XXXII Congreso Nacional de la Sociedad Española de Trombosis y Hemostasia

XXXII Congreso Nacional de la Sociedad Española de Trombosis y Hemostasia

and high-molecular-weight kininogen (HK) do not exhibit bleed-

ing symptoms as do FXI-deficient patients. Therefore, the role of

FXI in hemostasis is likely due to its involvement in the extrinsic,

TF-mediated pathway rather than the contact pathway.

From a clinical perspective, the balance between TFPI and

FXI may represent an important axis between bleeding and hemo-

stasis, respectively. TFPI inhibitory activity appears to assume a

central role in the pathogenesis of bleeding in patients with FVIII

deficiency (hemophilia A). TFPI-blocking antibodies shorten the

clotting time of FVIII-deficient plasma, restoring hemostasis, and

administration of TFPI-blocking antibodies also improves hemo-

stasis in hemophilic mice

. Meanwhile, our recent results demon-

strating the ability of FXIa to inactivate TPFI suggest that FXI may

play an important role in the counter-balancing the anti-hemostatic

function of TFPI. It has been shown that patients with severe FXI

deficiency and a history of bleeding exhibit higher levels of TFPI

than asymptomatic patients

. TFPI levels may therefore serve as

an important marker for bleeding risk in FXI-deficient patients.

FXI and thrombosis

Despite the recent discoveries of the modest role of FXI in

hemostasis, a number of studies have shown a significant role for

FXI in promoting thrombosis. While mice lacking the contact fac-

tors FXII, HK, PK or FXI are resistant to experimental-induced

thrombosis

14,15

, in humans, FXI seems to be strongest candidate for

playing a role in thrombosis. Patients with severe FXI deficiency

were reported to exhibit protection from ischemic stroke and a

lower incidence of venous thromboembolism (VTE)

. Converse-

ly, higher levels of FXI were associated with increased risk of

VTE and ischemic stroke

. Reducing factor XI levels in patients

undergoing unilateral total knee arthroplasty has been shown to

be an effective method for the prevention of postoperative VTE,

suggesting FXI inhibition as an effective method of anticoagula-

tion in surgery

The contact pathway and the TF-FVIIa complex together

have been shown to contribute to venous thrombosis in a mouse

model, suggesting a combined role for the intrinsic and extrinsic

pathways in thrombosis

. Our work suggests that FXI may pro-

vide the common link between these two pathways in thrombosis.

We have observed that inhibition of FXI activation by FXIIa is

protective in a mouse model of thrombosis and also beneficial in

mouse model of TF-induced pulmonary embolism

. Furthermore,

we have shown that in a non-human primate model of thrombosis,

the inhibition of FXI activation reduced intraluminal thrombus

growth initiated by TF

. Our observations suggest this thrombotic

potential of FXI can be explained by both the ability of FXIa to

promote the extrinsic pathway of thrombin generation via inacti-

vation of TFPI and by the feedback activation of FXI by thrombin

to further amplify the extrinsic pathway.

Research into the role of FXI in hemostasis and thrombosis

is ultimately focused on identifying new therapeutic targets to

prevent thrombosis without affecting hemostasis. Current anti-

coagulants inhibit the core pathways of thrombin generation

and as a result, all are associated with major bleeding complica-

tions. The development of agents to inhibit FXI is fully underway,

with the promise of safe and efficacious anti-thrombotic therapies

due to the modest role of FXI in hemostasis relative to its role in

thrombosis. Specifically, translational approaches are underway to

inhibit the enzymatic function of FXI through monoclonal anti-

bodies against FXI which block the activation of FIX or its activa-

tion by FXIIa, small-molecule inhibitors that block the active site

of FXIa

or targets FXIa and allosterically inhibits its activation

of FIX

, or using an antisense oligonucleotide (ASO) to reduce

the synthesis of FXI

. These translational efforts should take into

account that efforts to prevent thrombosis by effectively inducing

transient hemophilia C may potentiate a bleeding risk in some

patients. Prediction of bleeding in asymptomatic FXI deficiency,

whether inherited or pharmacologically induced, poses an import-

ant dilemma to surgeons and may become an increasing clinical

problem with the development of FXIa inhibitors that fully block

the promiscuous enzymatic activity of FXIa that may be required

for effective hemostasis.

Conclusion

Recent investigations have shown that FXIa can act on targets

other than FIX, which may be relevant to its role in both hemostasis

and thrombosis. The development of safe and effective antithrom-

botics targeting FXI should take into account that FXIa is able to

activate factors of the extrinsic pathway such as FX, FV, and FVIII

and also activate the TF-FVIIa pathway by inhibiting TFPI, and

that polyP released from activated platelets can further enhance

these activities of FXI significantly. In addition, companion diag-

nostics are required to identify which FXI-deficient patients and,

in the future, FXI-anticoagulated patients could be at a risk of

bleeding. Finally, further studies are needed to better understand

the role of FXI in thrombosis and hemostasis to identify possible

therapeutic targets against FXI that block its prothrombotic effect

without affecting its hemostatic function.

Acknowledgements

This work was supported by grants from the National Institutes

of Health (R01HL101972, R01GM116184).

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