Methods and models to evaluate shear-dependent and surface reactivity-dependent antithrombotic efficacy.
The purpose of the present communication is to evaluate the importance of blood flow and surface reactivity for measurement of antithrombotic drug activity or efficacy in selected model systems of thrombus formation. Such information is essential for proper evaluation of antithrombotic drug profiles. The continuous development of flow-dependent thrombosis models for in vitro (anticoagulated blood) and ex vivo (native blood) studies and their application in in vivo animal models from the early 1970s and onwards are briefly considered. Central to this process was the development of various types of perfusion chambers in which a thrombogenic surface is exposed to flowing blood. Such perfusion chambers have been inserted into arteriovenous (AV) shunts in baboon, pig, dog, and rabbit. These approaches have allowed reproducible testing of traditional and novel experimental antithrombotic drugs, and studies on novel drug strategies under well-defined shear conditions and surface reactivity. Shear-dependent antithrombotic efficacy in these models is observed with anticoagulants such as unfractionated heparin, low-molecular weight heparins, or selective inhibitors of thrombin, Factor Xa, or Factor VIIa. However, the degree of shear dependency depends on the nature of the thrombogenic surface, e.g., the inhibition is more pronounced on a tissue factor (TF)-rich surface than on a collagen-rich surface, particularly at venous or low arterial shear. Platelet antagonists such as the COX-1 inhibitor aspirin, inhibitors of thromboxane A2 (TxA2) synthetase, the TxA2 platelet receptor, and of von Willebrand factor (vWf) are shear dependent also, being more efficient at high arterial shear. In contrast, the platelet ADP antagonist clopidogrel, or antagonists to the active platelet membrane glycoprotein IIb-IIIa complex (GPIIb-IIIa) are shear independent. At extremely high arterial shear, which activates platelets and elicit aggregates of circulating platelets, aspirin looses its antithrombotic effect, whereas ADP and GPIIb-IIIa antagonists still interrupt thrombus formation. In general, results obtained with these models mimic and predict antithrombotic efficacy in man when comparison is possible. Information on antithrombotic efficacy in flow devices with various thrombogenic surfaces is now sufficiently available to suggest recommendations for experimental conditions, particularly with regard to blood flow and reactive surfaces.
Sakariassen
K S
KS
Department of Lead Pharmacology, Pharmacia Corporation, Uppsala and Stockholm, Sweden. kjell.sakariassen@serono.com
Hanson
S R
SR
Cadroy
Y
Y
D000818:Animals; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000295:instrumentation / Q000379:methods*; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D018056:Hemorheology / Q000187:drug effects* / Q000295:instrumentation / Q000379:methods; D006801:Humans; D008955:Models, Cardiovascular; D015539:Platelet Activation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D013314:Stress, Mechanical; D013810:Therapeutic Equivalency; D013927:Thrombosis / Q000097:blood / Q000188:drug therapy / Q000209:etiology
D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors