Thrombus dissolution

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. 

In a cocaine abuser, resolution of intracoronary thrombosis with direct thrombin has been successfully attempted (46). Medical treatment was started with tirofiban and low molecular weight heparin, and 48 hours later they were replaced with bivalirudin, a direct thrombin inhibitor, in an initial bolus dose of 0.1 mg/kg followed by an infusion of 0.25 mg/kg/hour. Repeat angiography 48 hours after bivalirudin showed near total thrombus dissolution with resolution of the electrocardiographic abnormalities. 

Circulating radiolabeled platelets adhered and aggregated on two polyethylene catheters inserted retrograde into the carotid arteries. Increasing platelet retention is shown in the sequence A through EThe beginning of thrombus dissolution is seen in F . The small platelet collection is best shown in the precatheter sample (A). Blood was drawn... 

The success of thrombus lysis depends mainly on how large the thrombus is and whether any blood flow stiU remains. The outcome is better the larger the surface of the entire thrombus exposed to the thrombolytic agent. As the clot ages, the polymerization of fibria cross-linking and other blood materials iacreases and it becomes more resistant to lysis. Therefore, the eadier the thrombolysis therapy starts, the higher the frequency of clot dissolution. Thrombolytic agents available are Hsted ia Table 7 (261—276). 

Partial or complete dissolution of the hemostatic plug or thrombus by plasmin. 

At present, the binary water-soluble preparation of heparin and proteolytic enzymes is being applied for the treatment of thromboses. For instance, injection into the bloodstream of heparin-plasmin complex or a heparin-plasmin-streptokinase preparation leads to the total dissolution of the thrombus, while if introduced separately, heparin and streptokinase do not display the lytic action at all, and plasmin, alone or together with streptokinase, dissolves the thrombus only partially 132>. The treatment of acute thrombophlebitis with trypsin resulted in a full dissolution of the thrombus and in an increase of antithrombin III in the blood 133). Administration of trypsin together with heparin has an effect similar in efficiency to the action of the heparin-plasmin complex 134>. The use of a mix of heparin and urokinase for improving tbrom-boresistance of polymeric materials was also described 13S). These substances were immobilized by preliminary coating of the surface of a polymer with a graphite layer and subsequent adsorption of heparin and the enzyme. 

Normal hemostasis is a balance between excessive and inadequate blood clotting. Overactive blood clotting is harmful because of the tendency for thrombus formation and occlusion of arteries and veins. Vessels may become directly blocked by the thrombus, or a portion of the thrombus may break off and create an embolism that lodges elsewhere in the vascular system. The tendency for excessive thrombus formation in the venous system is usually treated with anticoagulant drugs such as heparin and warfarin. Platelet inhibitors such as aspirin help prevent arterial thrombogenesis. Thrombolytic drugs (streptokinase, t-PA) that facilitate the dissolution of harmful clots may successfully reopen... 

The use of abciximab in a rescue manner (as opposed to the usual prophylactic use) when newly formed intracoronary thrombus occurs as a complication of coronary angioplasty has been examined in a small trial [173], Dissolution of thrombus and restoration of coronary blood flow were reported to be readily achieved using abciximab (0.25mg/kg i.v. bolus followed by 10 g/min infusion for 12h). 

The limitations of PDT are possibly the result of needing to keep the dose of the photosensitizer and the irradiating light low enough to avoid collateral damage. The low dose is most likely sufficient to cause thrombus formation but insufficient to achieve the desired effect of vascular wall damage. Such an occlusion may thus be temporary, due to dissolution of the clot and vessel re-canalization. 

Members of the biomaterials community continue to search for experimental animal models that assess the thromboresistance of polymers. We developed a new animal model involving rapid, simple retrograde cannu-lation of the goat s carotid arteries. The method promises to assess potential biomaterials, evaluate drugs that may decrease thrombus growth, and measure real-time thrombus growth and dissolution. A critical aspect of this new experimental model is that the continuously monitored net platelet retention data can be modeled mathematically. 

Figure 2. Thrombus growth and dissolution measured by carotid artery catheter region-of-interest scintillation counting.

Our experimental model continuously evaluates net platelet accumulation, not necessarily thrombus growth and dissolution. These platelet kinetics are very unusual (see Figure 2) ... 

The fibrinolytic system is activated in response to the presence of an intracellular thrombus or clot. The process of clot dissolution is initiated by the conversion of plasminogen to plasmin. Plasminogen activation is catalyzed by two endogenous highly specific serine proteases, urokinase-type plasminogen activator and tissue-type plasminogen activator (t-PA) (see Chapter 31). 

The idea that pharmacological dissolution of an occlusive coronary artery thrombus could result in myocardial salvage, with a smaller area of infarction and clinical benefit. 

Patients have a limited 3-h window starting at the onset of stroke symptoms to be treated with clot-dissolving (thrombolytic) drugs [42]. However, there is strict exclusion criteria for patients to be treated with thrombolytic drugs in an effort to prevent potential intracerebral and gastrointenstinal hemorrhaging associated with the treatment. Therefore researchers have proposed nonpharmaceutical treatments to retrieve the clot mechanically, in which blood flow would be restored immediately compared to therapeutic clot dissolution. Consequently, the FDA has approved the use of mechanical devices to retrieve a thrombus [43,44],... 

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