An update on factor XI structure and function

Mohammed, Bassem M.; Matafonov, Anton; Ivanov, Ivan; Sun, Mao-fu; Cheng, Qiufang; Dickeson, S. Kent; Li, Chan; Sun, Dayin; Verhamme, Ingrid M.; Emsley, Jonas; Gailani, David

doi:10.1016/j.thromres.2017.10.008

Cited by 134 publications

(155 citation statements)

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“…The absence of abnormal bleeding in FXII-deficient individuals indicates FXI is activated by FXII-independent processes during the normal response to injury. Thrombin may be the main activator of FXI during hemostasis (Fig.1C, blue arrow) [65,77]. In our current hypothesis, FXI can function as part of contact activation, or independently of it as a component of thrombin generation during hemostasis (Fig.1C).…”

Section: Contact Activation and Thrombin Generationmentioning

confidence: 82%

“…FXIIa promotes coagulation by catalyzing conversion of FXI, a homolog of PK, to the protease factor XIa (FXIa, Fig.1A, green arrow) [65]. FXIa then converts factor IX to factor IXa [65], driving thrombin generation in the aPTT assay (Fig.1B).…”

Section: Contact Activation and Thrombin Generationmentioning

confidence: 99%

“…In current coagulation models, FXIa contributes to clot integrity after the clot is formed, primarily by activating factor IX, but perhaps also through activation of factors V, VIII and X, and proteolytic inhibition of tissue factor pathway inhibitor (TFPI) [65,74–76]. The absence of abnormal bleeding in FXII-deficient individuals indicates FXI is activated by FXII-independent processes during the normal response to injury.…”

Section: Contact Activation and Thrombin Generationmentioning

confidence: 99%

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Plasma contact factors as therapeutic targets

et al. 2018

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Direct oral anticoagulants (DOACs) are small molecule inhibitors of the coagulation proteases thrombin and factor Xa that demonstrate comparable efficacy to warfarin for several common indications, while causing less serious bleeding. However, because their targets are required for the normal host-response to bleeding (hemostasis), DOACs are associated with therapy-induced bleeding that limits their use in certain patient populations and clinical situations. The plasma contact factors (factor XII, factor XI, and prekallikrein) initiate blood coagulation in the activated partial thromboplastin time assay. While serving limited roles in hemostasis, pre-clinical and epidemiologic data indicate that these proteins contribute to pathologic coagulation. It is anticipated that drugs targeting the contact factors will reduce risk of thrombosis with minimal impact on hemostasis. Here, we discuss the biochemistry of contact activation, the contributions of contact factors in thrombosis, and novel antithrombotic agents targeting contact factors that are undergoing pre-clinical and early clinical testing.

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Section: Contact Activation and Thrombin Generationmentioning

confidence: 82%

Section: Contact Activation and Thrombin Generationmentioning

confidence: 99%

Section: Contact Activation and Thrombin Generationmentioning

confidence: 99%

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Plasma contact factors as therapeutic targets

et al. 2018

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“…To further identify the preferred ABS, we utilized two full‐length, recombinant FXIa block mutants, rFXIa‐FL ABS1 and rFXIa‐FL ABS2 (Figure B). The two mutants have previously yielded key insights into heparin binding to FXIa . In comparison to the recombinant wild‐type enzyme (rFXIa‐FL WT ), the ABS2 mutant (rFXIa‐FL ABS2 ) was inhibited by SCI ~five‐fold weaker, while also displaying a reduction of ~20% in efficacy (Figure C, Tables and S4 in supporting information).…”

Section: Resultsmentioning

confidence: 99%

A synthetic heparin mimetic that allosterically inhibits factor XIa and reduces thrombosis in vivo without enhanced risk of bleeding

Al‐Horani

Abdelfadiel

Afosah

et al. 2019

Journal of Thrombosis and Haemostasis

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Background Human factor XIa (FXIa) is an actively pursued target for development of safer anticoagulants. Our long‐standing hypothesis has been that allosterism originating from heparin‐binding site(s) on coagulation enzymes is a promising approach to yield safer agents. Objectives To develop a synthetic heparin mimetic as an inhibitor of FXIa so as to reduce clot formation in vivo but not carry high bleeding risk. Methods We employed a gamut of methods involving synthetic chemistry, biophysical biochemistry, enzyme assays, blood and plasma coagulation assays, and in vivo thrombosis models in this work. Results Sulfated chiro‐inositol (SCI), a non‐saccharide mimetic of heparin, was synthesized in three steps in overall yields of >50%. SCI inhibited FXIa with potency of 280 nmol/L and preferentially engaged FXIa's heparin‐binding site to conformationally alter its active site. SCI inhibition of FXIa could be rapidly reversed by common antidotes, such as protamine. SCI preferentially prolonged plasma clotting initiated with recalcification, rather than thromboplastin, alluding to its intrinsic pathway‐based mechanism. Human blood thromboelastography indicated good ex vivo anticoagulation properties of SCI. Rat tail bleeding and maximum‐dose‐tolerated studies indicated that no major bleeding or toxicity concerns for SCI suggesting a potentially safer anticoagulation outcome. FeCl3‐induced arterial and thromboplastin‐induced venous thrombosis model studies in the rat showed reduced thrombus formation by SCI at 250 μg/animal, which matched enoxaparin at 2500 μg/animal. Conclusions Overall, SCI is a highly promising, allosteric inhibitor of FXIa that induces potent anticoagulation in vivo. Further studies are necessary to assess SCI in animal models mimicking human clinical indications.

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“…1,2 In vitro, FXI is converted to FXIa by the enzymes thrombin or factor XIIa (FXIIa). 1 Given the absence of abnormal bleeding in FXIIa-deficient individuals, 2 FXI activation by thrombin is likely more relevant for hemostasis. FXIIa-dependent FXI activation, while not required for hemostasis, may contribute to coagulation during the host-response to various inflammatory stimuli.…”

Section: Introductionmentioning

confidence: 99%