Antithrombin-heparin covalent complex: a possible alternative to heparin for arterial thrombosis prevention.
BACKGROUND
The anticoagulant effect of heparinoids is attributed to their cofactor activity for antithrombin (AT) and heparin cofactor II. In patients with thrombosis, however, thrombin is often protected from AT-dependent, heparin-mediated inactivation. The purpose of this study was to compare the properties of unfractionated/standard heparin (UFH/SH) and those of a novel covalent AT-heparin complex (ATH) in a rabbit arterial thrombosis prevention and bleeding model.


RESULTS
Thrombosis in the distal aorta was triggered by vessel wall injury and critical stenosis. Blood flow in the damaged arterial segment was monitored with a flow probe placed distal to the constrictor. Rabbits were given doses of SH (62.5 to 187.5 IU x kg(-1) x 90 min(-1)) or ATH (16 to 65 IU x kg(-1) x 90 min(-1)). Cumulative blood loss from skin incisions was used to assess drug safety. The antithrombotic effects of ATH were greater than those of SH as measured by clot weight, blood flow, and vessel patency; eg, complete thrombus resolution was achieved with ATH (33 to 65 IU/kg), but not SH (125.0 to 187.5 IU/kg). At doses that produced equivalent vessel patency (50% to 60%), blood loss induced by ATH (60.2 microL) was 2.6-fold lower (P<0.05) than that induced by SH (154.6 microL).


CONCLUSIONS
In our experimental system, ATH was able to control arterial thrombosis more effectively than its SH precursor, without pronounced bleeding.
Chan
Anthony K C
AK
Henderson Research Centre, McMaster University, Hamilton, Ontario, Canada.
Rak
Janusz
J
Berry
Leslie
L
Liao
Peng
P
Vlasin
Michal
M
Weitz
Jeffrey
J
Klement
Petr
P
D000818:Animals; D000925:Anticoagulants / Q000009:adverse effects / Q000627:therapeutic use*; D000991:Antithrombins / Q000009:adverse effects / Q000627:therapeutic use*; D001011:Aorta / Q000503:physiopathology; D001158:Arteries; D005337:Fibrin / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D006493:Heparin / Q000009:adverse effects / Q000627:therapeutic use*; D046911:Macromolecular Substances; D011817:Rabbits; D012039:Regional Blood Flow; D013917:Thrombin / Q000378:metabolism; D013927:Thrombosis / Q000503:physiopathology / Q000517:prevention & control*
D000925:Anticoagulants; D000991:Antithrombins; D005343:Fibrinolytic Agents; D046911:Macromolecular Substances; D005337:Fibrin; D006493:Heparin; D013917:Thrombin