Thrombosis surface

The influence of specific proteins in the complex mixture in the adsorbed layer on cellular reactions has yet to be demonstrated directly, but purified proteins preadsorbed to surfaces and then exposed to blood provide information on the potential of various proteins to influence cellular events. A much more comprehensive study of this type which includes proteins such as von Willebrand factor and a2-macroglobulin is presented in this volume (63). The ability of proteins to enhance or repress cellular reactions when used as pure preadsorbates does not indicate the magnitude of the role played by the protein when present in the complex layer adsorbed from plasma. The protein may be present in very small amounts in the plasma-derived adsorbate relative to the purified preadsorbed layer. For example, von Willebrand factor is present at very low concentrations in plasma (10-15 xg/mL) and is therefore probably present at very low levels in the absorbed layer formed on polymers exposed to plasma. Thus, although von Willebrand factor undoubtedly could be an important factor in surface thrombosis, its influence at the very low adsorption levels likely to exist in vivo must be demonstrated. However, the knowledge of which proteins are potentially important, derived from preadsorption studies, is extremely useful in focusing attention on specific proteins to study in the actual adsorbed layer. 

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. 

Thrombin, a serine protease, cleaves fibrinogen into fibrin to create a fibrous plug and also amplifies its own production through the activation of factor XI and cofactors V and Vlll. Thrombin also plays a crucial role in the activation of platelets through the cleavage of the protease-activated receptors on the platelet surface. Antagonists of G-protein-coupled protease-activated receptor PARi have been synthesised to study the role of thrombin PARi receptor in thrombosis and vascular injury. Thrombosis is the most common cause of death in the industrialised world and, whether through venous thromboembolism, myocardial infarction or stroke, ultimately involves the inappropriate activity of... 

It will be later proposed that an ideal blood-contacting surface would be one on which endothelial cells could adhere and grow normally to create a complete endothelium endowed with the physiological functions of such tissue. But the correct expression of such physiological functions requires normal blood flow conditions. And the correlation of thrombosis with regions of disturbed flow suggests that shear stress may alter the production of endothelial cell-derived products and directly affect endothelial cell function. 

P.N. Sawyer, S. Srinivasan, The role of electrochemical surface properties in thrombosis at vascular interfaces cumulative experience of studies in animals and man. Bull, N. Y. Acad. Med. 48 (1972) 235-256. 

Detection of thrombus is another clinically important goal. Contrast enhancement of vascular thrombosis has been achieved with a microbubble having a small peptide covalently attached to its surface that selectively binds to the GPIIb/llla fibrinogen receptor expressed on the surface of activated platelets that attach to thrombi. 

The increasing demand for synthetic biomaterials, especially polymers, is mainly due to their availability in a wide variety of chemical compositions and physical properties, their ease of fabrication into complex shapes and structures, and their easily tailored surface chemistries. Although the physical and mechanical performance of most synthetic biomaterials can meet or even exceed that of natural tissue (see Table 5.15), they are often rejected by a number of adverse effects, including the promotion of thrombosis, inflammation, and infection. As described in Section 5.5, biocompatibility is believed to be strongly influenced, if not dictated, by a layer of host proteins and cells spontaneously adsorbed to the surfaces upon their implantation. Thus, surface properties of biomaterials, such as chemistry, wettability, domain structure, and morphology, play an important role in the success of their applications. 

Another example of a serious adverse effect that can surface through close systematic monitoring is the association of clozapine treatment with venous thromboembolytic complications (514, 515). Six cases of pulmonary embolism and six cases of venous thrombosis were reported to the Swedish Adverse-Reaction... 

Schematic view of the role of coagulation factor Xa in arterial thrombosis. After endothelial injury, platelets adhere to the subendothelial matrix. The procoagulant activity of the arterial clot can be attributed to the formation of the prothrombinase complex on the platelet surface which cleaves prothrombin and produces thrombin. Thrombin subsequently acts as a strong agonist of further platelet aggregation.

In addition to the presently available treatments, a new concept is evolving that targets and inhibits the prothrombi-nase multienzyme complex on the platelet surface thus inhibiting further thrombin generation in arterial thrombosis. 

Optimal stent implantation and new antiplatelet therapy have reduced the thrombotic complication after stent implantation, dramatically. However, thrombosis remains a challenge in some lesions and patient subgroups. As an initial and unavoidable event during stent implantation, thrombosis and platelet activation are also involved in the development of neointimal hyperplasia. Stents coated with heparin and other antithrombotic drugs have been demonstrated to decrease thrombotic complications, although their effect on neointimal hyperplasia remains uncertain. As heparin is attached to the stent surface, we divide thromboresistant stents as heparin-coated stents and drug-eluting thromboresistant stents. 

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