Factor XII inhibition reduces thrombus formation in a primate thrombosis model

Matafonov, Anton; Leung, Paul; Gailani, Adam E.; Grach, Stephanie L.; Puy, Cristina; Cheng, Qiufang; Sun, Mao-fu; McCarty, Owen J. T.; Tucker, Erik I.; Kataoka, Hiroaki; Renné, Thomas; Morrissey, James H.; Gruber, András; Gailani, David

doi:10.1182/blood-2013-04-499111

Cited by 191 publications

(172 citation statements)

References 52 publications

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“…Monoclonal 15H8 not only protected mice from arterial thrombosis, but also reduced platelet accumulation and fibrin formation in a primate vascular graft occlusion model. 37 Antibody 15H8 inhibited factor XIIa generation, which reduces thrombus formation by decreasing thrombin generation. Interestingly, factor XIa inhibition had a more pronounced effect in these models, which suggests that factor XI might be a superior target for anticoagulation than factor XII.…”

Section: Factor XIImentioning

confidence: 99%

Recent insights into the role of the contact pathway in thrombo-inflammatory disorders

Montfoort

Meijers

2014

Hematology

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The contact pathway of coagulation consists of the proteins factor XI, factor XII, prekallikrein, and high-molecularweight kininogen. Activation of the contact system leads to procoagulant and proinflammatory reactions. The contact system is essential for surface-initiated coagulation, as exemplified by aPTT, but there is probably no role for the contact system in initiating physiologic in vivo coagulation. However, over the last few years, there has been renewed interest, especially because of experimental evidence suggesting that the contact system contributes to thrombosis. Knockout mice deficient in one of the contact proteins were protected against artificially induced thrombosis. Furthermore, inhibiting agents such as monoclonal antibodies, antisense oligonucleotides, and small molecules were found to prevent thrombosis in rodents and primates in both venous and arterial vascular beds. Although it remains to be established whether targeting the contact system will be effective in humans and which of the contact factors is the best target for anticoagulation, it would constitute a promising approach for future effective and safe antithrombotic therapy. Learning Objectives• To understand that the contact system consists of 4 proteins: factor XI, factor XII, PK, and HK • To understand that deficiency of factor XII, PK, or HK is not associated with a bleeding tendency in humans • To understand that targeting the contact system is an effective method to prevent thrombosis in mice •

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Section: Factor XIImentioning

confidence: 99%

Recent insights into the role of the contact pathway in thrombo-inflammatory disorders

Montfoort

Meijers

2014

Hematology

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“…7 The antibody 15H8 blocked thrombosis in mice and baboon. 14 The development of small molecule FXIIa inhibitors has been challenging. The high structural similarity of FXII to numerous homologous trypsin-like serine proteases makes it difficult to generate selective inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Peptide Macrocycle Inhibitor of Coagulation Factor XII with Subnanomolar Affinity and High Target Selectivity

et al. 2017

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Factor XII (FXII) is a plasma protease that has emerged in recent years as a potential target to treat or prevent pathological thrombosis, to inhibit contact activation in extracorporeal circulation, and to treat the swelling disorder hereditary angioedema. While several protein based inhibitors with high affinity for activated FXII (FXIIa) were developed, the generation of small molecule inhibitors has been challenging.In this work, we have generated a potent and selective FXIIa inhibitor by optimizing a peptide macrocycle that was recently evolved by phage display (K i = 0.84 ± 0.03 nM). A fluorine atom introduced in the paraposition of phenylalanine enhanced the binding affinity as much as 10-fold. Furthermore, we improved the proteolytic stability by substituting the N-terminal arginine by norarginine. The resulting inhibitor combines high inhibitory affinity and selectivity with a good stability in plasma (K i = 1.63 ± 0.18 nM, >27,000-fold selectivity, t 1/2 plasma = 16 ± 4 h). The inhibitor efficiently blocked activation of the intrinsic coagulation pathway in human blood ex vivo.

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“…In recent years, however, it has been shown that FXII −/− mice are resistant to experimentally induced thrombosis34, 35 and ischemic brain injury 19. As deficiency of FXII is not associated with abnormal hemorrhaging from injury sites (hemostasis) either in patients or in animals,19, 34 inhibition of activated FXII prevented arterial thrombosis and ischemic brain injury20, 36 without affecting hemostasis 20, 37. Our current study shows that FXII is a promising antithrombotic target for the acute treatment of TBI, without increasing the risk of intracranial hemorrhage.…”

Section: Discussionmentioning

confidence: 99%

Targeting coagulation factor XII as a novel therapeutic option in brain trauma

Hopp

Albert-Weißenberger

Mencl

et al. 2016

Annals of Neurology

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ObjectiveTraumatic brain injury is a major global public health problem for which specific therapeutic interventions are lacking. There is, therefore, a pressing need to identify innovative pathomechanism‐based effective therapies for this condition. Thrombus formation in the cerebral microcirculation has been proposed to contribute to secondary brain damage by causing pericontusional ischemia, but previous studies have failed to harness this finding for therapeutic use. The aim of this study was to obtain preclinical evidence supporting the hypothesis that targeting factor XII prevents thrombus formation and has a beneficial effect on outcome after traumatic brain injury.MethodsWe investigated the impact of genetic deficiency of factor XII and acute inhibition of activated factor XII with a single bolus injection of recombinant human albumin‐fused infestin‐4 (rHA‐Infestin‐4) on trauma‐induced microvascular thrombus formation and the subsequent outcome in 2 mouse models of traumatic brain injury.ResultsOur study showed that both genetic deficiency of factor XII and an inhibition of activated factor XII in mice minimize trauma‐induced microvascular thrombus formation and improve outcome, as reflected by better motor function, reduced brain lesion volume, and diminished neurodegeneration. Administration of human factor XII in factor XII–deficient mice fully restored injury‐induced microvascular thrombus formation and brain damage.InterpretationThe robust protective effect of rHA‐Infestin‐4 points to a novel treatment option that can decrease ischemic injury after traumatic brain injury without increasing bleeding tendencies. Ann Neurol 2016;79:970–982

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Factor XII inhibition reduces thrombus formation in a primate thrombosis model

Cited by 191 publications

References 52 publications

Recent insights into the role of the contact pathway in thrombo-inflammatory disorders

Recent insights into the role of the contact pathway in thrombo-inflammatory disorders

Peptide Macrocycle Inhibitor of Coagulation Factor XII with Subnanomolar Affinity and High Target Selectivity

Targeting coagulation factor XII as a novel therapeutic option in brain trauma

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