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

Hopp, Sarah C.; Albert-Weißenberger, Christiane; Mencl, Stine; Bieber, Michael; Schuhmann, Michael K.; Stetter, Christian; Nieswandt, Bernhard; Schmidt, P; Monoranu, Camelia‐Maria; Alafuzoff, Irina; Marklund, Niklas; Nolte, Marc W.; Sirén, Anna‐Leena; Kleinschnitz, Christoph

doi:10.1002/ana.24655

Cited by 31 publications

(35 citation statements)

References 44 publications

(116 reference statements)

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“…In previous works, a deleterious role was attributed to circulating FXII in models of cerebral ischemia 7 and brain trauma 8 , in which thrombosis is respectively a primary or a secondary cause of brain damage. In contrast, FXII turned out to be neuroprotective in the brain lesion model used here, where thrombosis plays very limited if any role in the development of lesions.…”

Section: Discussionmentioning

confidence: 98%

“…Indeed, the growth factor-like effects of tPA (produced by brain cells or exogenously administered) have been shown to induce protection to brain cells in several in vivo animal models of brain injury 10,18,28,29 independently of its effect in the circulation. Several studies in animal models of brain diseases have reported deleterious effects of FXII 8,30,31,32 . Noteworthy, these deleterious effects are attributed to pro-thrombotic or pro-in ammatory effects of FXII.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have shown that circulating FXII can exert detrimental effects in cerebral ischemia 7 and traumatic brain injury 8 by promoting thrombo-in ammation. Nevertheless, the question remains open whether FXII may directly impact neuronal cell fate within the brain parenchyma, independently of its intravascular effects.…”

Section: Introductionmentioning

confidence: 99%

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Coagulation Factor XII protects neurons from apoptosis by triggering a crosstalk between HGFR/c-Met and EGFR/ErbB1 signaling pathways

Garnier¹,

Levard²,

Ali³

et al. 2020

Preprint

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Background Factor XII (FXII) is a serine protease that participates in the intrinsic coagulation pathway. Several studies have shown that plasmatic FXII exert a deleterious role in cerebral ischemia and traumatic brain injury by promoting thrombo-inflammation. Nevertheless, the direct impact of FXII on neuronal cell fate remains unknown.Methods We investigated whether FXII influenced neuronal death induced in vivo by stereotaxic injection of N-methyl-D-Aspartate (NMDA) and in vitro by serum deprivation of cultured neurons.Results We found that FXII reduced brain lesions induced in vivo and protected cultured neurons from apoptosis through a growth factor-like effect. This mechanism was triggered by direct interaction with epidermal growth factor (EGF) receptor, activation of this receptor and engagement of anti-apoptotic intracellular pathways. Interestingly, the “proteolytically” active and two-chain form of FXII, αFXIIa, exerted additional protective effects by converting the pro-form of hepatocyte growth factor (HGF) into its mature form, which in turn activated HGF receptor (HGFR/c-Met) pathway. Lastly, the use of non-proteolytic FXII (αFXIIa-PPACK) unveiled an alternative EGFR and HGFR co-activation pathway, through co-receptor transphosphorylation. Conclusion This study describes novel mechanisms of action of FXII and discloses neurons as target cells for the protective effects of single and double-chain forms of FXII.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

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Coagulation Factor XII protects neurons from apoptosis by triggering a crosstalk between HGFR/c-Met and EGFR/ErbB1 signaling pathways

Garnier¹,

Levard²,

Ali³

et al. 2020

Preprint

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“…This effect was due to impaired pathological fibrin formation after FXII inhibition without increased bleeding (Kleinschnitz et al, 2006). Additionally, minimized trauma-induced microvascular thrombus formation and ischemic injury with factor XII inhibitor rHA-Infestin-4 in mice signify the thromboprotective effect of FXII inhibition (Hopp et al, 2016) (Oldgren et al, 2011) Dabigatran 50 mg (n = 369), 75 mg (n = 368), 110 mg (n = 406), 150 mg (n = 347), or placebo (n = 371).…”

Section: Factor XII Inhibitionmentioning

confidence: 99%

Factors IX, XI, and XII: potential therapeutic targets for anticoagulant therapy in atherothrombosis

Rai

2019

Reviews in Cardiovascular Medicine

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Atherosclerosis is a leading cause of cardiovascular and neurological ischemic events. Plaque rupture leads to the exposure of highly thrombogenic material with blood and results in the activation of the coagulation cascade, thrombus formation, and embolic events. Although antiplatelets and anticoagulants are used to prevent thromboembolic episodes, bleeding episodes remain the major adverse effect. Decreased ischemic events have been reported while comparing oral rivaroxaban and apixaban with aspirin to improve the therapeutic outcome in several clinical trials, including Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 51, Apixaban for Prevention of Acute Ischemic and Safety Events, and GEMINI-ACS-1 phase II clinical trials. However, there were bleeding episodes. Thus, there is an unmet need for better therapeutic strategies. Therefore, the current focus is to target Factors IX, XI, and XII to develop safer and efficient strategies. In this article, we critically reviewed and discussed the limitations of current therapies and the potential of targeting Factors IX, XI, and XII for anticoagulant therapy in atherothrombosis.

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“…Emerging studies also suggest that FXII is a key mediator in host defense and additional immuneinflammatory responses, via its downstream kallikrein/kinin system (Schmaier, 2016) and interactions with endothelial and immune cells (Göbel et al, 2016;Long et al, 2016). FXII is thus a promising target for treating not only thrombotic events but also a range of other disorders (Martini et al, 2014;Göbel et al, 2016;Hopp et al, 2016;Nickel et al, 2016;Zamolodchikov et al, 2016) without conferring a bleeding risk.…”

Section: Introductionmentioning

confidence: 99%

Factor XIIa as a Novel Target for Thrombosis: Target Engagement Requirement and Efficacy in a Rabbit Model of Microembolic Signals

Barbieri

Wang

et al. 2016

J Pharmacol Exp Ther

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Coagulation Factor XII (FXII) plays a critical role in thrombosis. What is unclear is the level of enzyme occupancy of FXIIa that is needed for efficacy and the impact of FXIIa inhibition on cerebral embolism. A selective activated FXII (FXIIa) inhibitor, recombinant human albumin-tagged mutant Infestin-4 (rHA-Mut-inf), was generated to address these questions. rHA-Mut-inf displayed potency comparable to the original wild-type HA-Infestin-4 (human FXIIa inhibition constant = 0.07 and 0.12 nM, respectively), with markedly improved selectivity against Factor Xa (FXa) and plasmin. rHA-Mut-inf binds FXIIa, but not FXII zymogen, and competitively inhibits FXIIa protease activity. Its mode of action is hence akin to typical small-molecule inhibitors. Plasma shift and aPTT studies with rHA-Mut-inf demonstrated that calculated enzyme occupancy for FXIIa in achieving a putative aPTT doubling target in human, nonhuman primate, and rabbit is more than 99.0%. The effects of rHA-Mut-inf in carotid arterial thrombosis and microembolic signal (MES) in middle cerebral artery were assessed simultaneously in rabbits. Dose-dependent inhibition was observed for both arterial thrombosis and MES. The ED of thrombus formation was 0.17 mg/kg i.v. rHA-Mut-inf for the integrated blood flow and 0.16 mg/kg for thrombus weight; the ED for MES was 0.06 mg/kg. Ex vivo aPTT tracked with efficacy. In summary, our findings demonstrated that very high enzyme occupancy will be required for FXIIa active site inhibitors, highlighting the high potency and exquisite selectivity necessary for achieving efficacy in humans. Our MES studies suggest that targeting FXIIa may offer a promising strategy for stroke prevention associated with thromboembolic events.

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

Cited by 31 publications

References 44 publications

Coagulation Factor XII protects neurons from apoptosis by triggering a crosstalk between HGFR/c-Met and EGFR/ErbB1 signaling pathways

Coagulation Factor XII protects neurons from apoptosis by triggering a crosstalk between HGFR/c-Met and EGFR/ErbB1 signaling pathways

Factors IX, XI, and XII: potential therapeutic targets for anticoagulant therapy in atherothrombosis

Factor XIIa as a Novel Target for Thrombosis: Target Engagement Requirement and Efficacy in a Rabbit Model of Microembolic Signals

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