Blood, Vol. 92 No. 9 (November 1), 1998:
pp. 3294-3301
Activation of Clotting Factor XI Without Detectable Contact
Activation in Experimental Human Endotoxemia
M.C. Minnema,
D. Pajkrt,
W.A. Wuillemin,
D. Roem,
W.K. Bleeker,
M. Levi,
S.J.H. van Deventer,
C.E. Hack, and
H. ten Cate
From the Center for Hemostasis, Thrombosis, Atherosclerosis and
Inflammation Research; the Central Laboratory of the Netherlands Red
Cross Blood Transfusion Service, Laboratory for Clinical and
Experimental Immunology; the Laboratory of Experimental Internal
Medicine, University of Amsterdam, Academic Medical Center; the
Department of Internal Medicine, Slotervaart Hospital, Amsterdam, The
Netherlands; and the Central Haematology Laboratory, University
Hospital, Bern, Switzerland.
Evidence of factor XI (FXI) activation in vivo is scarce. In
addition, it remains uncertain whether thrombin, factor XIIa (FXIIa),
or perhaps another protease is responsible for FXI conversion. We
investigated the activation of FXI in eight healthy volunteers after
infusion of a low dose of endotoxin (4 ng/kg of body weight). Activation of prekallikrein FXII, FXI, and prothrombin was measured with sensitive enzyme-linked immunosorbent assays (ELISAs), and FXI
activation was measured with a novel enzyme capture assay that detects
noncomplexed FXIa. Activation of FXI was apparent with a significant
plasma peak level of noncomplexed FXIa of 10 to 11 pmol/L at 1 and 2 hours after endotoxin infusion, followed by a gradual increase in
FXIa-FXIa inhibitor complexes, measured in the ELISAs, with a summit of
11 to 15 pmol/L at 6 and 24 hours, respectively. In accordance with
previous studies, thrombin generation was detected 1 hour after
endotoxin infusion to become maximal after 3 to 4 hours. In contrast,
we did not find any evidence of contact activation, because markers of
activation of prekallikrein and FXII remained undetectable. From the
FXIa data a theoretical model was constructed which suggested that
inhibition of FXIa does not take place in the plasma compartment, but
is localized on a surface. These data provide the first evidence for
FXI activation in low-grade endotoxemia and suggest that FXI is
activated independently of FXII.
© 1998 by The American Society of Hematology.
