Platelets Enzyme

R7. Ramot, B., Szeinberg, A., Adam. A., Sheba, C., and Gafni, D., A study of subjects with erythrocyte glucose-6-phosphate dehydrogenase deficiency Investigations of platelet enzymes. J. Clin. Invest. 38, 1659-1661 (1959). 

In small doses aspirin inactivates irreversibly platelet enzyme cyclooxygenase, hence thromboxane A is not synthesised. 

The mildness of this defect is supported by the fact that very modest hemostatic defects are noted in patients with diseases involving deficiencies of platelet COX and thromboxane synthase—eg, these patients have no history of increased or decreased bleeding. Blockade of either of these two enzymes inhibits secondary aggregation of platelets induced by ADP, by low concentrations of thrombin and collagen, or by epinephrine. Thus, these platelet enzymes are not necessary for platelet function but may amplify an aggregating stimulus. 

The platelet enzymes involved (90), the complexity of their interactions and of others (91), and their relationships, both physiologically and perhaps philogenetically, with the reactions of certain white blood cells (90, 92) help us to see platelets as living particles. Their aggregation is used as a quantitative aid in immunoassay (93) in a technique that may well be applicable to quantitation of heat aggregatable gammaglobulins (94) and of specific immunoglobulin G (95). 

Whole blood selenium levels can vary between 10 and 3000 ng Se/ml. These levels reflect dietary Intake. With an Se intake of about 50 pg/day, plasma Se levels in humans are about 70 ng/ml, and red blood cell Se is about 90 ng/ml (Levander et a ., 1983). Maximal activity of GSH peroxidase, as determined by assays of the platelet enzyme, is supported where the plasma selenium level is about 100 ng/ml. 

This area has however become even more complex by the abovementioned discovery that salicyclic acid, the major metabolite of aspirin in vivo, counteracts the inhibitory actions of aspirin [430-435]. Salicyclic acid has a much longer half-life in blood than its parent compound and may readily accumulate to plasma concentrations where this anti-inhibitory effect occurs. To complicate matters even further, it has recently been found in the rat that this anti-inhibitory or protective effect of salicyclic acid is considerably greater for the vascular cyclo-oxygenase than for the platelet enzyme [439],... 

ACE inhibitors inhibit the degradation of bradykinin and potentiate the effects of bradykinin by about 50-100-fold. The prevention of bradykinin degradation by ACE inhibitors is particularly protective for the heart. Increased bradykinin levels prevent postischemic reperfusion arrhythmia, delays manifestations of cardiac ischemia, prevents platelet aggregation, and probably also reduces the degree of arteriosclerosis and the development of cardiac hypertrophy. The role of bradykinin and bradykinin-induced NO release for the improvement of cardiac functions by converting enzyme inhibitors has been demonstrated convincingly with use of a specific bradykinin receptor antagonist and inhibitors of NO-synthase. 

The different pro- and anticoagulatory systems are complex regulated cascades involving blood cells (platelets, monocytes, endothelial cells), enzymes, cofactors, phospholipids, and calcium, which interact with each other... 

Fibrinolytic enzymes (proteases) are used to dissolve thrombus, the insoluble aggregate of fibrin and platelet including several additional cellular and molecular components of the blood. 

Enzymology of proteases in a water-phase is well known, but its alteration in a compartment is poorly understood. There are dramatical changes in reaction rates, in enzyme contractions and in enzyme sensitivity to inhibitors, which are not exactly described. In addition, besides fibrin and platelets there are several cellular and molecular components present in a thrombus compartment, where their influence on the basic fibrinolytic reactions is not known. To study this aspect of fibrinolysis is a task of the near future [4]. 

Acetylsalicylic acid irreversibly inhibits both COX-1 and COX-2 by acetylating the enzymes. Since mature platelets lack a nucleus, they are unable to synthesise new enzyme. The anti-platelet effects of acetylsalicylic acid persist therefore throughout the lifetime of the platelet and the half-life of this effect is thus being much longer than the elimination half-life of acetylsalicylic acid (15 min). Since new platelets are continuously launched into the circulation, the clinically relevant anti-platelet effect of aspirin lasts for up to five days. This is the reason why low doses of acetylsalicylic acid (ca. 100 mg per day) are sufficient in the prophylaxis of heart attacks. 

Unlike aspirin and other cyclooxygenase inhibitors that work on the COX-1 and COX-2 enzymes, acetaminophen works on the COX-3 enzyme, which is present in the spinal column and brain. This helps it to avoid shutting down prostaglandin function elsewhere in the body, which is why it has no anti-inflammatory effects and does not affect blood platelets or the stomach lining. 

Peroxidation is also catalyzed in vivo by heme compounds and by lipoxygenases found in platelets and leukocytes. Other products of auto-oxidation or enzymic oxidation of physiologic significance include oxysterols (formed from cholesterol) and isoprostanes (prostanoids). 

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