Increased local procoagulant action: a mechanism contributing to the favorable hemostatic effect of recombinant FVIIa in PLT disorders.
BACKGROUND
Recombinant FVIIa (rFVIIa) has been shown to improve hemostasis in patients with thrombocytopenia and to prevent or control bleeding episodes in patients with inherited deficiencies of major PLT glycoproteins, but the mechanism of action is not well understood.


METHODS
Effects of rFVIIa on hemostasis were explored with an in vitro perfusion technique. Blood samples, from healthy donors or from patients with congenital defects of PLT glycoprotein IIb-IIIa (GPIIb-IIIa), were anticoagulated with low-molecular-weight heparin. Experimental thrombocytopenia (<6000 PLTs/microL) was induced by a filtration procedure. rFVIIa was added to blood samples at therapeutic concentrations. A severe GPIIb-IIIa impairment was also induced by exposure of normal blood samples to a specific antibody. Perfusion studies were performed through annular chambers containing damaged vascular segments. The presence of fibrin and PLTs on the perfused subendothelium was morphometrically quantified.


RESULTS
Under conditions of experimental thrombocytopenia, addition of rFVIIa enhanced fibrin formation in a dose-dependent manner (p < 0.05). Improvements in local fibrin generation and partial restoration of PLT interactions were also observed after incubation of blood from patients with Glanzmann's thrombasthenia with rFVIIa at 5 microg per mL (180 microg/kg). Similar improvements were observed in blood samples incubated with antibodies to GPIIb-IIIa. rFVIIa in whole normal blood also enhanced fibrin formation but PLT deposition was unaffected. Evaluation of prothrombin fragments 1 and 2 in the perfusates confirmed that rFVIIa increased thrombin generation in all cases.


CONCLUSIONS
Our data indicate that rFVIIa promotes a procoagulant activity at sites of vascular damage. This mechanism could explain the beneficial hemostatic effect of rFVIIa in patients with thrombocytopenia or with Glanzmann's thrombasthenia.
Galán
Ana-María
AM
Hematherapy and Hemostasis Service, Hospital Clinic, Faculty of Medicine, IDIBAPS, Barcelona, Spain. agalan@clinic.ub.es
Tonda
Raúl
R
Pino
Marcos
M
Reverter
Juan Carlos
JC
Ordinas
Antonio
A
Escolar
Ginés
G
D001777:Blood Coagulation; D001791:Blood Platelet Disorders / Q000097:blood / Q000188:drug therapy*; D001792:Blood Platelets / Q000502:physiology; D015942:Factor VIIa / Q000008:administration & dosage* / Q000235:genetics; D005337:Fibrin / Q000378:metabolism; D006487:Hemostasis; D006801:Humans; D010446:Peptide Fragments / Q000097:blood; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000235:genetics / Q000502:physiology; D011516:Prothrombin; D011994:Recombinant Proteins / Q000008:administration & dosage; D013915:Thrombasthenia / Q000097:blood / Q000188:drug therapy; D013921:Thrombocytopenia / Q000097:blood / Q000188:drug therapy; D013925:Thromboplastin / Q000502:physiology
D010446:Peptide Fragments; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011994:Recombinant Proteins; C045879:prothrombin fragment 1.2; D011516:Prothrombin; D005337:Fibrin; D013925:Thromboplastin; D015942:Factor VIIa