Prevention of arterial thrombosis using a novel heparin with enhanced antiplatelet activity and reduced anticoagulant activity.
OBJECTIVE
Thrombosis after arterial injury is often initiated by von Willebrand factor (vWF)-dependent platelet accumulation. A promising antithrombotic strategy is the interruption of platelet/vWF interactions. Previously, we demonstrated how chemical and affinity modification can enhance heparin's anti-vWF activity while reducing conventional anticoagulation. Here, we investigated whether a modified heparin can block platelet-dominated arterial thrombosis.


METHODS
Standard heparin was oxidized with periodate, refined to have high vWF affinity and inhibitory potency, and tested in a guinea pig model of platelet-dependent arterial thrombosis. In this model, a controlled mechanical arterial injury yields cyclic flow variations (CFVs) caused by recurrent accumulation of platelet thrombi.


RESULTS
All six control animals developed CFVs (mean, 10.4 +/- 2.6 CFVs), and six of seven animals treated with standard heparin also developed CFVs (mean, 7.6 +/- 4.6). Only one of six animals treated with the anti-vWF heparin and one of six treated with AJvW-2 (an anti-vWF antibody) developed CFVs (mean, 2.0 +/- 4.9 and 0.5 +/- 1.2, respectively). Thus both the modified heparin and AJvW-2 were more effective than standard heparin (p < 0.03). Bleeding times and platelet counts were unaffected. A modified activated partial thromboplastin time was less prolonged by the modified high-affinity heparin (91 +/- 17) seconds) than by standard heparin (144 +/- 30 seconds; p < 0.01).


CONCLUSIONS
The modified heparin with high vWF affinity was a more effective arterial antithrombotic agent, with fewer conventional anticoagulant effects than standard heparin. Interruption of the vWF/platelet interaction is a promising antithrombotic strategy that may be met by novel heparin-based antithrombotic drugs.
Poletti
L F
LF
Division of Vascular Surgery, Medical College of Virginia, Virginia Commonwealth University, Richmond, USA.
Bird
K
K
Harris
R B
RB
Marques
D
D
Sobel
M
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000925:Anticoagulants / Q000627:therapeutic use*; D020212:Carotid Artery Injuries; D002341:Carotid Artery Thrombosis / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006168:Guinea Pigs; D006487:Hemostasis / Q000187:drug effects; D006493:Heparin / Q000627:therapeutic use*; D008297:Male; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D012008:Recurrence; D014841:von Willebrand Factor / Q000276:immunology / Q000627:therapeutic use*
D000911:Antibodies, Monoclonal; D000925:Anticoagulants; D010975:Platelet Aggregation Inhibitors; D014841:von Willebrand Factor; D006493:Heparin