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Biochem. and Medical Genetics
BGEN 3020
Jason Leboe- Mcgowan

Chapter 11 Thrombogenesis: The Coagulation System Hemostasis: things in our body that prevents clots from developing in BV’s. If these clots were not prevented, the pt either has DIC, thrombotic thrombocytopenic purpura (TTP), or HUS, and all of them lead to death. So, why don’t we form clots in our small BV’s? *small blood vessels include arterioles, venules, and capillaries, while small airways include terminal bronchioles, resp bronchioles, alveolar duct, and alveolus]. So, why don’t we form clots? B/c we have coagulation factors such as: heparin, PGI Protein 2,and S, and tissue plasminogen activator. So all of these things are used to prevent little clots occurring in our small blood vessels. 1. Heparin (a GAG, a mucopolysaccharide). It is normally found in the body and helps prevent formation of clots. How does heparin work? It ENHANCES antithrombin III. Antithrombin III is made In the Liver (like all other proteins). Therefore, heparin gets the credit for anticoagulating you, but its antithrombin III does all the work. Antithrombin III neutralizes most of the coagulation factors. So, we have a little bit of heparin in our small vessels, which prevents clotting from occurring. 2. PGI 2 prostacyclin, made from endothelial cells, a vasodilator. When the vessel is vasodilated, and blood flows faster, it is more difficult for things to stick; therefore, it’s more difficult for a thrombus to stick b/c it blows away so fast. Therefore, vasodilatation is antagonistic to forming thrombi in anything b/c everything is moving too quickly. PGI 2lso prevents platelet aggregation. 3. Protein C and S are Vit K dependent factors (as are factors 2, 7, 9, 10). Functions of protein C and S: they INACTIVATE (ie neutralize or get rid of) two things – factors 5 and 8. They actually inhibit factors 5 and 8 in our body. This is interesting b/c antithrombin III cannot inhibit these. Antithrombin III can only inhibit serine proteases, and Factor 5 and 8 are not serine proteases. 4. t-PA (tissue plasminogen activator) – this is what we use to dissolve a clot in a pt with coronary thrombosis – it activates plasminogen, which produces plasmin. Plasmin basically eats everything in site. Deficiency in any of the anticoagulants: So, if we are def in any of these things (heparin, PGI , 2 protein C and S, and t-PA), clots would form. In other words pt will be thrombogenic. Why are pts on birth control thrombogenic? B/c it increases the synthesis of 5 and 8, increases syn of fibrinogen, and inhibits antithrombin III. So, birth control pills are blocking heparin by inhibiting ATIII. Therefore, the estrogen of the pill is thrombogenic, thereby assisting in the formation of clots. Deadly duo: woman on birth control and smoking = bad; smoking is thrombogenic b/c it damages endothelial cells (so both are thrombogenic). Formation of a stable clot For example: a pt is shaving and cut himself. How do we stop bleeding when you cut a small BV (not talking about muscular arteries – need to plug that) – we’re referring to an injury/cut/damage of a small vessel (ie arteriole, venule, capillary. What will stop the bleeding? To determine this we use bleeding time as ie: bleeding time is used to evaluate platelet function. Example: If pt has hemophilia A and has no factor 8, the pt will still have a NORMAL bleeding time b/c bleeding time has NOTHING to do with coagulation factors. Bleeding time is purely a PLATELET thing. 1. How do they perform the test? Cut the pt (inflict wound), start stop watch, and dab wound every thirty sec; when the wound stops bleeding, this is the pt’s bleeding time – normally it is 7-9 mins. 2. The pathway of bleeding time: When the vessel is cut, tissue thromboplastin is released (which activates the extrinsic coagulation system, but has nothing to do with bleeding time). The cut exposes collagen and of course Hageman factor (factor 12) is activated by the exposed collagen; hence the intrinsic pathway is activated, but this has nothing to do with bleeding time, either. Endothelial cells and megakaryocytes make an adhesion product (a type of glue) whose special purpose is to stick to platelets – vWF. vWF is part of the factor 8 molecule and is made in 2 places – megakaryocytes in the BM and endothelial cells. What’s made from megakaryocytes? Platelets; which carry a little bit of glue with them in their granules. Also, platelets are made in the endothelial cells. So, when you damage the small BV’s, vWF is exposed and platelets have receptors for vWF – which is basically an adhesion molecule (just like neutrophils had receptors for the endothelial cell made by the endothelial cell). If neutrophils cannot stick to venules, then they cannot get out to kill bugs. Same concept here – platelets have to stick to before they can do their thing – so vWF is the adhesion molecule that allows them to do that. So, now the platelet sticks – called platelet adhesion. When the platelet sticks, it causes the platelet to release chemicals – most imp chemical is ADP – this is a potent aggregating agent, and causes platelets to stick together. They start to help form a thrombus to begin to stop the bleeding. However this is not enough to complete the process. So, this is called the release rxn – when the platelet sticks, it causes the platelet to release chemicals, and the most imp chemical is ADP. When platelets come by, they will stick together (b/c of the ADP) and the bleeding will go down. But still not enough; needs another chemical. As soon as the platelet has the release rxn, it starts synthesizing its own unique substance – Thromboxane A ; plate2ets make it b/c they are the only cell in the body that has thromboxane synthase. So, it can convert PgA into TxA , 2 2 potent vasoconstrictor. This is important in stopping bleeding, b/c if you slow rate of blood flow, it will make it easier for platelets to stick together and the platelets won’t get washed away. As opposed to prostacyclin, which is a vasodilator the platelets cannot stick b/c the blood flow has increased. TxA is2the vasoconstrictor in Prinzmetal’s angina. It’s also a bronchoconstrictor, so it has affects in asthmatics b/c it helps LT C4, D4, and E4. So, TxA 2s a vasoconstrictor, a bronchoconstrictor, and a platelet aggregator. It puts the finishing touches on it and causes the platelets to really aggregate, and blocks the injured vessels, and bleeding time has just ended. 3. Integration: Platelets do two things (1) release rxn, where chemical were already made in it were released – so, preformed chemicals were released and (2) it makes its own chemical called TxA 2. This is analogous to MAST CELLS. For example: two IgE’s bridged together, and pollen bridged the gap. This caused the mast cells to have a release rxn (release of preformed chemicals: histamine, serotonin, and eosinophil chemotactic factor). These chemicals then started the inflammatory rxn in a type I HPY rxn. The mast cell released arachidonic acid from its membrane and we ended up making PG’s and leukotrienes. They were released 30 minutes to an hour later and furthered/enhanced type I HPY (inflammatory) rxns. So the mast cell had a release rxn of preformed elements and it made its own PG’s/leukotrienes. That is what platelets did: released its preformed chemicals and made its own chemical: TxA . 2 Plug is temporary – it is a bunch of platelets stuck together and held together by fibrinogen, and is enough to prevent bleeding (to stop bleeding time), but if you scratch or try to open the wound, it would start bleeding again, so it’s not a stable plug. 4. Conditions that arise with increased or decreased bleeding time: Lets screw up bleeding time: (a) What would be an obvious mess up of bleeding time? Thrombocytopenia: decreased platelet count therefore if you have less than 90,000 platelets, you will have a prolonged bleeding time b/c you will not have enough to aggregate. Another dz that has a problem with adhesion molecule defect is vWB dz (MC genetic hereditary dz, AD) (b) MCC prolonged bleeding time = taking aspirin; mechanism? Aspirin blocks platelet COX, not TxA 2blocked by Dipyrramidal). Endothelial cells have COX, too; so why didn’t the endothelial cells inhibit COX from making PGI ? 2he platelet COX vs the endothelial COX reacts differently to aspirin. Different compounds act differently to non-steroidal. It’s a 9:1 ratio (aspirin block platelet COX more than endothelial COX);
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