LDL receptor‐related protein 1 contributes to the clearance of the activated factor VII–antithrombin complex

Fazavana, Judicaël; Muczynski, Vincent; Proulle, Valérie; Wohner, Nikolett; Olivier, Christophe; Lenting, Peter J.; Denis, Cécile V.

doi:10.1111/jth.13502

Cited by 6 publications

(2 citation statements)

References 48 publications

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“…Therefore, the desialylated glycans on CT‐001 will likely be the dominant clearance mechanism. It is important to note that other FVIIa‐binding partners such as alpha 2 ‐macroglobulin, 47 EPCR, 48‐50 low‐density lipoprotein receptor–related protein 1, 51 as well as megalin and cubilin on renal cells 52 could also be potential modulators of CT‐001 clearance. Thus, the hypothesis of desialylated glycans on CT‐001 being the dominant mechanism for activity clearance will need to be confirmed by in vivo pharmacokinetic and pharmacodynamic studies.…”

Section: Discussionmentioning

confidence: 99%

In vitro characterization of CT‐001—a short‐acting factor VIIa with enhanced prohemostatic activity

Sim

Mallari

Teare

et al. 2021

Research and Practice in Thrombosis and Haemostasis

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Background Traumatic injury and the associated acute bleeding are leading causes of death in people aged 1 to 44 years. Acute bleeding in pathological and surgical settings also represents a significant burden to the society. Yet there are no approved hemostatic drugs currently available. While clinically proven as an effective pro‐coagulant, activated factor VII (FVIIa) use in acute bleeding has been hampered by unwanted thromboembolic events. Enhancing the ability of FVIIa to quickly stop a bleed and clear rapidly from circulation may yield an ideal molecule suitable for use in patients with acute bleeding. Objectives To address this need and the current liability of FVIIa, we produced a novel FVIIa molecule (CT‐001) with enhanced potency and shortened plasma residence time by cell line engineering and FVIIa protein engineering for superior efficacy for acute bleeding and safety. Methods To address safety, CT‐001, a FVIIa protein with 4 desialylated N‐glycans was generated to promote active recognition and clearance via the asialoglycoprotein receptor. To enhance potency, the gamma‐carboxylated domain was modified with P10Q and K32E, which enhanced membrane binding. Results Together, these changes significantly enhanced potency and clearance while retaining the ability to interact with the key hemostatic checkpoint proteins antithrombin and tissue factor pathway inhibitor. Conclusions These results demonstrate that a FVIIa molecule engineered to combine supra‐physiological activity and shorter duration of action has the potential to overcome the current limitations of recombinant FVIIa to be a safe and effective approach to the treatment of acute bleeding.

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Section: Discussionmentioning

confidence: 99%

In vitro characterization of CT‐001—a short‐acting factor VIIa with enhanced prohemostatic activity

Sim

Mallari

Teare

et al. 2021

Research and Practice in Thrombosis and Haemostasis

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“…Antithrombin (AT) belongs to the serpin superfamily and regulates coagulation by inhibiting thrombin, activated factor X (FXa), and to a lesser extent FIXa, FXIa, FXIIa and FVIIa [2,3]. Hereditary AT deficiency is classified as type I (quantitative) and type II (qualitative) [4].…”

Section: Introductionmentioning

confidence: 99%

Clinical and laboratory characteristics of antithrombin deficiencies: A large cohort study from a single diagnostic center

Gindele

Selmeczi

Oláh

et al. 2017

Thrombosis Research

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Introduction: Inherited antithrombin (AT) deficiency is a heterogeneous disease. Due to low prevalence, only a few studies are available concerning genotype-phenotype associations. The aim was to describe the clinical, laboratory and genetic characteristics of AT deficiency in a large cohort including children and to add further laboratory data on the different sensitivity of functional AT assays.Patients and methods: Non-related AT deficient patients (n=156) and their family members (total n=246) were recruited. Clinical and laboratory data were collected, the mutation spectrum of SERPINC1 was described. Three different AT functional assays were explored.Results: Thirty-one SERPINC1 mutations including 11 novel ones and high mutation detection rate (98%) were detected. Heparin binding site deficiency (type IIHBS) was the most frequent (75.6%) including AT Budapest3 (ATBp3), AT Padua I and AT Basel (86%, 9% and 4% of type IIHBS, respectively). Clinical and laboratory phenotypes of IIHBS were heterogeneous and dependent on the specific mutation.Arterial thrombosis and pregnancy complications were the most frequent in AT Basel and AT Padua I, respectively. Median age at the time of thrombosis was the lowest in

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Regulation of the Extracellular SERPINA5 (Protein C Inhibitor) Penetration Through Cellular Membranes

Wahlmüller

Yang

Furtmüller

et al. 2017

Advances in Experimental Medicine and Biology

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It is generally accepted that the phospholipid bilayer of the cell membrane is impermeable for proteins and peptides and that these molecules require special mechanisms for their transport from the extra- to the intracellular space. Recently there is increasing evidence that certain proteins/peptides can also directly cross the phospholipid membrane. SERPINA5 (protein C inhibitor) is a secreted protease inhibitor with broad protease reactivity and wide tissue distribution. It binds glycosaminoglycans and certain phospoholipids, which can modulate its inhibitory activity. SERPINA5 has been shown to be internalized by platelets, granulocytes, HL-60 promyelocytic leukemia cells, and by Jurkat lymphoma cells. Once inside the cell it can translocate to the nucleus. There are several indications that SERPINA5 can directly cross the phospholipid bilayer of the cell membrane. In this review we will describe what is known so far about the conditions, as well as the cellular and molecular requirements for SERPINA5 translocation through the cell membrane and for its penetration of pure phospholipid vesicles.

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LDL receptor‐related protein 1 contributes to the clearance of the activated factor VII–antithrombin complex

Cited by 6 publications

References 48 publications

In vitro characterization of CT‐001—a short‐acting factor VIIa with enhanced prohemostatic activity

In vitro characterization of CT‐001—a short‐acting factor VIIa with enhanced prohemostatic activity

Clinical and laboratory characteristics of antithrombin deficiencies: A large cohort study from a single diagnostic center

Regulation of the Extracellular SERPINA5 (Protein C Inhibitor) Penetration Through Cellular Membranes

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