A Thrombin-Activatable Factor X Variant Corrects Hemostasis in a Mouse Model for Hemophilia A.

A Thrombin-Activatable Factor X Variant Corrects Hemostasis in a Mouse Model for Hemophilia A. Thromb Haemost. 2019 Oct 22;: Authors: Muczynski V, Verhenne S, Casari C, Chérel G, Panicot-Dubois L, Gueguen P, Trossaert M, Dubois C, Lenting PJ, Denis CV, Christophe OD Abstract Engineered recombinant factor X (FX) variants represent a promising strategy to bypass the tenase complex and restore hemostasis in hemophilia patients. Previously, a thrombin-activatable FX variant with fibrinopeptide-A replacing the activation peptide (FX-delAP/FpA) has been described in this regard. Here we show that FX-delAP/FpA is characterized by a sixfold shorter circulatory half-life compared with wild-type FX, limiting its therapeutical applicability. We therefore designed a variant in which the FpA sequence is inserted C-terminal to the FX activation peptide (FX/FpA). FX/FpA displayed a similar survival to wt-FX in clearance experiments and could be converted into FX by thrombin and other activating agents. In in vitro assays, FX/FpA efficiently restored thrombin generation in hemophilia A and hemophilia B plasmas, even in the presence of inhibitory antibodies. Expression following hydrodynamic gene transfer of FX/FpA restored thrombus formation in FVIII-deficient mice in a laser-induced injury model as well as hemostasis in a tail-clip bleeding model. Hemostasis after tail transection in FVIII-deficient mice was also corrected at 5 and 90 minutes after inject...
Source: Thrombosis and Haemostasis - Category: Hematology Authors: Tags: Thromb Haemost Source Type: research

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CONCLUSIONS: after 12 weeks of observation, both approaches significantly reduced bleeds per animal and increased the proportion of bleed-free animals compared to controls (43% vs. 0%, respectively [AAV]; 75% vs. 8%, respectively [injection]). Both approaches resulted in an anti-FVIII inhibitory response in 20-37% of treated animals, similar to HA patients. Inhibitory antibodies were refractory to clinical improvement (reduction of bleeds) only in the AAV-based prophylaxis. An integrated model-based analysis of data on FVIII exposure and bleeding events was performed. This predicted the bleeding risk at any given circulati...
Source: Thrombosis and Haemostasis - Category: Hematology Authors: Tags: J Thromb Haemost Source Type: research
CONCLUSION:  This extension study demonstrated the long-term safety and efficacy of weekly rIX-FP in pediatric patients. Additionally, it showed that adequate bleed protection can be achieved with 10- or 14-day rIX-FP regimens in selected pediatric patients while maintaining safety. PMID: 32185782 [PubMed - as supplied by publisher]
Source: Thrombosis and Haemostasis - Category: Hematology Authors: Tags: Thromb Haemost Source Type: research
CONCLUSIONS: CM in vitro is procoagulant and prothrombotic. CM in vivo can augment myocardial damage and can be prohemostatic in the presence of bleeding. CM's procoagulant and antifibrinolytic activities likely involve, at least in part, its ability to bind factor Xa and enhance thrombin generation. Future work is needed to clarify CM's pathophysiology and its mechanistic influences on hemostasis or thrombosis. PMID: 32102568 [PubMed - as supplied by publisher]
Source: Arteriosclerosis, Thrombosis and Vascular Biology - Category: Cardiology Authors: Tags: Arterioscler Thromb Vasc Biol Source Type: research
CONCLUSIONS: rIX-FP extended interval prophylaxis provides dosing flexibility and, in selected patients, a 21-day regimen may provide an alternative option to minimize treatment burden and individualize treatment. PMID: 32078256 [PubMed - as supplied by publisher]
Source: Thrombosis and Haemostasis - Category: Hematology Authors: Tags: J Thromb Haemost Source Type: research
Abstract Plasminogen deficiency is an ultra-rare multisystem disorder characterized by the development of fibrin-rich pseudomembranes on mucous membranes. Ligneous conjunctivitis, which can result in vision impairment or loss, is the most frequent symptom reported; affected systems may also include the respiratory tract, oropharynx, female reproductive tract, gingiva, middle ear, renal collecting system, skin and central nervous system. Untreated, plasminogen deficiency may result in significant reduction in quality of life and morbidity with potential life-threatening complications. Non-specific therapies are ina...
Source: Haematologica - Category: Hematology Authors: Tags: Haematologica Source Type: research
We present a case of liver transplantation in a hemophilia A donor to a recipient with no history of hemophilia A with literature review. To our knowledge, this is only the second case in humans of hemophilia A patient as a donor in liver transplantation. PMID: 31997485 [PubMed - as supplied by publisher]
Source: Thrombosis and Haemostasis - Category: Hematology Authors: Tags: J Thromb Haemost Source Type: research
CONCLUSIONS: This regimen may be considered to induce FVIII tolerance in HA patients with refractory inhibitors. Further characterization of the FVIII-specific immune response is necessary to clarify the mechanism of immune tolerance. PMID: 31985872 [PubMed - as supplied by publisher]
Source: Thrombosis and Haemostasis - Category: Hematology Authors: Tags: J Thromb Haemost Source Type: research
CONCLUSION: Emicizumab improved ex-vivo coagulation potential in plasma from AHA patients. PMID: 31984625 [PubMed - as supplied by publisher]
Source: Thrombosis and Haemostasis - Category: Hematology Authors: Tags: J Thromb Haemost Source Type: research
Abstract Acquired hemophilia A (AHA) is a rare, life-threatening bleeding disorder caused by autoantibodies against coagulation factor VIII (FVIII). Immunosuppressive therapy for AHA aims to arrest bleeding by eliminating FVIII inhibitors. Factor VIII activity overshoot after complete remission (CR) has been reported anecdotally, but details remain unclear. We retrospectively analyzed data from 17 patients with AHA who achieved CR under immunosuppressive therapy between 2009 and 2019 at Gunma University Hospital. FVIII activity overshoot was defined as ≥ 150%. All 17 patients had low FVIII activit...
Source: International Journal of Hematology - Category: Hematology Authors: Tags: Int J Hematol Source Type: research
This article gives an overview of the bleeding risks involved and therapeutic options to overcome them. [...] Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.Article in Thieme eJournals: Table of contents  |  Abstract  |  Full text
Source: Seminars in Thrombosis and Hemostasis - Category: Hematology Authors: Tags: Review Article Source Type: research
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