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Last update 23 Jan 2025

F5 x F8

Last update 23 Jan 2025

Basic Info

Related Targets

F5F8

Drugs associated with F5 x F8

Drotrecogin alfa(Savara Pharmaceuticals)

Target

F5 x F8

Mechanism

F8 inhibitors [+1]

Active Org.

Savara, Inc.

Originator Org.

Savara, Inc.

Active Indication

Respiratory Distress Syndrome, Newborn

Inactive Indication-

Drug Highest PhaseClinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Drotrecogin alfa (activated)

Target

F5 x F8

Mechanism

F8 inhibitors [+2]

Active Org.-

Originator Org.

Eli Lilly & Co.

Active Indication-

Inactive Indication

Hypotension [+5]

Drug Highest PhaseWithdrawn

First Approval Ctry. / Loc.

First Approval Date21 Nov 2001

Clinical Trials associated with F5 x F8

NL-OMON37362

/ CompletedNot ApplicableIIT

Hypoperfusion and activated protein C after out of hospital cardiac arrest: triggers for hyperfibrinolysis - LYSIS-OHCA

Start Date05 Sep 2012

Sponsor / Collaborator-

NCT01486524

/ Unknown statusNot Applicable

A Multicenter Pharmacogenomic Biomarker Study in Matched Patients With Severe Sepsis Treated With or Without Recombinant Human Activated Protein C [Xigris®, Drotrecogin Alfa (Activated)]

The overall purpose of the study is to determine whether either of the Improved Response Polymorphisms (IRPs) individually predicts a differential DrotAA treatment effect in patients with severe sepsis and high risk of death. This will be an international, multicenter, "prospective-retrospective", nonrandomized, controlled, outcome-blinded, genotype-blinded, matched-patients study. No prospective enrollment or treatment of patients will occur under this protocol. Retrospectively collected clinical data and DNA samples will be analyzed for existing cohorts of patients with severe sepsis who were previously treated with DrotAA (treatment group) or not (control group) as part of their standard care in an ICU.

Start Date01 Oct 2011

Sponsor / Collaborator

Sirius Genomics, Inc.

NL-OMON35983

/ CompletedNot ApplicableIIT

Effect of Intravenous Administration of Recombinant Human Activated Protein C on Local Inflammation and Coagulation after Bronchial Instillation of House Dust Mite Allergen and Lipopolysaccharide in Asthma Patients - ACHILLES study

Start Date28 Sep 2011

Sponsor / Collaborator-

100 Clinical Results associated with F5 x F8

100 Translational Medicine associated with F5 x F8

0 Patents (Medical) associated with F5 x F8

Literatures (Medical) associated with F5 x F8

01 Dec 2024·Zhongguo shi yan xue ye xue za zhi

[The Clinical Phenotype and Molecular Pathogenic Mechanism of a Family with Hereditary Coagulation Factor V Deficiency].

Article

Author: Yang, Lin-Hua ; Wang, Gang ; Guo, Li-Ping ; Dong, Chun-Xia ; Wang, Mei-Fang

OBJECTIVETo investigate the clinical phenotype and molecular pathogenic mechanism of a hereditary coagulation factor V deficiency (FⅤD) family.METHODSA phase I assay was used to measure coagulation factors II, V, VII, VIII, IX, X, Ⅺ, Ⅻ (FⅡ∶C, FⅤ∶C, FⅦ∶C, FⅧ∶C, FⅨ∶C, FⅩ∶C, FⅪ∶C, FⅫ∶C), activated partial thromboplastin time (APTT) and prothrombin time (PT) to determine the clinical phenotype and molecular pathogenesis of F VD. Prothrombin time (PT) were used for phenotypic identification; high-throughput exome sequencing was applied to screen the whole gene variants, and Sanger sequencing was used to verify the suspected variants in F5 gene; MutationTaster, PolyPhen-2 bioinformatics software was used to predict the pathogenicity of the variants, ClustalX software was used to analyze the amino acid conservatism, and PyMol software was used to simulate the model of the mutant protein.RESULTSThe pre-documented patient had significantly prolonged PT and APTT, FⅤ∶C was only 5.45%, and there was no significant abnormality in TT, FIB and the rest of the coagulation factors. The mother, father and sister of the proband had prolonged PT and APTT, and FⅤ∶C was reduced to different degrees. Genetic testing revealed the presence of a c.286G>C (p.Asp96His) pure missense variant in exon 3 of F5 in the prior witness, and a c.286G>C (p.Asp96His) heterozygous missense variant in father, mother, and sister of the proband. Bioinformatics analysis suggested that p.Asp96His was a pathogenic variant, and the associated amino acid site was highly conserved among 10 species. Protein simulation showed that the mutation of Asp96 to His96 could lead to the disappearance of the original hydrogen bond and the change of the distance, destroying the original hydrogen bond interaction force and affecting the stability of the protein structure.CONCLUSIONThe F5 exon 3 c.286G>C (p.Asp96His) missense variant may have contributed to the reduction of FⅤ∶C in the preexisting individual and family members, as well as being the genetic etiology of coagulation factor V deficiency.

01 Jun 2024·Journal of Thrombosis and Haemostasis

A novel factor V compound heterozygous mutation associated with thrombosis (Y1961C; FV-Kanazawa, together with 1982_1983del)

Article

Author: Horie, Kyoji ; Morishita, Eriko ; Nogami, Keiji ; Yoshida, Junko ; Shimonishi, Naruto ; Ogiwara, Kenichi ; Maruyama, Keiko

BACKGROUNDFactor (F)V is pivotal in both procoagulant and anticoagulant mechanisms. The present report describes a novel F5 mutation in a FV-deficient patient (FV activity, 6 IU/dL; FV antigen, 32 IU/dL) complicated by recurrent deep vein thrombosis. The patient demonstrated activated protein C resistance (APCR) with compound heterozygous mutations consisting of FV-Y1961C (FV_Kanazawa) and FV-1982_1983del.OBJECTIVESTo clarify thrombotic mechanisms associated with this FV abnormality.METHODS AND RESULTSLevels of FV-1982_1983del were below the detection sensitivity in our expression experiments using human embryonic kidney 293T cells, and analyses were targeted, therefore, on the FV-Y1961C mutation. Activated partial thromboplastin time-based clotting assays demonstrated that FV-Y1961C exhibited APCR and that the reduced activated protein C (APC) susceptibility in FVa-Y1961C resulted in a marked depression of APC-catalyzed inactivation with delayed cleavage at Arg506 and little cleavage at Arg306 with or without protein S. The APC cofactor activity of FV-Y1961C in APC-catalyzed FVIIIa inactivation promoted by Arg336 cleavage in FVIII was impaired. The binding affinity of FVa-Y1961C to phospholipid membranes was reduced in reactions involving APC/protein S-catalyzed inactivation and in prothrombinase activity. Furthermore, the addition of FVa-Y1961C to plasma failed to inhibit tissue factor-induced procoagulant function. These characteristics were similar to those of FV-W1920R (FV_Nara) and FV-A2086D (FV_Besançon).CONCLUSIONWe identified a compound heterozygous FV-Y1961C mutation in the C1 domain representing a novel FV mutation (FV_Kanazawa) resulting in not only APCR due to impaired FVa susceptibility and FV cofactor activity for APC function but also impaired inhibition of tissue factor-induced procoagulant function. These defects in anticoagulant function associated with FV in FV-Y1961C contributed to a prothrombotic state.

01 Jan 2024·Research and Practice in Thrombosis and Haemostasis

NXT007-mediated hemostatic potential is suppressed by activated protein C-catalyzed inactivation of activated factor V

Article

Author: Kitazawa, Takehisa ; Nogami, Keiji ; Ogiwara, Kenichi ; Nakajima, Yuto ; Inaba, Keito

BackgroundActivated protein C (APC) inactivates activated factor (F) V (FVa) and FVIIIa. NXT007, an emicizumab-based engineered therapeutic bispecific antibody, enhances the coagulation potential of FVIII-deficient plasma (FVIIIdef-plasma) to near normal levels. However, little is known about the effect of APC-induced inactivation in NXT007-mediated hemostatic function.ObjectivesTo investigate the contribution of APC-mediated reactions to NXT007-driven hemostasis.MethodsIn pooled normal plasma (PNP) or FVIIIdef-plasma spiked with NXT007 (10 μg/mL), effects of APC (0-16 nM) were measured using a thrombin generation assay (TGA). The direct effects of APC on cofactor activity of NXT007 or FVIIIa in a FXa generation assay were also measured. The FVdef-plasma and FV Leiden plasma (FV_Leiden plasma) were preincubated with 2 anti-FVIII monoclonal antibodies (termed FVIII-depleted), and the APC effect in the presence of NXT007 in FVIII-depleted FVdef-plasma with the addition of exogenous FV (7.5-30 nM) or FVIII-depleted FV_Leiden plasma was investigated.ResultsThe APC dose-dependent suppression effect in TGA of FVIIIdef-plasma spiked with NXT007 was similar to that of PNP. FXa generation with NXT007 was not impaired by the addition of APC, suggesting that the APC-induced reaction in TGA with NXT007 was attributed to the direct inactivation of FVa. The addition of APC to FVIII-depleted FVdef-plasma, along with NXT007 and various FV concentrations, showed a similar attenuation to PNP. The NXT007-driven thrombin generation in FVIII-depleted FV_Leiden plasma was suppressed by APC, similar to the reaction in native FV_Leiden plasma.ConclusionNXT007 did not impair APC-mediated downregulation of FVa in FVIIIdef-plasmas, regardless of the presence of FV mutation with APC resistance.

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