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Article ; Online: Serpins, New Therapeutic Targets for Hemophilia.

Aymonnier, Karen / Kawecki, Charlotte / Arocas, Véronique / Boulaftali, Yacine / Bouton, Marie Christine

2020 Volume 121, Issue 3, Page(s) 261–269

Abstract: Hemostasis is a tightly regulated process characterized by a finely tuned balance between procoagulant and anticoagulant systems. Among inherited hemostatic conditions, hemophilia is one of the most well-known bleeding disorders. Hemophilia A (HA) and B ( ...

Abstract	Hemostasis is a tightly regulated process characterized by a finely tuned balance between procoagulant and anticoagulant systems. Among inherited hemostatic conditions, hemophilia is one of the most well-known bleeding disorders. Hemophilia A (HA) and B (HB) are due to deficiencies in coagulation factor VIII (FVIII) or FIX, respectively, leading to unwanted bleeding. Until recently, hemophilia treatment has consisted of prophylactic replacement therapy using plasma-derived or recombinant FVIII in cases of HA or FIX in cases of HB. Because FVIII and FIX deficiencies lead to an imbalance between procoagulant and anticoagulant systems, a recent upcoming strategy implies blocking of endogenous anticoagulant proteins to compensate for the procoagulant factor deficit, thus restoring hemostatic equilibrium. Important physiological proteins of the anticoagulant pathways belong to the serpin (serine protease inhibitor) family and, recently, different experimental and clinical studies have demonstrated that targeting natural serpins could decrease bleeding in hemophilia. Here, we aim to review the different, recent studies demonstrating that blocking serpins such as antithrombin, protein Z-dependent protease inhibitor, and protease nexin-1 or modifying a serpin like α1-antitrypsin could rebalance coagulation in hemophilia. Furthermore, we underline the potential therapeutic use of serpins for the treatment of hemophilia.
MeSH term(s)	Animals ; Blood Coagulation/drug effects ; Drug Discovery ; Hemophilia A/blood ; Hemophilia A/drug therapy ; Hemophilia A/metabolism ; Hemophilia B/blood ; Hemophilia B/drug therapy ; Hemophilia B/metabolism ; Humans ; Serpins/blood ; Serpins/metabolism ; Serpins/therapeutic use
Chemical Substances	Serpins
Language	English
Publishing date	2020-09-28
Publishing country	Germany
Document type	Journal Article ; Review
ZDB-ID	518294-3
ISSN	2567-689X ; 0340-6245
ISSN (online)	2567-689X
ISSN	0340-6245
DOI	10.1055/s-0040-1716751
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Zs.MO 433: Show issues

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Article ; Online: von Willebrand Factor Is a Critical Mediator of Deep Vein Thrombosis in a Mouse Model of Diet-Induced Obesity.

Michels, Alison / Dwyer, Courtney N / Mewburn, Jeffrey / Nesbitt, Kate / Kawecki, Charlotte / Lenting, Peter / Swystun, Laura L / Lillicrap, David

Arteriosclerosis, thrombosis, and vascular biology

2020 Volume 40, Issue 12, Page(s) 2860–2874

Abstract: Objective: Obesity is characterized by chronic low-grade inflammation and consequentially a hypercoagulable state, associating with an increased incidence of venous thromboembolism. Increased VWF (von Willebrand factor) plasma concentration and ... ...

Abstract	Objective: Obesity is characterized by chronic low-grade inflammation and consequentially a hypercoagulable state, associating with an increased incidence of venous thromboembolism. Increased VWF (von Willebrand factor) plasma concentration and procoagulant function are independent risk factors for venous thromboembolism and are elevated in obese patients. Here, we explore the pathobiological role of VWF in obesity-associated venous thrombosis using murine models. Approach and Results: We first showed that diet-induced obese mice have increased VWF plasma levels and FVIII (factor VIII) activity compared with littermate controls. Elevated VWF levels appeared to be because of both increased synthesis and impaired clearance. Diet-induced obesity-associated venous thrombosis was assessed using the inferior vena cava-stenosis model of deep vein thrombosis. Diet-induced obese mice developed larger venous thrombi that were rich in VWF, erythrocytes, and leukocytes. Administering a polyclonal anti-VWF antibody or an anti-VWF A1 domain nanobody was protective against obesity-mediated thrombogenicity. Delayed administration (3 hours post-inferior vena cava stenosis) similarly reduced thrombus weight in diet-induced obese mice. Conclusions: This study demonstrates the critical role of VWF in the complex, thrombo-inflammatory state of obesity. It adds to the growing rationale for targeting VWF-specific interactions in thrombotic disease.
MeSH term(s)	ADAMTS13 Protein/genetics ; ADAMTS13 Protein/metabolism ; Animals ; Diet, High-Fat ; Disease Models, Animal ; Female ; Fibrinolytic Agents/pharmacology ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; Obesity/complications ; Obesity/metabolism ; Signal Transduction ; Single-Domain Antibodies/pharmacology ; Vena Cava, Inferior/drug effects ; Vena Cava, Inferior/metabolism ; Vena Cava, Inferior/pathology ; Venous Thrombosis/etiology ; Venous Thrombosis/metabolism ; Venous Thrombosis/pathology ; Venous Thrombosis/prevention & control ; von Willebrand Factor/antagonists & inhibitors ; von Willebrand Factor/genetics ; von Willebrand Factor/metabolism
Chemical Substances	Fibrinolytic Agents ; Single-Domain Antibodies ; von Willebrand Factor ; ADAMTS13 protein, mouse (EC 3.4.24.-) ; ADAMTS13 Protein (EC 3.4.24.87)
Language	English
Publishing date	2020-09-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1221433-4
ISSN	1524-4636 ; 1079-5642
ISSN (online)	1524-4636
ISSN	1079-5642
DOI	10.1161/ATVBAHA.120.314690
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Article: Serpins, New Therapeutic Targets for Hemophilia

Aymonnier, Karen / Kawecki, Charlotte / Arocas, Véronique / Boulaftali, Yacine / Bouton, Marie Christine

Thrombosis and Haemostasis

2020 Volume 121, Issue 03, Page(s) 261–269

Abstract	Hemostasis is a tightly regulated process characterized by a finely tuned balance between procoagulant and anticoagulant systems. Among inherited hemostatic conditions, hemophilia is one of the most well-known bleeding disorders. Hemophilia A (HA) and B (HB) are due to deficiencies in coagulation factor VIII (FVIII) or FIX, respectively, leading to unwanted bleeding. Until recently, hemophilia treatment has consisted of prophylactic replacement therapy using plasma-derived or recombinant FVIII in cases of HA or FIX in cases of HB. Because FVIII and FIX deficiencies lead to an imbalance between procoagulant and anticoagulant systems, a recent upcoming strategy implies blocking of endogenous anticoagulant proteins to compensate for the procoagulant factor deficit, thus restoring hemostatic equilibrium. Important physiological proteins of the anticoagulant pathways belong to the serpin (serine protease inhibitor) family and, recently, different experimental and clinical studies have demonstrated that targeting natural serpins could decrease bleeding in hemophilia. Here, we aim to review the different, recent studies demonstrating that blocking serpins such as antithrombin, protein Z-dependent protease inhibitor, and protease nexin-1 or modifying a serpin like α1-antitrypsin could rebalance coagulation in hemophilia. Furthermore, we underline the potential therapeutic use of serpins for the treatment of hemophilia.
Keywords	coagulation inhibitors ; hemophilia A/B ; Serpins
Language	English
Publishing date	2020-09-28
Publisher	Georg Thieme Verlag KG
Publishing place	Stuttgart ; New York
Document type	Article
ZDB-ID	518294-3
ISSN	2567-689X ; 0340-6245
ISSN (online)	2567-689X
ISSN	0340-6245
DOI	10.1055/s-0040-1716751
Database	Thieme publisher's database

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Article ; Online: Development of a dual hybrid AAV vector for endothelial-targeted expression of von Willebrand factor.

Barbon, Elena / Kawecki, Charlotte / Marmier, Solenne / Sakkal, Aboud / Collaud, Fanny / Charles, Severine / Ronzitti, Giuseppe / Casari, Caterina / Christophe, Olivier D / Denis, Cécile V / Lenting, Peter J / Mingozzi, Federico

Gene therapy

2021 Volume 30, Issue 3-4, Page(s) 245–254

Abstract: Von Willebrand disease (VWD), the most common inherited bleeding disorder in humans, is caused by quantitative or qualitative defects in von Willebrand factor (VWF). VWD represents a potential target for gene therapy applications, as a single treatment ... ...

Abstract	Von Willebrand disease (VWD), the most common inherited bleeding disorder in humans, is caused by quantitative or qualitative defects in von Willebrand factor (VWF). VWD represents a potential target for gene therapy applications, as a single treatment could potentially result in a long-term correction of the disease. In recent years, several liver-directed gene therapy approaches have been exploited for VWD, but their efficacy was generally limited by the large size of the VWF transgene and the reduced hemostatic activity of the protein produced from hepatocytes. In this context, we aimed at developing a gene therapy strategy for gene delivery into endothelial cells, the natural site of biosynthesis of VWF. We optimized an endothelial-specific dual hybrid AAV vector, in which the large VWF cDNA was put under the control of an endothelial promoter and correctly reconstituted upon cell transduction by a combination of trans-splicing and homologous recombination mechanisms. In addition, we modified the AAV vector capsid by introducing an endothelial-targeting peptide to improve the efficiency for endothelial-directed gene transfer. This vector platform allowed the reconstitution of full-length VWF transgene both in vitro in human umbilical vein endothelial cells and in vivo in VWD mice, resulting in long-term expression of VWF.
MeSH term(s)	Animals ; Humans ; Mice ; Endothelial Cells/metabolism ; Gene Transfer Techniques ; Genetic Therapy/methods ; von Willebrand Diseases/genetics ; von Willebrand Diseases/metabolism ; von Willebrand Diseases/therapy ; von Willebrand Factor/genetics ; von Willebrand Factor/metabolism ; Genetic Vectors
Chemical Substances	von Willebrand Factor
Language	English
Publishing date	2021-01-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1191036-7
ISSN	1476-5462 ; 0969-7128
ISSN (online)	1476-5462
ISSN	0969-7128
DOI	10.1038/s41434-020-00218-6
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Zs.A 3991: Show issues

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Article ; Online: A single-domain antibody that blocks factor VIIa activity in the absence but not presence of tissue factor.

Ferrière, Stephen / Kawecki, Charlotte / Ottavi, Jean-François / Denis, Cécile V / Kauskot, Alexandre / Christophe, Olivier D / Lenting, Peter J

Journal of thrombosis and haemostasis : JTH

2019 Volume 17, Issue 12, Page(s) 2035–2046

Abstract: Background: Activated factor VII (FVIIa) is pertinent to the initiation of blood coagulation. Proteolytic and amidolytic activity of FVIIa are greatly enhanced by its cofactor, tissue factor (TF).: Objective: We aimed to generate a single-domain ... ...

Abstract	Background: Activated factor VII (FVIIa) is pertinent to the initiation of blood coagulation. Proteolytic and amidolytic activity of FVIIa are greatly enhanced by its cofactor, tissue factor (TF). Objective: We aimed to generate a single-domain antibody (sdAb) that recognizes free FVIIa rather than TF-bound FVIIa. Methods: A llama-derived phage library was used to screen for anti-FVIIa sdAbs. Results: One sdAb, KB-FVIIa-004, bound to FVIIa, but not to its precursor FVII or to homologous proteins (prothrombin, factor X, or their activated derivatives). FVIIa amidolytic activity was inhibited by KB-FVIIa-004 (K Discussion: This observation is compatible with the view that FVIIa functions independently of TF under these conditions. In conclusion, we have generated a sdAb that specifically blocks TF-independent activity of FVIIa. This antibody can be used to gain insight into the roles of TF-bound and TF-free FVIIa.
MeSH term(s)	Animals ; Anticoagulants/pharmacology ; Blood Coagulation/drug effects ; Coagulants/antagonists & inhibitors ; Coagulants/pharmacology ; Disease Models, Animal ; Factor VIII/genetics ; Factor VIIa/antagonists & inhibitors ; Factor VIIa/immunology ; Factor VIIa/metabolism ; Factor VIIa/pharmacology ; Female ; Hemophilia A/blood ; Hemophilia A/drug therapy ; Hemophilia A/genetics ; Humans ; Male ; Mice, Inbred C57BL ; Protein Binding ; Single-Domain Antibodies/pharmacology ; Thromboplastin/metabolism
Chemical Substances	Anticoagulants ; Coagulants ; Single-Domain Antibodies ; Factor VIII (9001-27-8) ; Thromboplastin (9035-58-9) ; Factor VIIa (EC 3.4.21.21)
Language	English
Publishing date	2019-09-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2112661-6
ISSN	1538-7836 ; 1538-7933
ISSN (online)	1538-7836
ISSN	1538-7933
DOI	10.1111/jth.14615
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Article ; Online: Receptor for Advanced Glycation End Products is Involved in Platelet Hyperactivation and Arterial Thrombosis during Chronic Kidney Disease.

Ortillon, Jérémy / Hézard, Nathalie / Belmokhtar, Karim / Kawecki, Charlotte / Terryn, Christine / Fritz, Guenter / Kauskot, Alexandre / Schmidt, Ann Marie / Rieu, Philippe / Nguyen, Philippe / Maurice, Pascal / Touré, Fatouma

Thrombosis and haemostasis

2020 Volume 120, Issue 9, Page(s) 1300–1312

Abstract: Background: Chronic kidney disease (CKD) is associated with a high cardiovascular mortality due to increased rates of vascular lesions and thrombotic events, as well as serum accumulation of uremic toxins. A subgroup of these toxins (advanced glycation ...

Abstract	Background: Chronic kidney disease (CKD) is associated with a high cardiovascular mortality due to increased rates of vascular lesions and thrombotic events, as well as serum accumulation of uremic toxins. A subgroup of these toxins (advanced glycation end products [AGEs] and S100 proteins) can interact with the receptor for AGEs (RAGE). In this study, we analyzed the impact of CKD on platelet function and arterial thrombosis, and the potential role of RAGE in this process. Methods: Twelve weeks after induction of CKD in mice, platelet function and time to complete carotid artery occlusion were analyzed in four groups of animals (sham-operated, CKD, apolipoprotein E [Apoe] Results: Analysis of platelet function from whole blood and platelet-rich plasma showed hyperactivation of platelets only in CKD Apoe Conclusion: Our results show that CKD induces platelet hyperactivation, accelerates thrombus formation in a murine model of arterial thrombosis, and that RAGE deletion has a protective role. We propose that RAGE ligands binding to RAGE is involved in CKD-induced arterial thrombosis.
Language	English
Publishing date	2020-07-29
Publishing country	Germany
Document type	Journal Article
ZDB-ID	518294-3
ISSN	2567-689X ; 0340-6245
ISSN (online)	2567-689X
ISSN	0340-6245
DOI	10.1055/s-0040-1714101
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Article ; Online: A hemophilia A mouse model for the in vivo assessment of emicizumab function.

Ferrière, Stephen / Peyron, Ivan / Christophe, Olivier D / Kawecki, Charlotte / Casari, Caterina / Muczynski, Vincent / Nathwani, Amit / Kauskot, Alexandre / Lenting, Peter J / Denis, Cécile V

Blood

2020 Volume 136, Issue 6, Page(s) 740–748

Abstract: The bispecific antibody emicizumab is increasingly used for hemophilia A treatment. However, its specificity for human factors IX and X (FIX and FX) has limited its in vivo functional analysis to primate models of acquired hemophilia. Here, we describe a ...

Abstract	The bispecific antibody emicizumab is increasingly used for hemophilia A treatment. However, its specificity for human factors IX and X (FIX and FX) has limited its in vivo functional analysis to primate models of acquired hemophilia. Here, we describe a novel mouse model that allows emicizumab function to be examined. Briefly, FVIII-deficient mice received IV emicizumab 24 hours before tail-clip bleeding was performed. A second infusion with human FIX and FX, administered 5 minutes before bleeding, generated consistent levels of emicizumab (0.7-19 mg/dL for 0.5-10 mg/kg doses) and of both FIX and FX (85 and 101 U/dL, respectively, after dosing at 100 U/kg). Plasma from these mice display FVIII-like activity in assays (diluted activated partial thromboplastin time and thrombin generation), similar to human samples containing emicizumab. Emicizumab doses of 1.5 mg/kg and higher significantly reduced blood loss in a tail-clip-bleeding model using FVIII-deficient mice. However, reduction was incomplete compared with mice treated with human FVIII concentrate, and no difference in efficacy between doses was observed. From this model, we deducted FVIII-like activity from emicizumab that corresponded to a dose of 4.5 U of FVIII per kilogram (ie, 9.0 U/dL). Interestingly, combined with a low FVIII dose (5 U/kg), emicizumab provided enough additive activity to allow complete bleeding arrest. This model could be useful for further in vivo analysis of emicizumab.
MeSH term(s)	Animals ; Antibodies, Bispecific/administration & dosage ; Antibodies, Bispecific/immunology ; Antibodies, Bispecific/therapeutic use ; Antibodies, Monoclonal, Humanized/administration & dosage ; Antibodies, Monoclonal, Humanized/immunology ; Antibodies, Monoclonal, Humanized/therapeutic use ; Drug Therapy, Combination ; Factor IX/administration & dosage ; Factor IX/analysis ; Factor IX/immunology ; Factor VIII/administration & dosage ; Factor VIII/analysis ; Factor VIII/therapeutic use ; Factor X/administration & dosage ; Factor X/analysis ; Factor X/immunology ; Factor XIa/pharmacology ; Female ; Hemophilia A/blood ; Hemophilia A/complications ; Hemophilia A/drug therapy ; Hemophilia A/immunology ; Hemorrhage/drug therapy ; Hemorrhage/etiology ; Infusions, Intravenous ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Models, Animal ; Partial Thromboplastin Time ; Tail/injuries ; Thrombin/biosynthesis
Chemical Substances	Antibodies, Bispecific ; Antibodies, Monoclonal, Humanized ; emicizumab (7NL2E3F6K3) ; F8 protein, human (839MOZ74GK) ; Factor VIII (9001-27-8) ; Factor IX (9001-28-9) ; Factor X (9001-29-0) ; Factor XIa (EC 3.4.21.27) ; Thrombin (EC 3.4.21.5)
Language	English
Publishing date	2020-05-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2019004334
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Zs.MO 364: Show issues

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Article ; Online: Development and characterization of single-domain antibodies neutralizing protease nexin-1 as tools to increase thrombin generation.

Kawecki, Charlotte / Aymonnier, Karen / Ferrière, Stephen / Venisse, Laurence / Arocas, Véronique / Boulaftali, Yacine / Christophe, Olivier D / Lenting, Peter J / Bouton, Marie-Christine / Denis, Cécile V

Journal of thrombosis and haemostasis : JTH

2020 Volume 18, Issue 9, Page(s) 2155–2168

Abstract: Background: Protease nexin-1 (PN-1) is a member of the serine protease inhibitor (Serpin)-family, with thrombin as its main target. Current polyclonal and monoclonal antibodies against PN-1 frequently cross-react with plasminogen activator inhibitor-1 ( ... ...

Abstract	Background: Protease nexin-1 (PN-1) is a member of the serine protease inhibitor (Serpin)-family, with thrombin as its main target. Current polyclonal and monoclonal antibodies against PN-1 frequently cross-react with plasminogen activator inhibitor-1 (PAI-1), a structurally and functionally homologous Serpin. Objectives: Here, we aimed to develop inhibitory single-domain antibodies (VHHs) that show specific binding to both human (hPN-1) and murine (mPN-1) PN-1. Methods: PN-1-binding VHHs were isolated via phage-display using llama-derived or synthetic VHH-libraries. Following bacterial expression, purified VHHs were analyzed in binding and activity assays. Results and conclusions: By using a llama-derived library, 2 PN-1 specific VHHs were obtained (KB-PN1-01 and KB-PN1-02). Despite their specificity, none displayed inhibitory activity toward hPN-1 or mPN-1. From the synthetic library, 4 VHHs (H12, B11, F06, A08) could be isolated that combined efficient binding to both hPN-1 and mPN-1 with negligible binding to PAI-1. Of these, B11, F06, and A08 were able to fully restore thrombin activity by blocking PN-1. As monovalent VHH, half-maximal inhibitory concentration values for hPN-1 were 50 ± 10, 290 ± 30, and 960 ± 390 nmol/L, for B11, F06, and A08, respectively, and 1580 ± 240, 560 ± 130, and 2880 ± 770 nmol/L for mPN-1. The inhibitory potential was improved 4- to 7-fold when bivalent VHHs were engineered. Importantly, all VHHs could block PN-1 activity in plasma as well as PN-1 released from activated platelets, one of the main sources of PN-1 during hemostasis. In conclusion, we report the generation of inhibitory anti-PN-1 antibodies using a specific approach to avoid cross-reactivity with the homologous Serpin PAI-1.
MeSH term(s)	Animals ; Antibodies, Monoclonal ; Cell Surface Display Techniques ; Humans ; Mice ; Serpin E2/genetics ; Single-Domain Antibodies ; Thrombin
Chemical Substances	Antibodies, Monoclonal ; Serpin E2 ; Single-Domain Antibodies ; Thrombin (EC 3.4.21.5)
Language	English
Publishing date	2020-06-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2112661-6
ISSN	1538-7836 ; 1538-7933
ISSN (online)	1538-7836
ISSN	1538-7933
DOI	10.1111/jth.14940
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Article ; Online: Towards the Therapeutic Use of Thrombospondin 1/CD47 Targeting TAX2 Peptide as an Antithrombotic Agent.

Jeanne, Albin / Sarazin, Thomas / Charlé, Magalie / Kawecki, Charlotte / Kauskot, Alexandre / Hedtke, Tobias / Schmelzer, Christian E H / Martiny, Laurent / Maurice, Pascal / Dedieu, Stéphane

Arteriosclerosis, thrombosis, and vascular biology

2020 Volume 41, Issue 1, Page(s) e1–e17

Abstract: Objective: TSP-1 (thrombospondin 1) is one of the most expressed proteins in platelet α-granules and plays an important role in the regulation of hemostasis and thrombosis. Interaction of released TSP-1 with CD47 membrane receptor has been shown to ... ...

Abstract	Objective: TSP-1 (thrombospondin 1) is one of the most expressed proteins in platelet α-granules and plays an important role in the regulation of hemostasis and thrombosis. Interaction of released TSP-1 with CD47 membrane receptor has been shown to regulate major events leading to thrombus formation, such as, platelet adhesion to vascular endothelium, nitric oxide/cGMP (cyclic guanosine monophosphate) signaling, platelet activation as well as aggregation. Therefore, targeting TSP-1:CD47 axis may represent a promising antithrombotic strategy. Approach and Results: A CD47-derived cyclic peptide was engineered, namely TAX2, that targets TSP-1 and selectively prevents TSP-1:CD47 interaction. Here, we demonstrate for the first time that TAX2 peptide strongly decreases platelet aggregation and interaction with collagen under arterial shear conditions. TAX2 also delays time for complete thrombotic occlusion in 2 mouse models of arterial thrombosis following chemical injury, while Conclusions: Overall, this study sheds light on the major contribution of TSP-1:CD47 interaction in platelet activation and thrombus formation while putting forward TAX2 as an innovative antithrombotic agent with high added-value.
MeSH term(s)	Animals ; Arterial Occlusive Diseases/blood ; Arterial Occlusive Diseases/metabolism ; Arterial Occlusive Diseases/prevention & control ; CD47 Antigen/antagonists & inhibitors ; CD47 Antigen/metabolism ; Collagen/metabolism ; Disease Models, Animal ; Fibrinolytic Agents/pharmacology ; Fibrinolytic Agents/toxicity ; Humans ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; Peptides, Cyclic/pharmacology ; Peptides, Cyclic/toxicity ; Platelet Aggregation/drug effects ; Platelet Aggregation Inhibitors/pharmacology ; Platelet Aggregation Inhibitors/toxicity ; Rats, Sprague-Dawley ; Signal Transduction ; Thrombosis/blood ; Thrombosis/metabolism ; Thrombosis/prevention & control ; Thrombospondin 1/antagonists & inhibitors ; Thrombospondin 1/genetics ; Thrombospondin 1/metabolism ; Time Factors ; Mice ; Rats
Chemical Substances	CD47 Antigen ; Fibrinolytic Agents ; Peptides, Cyclic ; Platelet Aggregation Inhibitors ; TAX2 peptide ; Thrombospondin 1 ; Thbs1 protein, mouse ; Collagen (9007-34-5)
Language	English
Publishing date	2020-11-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1221433-4
ISSN	1524-4636 ; 1079-5642
ISSN (online)	1524-4636
ISSN	1079-5642
DOI	10.1161/ATVBAHA.120.314571
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Article ; Online: Targeting protease nexin-1, a natural anticoagulant serpin, to control bleeding and improve hemostasis in hemophilia.

Aymonnier, Karen / Kawecki, Charlotte / Venisse, Laurence / Boulaftali, Yacine / Christophe, Olivier D / Lenting, Peter J / Arocas, Véronique / de Raucourt, Emmanuelle / Denis, Cécile V / Bouton, Marie-Christine

Blood

2019 Volume 134, Issue 19, Page(s) 1632–1644

Abstract: Hemophilia A and B, diseases caused by the lack of factor VIII (FVIII) and factor IX (FIX) respectively, lead to insufficient thrombin production, and therefore to bleeding. New therapeutic strategies for hemophilia treatment that do not rely on clotting ...

Abstract	Hemophilia A and B, diseases caused by the lack of factor VIII (FVIII) and factor IX (FIX) respectively, lead to insufficient thrombin production, and therefore to bleeding. New therapeutic strategies for hemophilia treatment that do not rely on clotting factor replacement, but imply the neutralization of natural anticoagulant proteins, have recently emerged. We propose an innovative approach consisting of targeting a natural and potent thrombin inhibitor, expressed by platelets, called protease nexin-1 (PN-1). By using the calibrated automated thrombin generation assay, we showed that a PN-1-neutralizing antibody could significantly shorten the thrombin burst in response to tissue factor in platelet-rich plasma (PRP) from patients with mild or moderate hemophilia. In contrast, in PRP from patients with severe hemophilia, PN-1 neutralization did not improve thrombin generation. However, after collagen-induced platelet activation, PN-1 deficiency in F8-/-mice or PN-1 blocking in patients with severe disease led to a significantly improved thrombin production in PRP, underlining the regulatory role of PN-1 released from platelet granules. In various bleeding models, F8-/-/PN-1-/- mice displayed significantly reduced blood loss and bleeding time compared with F8-/-mice. Moreover, platelet recruitment and fibrin(ogen) accumulation were significantly higher in F8-/-/PN-1-/- mice than in F8-/-mice in the ferric chloride-induced mesenteric vessel injury model. Thromboelastometry studies showed enhanced clot stability and lengthened clot lysis time in blood from F8-/-/PN-1-/- and from patients with hemophilia A incubated with a PN-1-neutralizing antibody compared with their respective controls. Our study thus provides proof of concept that PN-1 neutralization can be a novel approach for future clinical care in hemophilia.
MeSH term(s)	Animals ; Antibodies, Neutralizing/pharmacology ; Blood Coagulation Disorders, Inherited/complications ; Blood Coagulation Disorders, Inherited/enzymology ; Hemorrhage/etiology ; Hemostasis/drug effects ; Humans ; Mice ; Mice, Knockout ; Platelet Activation/drug effects ; Serpin E2/antagonists & inhibitors
Chemical Substances	Antibodies, Neutralizing ; Serpin E2
Language	English
Publishing date	2019-07-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2019000281
Database	MEDical Literature Analysis and Retrieval System OnLINE

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