Clots dissolution

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). 

Tissue Plasminogen Aetivator (tPA). While streptokinase and urokinase can effectively induce clot dissolution in the majority of patients if given early, they lack clot specificity. Treatment with these enzymes results in a systemic lytic state attributable to their degradative action on circulating fibrinogen. Tissue plasminogen activator (tPA) was developed to achieve rapid and specific thrombolysis. 

Certain enzymes, proenzymes, and their substrates are present at all times in the circulation of normal individuals and perform a physiologic function in the blood. Examples of these functional plasma enzymes include lipoprotein Upase, pseudocholinesterase, and the proenzymes of blood coagulation and blood clot dissolution (Chapters 9 and 51). The majority of these enzymes are synthesized in and secreted by the liver. 

Phillips DA, Davis MA, Fisher M. Selective embolization and clot dissolution with tPA in the internal carotid artery circulation of the rabbit. AJNR Am J Neuroradiol. 1988 9 899-902. 

Little intravascular coagulation of blood occurs in normal physiological conditions. Hemostasis involves the interplay of three procoagulant phases vascular, platelet, and coagulation) that promote blood clotting to prevent blood loss (Fig. 22.1). The fibrinolytic system prevents propagation of clotting beyond the site of vascular injury and is involved in clot dissolution, or lysis (Fig. 22.2). 

Thrombolytics Facilitate clot dissolution used to reopen occluded vessels in arterial... 

Within the blood vessels. Example blood coagulation / clot dissolution. No problems of distribution here, drug molecules of any size and shape can be used (when intravenously applied). 

Ultrasound-assisted soft digestion has been used for other practical purposes from which analytical chemists can derive new applications. One case in point is in medicine, where ultrasound has been used as an adjunctive therapeutic treatment for clot dissolution of pharmacological thrombolysis. The combination of externally applied low-frequency high-intensity US with fibrinolytic therapy resulted in more rapid and complete reperfusion than the application of US or administration of fibrinolytic agents alone [42]. 

Enzyme inhibition is one of the ways in which enzyme activity is regulated experimentally or naturally. Most therapeutic drugs function by inhibition of a specific enzyme. Inhibitor studies have contributed much of the available information about enzyme kinetics and mechanisms. In the body, some of the processes controlled by enzyme inhibition are blood coagulation (hemostasis), blood clot dissolution (fibrinolysis), complement activation, connective tissue turnover, and inflammatory reactions. 

Elevated Lp(a) is a major independent risk factor for atherosclerosis in patients with familial hypercholesterolemia. This risk is independent of levels of LDL, HDL, age, sex, and smoking habits, and is primarily dependent on genetic factors. The exact mechanism of Lp(a) acceleration of atherosclerosis is not understood but may be attributable to its potential inhibition of blood clot dissolution caused by its structural similarity with plasminogen (see above and Chapter 36). 

Intravenous pantoprazole or lansoprazole clearly is the preferred therapy in patients with acute bleeding ulcers. The theoretical benefit of maximal acid suppression in this setting is to accelerate healing of the underlying ulcer. In addition, a higher gastric pH enhances clot formation and retards clot dissolution. 

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). 

Explain the effects of each of the following substances on blood coagulation or clot dissolution ... 

Tissue-type plasminogen activator facilitates clot dissolution by converting plasminogen into plasmin directly on the clot. 

When blood is lost or clotting is initiated in some other way, a complex cascade of biochemical reactions is set in motion, which ends in the formation of a network or clot of insoluble protein threads enmeshing the blood cells. These threads are produced by the polymerisation of the molecules of fibrinogen (a soluble protein present in the plasma) into threads of insoluble fibrin. The penultimate step in the chain of reactions requires the presence of an enzyme, thrombin, which is produced from its precursor prothrombin, already present in the plasma. This is initiated by factor lit (tissue thromboplastin), and subsequently involves various factors including activated factor Vn, DC, X, XI and XII, and is inhibited by antithrombin in. Platelets are also involved in the coagulation process. Fibrinolysis is the mechanism of dissolution of fibrin clots, which can be promoted with thrombolytics. For further information on platelet aggregation and clot dissolution, see Antiplatelet drugs and thrombolytics , (p.697). 

Diamond, S.L., Engineering design of optimal strategies for blood clot dissolution, Annu. Rev. Biomed. Eng., 1, 427 461, 1999. 

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],... 

This approach is based on the fact that fibrin forms the frame- rork or structural support of a clot. Dissolution of the fibrin should result in lysis of the clot with restoration of blood flow. The significance of fibrinolysis the mtential of thrombolysis in treatment of thrombotic coronary occlusion and fibrinolytic mechanisms have been reviewed. 

Diabetes management Treatment for hemophilia A Treatment for hemophilia B Treatment of dwarfism Treatment of anemia Blot clot dissolution Augment immune system fimction... 

Tissue plasminogen activator Blot clot dissolution... 

The present investigations, although limited to the local application of fibrolase, demonstrate that under these conditions the enzyme lyses venous or arterial thrombi rapidly and with no observable systemic or hematologic side effects. In these thrombosis model systems the enzyme, either alone or in combination with antiplatelet therapy, offers a unique, safe, and specific mechanism for clot dissolution and may prove useful as a clinically effective alternative to, or for use in synergistic combination with, presently used thrombolytic agents. 

---