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Lipoprotein-associated coagulation inhibitor (LACI) is a cofactor for
heparin: synergistic anticoagulant action between LACI and sulfated
polysaccharides
TC Wun
Monsanto Co, Chesterfield, MO 63198.
Lipoprotein-associated coagulation inhibitor (LACI) is a plasma-derived
protein that inhibits tissue factor (TF)/factor VIIa-induced coagulation in
a factor Xa-dependent manner. The roles of endogenous plasma LACI and
exogenously added LACI and heparin, in the regulation of coagulation,
initiated via the intrinsic and extrinsic pathways, were studied using the
activated partial thromboplastin time (APTT) and the modified prothrombin
time (PT) assays, respectively. Both LACI- depleted plasma and normal
plasma have identical APTTs and similar prolongations of the APTT in
response to heparin; both are fully anticoagulated (arbitrarily defined as
clotting times of greater than 1 hour) at similar concentrations of
heparin. These results indicate that heparin is an effective anticoagulant
when coagulation is initiated by the intrinsic pathway and that endogenous
LACI is not significantly involved in the regulation of this pathway. The
PT of normal plasma is only marginally longer than that of LACI-depleted
plasma in the absence of heparin, suggesting that endogenous plasma LACI
has a very limited capacity to inhibit TF-induced clotting. However, in the
presence of heparin, the PTs of LACI-depleted plasma and normal plasma are
different. Prolongation of the PT occurred only moderately and linearly
with increasing concentrations of heparin in LACI-depleted plasma. In
contrast, normal plasma showed a greater extent of PT prolongation in
response to heparin and the plasma became fully anticoagulated at a certain
threshold concentration of heparin. These results suggest that LACI serves
as a cofactor for heparin and thus greatly enhances the inhibition of
TF-induced coagulation. LACI-depleted plasma was supplemented with purified
recombinant LACI and/or heparin and the effects on TF-induced clotting were
studied. A combination of LACI and heparin greatly enhanced anticoagulation
compared with LACI or heparin alone. Many sulfated polysaccharides were
also found to enhance the LACI-dependent inhibition of TF-induced clotting.
By weight, the relative potencies of these compounds are: low molecular
weight heparin (mean Mr, 5,100) greater than unfractionated heparin greater
than low molecular weight heparin (mean Mr, 3,700) greater than pentosan
polysulfate greater than dermatan sulfate greater than dextran sulfate
greater than heparan sulfate. Based on the above results, it is concluded
that LACI is a cofactor for heparin in the inhibition of TF- induced
clotting and that LACI and sulfated polysaccharides act synergistically in
whole plasma.
Volume 79,
Issue 2,
pp. 430-438,
01/15/1992
Copyright © 1992 by The American Society of Hematology
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