Animal models of thrombosis

In most animal models of thrombosis, healthy animals are challenged with thrombogenic (pathophysiologic) stimuli and/or physical stimuli to produce thrombotic or occlusive conditions. These models are useful for the screening of antithrombotic drugs. 

Table 10 Animal models of thrombosis and their clinical correlates.

Whether endogenous prostacyclin modulates platelet activity in vivo is uncertain, but studies using cyclo-oxygenase and thromboxane synthase inhibitors in animal models of thrombosis support this hypothesis. Inhibition of platelet deposition on de-endothelialized rabbit abdominal aorta by aspirin is dose dependent, being less at higher doses at which coincident inhibition... 

A number of reports on to vivo studies of the antithrombogenic properties of aspirin have appeared recently. In this regard, it is important to realize that the validity of animal models of thrombosis remains open to question. Platelets from aspirin treated rabbits were found to be morphologically normal, but did not aggregate in the presence of collagen to vitro.23 Thrombus formation induced in rats by typhosa endotoxin was inhibited by aspirin previously administered by stomach tube. 4 Platelets from these animals exhibited a reduced tendency to aggregate vitro and the prevention of thrombus formation could be... 

Pyrlmidopyrimidlnes - Dipyridamole and two analogs, RA233 and RA433, have been studied extensively as platelet aggregation Inhibitors rn vitro and in various animal models of thrombosis.53,54 The mechanism of action of these compounds on platelets appears to involve inhibitory effects on glucose metabolism55 55 cydic AMP phosphodiesterase.27... 

Since the early 1980s, much effort has focused on animal models of acute and chronic neurodegeneration in search of therapeutics for stroke. Neuronal cell death follows strokes, acute ischemic insults, and chronic neurodegeneration, such as Parkinson s disease, Alzheimer s disease (AD), epilepsy, and Huntington s disease. Up to 80% of all strokes result from focal infarcts and ischemia in the middle cerebral artery (MCA), so the commonly used animal models for neuroprotection are produced by temporary or permanent occlusion of the MCA.5 Lesions of the MCA include occlusion by electrocoagulation, intraluminal monofilaments, photochemical effects, thrombosis, and endothelin-1, but all of these models necessitate studying reperfusion events and validating MCA occlusion by behavioral assessments. 

Table 2.3. ANIMAL MODELS OF ARTERIAL THROMBOSIS AND THROMBOLYSIS... 

The rat carotid artery injured by a balloon catheter has been widely used as a model of angioplasty. The rat model is a proliferation model without foam cells (93). This form of injury causes immediate coagulation and thrombosis cascade in which platelets adhere, spread, and degranulate on the denuded surface of the artery, and approximately 24 hours later SMC begin to proliferate. Liposomal BPs, clodronate, and alendronate were injected to male sabra rats, 15 and 3mg/kg, respectively (52,69,76). Marked neointimal formation and decreased luminal area were observed in control animals. Neointima/media (N/M) ratio was 1.3 0.2, and luminal stenosis was 44 3%. LC and LA suppressed intimal growth when administered intravenously on day -1 and day 6. N/M ratios were reduced by 60% and 69% for LC and LA, respectively. 

TFPI, when administered to rabbits, has been shown to have an antithrombotic effect when thromboplastin was used as a thrombogenic challenge (I 10). TFPI was also shown to be an effective inhibitor when thrombosis was induced in rabbit jugular veins by endothelial destruction and restricted blood flow. The antithrombotic and antiprotease actions of TFPI have been tested in several other animal models. Warn-Cramer et al. investigated the effect of immunodepletion of TFPI in factor Vila and Xa induced coagulation in rabbits (III). These rabbits were observed to be sensitized to the procoagulant effects of factor Vila, but not factor Xa in the absence of factor Vila. Two studies have indicated that TFPI administration reduces the lethal effects of . coli administration in a septic shock model in baboons (I 12). These studies also indicated that TFPI may have an anti-inflammatory effect, as an attenuation of the IL-6 response was also observed. Administration of TFPI has been observed to prevent... 

As low levels of protein C activation peptide are found in healthy individuals, it is suggested that protein C is constantly activated to a small degree (124). Protein C administration has been shown to inhibit both arterial and venous thrombosis in animal models (125). Heterozygous protein C deficiency or activated protein C resistance due to factor V mutation is thought to explain 60% to 70% of the cases of familial thrombophilia (I 16). 

Elevated TAFI levels have been found in men with symptomatic coronary artery disease (142). TAFI is also reported to be a risk factor for deep venous thrombosis, A recent report on the high levels of TAFI in the acute phase of ischemic stroke revealed not only elevated levels but also an incremental increase in TAFI with the degree of neurologic deterioration (143). Therefore, the observation by Boffa et al. on the acute phase nature of this protein requires further validation, In addition, Juhan-Vague et al, stated that there is a correlation between TAFI levels and cardiovascular risk factors (144). Animal models may be needed to truly validate studies on TAFI upregulation and its relation to thrombosis. 

Ischemia results from an imbalance of oxygen supply and demand. In patients with ACS, multiple studies of atheroma have implicated inflammation as a critical part of the syndrome. Signs of inflammation in animal models and humans occur with lipid accumulation in the artery wall and plaque development. Plaque rupture and thrombosis have abruptly narrowed or occluded the coronary arteries precipitating ACS (14). 

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