Thrombus formation control

The major drawback of these classical views is that they fail to take into account the electrical nature of the stable constituents in blood (which are colloidal) and that thrombus formation depends upon factors known to control the aggregation of colloids, namely the electric charge, and its sign and magnitude on the colloids in comparison with that on the arterial walls. 

Venous thrombosis is produced in rats by insertion of a stainless steel wire coil into the inferior caval vein. Platelets as well as plasmatic coagulation are activated on the wire coil. Thrombus formation onto the wire is quantitated by measuring the protein content of the thrombotic material isolated. The kinetics of thrombus formation show an increase in weight and protein content within the first 30 min followed by a steady state between thrombus formation and endogenous thrombolysis leading to a constant protein content of thrombi between 1 and up to 48 h following implantation of the wire coil. Thrombosis incidence in untreated control animals in this model is 100%. The test is used to evaluate antithrombotic and thrombolytic properties of compounds in an in vivo-model of venous thrombosis in rats. 

There have been various reports that metformin increases fibrinolysis, reduces thrombus formation (Weichert and Breddin, 1988) and reduces platelet adhesiveness and aggregation (Holmes et al., 1984). This, however, was mostly felt to be secondary to improved glycaemic control, because similar effects have been reported with sulphonylureas (Vague et al., 1987). In healthy subjects, biguanides should therefore not be used to increase fibrinolytic activity. 

Since anticoagulants such as heparin and vitamin k antagonists have not been found to effectively control arterial thrombosis, the main attention for the past 15 years has been to study platelet function and develop compounds to control the role of the platelet in arterial thrombosis, mainly through the control of platelet aggregation or white thrombus formation. The greatest advance in the last several years has been the discovery, structure determination and biological character-... 

Feng et al. [139] studied the activity of TM reconstituted into the PEM/HBM assembly described in Sect. 2.1. TM is a type ITMP that is a receptor for thrombin and mediates protein C activity in anticoagulant and antiinflammatory pathways. TM functionalization represents a promising strategy to control thrombus formation on the surface of a biomaterial that comes into direct contact with blood, such as the inner surface of an arterial graft. TM was incorporated into vesicles of mono-acrylatePC (Fig. 1) that were then fused onto an amphiphilic terpolymer/PEM/glass coverslip (see Fig. 2). The eosin Y/triethanolamine method [56] was used to polymerize the lipids, after which the supported assembly could be removed from solution for characterization purposes. 

Phlebitis refers to inflammation of the vein wall. It can result in clinical symptoms such as pain and oedema, and can cause thrombus formation which may have serious consequences. Particulate matter is the most widely implicated cause of phlebitis. It is not surprising, therefore, that a link has been proposed between precipitation and phlebitis. The in vitro precipitation models described above may therefore be a good indicator of the phlebitic potential of a formulation. Phlebitis can be tested in vivo, usually by means of a rabbit ear vein model in which the test ear is visually compared with the control ear. 

In this laboratory, an ex vivo test system was developed and utilized to delineate some of the factors affecting thrombus formation on surfaces. The system consisted of a flow-through couette device (Figure 1) placed in an arteriovenous shunt in a dog. The device was designed to allow independent control of blood flow and shear by separate control of the flow rate through the chamber, and of the rotation speed of a central rod, which is coated with the material to be studied. The validation of the method with respect to flow conditions, hematological considerations, and reproducibility has been reported previously (2—4). 

When a synthetic material is exposed to blood, a complicated sequence of events is initiated that can lead to thrombus formation. Two of the early events in the sequence are protein adsorption and subsequently cellular adhesion (I. 2) however the extent to which the cellular adhesion is controlled by the interaction between the adsorbed proteins and the biomaterial has not been clarified, nor has the role which the properties of the biomaterial play in the process. 

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