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Australian Family Physician Jul 2014There have been rapid advances in genetics in recent years. DNA tests available on the Medicare Benefits Schedule (MBS) include HFE (haemochromatosis), Fragile X... (Review)
Review
There have been rapid advances in genetics in recent years. DNA tests available on the Medicare Benefits Schedule (MBS) include HFE (haemochromatosis), Fragile X syndrome and Factor V Leiden.
Topics: Factor V; Genetic Testing; Hemochromatosis; Humans
PubMed: 25006599
DOI: No ID Found -
Blood Jun 2021
Topics: Factor V; Factor Va
PubMed: 34081120
DOI: 10.1182/blood.2021011573 -
Archives of Pathology & Laboratory... Dec 2017Historically, inhibitors to coagulation factor V (FV) most often have developed in patients treated with bovine thrombin, a topical hemostatic agent used during surgical... (Review)
Review
Historically, inhibitors to coagulation factor V (FV) most often have developed in patients treated with bovine thrombin, a topical hemostatic agent used during surgical procedures. With the advent of newer hemostatic agents, and the concurrent diminished use of bovine thrombin, the incidence of FV inhibitors has fallen. Nevertheless, FV inhibitors are occasionally seen on an idiopathic basis as well as in association with medications, malignancies, autoimmune disorders, pregnancy, and infections. Factor V inhibitors may present with life-threatening bleeding or thrombosis, or they may be discovered incidentally as a coagulation screening test abnormality. Management of patients with FV inhibitors is challenging and consists of control of bleeding and eradication of the inhibitor. In this short overview we review the role of platelet and plasma FV in hemostasis and discuss the unique characteristics, clinical features, diagnosis, treatment, and prognosis associated with FV inhibitors.
Topics: Animals; Autoantibodies; Cattle; Diagnosis, Differential; Factor V; Female; Hemorrhage; Hemostatics; Humans; Pregnancy; Thrombin
PubMed: 29189062
DOI: 10.5858/arpa.2016-0445-RS -
Vascular Medicine (London, England) Apr 2015
Review
Topics: Factor V; Fibrinolytic Agents; Hemostasis; Humans; Thromboembolism; Thrombophilia
PubMed: 25832606
DOI: 10.1177/1358863X15575769 -
Blood Advances Jun 2023Factor V (FV) plays pivotal roles in both procoagulant and anticoagulant mechanisms. Genetic mutations, FV-W1920R (FVNara) and FV-A2086D (FVBesançon), in the C1 and C2...
Factor V (FV) plays pivotal roles in both procoagulant and anticoagulant mechanisms. Genetic mutations, FV-W1920R (FVNara) and FV-A2086D (FVBesançon), in the C1 and C2 domains of FV light chain, respectively, seem to be associated with deep vein thrombosis. However, the detailed mechanism(s) through which these mutations are linked to thrombophilia remains to be fully explored. The aim of this study was to clarify thrombotic mechanism(s) in the presence of these FV abnormalities. Full-length wild-type (WT) and mutated FV were prepared using stable, human cell lines (HEK293T) and the piggyBac transposon system. Susceptibility of FVa-A2086D to activated protein C (APC) was reduced, resulting in significant inhibition of APC-catalyzed inactivation with limited cleavage at Arg306 and delayed cleavage at Arg506. Furthermore, APC cofactor activity of FV-A2086D in APC-catalyzed inactivation of FVIIIa through cleavage at Arg336 was impaired. Surface plasmon resonance-based assays demonstrated that FV-A2086D bound to Glu-Gly-Arg-chloromethylketone active site-blocked APC and protein S (P) with similar affinities to that of FV-WT. However, weakened interaction between FVa-A2086D and phospholipid membranes was evident through the prothrombinase assay. Moreover, addition of FVa-A2086D to plasma failed to inhibit tissue factor (TF)-induced thrombin generation and reduce prothrombin times. This inhibitory effect was independent of PC, PS, and antithrombin. The coagulant and anticoagulant characteristics of FV(a)-W1920R were similar to those of FV(a)-A2086D. FV-A2086D presented defects in the APC mechanisms associated with FVa inactivation and FV cofactor activity, similar to FV-W1920R. Moreover, both FV proteins that were mutated in the light chain impaired inhibition of TF-induced coagulation reactions. These defects were consistent with congenital thrombophilia.
Topics: Humans; Factor V; Anticoagulants; HEK293 Cells; Mutation; Thrombophilia; Thromboplastin; Venous Thrombosis
PubMed: 36780344
DOI: 10.1182/bloodadvances.2022008918 -
Cells Nov 2023Statins are powerful lipid-lowering drugs that inhibit cholesterol biosynthesis via downregulation of hydroxymethylglutaryl coenzyme-A reductase, which are largely used... (Review)
Review
Statins are powerful lipid-lowering drugs that inhibit cholesterol biosynthesis via downregulation of hydroxymethylglutaryl coenzyme-A reductase, which are largely used in patients with or at risk of cardiovascular disease. Available data on thromboembolic disease include primary and secondary prevention as well as bleeding and mortality rates in statin users during anticoagulation for VTE. Experimental studies indicate that statins alter blood clotting at various levels. Statins produce anticoagulant effects via downregulation of tissue factor expression and enhanced endothelial thrombomodulin expression resulting in reduced thrombin generation. Statins impair fibrinogen cleavage and reduce thrombin generation. A reduction of factor V and factor XIII activation has been observed in patients treated with statins. It is postulated that the mechanisms involved are downregulation of factor V and activated factor V, modulation of the protein C pathway and alteration of the tissue factor pathway inhibitor. Clinical and experimental studies have shown that statins exert antiplatelet effects through early and delayed inhibition of platelet activation, adhesion and aggregation. It has been postulated that statin-induced anticoagulant effects can explain, at least partially, a reduction in primary and secondary VTE and death. Evidence supporting the use of statins for prevention of arterial thrombosis-related cardiovascular events is robust, but their role in VTE remains to be further elucidated. In this review, we present biological evidence and experimental data supporting the ability of statins to directly interfere with the clotting system.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Thrombin; Venous Thromboembolism; Factor V; Blood Coagulation; Thrombosis; Anticoagulants
PubMed: 38067146
DOI: 10.3390/cells12232719 -
The Journal of Biological Chemistry 2021Coagulation factor V (FV) plays an anticoagulant role but serves as a procoagulant cofactor in the prothrombinase complex once activated to FVa. At the heart of these...
Coagulation factor V (FV) plays an anticoagulant role but serves as a procoagulant cofactor in the prothrombinase complex once activated to FVa. At the heart of these opposing effects is the proteolytic removal of its central B-domain, including conserved functional landmarks (basic region, BR; 963-1008 and acidic region 2, AR2; 1493-1537) that enforce the inactive FV procofactor state. Tissue factor pathway inhibitor α (TFPIα) has been associated with FV as well as FV-short, a physiologically relevant isoform with a shortened B-domain missing the BR. However, it is unclear which forms of FV are physiologic ligands for TFPIα. Here, we characterize the binding and regulation of FV and FV-short by TFPIα via its positively charged C-terminus (TFPIα-BR) and examine how bond cleavage in the B-domain influences these interactions. We show that FV-short is constitutively active and functions in prothrombinase like FVa. Unlike FVa, FV-short binds with high affinity (K ∼1 nM) to TFPIα-BR, which blocks procoagulant function unless FV-short is cleaved at Arg, removing AR2. Importantly, we do not observe FV binding (μM detection limit) to TFPIα. However, cleavage at Arg and Arg displaces the FV BR, exposing AR2 and allowing TFPIα to bind via its BR. We conclude that for full-length FV, the detachment of FV BR from AR2 is necessary and sufficient for TFPIα binding and regulation. Our findings pinpoint key forms of FV, including FV-short, that act as physiologic ligands for TFPIα and establish a mechanistic framework for assessing the functional connection between these proteins.
Topics: Blood Coagulation; Factor V; Factor Va; Factor Xa; Humans; Ligands; Lipoproteins; Protein Binding; Protein Domains; Proteolysis; Thrombin; Thromboplastin
PubMed: 33376137
DOI: 10.1074/jbc.RA120.016341 -
Genes Jun 2022Recurrent pregnancy loss (RPL) is defined as the loss of two or more pregnancies, affecting approximately 1 to 3% of women worldwide. Scientific data highlight a...
Recurrent pregnancy loss (RPL) is defined as the loss of two or more pregnancies, affecting approximately 1 to 3% of women worldwide. Scientific data highlight a possible correlation between thrombophilic genetic variants and RPL. H1299R variant in the factor V gene would lead to an increased thrombotic risk associated with frequent miscarriages. However, the data are often conflicting, making this an interesting question for further investigations by evaluating genotype-phenotype correlations to improve the clinical management and genetic counseling of couples. A systematic review and meta-analysis will follow the preferred reporting elements for systematic review and meta-analysis protocols (PRISMA-P). The Pubmed (MEDLINE) and Embase (OVID) databases will be explored to identify suitable articles based on inclusion and exclusion criteria. Inclusion criteria are: (a) H1299R genotyping with clear data reported, referred to as Heterozygous (Het) and/or Homozygous (Hom); (b) articles written in English; (c) analyses of only RPL female patients having at least two or more previous pregnancy losses and compared with a control group. This analysis will present selected scientific evidence, addressing the questions concerning the association between the H1299R variant and RPL, hoping to clarify this still unresolved issue. PROSPERO registration number: CRD42022330077.
Topics: Female; Humans; Pregnancy; Abortion, Habitual; Factor V; Meta-Analysis as Topic; Thrombophilia; Systematic Reviews as Topic
PubMed: 35741781
DOI: 10.3390/genes13061019 -
International Journal of Molecular... May 2022Factor V deficiency, an ultra-rare congenital coagulopathy, is characterized by bleeding episodes that may be more or less intense as a function of the levels of...
Factor V deficiency, an ultra-rare congenital coagulopathy, is characterized by bleeding episodes that may be more or less intense as a function of the levels of coagulation factor activity present in plasma. Fresh-frozen plasma, often used to treat patients with factor V deficiency, is a scarcely effective palliative therapy with no specificity to the disease. CRISPR/Cas9-mediated gene editing, following precise deletion by non-homologous end-joining, has proven to be highly effective for modeling on a HepG2 cell line a mutation similar to the one detected in the factor V-deficient patient analyzed in this study, thus simulating the pathological phenotype. Additional CRISPR/Cas9-driven non-homologous end-joining precision deletion steps allowed correction of 41% of the factor V gene mutated cells, giving rise to a newly developed functional protein. Taking into account the plasma concentrations corresponding to the different levels of severity of factor V deficiency, it may be argued that the correction achieved in this study could, in ideal conditions, be sufficient to turn a severe phenotype into a mild or asymptomatic one.
Topics: CRISPR-Cas Systems; Factor V; Factor V Deficiency; Gene Editing; Humans; Mutation
PubMed: 35628611
DOI: 10.3390/ijms23105802 -
Journal of Thrombosis and Haemostasis :... Mar 2022The factor V east Texas bleeding disorder (FVETBD) is caused by increased plasma tissue factor pathway inhibitor-α (TFPIα) concentration. The underlying cause is a...
BACKGROUND
The factor V east Texas bleeding disorder (FVETBD) is caused by increased plasma tissue factor pathway inhibitor-α (TFPIα) concentration. The underlying cause is a variant in F5 causing alternative splicing within exon 13 and producing FV-short, which tightly binds the C-terminus of TFPIα, prolonging its circulatory half-life.
OBJECTIVES
To diagnose a family presenting with variable bleeding and laboratory phenotypes.
PATIENTS/METHODS
Samples were obtained from 17 family members for F5 exon 13 sequencing. Plasma/platelet TFPI and platelet FV were measured by ELISA and/or western blot. Plasma thrombin generation potential was evaluated using calibrated automated thrombography.
RESULTS
The FVET variant was identified in all family members with bleeding symptoms and associated with elevated plasma TFPIα (4.5- to 13.4-fold) and total TFPI (2- to 3-fold). However, TFPIα and FV-short were not elevated in platelets. TF-initiated thrombin generation in patient plasma was diminished but was restored by a monoclonal anti-TFPI antibody or factor VIIa. TFPIα localized within vascular extracellular matrix in an oral lesion biopsy from an affected family member.
CONCLUSIONS
Factor V east Texas bleeding disorder was diagnosed in an extended family. The variant was autosomal dominant and highly penetrant. Elevated plasma TFPIα, rather than platelet TFPIα, was likely the primary cause of bleeding. Plasma FV-short did not deplete TFPIα from extracellular matrix. In vitro thrombin generation was restored with an anti-TFPI antibody or factor VIIa suggesting effective therapies may be available. Increased awareness of, and testing for, bleeding disorders associated with F5 exon 13 variants and elevated plasma TFPI are needed.
Topics: Blood Coagulation; Blood Coagulation Disorders; Blood Coagulation Tests; Factor V; Humans; Thrombin
PubMed: 34847292
DOI: 10.1111/jth.15612