“In vitro” correction of the severe factor V deficiency‐related coagulopathy by a novel plasma‐derived factor V concentrate

Bulato, Cristiana; Novembrino, Cristina; Anzoletti, Massimo Boscolo; Spiezia, Luca; Gavasso, Sabrina; Berbenni, C; Tagariello, Giuseppe; Farina, Claudio; Nardini, Ilaria; Campello, Elena; Peyvandi, Flora; Simioni, Paolo

doi:10.1111/hae.13465

Cited by 18 publications

(16 citation statements)

References 37 publications

(64 reference statements)

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“…8 Treatment options are limited, because only recently has a purified FV concentration been developed. 9 Multifactor concentrates contain inadequate concentrations of FV to be effective. For major bleeding, fresh frozen plasma or platelet transfusions are typically used.…”

Section: Introductionmentioning

confidence: 99%

Analysis of factor V in zebrafish demonstrates minimal levels needed for early hemostasis

et al. 2019

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In humans, coagulation factor V (FV) deficiency is a rare, clinically heterogeneous bleeding disorder, suggesting that genetic modifiers may contribute to disease expressivity. Zebrafish possess many distinct advantages including high fecundity, optical clarity, external development, and homology with the mammalian hemostatic system, features that make it ideal for genetic studies. Our aim was to study the role of FV in zebrafish through targeted mutagenesis and apply the model to the study of human F5 variants. CRISPR-mediated genome editing of the zebrafish f5 locus was performed, generating mutants homozygous for a 49 base pair deletion in exon 4. Thrombus formation secondary to vascular endothelial injury was absent in f5−/− mutant embryos and larvae. Despite this severe hemostatic defect, homozygous mutants survived before succumbing to severe hemorrhage in adulthood. Human F5 variants of uncertain significance from patients with FV deficiency were evaluated, and the causative mutations identified and stratified by their ability to restore thrombus formation in larvae. Analysis of these novel mutations demonstrates variable residual FV function, with minimal activity being required to restore hemostasis in response to laser-induced endothelial injury. This in vivo evaluation may be beneficial for patients whose factor activity levels lack correlation with bleeding symptomatology, although limitations exist. Furthermore, homozygous mutant embryos tolerate what is a severe and lethal defect in mammals, suggesting the possibility of species-specific factors enabling survival, and allowing further study not possible in the mouse. Identification of these factors or other genetic modifiers could lead to novel therapeutic modalities.

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Section: Introductionmentioning

confidence: 99%

Analysis of factor V in zebrafish demonstrates minimal levels needed for early hemostasis

et al. 2019

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“…58 The first FV concentrate for clinical use in FVdeficient patients has been recently developed, and it has been shown to correct laboratory parameters (prothrombin time, partial thromboplastin time, and thrombin generation) in severe FV-deficiency plasmas. 59 However, it is not yet commercially available and its outcomes in FV-deficient patients remain to be clarified. PCCs and cryoprecipitate do not contain substantial quantities of FV to be effective.…”

Section: Prothrombin Deficiencymentioning

confidence: 99%

Treatment of rare factor deficiencies other than hemophilia

Menegatti

Peyvandi

2019

Blood

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The deficiency of fibrinogen, prothrombin, factor V (FV), FVII, FVIII, FIX, FX, FXI, and FXIII, called rare coagulation disorders (RCDs), may result in coagulopathies leading to spontaneous or posttrauma and postsurgery hemorrhages. RCDs are characterized by a wide variety of symptoms, from mild to severe, which can vary significantly from 1 disease to another and from 1 patient to another. The most typical symptoms of all RCDs are mucosal bleedings and bleeding at the time of invasive procedures, whereas other life-threatening symptoms such as central nervous system bleeding and hemarthroses are mostly present only in some deficiencies (afibrinogenemia, FX, and FXIII). At variance with hemophilia A and B and von Willebrand disease, RCDs are much less prevalent, ranging from 1 case in 500 000 to 1 in 2 million in the general population. Their clinical heterogeneity associated with the low number of patients has led to a delay in the development of appropriate therapies. Indeed, a similar heterogeneity can also be found in the treatment products available, ranging from the specific recombinant proteins to treat FVII- and FXIII-deficient patients to the complete absence of specific products to treat patients with FII or FV deficiencies, for whom prothrombin complex concentrates or fresh frozen plasma are, to date, the only option. The recent development of novel hemostatic approaches for hemophilia, such as the use of nonsubstitutive therapy as RNA interference, anti–tissue factor pathway inhibitor, and the gene therapy aimed at improving the patient’s quality of life may also have an important role in the treatment of patients with RCDs in the future.

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“…Alternatively, platelet transfusion has been shown to be effective in treating Factor V deficiency due to the presence of activated Factor V in platelets. A new plasma-derived Factor V concentrate is currently under investigation but not yet in clinical trials [125 , 126] . More common are mutations such as Factor V Leiden which result in resistance to degradation and increased risk of thrombosis, but these patients are treated with anticoagulants rather than additional clotting factors [127] .…”

Section: The Uses Of Clotting Factor Concentrate In Hematologic Diseamentioning

confidence: 99%

Recent advances in use of fresh frozen plasma, cryoprecipitate, immunoglobulins, and clotting factors for transfusion support in patients with hematologic disease

Nair

Rendo

Reddoch-Cardenas

et al. 2020

Seminars in Hematology

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Hematologic diseases include a broad range of acquired and congenital disorders, many of which affect plasma proteins that control hemostasis and immune responses. Therapeutic interventions for these disorders include transfusion of plasma, cryoprecipitate, immunoglobulins, or convalescent plasma-containing therapeutic antibodies from patients recovering from infectious diseases, as well as concentrated pro- or anticoagulant factors. This review will focus on recent advances in the uses of plasma and its derivatives for patients with acquired and congenital hematologic disorders.

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“In vitro” correction of the severe factor V deficiency‐related coagulopathy by a novel plasma‐derived factor V concentrate

Abstract: The novel plasma-derived FV concentrate was effective to correct "in vitro" severe FV deficiency in patients. The optimal FV concentration to fully normalize both global clotting times and thrombin generation parameters using the novel plasma-derived FV concentrate was 25 IU/dL.

Cited by 18 publications

References 37 publications

Analysis of factor V in zebrafish demonstrates minimal levels needed for early hemostasis

Analysis of factor V in zebrafish demonstrates minimal levels needed for early hemostasis

Treatment of rare factor deficiencies other than hemophilia

Recent advances in use of fresh frozen plasma, cryoprecipitate, immunoglobulins, and clotting factors for transfusion support in patients with hematologic disease

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