title: Reduced thrombus formation in native blood of homozygous factor VII-deficient patients at high arterial wall shear rate.
abstract: Inhibition of thrombin formation in flowing native blood reduces thrombus formation on subendothelium, dacron, or collagen fibrils at arterial wall shear rates of 450 to 650 s-1. In the present study, we have investigated the role of low levels of factor VII (FVII) in thrombus formation on collagen fibrils at arterial wall shear rates of 650 s-1 (coronary arteries), 2,600 s-1 (mildly stenosed arteries), and 10,510 s-1 (severely stenosed arteries) in parallel-plate perfusion chambers. In the perfusion chamber with the highest wall shear rate, thrombus formation took place at the apex of an eccentric stenosis, which reduced the cross-sectional area of the blood flow channel by 80%, thus simulating thrombus formation at an atherosclerotic plaque rupture. Native blood from 21 healthy volunteers and 12 homozygous FVII-deficient patients was drawn by a pump directly from an antecubital vein over a surface of fibrillar collagen positioned in the respective perfusion chambers. The patients had FVII coagulant activities ranging from 1.3% to 4.5% and FVII antigen levels of 16% to 23% of normal. Immunoaffinity purification of the patients' FVII followed by electrophoresis (sodium dodecyl sulfate-polyacrylamide gel electrophoresis [SDS-PAGE]) and immunoblotting showed a protein with similar molecular mass as normal FVII. In the perfusion studies, a reduction in thrombus volume of 54% of normal (P < .007) at 10,510 s-1 was observed. The deposition of fibrin on the thrombogenic surface and the plasma level of fibrinopeptide A (FPA) in blood samples collected distal to the perfusion chamber were concomitantly reduced (P < .002 and P < .04, respectively). The plasma FPA level was also reduced at 2,600 s-1 (P < .04), but not at 650 s-1. However, at the lower shear conditions, the thrombus volume and the fibrin deposition were within the ranges observed in normal blood. The platelet-collagen adhesion was not affected at any of the three shear conditions. Thus, low plasma levels of FVII result in significantly less formation of thrombin and fibrin in and around growing platelet masses at high shear condition. This may weaken the thrombus stability and reduce platelet recruitment, thereby lowering thrombus volume. In support of this theory, one patient with afibrinogenemia had an 83% reduction in thrombus volume at this high shear condition.
authors.affiliation: Nycomed Bioreg AS, Oslo, Norway.
authors.forename: R M
authors.initials: RM
authors.lastname: Barstad
authors.forename: H
authors.initials: H
authors.lastname: Stormorken
authors.forename: L
authors.initials: L
authors.lastname: Orning
authors.forename: R W
authors.initials: RW
authors.lastname: Stephens
authors.forename: L B
authors.initials: LB
authors.lastname: Petersen
authors.forename: P
authors.initials: P
authors.lastname: Kierulf
authors.forename: K S
authors.initials: KS
authors.lastname: Sakariassen
mesh_terms: D000347:Afibrinogenemia / Q000097:blood / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005167:Factor VII / Q000032:analysis / Q000378:metabolism*; D005168:Factor VII Deficiency / Q000097:blood* / Q000235:genetics / Q000473:pathology; D005260:Female; D005344:Fibrinopeptide A / Q000032:analysis; D006720:Homozygote; D006801:Humans; D008297:Male; D012016:Reference Values; D013927:Thrombosis / Q000473:pathology*; D001620:beta-Thromboglobulin / Q000032:analysis
chemical_list: D001620:beta-Thromboglobulin; D005344:Fibrinopeptide A; D005167:Factor VII