Phospholipids blood clotting

Another vasoactive substance produced by the endothelium is thromboxane A2 (TxA2). Normally, small amounts of TxA2 are released continuously however, increased synthesis appears to be associated with some cardiac diseases. Synthesized from arachidonic acid, a plasma membrane phospholipid, TxA2 is a potent vasoconstrictor. Furthermore, this substance stimulates platelet aggregation, suggesting that it plays a role in thrombotic events such as myocardial infarction (heart attack). Nonsteroidal anti-inflammatory drugs such as aspirin and ibuprofen block formation of TxA2 and reduce formation of blood clots. 

In blood clotting, the binding of Ca2+ by prothrombin anchors it to phospholipid membranes derived from blood platelets, thus bringing the prothrombin close to the proteins that mediate its... 

Trans fatty acids are produced during the commercial hydrogenation of plant oils (Chapter 11). Some margarines contain these fatty acids, as do some commercially prepared snack foods (e.g. biscnits, cookies, cakes, crisps, chips). In addition, bacteria in the rnmen of rnminants prodnce trans fatty acids, which are therefore present in dairy prodnce and meat. Trans fatty acids can be incorporated into the phospholipids of the plasma membrane of endothelial and other cells, resulting in damage to the membranes. Furthermore, these abnormal fatty acids can interfere in the production of thromboxanes, prostacyclins or leucotrienes and hence interfere in control of blood clotting, immune cell activity and inflammation (Chapter 11). 

Since predators of snakes (and humans) have to deal with snake venoms as defenses, they are included here, even though they serve in predation. Snake venoms are primarily enzymes (proteins), especially of the phospholipase A2 type, which breaks down cell membrane phospholipids hydrolytically. Other snake venoms such as cobrotoxin contain peptides with 60-70 amino acid residues. Pharmacologically, they have neurotoxic, cytotoxic, anticoagulant, and other effects. The neurotoxins, in turn, can have pre- or postsynaptic effects. Snake venoms with both neurotoxic and hemolytic effects on the heart are known as cardiotoxins. Cytotoxins attach to the cells of blood vessels and cause hemorrhage. Snake venom factors may stimulate or inhibit blood clotting. Finally, platelet-active factors can contribute to hemorrhage. 

Messenger substances derived from phospholipids can also function as hormones and serve for communication between cells. An important extracellular messenger substance formed from phospholipids is lysophosphatidic acid (l-acyl-sn-glycerine-3-phos-phate). Lysophosphatidic acid (lysophosphatidic acid, LPA) is released by platelets and other cells and reaches its target cells via the circulation. As a product of the blood clotting process, LPA is an abimdant constituent of serum, where it is found in an albu-min-boimd form. 

The most obvious effect of a deficiency in vitamin K in animals is delayed blood clotting, which has been traced to a decrease in the activity of prothrombin and of clotting factors VII, IX, and X (Chapter 12, Fig. 12-17). Prothrombin formed by the liver in the absence of vitamin K lacks the ability to chelate calcium ions essential for the binding of prothrombin to phospholipids and to its activation to thrombin. The structural differences between this abnormal protein and the normal prothrombin have been pinpointed at the N terminus of the 560 residue glycoprotein.e f Tryptic peptides from the N termini differed in electrophoretic mobility. As detailed in Chapter 12, ten residues within the first 33, which were identified as glutamate residues by the sequence analysis on normal prothrombin, are actually y-carboxyglutamate (Gla). The same amino acid is present near the N termini of clotting factors VII, IX, and X. 

Arachidonic acid is not present in significant amounts in tissues as the free acid but is stored as a fatty acid at the sn-2 position of phospholipids. Prostaglandin biosynthesis is initiated by the interaction of a stimulus with the cell surface. Depending on the cell type, the stimulus can take the form of a hormone, such as angiotensin II or antidiuretic hormone, or a protease such as thrombin (involved in blood clotting), or both hormone and protease. These agents bind to a specific receptor that activates a phospholipase A2 that specifically releases the arachidonic acid from a phospholipid such as phosphatidylcholine. The release of arachidonic acid by phospholipase A2 is believed to be the rate-limiting step for the biosynthesis of eicosanoids. 

Platelets adhere to each other and to foreign surfaces and this property is referred to as platelet adhesion or aggregation or similar terms. Platelet aggregation is the initial stage of formation of a blood clot and is accompanied by release of phospholipids and specific clotting factors that trigger blood coagulation. 

The binding of prothrombin to phospholipids can be inhibited by chelating Ca2+ by EDTA 0ethylenediaminetetraacetate), which binds both Mg2+ and Ca2+ and inhibits several stages of blood clotting it can also be used to inhibit clotting in blood samples. 

Liposomes were discovered by Dr. Alec Bangham in 1961. During his studies on phospholipids and blood clotting, he found that if he mixed phospholipids and water, tiny phospholipid bilayer sacs, called liposomes, would form spontaneously. Since that first observation, liposomes have been developed as efficient delivery systems for everything from antitumor and antiviral drugs, to the hair-loss therapy minoxidil ... 

Figure 2. Proposed mechanism for blood clotting in mammalian plasma in the intrinsic system. The factor on the left side of reaction (zymogen) is converted to active enzyme by proteolysis. PL = phospholipids. (16a)...

Warfarin (Coumadin ) is a slow-and long-acting blood anticoagulant with a structure resembling that of vitamin K. The structural similarity allows the compound to compete with vitamin K and prevent -y-carboxylation of glutamate residues in Factors II, VII, IX, X, and proteins C and S. The noncarboxylated blood clotting protein precursors increase in both the blood and plasma, but they are unable to promote blood coagulation because they cannot bind calcium and thus cannot bind to their phospholipid membrane sites of activation. 

Blood clotting proteins bind to charged surfaces mainly by ionic forces often reinforced by hydrophobic contribution. Cardiotoxin binding to heparin, phospholipids and polymers illustrates both possibilities. 

The binding site of blood clotting proteins on phospholipids involves both charged and zwitterionic lipids. 

First, phospholipid bilayers which mimic cellular membrane and platelet factor 3, on which several blood clotting factors bind in order to generate the more efficient cascade of enzymatic reactions (J ). They are the vitamin K-dependent proteins II, X and IX which are... 

Search for Topological Changes in the Distribution of Charged Groups at the Phospholipid Interface, Induced by Blood Clotting Factors... 

Thermotropic behavior of phospholipids in the presence of blood clotting factors. The changes in the transition temperature (Tm) of phospholipid mixtures induced by the presence of the proteins were monitored by fluorescence polarization of the hydrophobic probe, DPH, inserted in the bilayers. These changes are generally interpreted as indicative of phase separation, as already demonstrated for the effect of calcium, at concentrations higher than 10 mM in PS-rich bilayers (23), and in the case of some proteins (24). 

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