Inhibition of thrombus formation

The year of 1961, when Vincent Gott11 observed the inhibition of thrombus formation by immobilized heparin for the first time, was marked as the second birth date of heparin, since it was for the first time isolated from liver tissue. Its anticoagulant action was detected in 1892. Although more than 20 years have passed since Gott s publication, there is still much confusion concerning the views on the mechanism of enhanced thromboresistance of heparin-modified polymers, which greatly hinders the introduction of HCP into clinical practice. 

Gruber A, Hanson SR, Kelly AB, et al. Inhibition of thrombus formation by activated recombinant protein C in a primate model of arterial thrombosis. Circulation 1990 82 578-585. 

Prostacyclin (5 og/kg/min IV) plus aspirin plus dipyrimadole 27.0 Platelet inhibition and vasodilation Inhibition of thrombus formation (84)... 

Most drug discovery efforts focus on thrombin inhibition as a means to prevent the serious consequences of thrombus formation in myocardial infarction and stroke. Thrombin inhibitors may also prevent clot formation in patients prone to deep vein thrombosis or repeat heart attack. In combination with thrombus dissolution therapies, thrombin inhibitors may decrease the incidence of reocclusion due, in part, to the release of active clot-bound thrombin. 

Liu MW, Hearn JA, Luo J F et al. Reduction of thrombus formation without inhibiting coagulation factors does not inhibit intimal hyperplasia after balloon injury in pig coronary arteries. Coron Artery Dis I 996 7(9) 667-671. 

Rowntree LG, Shionoya T (1927) Studies in extracorporeal thrombosis. I. A method for the direct observation of extracorporal thrombus formation. II. Thrombosis formation in normal blood in the extracorporeal vascular loop. III. Effects of certain anticoagulants (heparin and hirudin) on extracorporeal thrombosis and on the mechanism of thrombus formation. J Exp Med 46 7-26 Scott NA, Nunes GL, King SB III et al. (1994) Local delivery of an antithrombin inhibits platelet-dependent thrombosis. Circulation 90 1951-1955... 

PGI 2 (Epoprostenol) Inhibits platelet aggregation. Reduce incidence of thrombus formation. Also used in angina, pulmonary hypertension, and Raynaud s phenomenon. Headache, nausea, vomiting, anxiety, Gl upset. 

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... 

Due to the pivotal role of platelets in thrombus formation, especially in the arterial system, inhibition of platelet function has become a central pharmacological approach. Antiplatelet drugs are given in order to prevent and treat thromboembolic diseases such as coronary heart disease, peripheral and cerebrovascular disease. They have also revolutionized the procedures of invasive coronary interventions as they reduce the risk of restenosis and thrombosis. 

The aggregation of platelets contributes to the development of atherosclerosis and to the formation of acute thrombus. The activated platelets that adhere to the vascular endothelium generate lipid peroxides and oxygen free radicals, inhibiting the endothelial formation of prostacyclin and nitric oxide. 

N-Nitrosamines have been shown to be inhibitors of cysteine-containing enzymes. For example, dephostatin and other N-methyl-N-nitrosoanilines (1) were found to be inhibitors of the protein tyrosin phosphatases, papain and caspase [90,91]. Inhibition results from the S-nitrosation of the critical cysteine residues in the active sites of the enzymes by the nitrosamines. Compounds 6 and 7 have been found to inhibit thrombus formation in arterioles and venules of rats [92], while N-nitrosamide 9 exhibited vasodilation and mutagenicity as a result of NO release [93]. 

Figure 22.5 (a) Injury to endothelial cells can lead to thrombosis. Healthy endothelial cells secrete two factors that inhibit thrombus formation (i) prostacyclins, which inhibit aggregation of platelets and (ii) a factor that facilitates conversion of plasminogen to plasmin. Injury to endothelial cells can facilitate thrombosis since (i) they do not secrete prostacyclins (ii) they do not secrete plasminogen activator and (iii) they secrete a factor that stimulates thrombosis. (b) Diagram of an atheroscle-rosed artery containing a thrombus. A thrombus is blocking the lumen of the artery that is not totally blocked by plaque. 

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