors target enzymes of the coagulation and requires multiple parenteral ASO applications. In con-
cascade that are important for fibrin formation and, therefore, trast, small-molecule FXIIa inhibitors that can be taken orally
bear an inherent risk for bleeding complications. Because of are more suitable for long-term indications. These inhibitors
the selective importance of FXII in thrombus formation while are still under development.69
being dispensable for hemostasis, the development of drugs Taken together, pharmacological targeting of FXII has
targeting FXII(a) seems to be a promising approach. To date, been identified as potent and safe strategy to interfere with
several classes of FXII(a) inhibitors have been developed thrombosis in mice, rats, rabbits, and baboons, and edema
including recombinant proteins,67 synthetic peptides,28,68 small formation and hypotension in mice with possible implications
molecular weight FXIIa inhibitors,69 antibodies,20,34 and anti- for patients. The broad impact of FXII beyond thrombosis
sense oligonucleotides (ASO) that knockdown FXII expres- provides a promising treatment strategy, but future in-depth
sion.70 Most of these inhibitors have already been tested in analysis is required to exclude potential limitations.
 18   Arterioscler Thromb Vasc Biol   January 2017

Conclusions and Future Directions polyphosphates are proinflammatory and procoagulant mediators in vivo.
Cell. 2009;139:1143–1156. doi: 10.1016/j.cell.2009.11.001.
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(100615), Hjärt Lungfonden (20140741), Stockholms läns landst- thromres.2012.08.284.
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German Research Society (SFB877, TP A11 and SFB841, TP B8), and Adams TC, Smith SA, Hanson SR, McCarty OJ, Renné T, Gruber
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a European Research Council grant (ERC-StG-2012-311575_F-12) A, Gailani D. A role for factor XIIa-mediated factor XI activation in
to T. Renné and a Marie Sklodowska-Curie Fellowship (H2020- thrombus formation in vivo. Blood. 2010;116:3981–3989. doi: 10.1182/
MSCA-IF-2015–708495) to K.F. Nickel. blood-2010-02-270918.
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body provides thromboprotection in extracorporeal circulation without
Disclosures increasing bleeding risk. Sci Transl Med. 2014;6:222ra17. doi: 10.1126/
None. scitranslmed.3006804.
21. Borissoff JI, Heeneman S, Kilinç E, Kassák P, Van Oerle R, Winckers
K, Govers-Riemslag JW, Hamulyák K, Hackeng TM, Daemen MJ,
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Highlights
• Coagulation factor XII activates the procoagulant intrinsic pathway of coagulation and the proinflammatory kallikrein-kinin system.
• Animal models have established a central role of factor XII in pathological thrombus formation. Despite its central function in thrombosis,
deficiency in factor XII does not impair hemostasis in mice and humans.
• Factor XII contributes to several disease states. Although the factor XII–driven intrinsic coagulation pathway plays a role in atherothrombo-
sis, ischemic stroke, and venous thromboembolism, the factor XII–driven kallikrein-kinin system contributes to hereditary and angiotensin-
converting enzyme inhibitor–induced angioedema, allergic and anaphylactic reactions, and vascular dysfunction in patients with Alzheimer’s
disease.
• Several classes of factor XII inhibitors are developed. Neutralizing factor XII provided safe thromboprotection with additional anti-inflammatory
properties in animal models with possible implications for patients.
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