factor viia
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2022 ◽  
Vol 2022 ◽  
pp. 1-10
Author(s):  
Zhenzhen Wang ◽  
Yating Mou ◽  
Hao Li ◽  
Rui Yang ◽  
Yanxun Jia

Cerebral haemorrhage is a serious subtype of stroke, with most patients experiencing short-term haematoma enlargement leading to worsening neurological symptoms and death. The main hemostatic agents currently used for cerebral haemorrhage are antifibrinolytics and recombinant coagulation factor VIIa. However, there is no clinical evidence that patients with cerebral haemorrhage can benefit from hemostatic treatment. We provide an overview of the mechanisms of haematoma expansion in cerebral haemorrhage and the progress of research on commonly used hemostatic drugs. To improve the semantic segmentation accuracy of cerebral haemorrhage, a segmentation method based on RGB-D images is proposed. Firstly, the parallax map was obtained based on a semiglobal stereo matching algorithm and fused with RGB images to form a four-channel RGB-D image to build a sample library. Secondly, the networks were trained with 2 different learning rate adjustment strategies for 2 different structures of convolutional neural networks. Finally, the trained networks were tested and compared for analysis. The 146 head CT images from the Chinese intracranial haemorrhage image database were divided into a training set and a test set using the random number table method. The validation set was divided into four methods: manual segmentation, algorithmic segmentation, the exact Tada formula, and the traditional Tada formula to measure the haematoma volume. The manual segmentation was used as the “gold standard,” and the other three algorithms were tested for consistency. The results showed that the algorithmic segmentation had the lowest percentage error of 15.54 (8.41, 23.18) % compared to the Tada formula method.


2021 ◽  
Vol 23 (1) ◽  
pp. 358
Author(s):  
Stefano Navarro ◽  
David Stegner ◽  
Bernhard Nieswandt ◽  
Johan W. M. Heemskerk ◽  
Marijke J. E. Kuijpers

In hemostasis and thrombosis, the complex process of thrombus formation involves different molecular pathways of platelet and coagulation activation. These pathways are considered as operating together at the same time, but this has not been investigated. The objective of our study was to elucidate the time-dependency of key pathways of thrombus and clot formation, initiated by collagen and tissue factor surfaces, where coagulation is triggered via the extrinsic route. Therefore, we adapted a microfluidics whole-blood assay with the Maastricht flow chamber to acutely block molecular pathways by pharmacological intervention at desired time points. Application of the technique revealed crucial roles of glycoprotein VI (GPVI)-induced platelet signaling via Syk kinase as well as factor VIIa-induced thrombin generation, which were confined to the first minutes of thrombus buildup. A novel anti-GPVI Fab EMF-1 was used for this purpose. In addition, platelet activation with the protease-activating receptors 1/4 (PAR1/4) and integrin αIIbβ3 appeared to be prolongedly active and extended to later stages of thrombus and clot formation. This work thereby revealed a more persistent contribution of thrombin receptor-induced platelet activation than of collagen receptor-induced platelet activation to the thrombotic process.


Author(s):  
Revathi Raman ◽  
Weam Fallatah ◽  
Ayah Al Qaryoute ◽  
Mia Ryon ◽  
Pudur Jagadeeswaran

Tissue Factor Pathway Inhibitor (TFPI) is an anticoagulant that inhibits factor VIIa and Xa in the blood coagulation pathways. TFPI contains three Kunitz domains, K1, K2, and K3. K1 and K2 inhibit factor VIIa and Xa, respectively. However, the regulation of TFPI is poorly studied. Since zebrafish has become an alternate model to discover novel actors in hemostasis, we hypothesized that TFPI regulation could be studied using this model. As a first step, we confirmed the presence of tfpia in zebrafish using RT-PCR. We then performed piggyback knockdowns of tfpia and found increased coagulation activity in tfpia knockdown. We then created a deletion mutation in tfpia locus using CRISPR/Cas9 method. The tfpia homozygous deletion mutants showed increased coagulation activities similar to that found in tfpia knockdown. Taken together, our data suggest that tfpia is a negative regulator for zebrafish coagulation, and silencing it leads to thrombotic phenotype. Also, the zebrafish tfpia knockout model could be used for reversing this thrombotic phenotype to identify antithrombotic novel factors by the genome-wide piggyback knockdown method.


Author(s):  
Alexandre Bridoux ◽  
Shaker A. Mousa

Background: As an alternative to the anticoagulant’s strategy using direct or indirect anti-Xa drugs, considering other targets upstream in the coagulation cascade such as anti-Factor VIIa could represent an effective and safer strategy in coagulation and pathological angiogenesis. Objective: The objective of the study was to assess a high technology methodology composed of virtual screening, anticoagulant, and anti-angiogenesis assays to identify potent small-molecule FVIIa inhibitors. Methods: Chemical databanks were screened to select molecules bearing functional groups that could fit into the active site of FVIIa, which were then tested. Ligands assigned with the lowest scores were retained and then biologically assessed. Results: From the 500 molecules considered, 8 chemical structures revealed to be effective compounds in vitro and to inhibit angiogenesis in the chick chorioallantoic membrane (CAM) model. Conclusion: New potent small-molecule FVIIa inhibitors have been identified; further biochemical and chemical developments would be investigated directly from the selected scaffolds.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4246-4246
Author(s):  
Glaivy Batsuli ◽  
Duc Quang Tran ◽  
Guy Young ◽  
Robert F. Sidonio

Abstract Introduction: Activated prothrombin complex concentrate (FEIBA, Takeda) and recombinant factor VIIa (rFVIIa, Novoseven, NovoNordisk) remain the primary bypassing agents (BPA) available for bleeding management in patients with hemophilia and inhibitors. Eptacog beta [rFVIIa-B, Coagulation factor VIIa (recombinant)-jncw, Sevenfact, HEMA Biologics & LFB] is a recombinant human FVIIa approved by the FDA in 2020 for the treatment of acute bleeding events in adult and adolescent patients ≥12 years old with hemophilia A or B with inhibitors. rFVIIa-B demonstrated hemostatic efficacy of 86% in a phase 3, randomized cross-over study of 465 mild/moderate bleeding events in 27 patients with hemophilia A and B with inhibitors. The purpose of this study is to report real-world data on the hemostatic efficacy of rFVIIa-B for acute bleeding management in patients with hemophilia A and B with inhibitors. Methods: This is a retrospective chart-review of individuals ≥12 years of age with severe hemophilia A (factor VIII <1%) or hemophilia B (factor IX <1%) with an active inhibitor from 3 U.S. hemophilia treatment centers who utilized rFVIIa-B for acute bleed management. Results: Seven bleeds were treated among the 3 patients identified. Patient characteristics and bleeding events are summarized in Table 1. The 3 patients were 12, 13, and 31 years of age. Two patients had hemophilia A and 1 patient had hemophilia B. The 2 patients with hemophilia A were on emicizumab prophylaxis per standard dosing regimens for bleeding prevention. The individual patient with hemophilia B had a history of anaphylaxis at inhibitor development and received on-demand BPA for acute bleeding events. All 7 bleeds consisted of hemarthroses with the knee being the primary site in 57% of the bleeds. Five of the 7 bleeds (71%) received a severe bleeding dose of 210-225 microgram per kilogram (mcg/kg) for the initial rFVIIa-B dose followed by 70-75 mcg/kg for subsequent doses. Final dosing regimens were dependent on available vial sizes. rFVIIa-B resulted in complete resolution of all bleeds (100%) at a median of 4 doses (range 1-8 doses) and a median of 24 hours (range 3-48 hours). There were no failures in bleeding resolution following treatment. No adverse events with infusions were reported including infusion-related reactions, hypersensitivity reactions, thrombosis, or thrombotic microangiopathy. Conclusions: Administration of rFVIIa-B in the real-world setting appears to demonstrate hemostatic efficacy in a cohort of pediatric and adult patients with hemophilia A and B with inhibitors and may serve as an alternative human rFVIIa therapy for the management of acute bleeds in this population. Further post-marketing studies are warranted to expand the indication to younger children (<12 years of age) and to continue to monitor drug efficacy and adverse events in a larger population of patients over time including individuals on non-factor therapies such as emicizumab. Figure 1 Figure 1. Disclosures Batsuli: Bio Product Laboratory: Honoraria; Kedrion: Honoraria. Tran: HEMA Biologics: Honoraria. Young: Apcintex, BioMarin, Genentech/Roche, Grifols, Novo Nordisk, Pfizer, Rani, Sanofi Genzyme, Spark, Takeda, and UniQure: Consultancy; Genentech/Roche, Grifols, and Takeda: Research Funding. Sidonio: Guardian Therapeutics: Consultancy; Octapharma: Consultancy, Research Funding; Catalyst: Consultancy; Pfizer: Consultancy; Takeda: Consultancy, Research Funding; Biomarin: Consultancy; Novo Nordisk: Consultancy; Bayer: Consultancy; Genentech: Consultancy, Research Funding.


PLoS ONE ◽  
2021 ◽  
Vol 16 (10) ◽  
pp. e0258192
Author(s):  
Subhajit Ghosh ◽  
Wilfred Krege ◽  
Baerbel Doerr ◽  
Marcel Mischnik ◽  
Ingo Pragst ◽  
...  

Objectives Acquired coagulopathy may be associated with bleeding risk. Approaches to restore haemostasis include administration of coagulation factor concentrates, but there are concerns regarding potential prothrombotic risk. The present study assessed the prothrombotic potential of four-factor prothrombin complex concentrate (4F-PCC) versus activated PCC (aPCC) and recombinant factor VIIa (rFVIIa), using three preclinical animal models. Methods The first model was a modified Wessler model of venous stasis-induced thrombosis in rabbit, focusing on dilutional coagulopathy; the second model employed the same system but focused on direct oral anticoagulant reversal (i.e. edoxaban). The third model assessed the prothrombotic impact of 4F-PCC, aPCC and rFVIIa in a rat model of ferric chloride-induced arterial thrombosis. Results In the first model, thrombi were observed at aPCC doses ≥10 IU/kg (therapeutic dose 100 IU/kg) and rFVIIa doses ≥50 μg/kg (therapeutic dose 90 μg/kg), but not 4F-PCC 50 IU/kg (therapeutic dose 50 IU/kg). The impact of 4F-PCC (up to 300 IU/kg) on thrombus formation was evident from 10 minutes post-administration, but not at 24 hours post-administration; this did not change with addition of tranexamic acid and/or fibrinogen concentrate. 4F-PCC-induced thrombus formation was lower after haemodilution versus non-haemodilution. In the second model, no prothrombotic effect was confirmed at 4F-PCC 50 IU/kg. The third model showed lower incidence of thrombus formation for 4F-PCC 50 IU/kg versus aPCC (50 U/kg) and rFVIIa (90 μg/kg). Conclusions These results suggest that 4F-PCC has a low thrombotic potential versus aPCC or rFVIIa, supporting the clinical use of 4F-PCC for the treatment of coagulopathy-mediated bleeding.


2021 ◽  
Vol 12 ◽  
Author(s):  
Hyejin Joo ◽  
Jinhyun Bae ◽  
Jae-Woo Park ◽  
Beom-Joon Lee ◽  
Byoung Dae Lee ◽  
...  

To date, many studies using the controlled cortical impact (CCI) mouse model of traumatic brain injury (TBI) have presented results without presenting the pathophysiology of the injury-core itself or the temporal features of hemorrhage (Hrr). This might be owing to the removal of the injury-core during the histological procedure. We therefore developed a modified protocol to preserve the injury-core. The heads of mice were obtained after perfusion and were post-fixed. The brains were then harvested, retaining the ipsilateral skull bone; these were post-fixed again and sliced using a cryocut. To validate the utility of the procedure, the temporal pattern of Hrr depending on the impacting depth was analyzed. CCI-TBI was induced at the following depths: 1.5 mm (mild Hrr), 2.5 mm (moderate Hrr), and 3.5 mm (severe Hrr). A pharmacological study was also conducted using hemodynamic agents such as warfarin (2 mg/kg) and coagulation factor VIIa (Coa-VIIa, 1 mg/kg). The current protocol enabled the visual observation of the Hrr until 7 days. Hrr peaked at 1–3 days and then decreased to the normal range on the seventh day. It expanded from the affected cortex (mild) to the periphery of the hippocampus (moderate) and the brain ventricle (severe). Pharmacological studies showed that warfarin pre-treatment produced a massively increased Hrr, concurrent with the highest mortality rate and brain injury. Coa-VIIa reduced the side effects of warfarin. Therefore, these results suggest that the current method might be suitable to conduct studies on hemorrhage, hematoma, and the injury-core in experiments using the CCI-TBI mouse model.


Blood ◽  
2021 ◽  
Author(s):  
Kaushik Das ◽  
Shiva Keshava ◽  
Usha R. Pendurthi ◽  
L. Vijaya Mohan Rao

Coagulation protease, factor VIIa (FVIIa) binds endothelial cell protein C receptor (EPCR) and induces anti-inflammatory and endothelial barrier protective responses via protease-activated receptor-1 (PAR1)-mediated biased signaling. Our recent studies showed that the FVIIa-EPCR-PAR1 axis induces the release of extracellular vesicles (EVs) from endothelial cells. The present study investigates the mechanism of FVIIa release of endothelial EVs (EEVs) and the contribution of FVIIa-released EEVs to anti-inflammatory and vascular barrier protective effects both in vitro and in vivo models. Data presented in the manuscript show multiple signaling pathways regulate FVIIa release of EVs from endothelial cells, but the ROCK-dependent pathway appears to be a major mechanism. FVIIa-released EEVs are enriched with anti-inflammatory micro RNAs, mostly miR10a. FVIIa-released EEVs were taken up readily by monocytes/macrophages and endothelial cells. The uptake of FVIIa-released EEVs by monocytes conferred anti-inflammatory phenotype to monocytes, whereas EEVs uptake by endothelial cells resulted in barrier protection. Additional studies showed that EEVs-mediated delivery of miR10a to monocytes downregulates the expression of TAK1 and activation of the NF-ĸB-mediated inflammatory pathway. In vivo studies showed that administering FVIIa-released EEVs to wild-type mice attenuated LPS-induced increased inflammatory cytokines in plasma and vascular leakage into vital tissues. The incorporation of anti-miR10a into FVIIa-released EEVs diminished the ability of FVIIa-released EEVs to confer cytoprotective effects. Administration of ROCK inhibitor Y27632 to mice, which significantly inhibits FVIIa release of EEVs into circulation, attenuates the cytoprotective effects of FVIIa. Overall, our present study reveals novel insights into how FVIIa induces cytoprotective effects and communicates with various cell types.


2021 ◽  
pp. 174749302110427
Author(s):  
Andrew Naidech ◽  
James C Grotta ◽  
Jordan Elm ◽  
Scott Janis ◽  
Dar Dowlatshahi ◽  
...  

Introduction: Intracerebral hemhaemorrhage (ICH) is the deadliest form of stroke. HemHaematoma expansion (HE), growth of the hemhaematoma between the baseline computed tomography (CT) scan and a follow-up CT scan at 24±6 hours, predicts long-term disability or death. Recombinant Factor VIIa (rFVIIa) has reduced HE in previous clinical trials with a variable effect on clinical outcomes, with the greatest impact on HE and potential benefit when administered within two hours of symptom onset. Methods: Factor VIIa for HemHaemorrhagic Stroke Treatment at Earliest Possible Time (FASTEST, NCT03496883) is a randomized controlled trial that will enroll 860 patients at ~100 emergency departments and mobile stroke units in five countries. Patients are eligible for enrollment if they have acute ICH within two hours of symptom onset confirmed by CT, a hemhaematoma volume of 2 to 60 mL, no or small volumes of intraventricular hemhaemorrhage, do not take anticoagulant medications or concurrent heparin/heparinoids (antiplatelet medications are permissible), and are not deeply comatose. Enrolled patients will receive rFVIIa 80 mcg/kg or placebo intravenously over 2 minutes. The primary outcome measure is the distribution of the ordinal modified Rankin Scale at 180 days. FASTEST is monitored by a Data Safety Monitoring Board. Safety endpoints include thrombotic events (e.g., myocardial infarction). Human subjects research is monitored by an external Institutional Review Board in participating countries. Discussion: In the US, FASTEST will be first NIH StrokeNet Trial with an Exception from Informed Consent which allows enrollment of non-communicative patients without an immediately identifiable proxy.


2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Elizabeth Cotter ◽  
Akshit Sharma ◽  
Alice Campton ◽  
Guangyi Gao ◽  
Jianghua He ◽  
...  

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