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Enhanced in vitro procoagulant and antifibrinolytic potential of superactive variants of recombinant factor VIIa in severe hemophilia A.
J Thromb Haemost 2003; 1(10):2175-8JT

Abstract

BACKGROUND

Recombinant coagulation factor VIIa (rFVIIa) is generally accepted for treatment of patients with inhibitor-complicated hemophilia. Recently, rFVIIa variants with a specific enhancement of the tissue factor (TF)-independent proteolytic activity have been described.

OBJECTIVES

The procoagulant and [thrombin-activatable fibrinolysis inhibitor (TAFI)-dependent] antifibrinolytic potentials of two superactive rFVIIa variants were compared with those of wild-type rFVIIa in a hemophilic setting.

PATIENTS AND METHODS

Clot lysis assays were performed in plasma from six patients with inhibitor-complicated hemophilia A or in antibody-induced factor VIII-deficient platelet-rich plasma in the presence of different concentrations of the rFVIIa variants.

RESULTS AND DISCUSSION

In the plasma model, M298Q-rFVIIa had a moderately increased procoagulant and antifibrinolytic potential, whereas V158D/E296V/M298Q/K337A-rFVIIa had a strongly increased procoagulant and antifibrinolytic activity compared with wild-type rFVIIa. The increased antifibrinolytic potential of the rFVIIa variants was completely dependent on enhancement of TAFI activation. In the platelet-rich plasma model similar results were obtained. The presence of TF was mandatory for clot formation in the absence of exogenous rFVIIa. At lower concentrations of rFVIIa (wild-type or variants), clot formation did occur but was significantly slower when TF activity was blocked. At increasing concentrations of rFVIIa, clotting times were no longer dependent on TF. In conclusion, should a TF-independent mechanism be involved in the efficacy of rFVIIa in patients with hemophilia, the superactive rFVIIa variants studied here might be clinically advantageous, as both procoagulant and antifibrinolytic potencies are significantly enhanced compared with those of wild-type rFVIIa. This ought to result in more efficient cessation of bleeding episodes and reduced risk of rebleeding.

Authors+Show Affiliations

Thrombosis and Hemostasis Laboratory, G03.647, Department of Hematology, University Medical Center, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands. j.a.lisman@azu.nlNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

14521601

Citation

Lisman, T, et al. "Enhanced in Vitro Procoagulant and Antifibrinolytic Potential of Superactive Variants of Recombinant Factor VIIa in Severe Hemophilia A." Journal of Thrombosis and Haemostasis : JTH, vol. 1, no. 10, 2003, pp. 2175-8.
Lisman T, de Groot PG, Lambert T, et al. Enhanced in vitro procoagulant and antifibrinolytic potential of superactive variants of recombinant factor VIIa in severe hemophilia A. J Thromb Haemost. 2003;1(10):2175-8.
Lisman, T., de Groot, P. G., Lambert, T., Røjkjaer, R., & Persson, E. (2003). Enhanced in vitro procoagulant and antifibrinolytic potential of superactive variants of recombinant factor VIIa in severe hemophilia A. Journal of Thrombosis and Haemostasis : JTH, 1(10), pp. 2175-8.
Lisman T, et al. Enhanced in Vitro Procoagulant and Antifibrinolytic Potential of Superactive Variants of Recombinant Factor VIIa in Severe Hemophilia A. J Thromb Haemost. 2003;1(10):2175-8. PubMed PMID: 14521601.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Enhanced in vitro procoagulant and antifibrinolytic potential of superactive variants of recombinant factor VIIa in severe hemophilia A. AU - Lisman,T, AU - de Groot,P G, AU - Lambert,T, AU - Røjkjaer,R, AU - Persson,E, PY - 2003/10/3/pubmed PY - 2004/7/17/medline PY - 2003/10/3/entrez SP - 2175 EP - 8 JF - Journal of thrombosis and haemostasis : JTH JO - J. Thromb. Haemost. VL - 1 IS - 10 N2 - BACKGROUND: Recombinant coagulation factor VIIa (rFVIIa) is generally accepted for treatment of patients with inhibitor-complicated hemophilia. Recently, rFVIIa variants with a specific enhancement of the tissue factor (TF)-independent proteolytic activity have been described. OBJECTIVES: The procoagulant and [thrombin-activatable fibrinolysis inhibitor (TAFI)-dependent] antifibrinolytic potentials of two superactive rFVIIa variants were compared with those of wild-type rFVIIa in a hemophilic setting. PATIENTS AND METHODS: Clot lysis assays were performed in plasma from six patients with inhibitor-complicated hemophilia A or in antibody-induced factor VIII-deficient platelet-rich plasma in the presence of different concentrations of the rFVIIa variants. RESULTS AND DISCUSSION: In the plasma model, M298Q-rFVIIa had a moderately increased procoagulant and antifibrinolytic potential, whereas V158D/E296V/M298Q/K337A-rFVIIa had a strongly increased procoagulant and antifibrinolytic activity compared with wild-type rFVIIa. The increased antifibrinolytic potential of the rFVIIa variants was completely dependent on enhancement of TAFI activation. In the platelet-rich plasma model similar results were obtained. The presence of TF was mandatory for clot formation in the absence of exogenous rFVIIa. At lower concentrations of rFVIIa (wild-type or variants), clot formation did occur but was significantly slower when TF activity was blocked. At increasing concentrations of rFVIIa, clotting times were no longer dependent on TF. In conclusion, should a TF-independent mechanism be involved in the efficacy of rFVIIa in patients with hemophilia, the superactive rFVIIa variants studied here might be clinically advantageous, as both procoagulant and antifibrinolytic potencies are significantly enhanced compared with those of wild-type rFVIIa. This ought to result in more efficient cessation of bleeding episodes and reduced risk of rebleeding. SN - 1538-7933 UR - https://www.unboundmedicine.com/medline/citation/14521601/Enhanced_in_vitro_procoagulant_and_antifibrinolytic_potential_of_superactive_variants_of_recombinant_factor_VIIa_in_severe_hemophilia_A_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=1538-7933&date=2003&volume=1&issue=10&spage=2175 DB - PRIME DP - Unbound Medicine ER -