Reduced thrombus formation in native blood of homozygous factor VII-
deficient patients at high arterial wall shear rate
RM Barstad, H Stormorken, L Orning, RW Stephens, LB Petersen, P Kierulf and KS Sakariassen
Nycomed Bioreg AS, Oslo, Norway.
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.
Volume 84,
Issue 10,
pp. 3371-3377,
11/15/1994
Copyright © 1994 by The American Society of Hematology
