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Genetic, Functional and Therapeutic Aspects of Procoagulant and Anticoagulant Factors

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (15 March 2023) | Viewed by 18428

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Special Issue Editors

Dr. Rima Dardik

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Guest Editor

National Hemophilia Center, Sheba Medical Center, Ramat Gan 52621, Israel
Interests: procoagulant factors; anticoagulant factors; hemostasis
Special Issues, Collections and Topics in MDPI journals

Prof. Tami Livnat

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Guest Editor

1. Director, Amalia Biron Research Institute of Thrombosis and Hemostasis, Faculty of Medical and Health Sciences, Tel-Aviv University Sheba Medical Center, Tel Hashomer 52621, Israel
2. Rabin Medical Centre, Ophthalmology Department and Laboratory of Eye Research Felsenstein Medical Research Centre, Petah-Tikva 49100, Israel
Interests: procoagulant factors; anticoagulant factors; hemostasis; neuroprotection; ocular diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Normal hemostasis is highly dependent on the balance between procoagulant systems (e.g. platelets, procoagulant factors) and anticoagulant systems (e.g. protein C, protein S, antithrombin). Lack or dysfunction of a major procoagulant factor results in a bleeding disorder (e.g. factor VIII deficiency leading to hemophilia A), whereas a defect in an essential anticoagulant system (e.g. protein C deficiency) leads to a thrombotic disorder. Beyond their function in hemostasis, cell signaling pathways which are induced by procoagulant (e.g thrombin, FVII) and anticoagulant factors (e.g APC), mediated by specific receptors, have become the focus of increasing attention, with some of them being explored as promising therapeutic targets.

This special issue will focus on genetic, functional and therapeutic aspects of procoagulant and anticoagulant systems. We invite research studies and reviews on genetics of bleeding and thrombotic disorders, functional and therapeutic studies of procoagulant and anticoagulant factors, as well as studies exploring their involvement in the crosstalk between hemostasis and inflammation.

Dr. Rima Dardik
Prof. Tami Livnat
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

procoagulant factors
anticoagulant factors
hemostasis
inflammation
genetics
therapeutics
cell signaling

Published Papers (10 papers)

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Research

Jump to: Review

10 pages, 1395 KiB

Open AccessArticle

Galectin-3 as a Marker for Increased Thrombogenicity in COVID-19

by Marianna Puccini, Kai Jakobs, Leander Reinshagen, Julian Friebel, Philipp-Alexander Schencke, Emily Ghanbari, Ulf Landmesser, Arash Haghikia, Nicolle Kränkel and Ursula Rauch

Int. J. Mol. Sci. 2023, 24(9), 7683; https://doi.org/10.3390/ijms24097683 - 22 Apr 2023

Cited by 5 | Viewed by 1536

Abstract

Galectin-3 is a beta-galactoside-binding lectin involved in inflammation and lung fibrosis and postulated to enhance thrombosis. In COVID-19, it is considered to be a prognostic marker of severity. The aim of this study was to evaluate whether galectin-3 is associated with thrombogenicity in COVID-19. Patients with moderate-to-severe COVID-19 (COVpos; n = 55) and patients with acute respiratory diseases, but without COVID-19 (COVneg; n = 35), were included in the study. We measured the amount of galectin-3, as well as other platelet and coagulation markers, and correlated galectin-3 levels with these markers of thrombogenicity and with the SOFA Score values. We found that galectin-3 levels, as well as von Willebrand Factor (vWF), antithrombin and tissue plasminogen activator levels, were higher in the COVpos than they were in the COVneg cohort. Galectin-3 correlated positively with vWF, antithrombin and D-dimer in the COVpos cohort, but not in the COVneg cohort. Moreover, galactin-3 correlated also with clinical disease severity, as measured by the SOFA Score. In patients with acute respiratory diseases, galectin-3 can be considered as a marker not only for disease severity, but also for increased hypercoagulability. Whether galectin-3 might be a useful therapeutic target in COVID-19 needs to be assessed in future studies. Full article

(This article belongs to the Special Issue Genetic, Functional and Therapeutic Aspects of Procoagulant and Anticoagulant Factors)

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17 pages, 7757 KiB

Open AccessArticle

Simultaneous Inhibition of Thrombosis and Inflammation Is Beneficial in Treating Acute Myocardial Infarction

by Ian Vargas, Ryan P. Grabau, Junjie Chen, Carla Weinheimer, Attila Kovacs, William Dominguez-Viqueira, Adam Mitchell, Samuel A. Wickline and Hua Pan

Int. J. Mol. Sci. 2023, 24(8), 7333; https://doi.org/10.3390/ijms24087333 - 15 Apr 2023

Cited by 1 | Viewed by 1803

Abstract

Myocardial ischemia reperfusion injury (IRI) in acute coronary syndromes is a condition in which ischemic/hypoxic injury to cells subtended by the occluded vessel continues despite successful resolution of the thrombotic obstruction. For decades, most efforts to attenuate IRI have focused on interdicting singular molecular targets or pathways, but none have successfully transitioned to clinical use. In this work, we investigate a nanoparticle-based therapeutic strategy for profound but local thrombin inhibition that may simultaneously mitigate both thrombosis and inflammatory signaling pathways to limit myocardial IRI. Perfluorocarbon nanoparticles (PFC NP) were covalently coupled with an irreversible thrombin inhibitor, PPACK (Phe[D]-Pro-Arg-Chloromethylketone), and delivered intravenously to animals in a single dose prior to ischemia reperfusion injury. Fluorescent microscopy of tissue sections and ¹⁹F magnetic resonance images of whole hearts ex vivo demonstrated abundant delivery of PFC NP to the area at risk. Echocardiography at 24 h after reperfusion demonstrated preserved ventricular structure and improved function. Treatment reduced thrombin deposition, suppressed endothelial activation, inhibited inflammasome signaling pathways, and limited microvascular injury and vascular pruning in infarct border zones. Accordingly, thrombin inhibition with an extraordinarily potent but locally acting agent suggested a critical role for thrombin and a promising therapeutic strategy in cardiac IRI. Full article

(This article belongs to the Special Issue Genetic, Functional and Therapeutic Aspects of Procoagulant and Anticoagulant Factors)

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10 pages, 8557 KiB

Open AccessArticle

Usefulness and Limitations of Multiple Ligation-Dependent Probe Amplification in Antithrombin Deficiency

by Rosa Cifuentes, José Padilla, María Eugenia de la Morena-Barrio, Belén de la Morena-Barrio, Carlos Bravo-Pérez, Pedro Garrido-Rodríguez, María Llamas, Antonia Miñano, Vicente Vicente, María Luisa Lozano and Javier Corral

Int. J. Mol. Sci. 2023, 24(5), 5023; https://doi.org/10.3390/ijms24055023 - 6 Mar 2023

Viewed by 1689

Abstract

Multiplex ligation-dependent probe amplification (MLPA) identifies genetic structural variants in SERPINC1 in 5% of cases with antithrombin deficiency (ATD), the most severe congenital thrombophilia. Our aim was to unravel the utility and limitations of MLPA in a large cohort of unrelated patients with ATD (N = 341). MLPA identified 22 structural variants (SVs) causing ATD (6.5%). MLPA did not detect SVs affecting introns (four cases), and the diagnosis was inaccurate in two cases according to long-range PCR or nanopore sequencing. MLPA was used to detect possible hidden SVs in 61 cases with type I deficiency with single nucleotide variations (SNVs) or small insertion/deletion (INDEL). One case had a false deletion of exon 7, as the 29-bp deletion affected an MLPA probe. We evaluated 32 variants affecting MLPA probes: 27 SNVs and 5 small INDELs. In three cases, MLPA gave false-positive results, all diagnosed as deletions of the affected exon: a small INDEL complex, and two SNVs affecting MLPA probes. Our study confirms the utility of MLPA to detect SVs in ATD, but also shows some limitations in detecting intronic SVs. MLPA renders imprecise and false-positive results for genetic defects which affect MLPA probes. Our results encourage the validation of MLPA results. Full article

(This article belongs to the Special Issue Genetic, Functional and Therapeutic Aspects of Procoagulant and Anticoagulant Factors)

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13 pages, 2939 KiB

Open AccessArticle

ProCPU Is Expressed by (Primary) Human Monocytes and Macrophages and Expression Differs between States of Differentiation and Activation

by Karen Claesen, Joni De Loose, Pieter Van Wielendaele, Emilie De bruyn, Yani Sim, Sofie Thys, Ingrid De Meester and Dirk Hendriks

Int. J. Mol. Sci. 2023, 24(4), 3725; https://doi.org/10.3390/ijms24043725 - 13 Feb 2023

Cited by 1 | Viewed by 1452

Abstract

Carboxypeptidase U (CPU, TAFIa, CPB2) is a potent attenuator of fibrinolysis that is mainly synthesized by the liver as its inactive precursor proCPU. Aside from its antifibrinolytic properties, evidence exists that CPU can modulate inflammation, thereby regulating communication between coagulation and inflammation. Monocytes and macrophages play a central role in inflammation and interact with coagulation mechanisms resulting in thrombus formation. The involvement of CPU and monocytes/macrophages in inflammation and thrombus formation, and a recent hypothesis that proCPU is expressed in monocytes/macrophages, prompted us to investigate human monocytes and macrophages as a potential source of proCPU. CPB2 mRNA expression and the presence of proCPU/CPU protein were studied in THP-1, PMA-stimulated THP-1 cells and primary human monocytes, M-CSF-, IFN-γ/LPS-, and IL-4-stimulated-macrophages by RT-qPCR, Western blotting, enzyme activity measurements, and immunocytochemistry. CPB2 mRNA and proCPU protein were detected in THP-1 and PMA-stimulated THP-1 cells as well as in primary monocytes and macrophages. Moreover, CPU was detected in the cell medium of all investigated cell types and it was demonstrated that proCPU can be activated into functionally active CPU in the in vitro cell culture environment. Comparison of CPB2 mRNA expression and proCPU concentrations in the cell medium between the different cell types provided evidence that CPB2 mRNA expression and proCPU secretion in monocytes and macrophages is related to the degree to which these cells are differentiated. Our results indicate that primary monocytes and macrophages express proCPU. This sheds new light on monocytes and macrophages as local proCPU sources. Full article

(This article belongs to the Special Issue Genetic, Functional and Therapeutic Aspects of Procoagulant and Anticoagulant Factors)

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14 pages, 2051 KiB

Open AccessArticle

Deletion of Annexin A1 in Mice Upregulates the Expression of Its Receptor, Fpr2/3, and Reactivity to the AnxA1 Mimetic Peptide in Platelets

by Olga Zharkova, Maryam F. Salamah, Maria V. Babak, Elanchezhian Rajan, Lina H. K. Lim, Frans Andrade, Cristiane D. Gil, Sonia M. Oliani, Leonardo A. Moraes and Sakthivel Vaiyapuri

Int. J. Mol. Sci. 2023, 24(4), 3424; https://doi.org/10.3390/ijms24043424 - 8 Feb 2023

Cited by 4 | Viewed by 1855

Abstract

Annexin A1 (ANXA1) is an endogenous protein, which plays a central function in the modulation of inflammation. While the functions of ANXA1 and its exogenous peptidomimetics, N-Acetyl 2-26 ANXA1-derived peptide (ANXA1_Ac2-26), in the modulation of immunological responses of neutrophils and monocytes have been investigated in detail, their effects on the modulation of platelet reactivity, haemostasis, thrombosis, and platelet-mediated inflammation remain largely unknown. Here, we demonstrate that the deletion of Anxa1 in mice upregulates the expression of its receptor, formyl peptide receptor 2/3 (Fpr2/3, orthologue of human FPR2/ALX). As a result, the addition of ANXA1_Ac2-26 to platelets exerts an activatory role in platelets, as characterised by its ability to increase the levels of fibrinogen binding and the exposure of P-selectin on the surface. Moreover, ANXA1_Ac2-26 increased the development of platelet-leukocyte aggregates in whole blood. The experiments carried out using a pharmacological inhibitor (WRW4) for FPR2/ALX, and platelets isolated from Fpr2/3-deficient mice ascertained that the actions of ANXA1_Ac2-26 are largely mediated through Fpr2/3 in platelets. Together, this study demonstrates that in addition to its ability to modulate inflammatory responses via leukocytes, ANXA1 modulates platelet function, which may influence thrombosis, haemostasis, and platelet-mediated inflammation under various pathophysiological settings. Full article

(This article belongs to the Special Issue Genetic, Functional and Therapeutic Aspects of Procoagulant and Anticoagulant Factors)

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15 pages, 1836 KiB

Open AccessArticle

PARIN5, a Novel Thrombin Receptor Antagonist Modulates a Streptozotocin Mice Model for Diabetic Encephalopathy

by Valery Golderman, Zehavit Goldberg, Shany Guly Gofrit, Amir Dori, Nicola Maggio, Joab Chapman, Ifat Sher, Ygal Rotenstreich and Efrat Shavit-Stein

Int. J. Mol. Sci. 2023, 24(3), 2021; https://doi.org/10.3390/ijms24032021 - 19 Jan 2023

Viewed by 1273

Abstract

Diabetic encephalopathy (DE) is an inflammation-associated diabetes mellitus (DM) complication. Inflammation and coagulation are linked and are both potentially modulated by inhibiting the thrombin cellular protease-activated receptor 1 (PAR1). Our aim was to study whether coagulation pathway modulation affects DE. Diabetic C57BL/6 mice were treated with PARIN5, a novel PAR1 modulator. Behavioral changes in the open field and novel object recognition tests, serum neurofilament (NfL) levels and thrombin activity in central and peripheral nervous system tissue (CNS and PNS, respectively), brain mRNA expression of tumor necrosis factor α (TNF-α), Factor X (FX), prothrombin, and PAR1 were assessed. Subtle behavioral changes were detected in diabetic mice. These were accompanied by an increase in serum NfL, an increase in central and peripheral neural tissue thrombin activity, and TNF-α, FX, and prothrombin brain intrinsic mRNA expression. Systemic treatment with PARIN5 prevented the appearance of behavioral changes, normalized serum NfL and prevented the increase in peripheral but not central thrombin activity. PARIN5 treatment prevented the elevation of both TNF-α and FX but significantly elevated prothrombin expression. PARIN5 treatment prevents behavioral and neural damage in the DE model, suggesting it for future clinical research. Full article

(This article belongs to the Special Issue Genetic, Functional and Therapeutic Aspects of Procoagulant and Anticoagulant Factors)

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16 pages, 2571 KiB

Open AccessArticle

3K3A-Activated Protein C Prevents Microglia Activation, Inhibits NLRP3 Inflammasome and Limits Ocular Inflammation

by Dahlia Palevski, Gil Ben-David, Yehonatan Weinberger, Rabeei Haj Daood, José A. Fernández, Ivan Budnik, Sarina Levy-Mendelovich, Gili Kenet, Yael Nisgav, Dov Weinberger, John H. Griffin and Tami Livnat

Int. J. Mol. Sci. 2022, 23(22), 14196; https://doi.org/10.3390/ijms232214196 - 17 Nov 2022

Cited by 7 | Viewed by 1773

Abstract

3K3A-Activated Protein C (APC) is a recombinant variant of the physiological anticoagulant APC with pleiotropic cytoprotective properties albeit without the bleeding risks. The anti-inflammatory activities of 3K3A-APC were demonstrated in multiple preclinical injury models, including various neurological disorders. We determined the ability of 3K3A-APC to inhibit ocular inflammation in a murine model of lipopolysaccharide (LPS)-induced uveitis. Leukocyte recruitment, microglia activation, NLRP3 inflammasome and IL-1β levels were assessed using flow cytometry, retinal cryosection histology, retinal flatmount immunohistochemistry and vascular imaging, with and without 3K3A-APC treatment. LPS triggered robust inflammatory cell recruitment in the posterior chamber. The 3K3A-APC treatment significantly decreased leukocyte numbers and inhibited leukocyte extravasation from blood vessels into the retinal parenchyma to a level similar to controls. Resident microglia, which underwent an inflammatory transition following LPS injection, remained quiescent in eyes treated with 3K3A-APC. An inflammation-associated increase in retinal thickness, observed in LPS-injected eyes, was diminished by 3K3A-APC treatment, suggesting its clinical relevancy. Finally, 3K3A-APC treatment inhibited inflammasome activation, determined by lower levels of NLRP3 and its downstream effector IL-1β. Our results highlight the anti-inflammatory properties of 3K3A-APC in ocular inflammation and suggest its potential use as a novel treatment for retinal diseases associated with inflammation. Full article

(This article belongs to the Special Issue Genetic, Functional and Therapeutic Aspects of Procoagulant and Anticoagulant Factors)

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14 pages, 1177 KiB

Open AccessArticle

Decreased Platelet Specific Receptor Expression of P-Selectin and GPIIb/IIIa Predict Future Non-Surgical Bleeding in Patients after Left Ventricular Assist Device Implantation

by Kristin Klaeske, Anna L. Meyer, Diyar Saeed, Sandra Eifert, Khalil Jawad, Franz Sieg, Josephina Haunschild, Michael A. Borger and Maja-Theresa Dieterlen

Int. J. Mol. Sci. 2022, 23(18), 10252; https://doi.org/10.3390/ijms231810252 - 6 Sep 2022

Cited by 3 | Viewed by 1249

Abstract

Non-surgical bleeding (NSB) is one of the major clinical complications in patients under continuous-flow left ventricular assist device (LVAD) support. The increased shear stress leads to an altered platelet receptor composition. Whether these changes increase the risk for NSB is unclear. Thus, we compared the platelet receptor composition of patients with (bleeder group, n = 18) and without NSB (non-bleeder group, n = 18) prior to LVAD implantation. Blood samples were obtained prior to LVAD implantation and after bleeding complications in the post-implant period. Platelet receptor expression of GPIbα, GPIIb/IIIa, P-selectin and CD63 as well as intra-platelet oxidative stress levels were quantified by flow cytometry. Bleeders and non-bleeders were comparable regarding clinical characteristics, von Willebrand factor diagnostics and the aggregation capacity before and after LVAD implantation (p > 0.05). LVAD patients in the bleeder group suffered from gastrointestinal bleeding (33%; n = 6), epistaxis (22%; n = 4), hematuria or hematoma (17%; n = 3, respectively) and cerebral bleeding (11%; n = 2). Prior to LVAD implantation, a restricted surface expression of the platelet receptors P-selectin and GPIIb/IIIa was observed in the bleeder group (P-selectin: 7.2 ± 2.6%; GPIIb/IIIa: 26,900 ± 13,608 U) compared to non-bleeders (P-selectin: 12.4 ± 8.1%, p = 0.02; GPIIb/IIIa: 36,259 ± 9914 U; p = 0.02). We hypothesized that the reduced platelet receptor expression of P-selectin and GPIIb/IIIa prior to LVAD implantation may be linked to LVAD-related NSB. Full article

(This article belongs to the Special Issue Genetic, Functional and Therapeutic Aspects of Procoagulant and Anticoagulant Factors)

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Review

Jump to: Research

13 pages, 527 KiB

Open AccessReview

Four Decades of Carrier Detection and Prenatal Diagnosis in Hemophilia A: Historical Overview, State of the Art and Future Directions

by Rima Dardik, Szymon Janczar, Shadan Lalezari, Einat Avishai, Sarina Levy-Mendelovich, Assaf Arie Barg, Uri Martinowitz, Katarzyna Babol-Pokora, Wojciech Mlynarski and Gili Kenet

Int. J. Mol. Sci. 2023, 24(14), 11846; https://doi.org/10.3390/ijms241411846 - 24 Jul 2023

Cited by 2 | Viewed by 1855

Abstract

Hemophilia A (HA), a rare recessive X-linked bleeding disorder, is caused by either deficiency or dysfunction of coagulation factor VIII (FVIII) resulting from deleterious mutations in the F8 gene encoding FVIII. Over the last 4 decades, the methods aimed at determining the HA carrier status in female relatives of HA patients have evolved from phenotypic studies based on coagulation tests providing merely probabilistic results, via genetic linkage studies based on polymorphic markers providing more accurate results, to next generation sequencing studies enabling highly precise identification of the causative F8 mutation. In parallel, the options for prenatal diagnosis of HA have progressed from examination of FVIII levels in fetal blood samples at weeks 20–22 of pregnancy to genetic analysis of fetal DNA extracted from chorionic villus tissue at weeks 11–14 of pregnancy. In some countries, in vitro fertilization (IVF) combined with preimplantation genetic diagnosis (PGD) has gradually become the procedure of choice for HA carriers who wish to prevent further transmission of HA without the need to undergo termination of pregnancies diagnosed with affected fetuses. In rare cases, genetic analysis of a HA carrier might be complicated by skewed X chromosome inactivation (XCI) of her non-hemophilic X chromosome, thus leading to the phenotypic manifestation of moderate to severe HA. Such skewed XCI may be associated with deleterious mutations in X-linked genes located on the non-hemophilic X chromosome, which should be considered in the process of genetic counseling and PGD planning for the symptomatic HA carrier. Therefore, whole exome sequencing, combined with X-chromosome targeted bioinformatic analysis, is highly recommended for symptomatic HA carriers diagnosed with skewed XCI in order to identify additional deleterious mutations potentially involved in XCI skewing. Identification of such mutations, which may profoundly impact the reproductive choices of HA carriers with skewed XCI, is extremely important. Full article

(This article belongs to the Special Issue Genetic, Functional and Therapeutic Aspects of Procoagulant and Anticoagulant Factors)

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20 pages, 1501 KiB

Open AccessReview

Plasma Clearance of Coagulation Factor VIII and Extension of Its Half-Life for the Therapy of Hemophilia A: A Critical Review of the Current State of Research and Practice

by Andrey G. Sarafanov

Int. J. Mol. Sci. 2023, 24(10), 8584; https://doi.org/10.3390/ijms24108584 - 11 May 2023

Cited by 6 | Viewed by 2764

Abstract

Factor VIII (FVIII) is an important component of blood coagulation as its congenital deficiency results in life-threatening bleeding. Current prophylactic therapy of the disease (hemophilia A) is based on 3–4 intravenous infusions of therapeutic FVIII per week. This poses a burden on patients, demanding reduction of infusion frequency by using FVIII with extended plasma half-life (EHL). Development of these products requires understanding FVIII plasma clearance mechanisms. This paper overviews (i) an up-to-date state of the research in this field and (ii) current EHL FVIII products, including recently approved efanesoctocog alfa, for which the plasma half-life exceeds a biochemical barrier posed by von Willebrand factor, complexed with FVIII in plasma, which results in ~1 per week infusion frequency. We focus on the EHL FVIII products’ structure and function, in particular related to the known discrepancy in results of one-stage clotting (OC) and chromogenic substrate (CS) assays used to assign the products’ potency, dosing, and for clinical monitoring in plasma. We suggest a possible root cause of these assays’ discrepancy that is also pertinent to EHL factor IX variants used to treat hemophilia B. Finally, we discuss approaches in designing future EHL FVIII variants, including those to be used for hemophilia A gene therapy. Full article

(This article belongs to the Special Issue Genetic, Functional and Therapeutic Aspects of Procoagulant and Anticoagulant Factors)

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