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Prepublished online as a Blood First Edition Paper on November 27, 2002; DOI 10.1182/blood-2002-07-1951.
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Blood, 1 April 2003, Vol. 101, No. 7, pp. 2628-2636
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Lactadherin inhibits enzyme complexes of blood coagulation by
competing for phospholipid-binding sites
Jialan Shi and
Gary E. Gilbert
From the Department of Medicine, VA Boston Healthcare
System; and the Department of Medicine, Brigham and
Women's Hospital and Harvard Medical School, Boston, MA.
Lactadherin, a glycoprotein of the milk-fat globule membrane,
contains tandem C domains with homology to discoidin-type lectins and
to membrane-binding domains of blood-clotting factors V and VIII. We
asked whether the structural homology confers the capacity to compete
for the membrane-binding sites of factor VIII and factor V and to
function as an anticoagulant. Our results indicate that lactadherin
competes efficiently with factor VIII and factor V for binding sites on
synthetic phosphatidylserine-containing membranes with
half-maximal displacement at lactadherin concentrations of 1 to 4 nM.
Binding competition correlated to functional inhibition of factor
VIIIa-factor IXa (factor Xase) enzyme complex. In contrast to annexin
V, lactadherin was an efficient inhibitor of the prothrombinase and the
factor Xase complexes regardless of the degree of membrane curvature
and the phosphatidylserine content. Lactadherin also inhibited the
factor VIIa-tissue factor complex efficiently whereas annexin V was
less effective. Because the inhibitory concentration of lactadherin was
proportional to the phospholipid concentration, and because lactadherin
was not an efficient inhibitor in the absence of phospholipid, the
major inhibitory effect of lactadherin relates to blocking phospholipid
sites rather than forming inhibitory protein-protein complexes.
Lactadherin was also an effective inhibitor of a modified whole blood
prothrombin time assay in which clotting was initiated by dilute tissue
factor; 60 nM lactadherin prolonged the prothrombin time 150% versus
20% for 60 nM annexin V. These results indicate that lactadherin can
function as a potent phospholipid-blocking anticoagulant.
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