Thromboxane TXA

Effect on blood Platelets are the important factors in thrombus formation and aspirin has been shown to inhibit platelet aggregation. They reduce the blood prothrombin level by inhibition of prothrombin synthesis and prothrombin time is prolonged. The aspirin suppresses the synthesis of thromboxane (TXA ) in the platelets. They also prolong the bleeding time due to prevention of platelet aggregation which may be due to inhibition of release of adenosine diphosphate (ADP) from the platelets by salicylates. 

Regulation of blood flow and urine processing in the kidney Prostaglandin E (PGE), PGF, PGl (also called prostacyclin), and thromboxanes (TXA)... 

PG synthesis involves four steps (Figme 2). The first two steps are common to all cells involved in prostaglandin synthesis while the final two steps are cell-specific (14-16). Release of the substrate, arachidonic acid, from membrane phospholipid stores by phospholipase is the initial event in prostaglandin synthesis, and this is followed by formation of the common PG intermediate, PGHj catalyzed by PGH synthase. At this point, rearrangement of PGH to form either stabk (PGD / Ej/ F, ) or unstable (platelet thromboxane - TxA, endothelial prostacyclin - PGy products takes place. The final step, also cell-specific, involves breakdown of the active compounds to irractive metabolites. 

Synthesis of Thromboxanes - TXA (28) still remains elusive to isolation and chemical synthesis. Thromboxane B (TXB2) (29), however, with its more accessible structure has been synthesized by several groups and is readily available. 

Eicosanoids are synthesized and released on demand to interact with specific G-protein-coupied receptors. They include the leukotrienes (LTs), prostaglandins (PCs), and thromboxanes (TxAs). 

The enzyme system responsible for the biosynthesis of PGs is widely distributed in mammalian tissues and has been extensively studied (2). It is referred to as prostaglandin H synthase (PGHS) and exhibits both cyclooxygenase and peroxidase activity. In addition to the classical PGs two other prostanoid products, thromboxane [57576-52-0] (TxA ) (3) and prostacyclin [35121 -78-9] (PGI2) (4) are also derived from the action of the enzyme system on arachidonic acid (Fig. 1). 

In blood platelets and in some other tissues PGG is also transformed to another series of compounds, the thromboxanes,270 which were identified in 1975. Labile hemiacetals, the thromboxanes A (TXA, Fig. 21-7), are derived by rearrangement of PGH (step g). Thromboxane synthase,271-273 which catalyzes the reaction, has characteristics of a cytochrome P450. Cytochromes P450 are known to react with peroxides as well as with 02, and the endoperoxide of PGH may be opened by the synthase prior to rearrangement to TXA.273 Thromboxane A2 is so unstable that its half-life at 37°C in water is 36 s. It is spontaneously converted to TXB2 (Fig. 21-7), which contains an -OH group at C-15. The thromboxanes B are much more stable than TXA but are not very active physiologically. 

Figure 12.11. StractuiES of two thromboxane A receptor blockers (a), and of BM 573, a combined antagonist of both TXA receptor and TXA synthase (b). BM 573 was derived from the diuretic torasemide.

Fuse I, Hattori A, Mito M, Higuchi W, Yahata K, Shibata A, Aizawa Y. Pathogenetic analysis of five cases with a platelet disorder ehvacterized by the absence of thromboxane Aj (TXA2)-induced platelet aggregation in spite of normal TXA binding activity. Thromb Haemost 1996 76 1080-5... 

Phospholipase C (both p and y) catalyzes the hydrolysis of Phosphatidyl inositol bisphosphate (PIPj) leading to the generation of diacylglycerol (DAG) and inositol trisphosphate (IP,). In platelets, thrombin and thromboxane-A, (TxA,) stimulate PLC-p. PLC-P has three isotypes. It is known that PLC-pi and PLC-P3 are activated by G-protein... 

Platelet adenylate cyclase formation in turn is stimulated by prostacyclin (from the endothelium, also called PGy and inhibited by thromboxane-A (from within platelets, also called TXA ). 

Thromboxane A2 also causes contraction of the smooth muscles in the artery, thus minimizing blood loss in the artery in the vicinity of the injury. As mentioned earlier, TXA binds to a "contractile receptor."... 

Thromboxane synthetase has been solubilized and partially purified from human >53 gnd bovine blood platelets and from sheep and bovine lung. The enzyme activity also has been studied in platelet membranes by several workers.39-63 Recent studies indicate that the same enzyme catalyses the formation of TXA2 and hydroxyheptadecatrienoic acid (HHT) in a bimolecular reaction and that the formation of both products is inhibited in parallel.34,60,61 These studies also show that the formation of HHT does not involve TXA2 as an Intermediate and that TXA2 is converted exclusively into TXB2. PGH, the endoperoxlde from eicosapentaenoic acid (C2O 5 3,8,11,14,17) is converted into thromboxane A (TXA ) by platele... 

Although TXA contracts rabbit aorta, as does TXA2, not induce platelet aggregation. Eicosatrienoic acid (C2Q.o,5,8,11) and its endoperoxlde PGH, do not Induce platelet aggregation as do AA or PGH-. ° Eicosatrienoic acid and PGHj are converted only in low yield to nydroxyheptadecadienoic acid and hardly at all into thromboxane... 

In blood platelets and in some other tissues PCC is also transformed to another series of compounds, the thromboxanes, which were identified in 1975. Labile hemiacefals, the thromboxanes A (TXA, Fig. 21-... 

INHIBITION OF PROSTAGLANDIN BIOSYNTHESIS BY NSAIDS The first enzyme in the prostaglandin synthetic pathway is prostaglandin G/H synthase, also known as COX. This enzyme converts arachidonic acid (AA) to the unstable intermediates PGGj and PGH and leads to the production of thromboxane A (TXA ) and a variety of prostaglandins (see Chapter 25). 

PGH2 may be converted to the thromboxane TXA2, a reaction catalyzed by TXA synthase (see Fig. 35.8). This enzyme is present in high concentration in platelets. In the vascnlar endothelium, however, PGH2 is converted to the prostaglandin PGI2... 

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