Circulation, Vol 89, 1523-1529, Copyright © 1994 by American Heart Association
DT Eitzman, L Chi, L Saggin, RS Schwartz, BR Lucchesi and WP Fay
BACKGROUND: Platelets contain several factors that inhibit heparin. This
study was designed to assess the heparin-neutralizing activity present in
acute, platelet-rich arterial thrombi formed at sites of arterial injury in
animals. METHODS AND RESULTS: Platelet-rich thrombi (n = 3) were induced in
pig coronary arteries by balloon catheter- mediated arterial injury.
Soluble extracts were prepared from each thrombus and assayed for the
capacity to inhibit heparin in an in vitro clotting assay (activated
partial thromboplastin time). Mean heparin- neutralizing activity was 28 U
of heparin neutralized per milliliter of thrombus, indicating that 1 vol of
coronary thrombus completely inhibited the heparin present in 140 vols of
therapeutically anticoagulated (0.2 U heparin/mL) plasma. In contrast,
thrombus extracts had no effect on the anticoagulant activity of hirudin, a
direct-acting thrombin inhibitor. The heparin-neutralizing activity present
in coronary thrombi bound to heparin-agarose and was eluted from it by 1.4
mol/L NaCl, suggesting that platelet factor 4 mediated the antiheparin
effect of thrombi. Consistent with this hypothesis, a murine monoclonal
antibody to rabbit platelet factor 4 nearly completely inhibited the
heparin-neutralizing activity present in rabbit thrombi (n = 3) generated
by carotid artery injury. CONCLUSIONS: Extracts prepared from platelet-rich
arterial thrombi significantly inhibit the in vitro anticoagulant potency
of heparin but not of hirudin. This antiheparin effect appears to be
mediated by platelet factor 4. These results are consistent with the
hypothesis that localized inhibition of heparin at sites of platelet
activation may reduce its antithrombotic efficacy. In addition, they
suggest an additional mechanism for the apparent superiority of hirudin
over heparin as a thrombin inhibitor at sites of arterial injury.
ARTICLES
Heparin neutralization by platelet-rich thrombi. Role of platelet factor 4
Departments of Internal Medicine (Cardiology), University of Michigan Medical School, Ann Arbor.
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