title: Recombinant factor VIIa enhances deposition of platelets with congenital or acquired alpha IIb beta 3 deficiency to endothelial cell matrix and collagen under conditions of flow via tissue factor-independent thrombin generation.
abstract: A novel approach to treat bleeding episodes in patients with Glanzmann thrombasthenia (GT) and perhaps also in patients receiving alpha IIb beta 3 inhibitors is the administration of recombinant factor VIIa (rFVIIa). The mechanism of action of rFVIIa in these patients is, however, still unclear. We studied the effect of rFVIIa-mediated thrombin formation on adhesion of alpha IIb beta 3-deficient platelets under flow conditions. Adhesion of alpha IIb beta 3-deficient platelets to the extracellular matrix (ECM) of stimulated human umbilical vein endothelial cells or to collagen type III was studied using a model system with washed platelets and red cells. When alpha IIb beta 3-deficient platelets were perfused over the surface at arterial shear rate for 5 minutes, a low surface coverage was observed (GT platelets, mean +/- SEM, 37.5% +/- 5.0%; normal platelets preincubated with an RGD-containing peptide, 7.4% +/- 2.1%). When rFVIIa, together with factors X and II, was added to the perfusate, platelet deposition significantly increased (GT platelets, mean +/- SEM, 67.0% +/- 4.3%; normal platelets preincubated with an RGD-containing peptide, 48.2% +/- 2.9%). The same effect was observed when normal platelets were pretreated with the commercially available anti-alpha IIb beta 3 drugs abciximab, eptifibatide, or tirofiban. It was shown that tissue factor-independent thrombin generation (presumably induced by binding of rFVIIa to adhered platelets) was responsible for the increase in platelet deposition. In conclusion, defective adhesion of alpha IIb beta 3-deficient platelets to ECM can be restored by tissue factor-independent rFVIIa-mediated thrombin formation. The enhanced generation of platelet procoagulant surface facilitates fibrin formation, so that lack of platelet aggregate formation might be compensated for.
authors.affiliation: Thrombosis and Haemostasis Laboratory, Department of Haematology, University Medical Centre, Utrecht, The Netherlands. j.a.lisman@lab.azu.nl
authors.forename: Ton
authors.initials: T
authors.lastname: Lisman
authors.forename: Sultana
authors.initials: S
authors.lastname: Moschatsis
authors.forename: Jelle
authors.initials: J
authors.lastname: Adelmeijer
authors.forename: H Karel
authors.initials: HK
authors.lastname: Nieuwenhuis
authors.forename: Philip G
authors.initials: PG
authors.lastname: De Groot
mesh_terms: D000077284:Abciximab; D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects*; D002478:Cells, Cultured / Q000187:drug effects; D003094:Collagen / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D000077542:Eptifibatide; D005109:Extracellular Matrix / Q000378:metabolism*; D015942:Factor VIIa / Q000494:pharmacology*; D005170:Factor X / Q000494:pharmacology; D018056:Hemorheology; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D010973:Platelet Adhesiveness / Q000187:drug effects* / Q000502:physiology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000235:genetics / Q000502:physiology*; D011516:Prothrombin / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013915:Thrombasthenia / Q000097:blood / Q000628:therapy*; D013917:Thrombin / Q000096:biosynthesis*; D013925:Thromboplastin / Q000502:physiology; D000077466:Tirofiban; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D009842:Oligopeptides; D010455:Peptides; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011994:Recombinant Proteins; C082481:arginyl-glycyl-aspartyl-tryptophan; D014443:Tyrosine; D011516:Prothrombin; D005170:Factor X; D003094:Collagen; D013925:Thromboplastin; D015942:Factor VIIa; D013917:Thrombin; D000077466:Tirofiban; D000077542:Eptifibatide; D013755:Tetradecanoylphorbol Acetate; D000077284:Abciximab