Blood, 15 March 2001, Vol. 97, No. 6, pp. 1523-1523
Boosting a natural anticoagulant
The protein C pathway performs a critical anticoagulant
function by subverting the procoagulant effects of thrombin, and a paper by Taylor and colleagues (page 1685) suggests that an endothelial membrane cofactor besides thrombomodulin modulates this function in
vivo. The protein C pathway begins with the binding of thrombin to
thrombomodulin on endothelial cells, and the thrombin-thrombomodulin complex then activates protein C, a serine protease zymogen. In a
reaction that is facilitated by plasma protein S, activated protein C
(APC) degrades clotting factors Va and VIIIa, shutting down blood
clotting. Defects in the protein C pathway are common causes of
thrombosis, underlining the importance of this regulatory mechanism.
Even a modest acquired or inherited decrease in the level of protein C
or protein S confers a substantially increased risk of venous
thrombosis, and total deficiency of protein C causes purpura fulminans,
a neonatal thrombohemorrhagic disorder that is fatal if untreated.
The endothelial protein C receptor (EPCR) is a plasma membrane protein
that binds protein C and accelerates its activation by
thrombin-thrombomodulin at least 5-fold in vitro. Changes of this
magnitude could have large effects on hemostatic balance. But the
concentration of EPCR in vivo is highest in large vessels, whereas
protein C activation by thrombin-thrombomodulin occurs mainly in
the microcirculation. The apparent discrepancy between the
localization of EPCR and protein C activation has raised questions about the biological relevance of EPCR to the protein C
anticoagulant pathway function, although the
immunohistochemical detection of EPCR in the microcirculation may
not be sufficiently sensitive or quantitative to support conclusions
about function.
Taylor and colleagues now have shown that EPCR plays a
substantial role in protein C activation. Administration of low doses of thrombin to baboons causes a large increase (more than 200-fold) in
circulating APC levels, and coadministration of a blocking antibody to
EPCR inhibited this response by almost 90%. Thus the relatively low
levels of EPCR in microvessels appear sufficient to strongly stimulate
the protein C pathway in vivo. These data suggest that inherited or
acquired variations in EPCR activity in specific vascular beds could
determine the probability of thrombosis and, possibly, its location.
J. Evan Sadler
Washington University
