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Bio.blood Clutting

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Dela Cruz, Ann Justine H. BSBA-MM Dr.Pueyo Blood Clotting When blood vessels are cut or damaged, the loss of blood from the system must be stopped before shock and possible death occur. This is accomplished by solidification of the blood, a process called coagulation or clotting. A blood clot consists of y y a plug of platelets enmeshed in a network of insoluble fibrin molecules. Platelet aggregation and fibrin formation both require the proteolytic enzyme thrombin. Clotting also requires: y
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  Dela Cruz, Ann Justine H.BSBA-MMDr.Pueyo Blood Clotting When blood vessels are cut or damaged, the loss of blood from the system must be stopped before shock and possible death occur. This is accomplished by solidification of the blood, a process called coagulation or clotting.A blood clot consists of  y   a p lug of  p latelets enmeshed in a y   network of insoluble fibrin molecules.Platelet aggregation and fibrin formation both require the proteolytic enzyme thrombin . Clotting also requires: y   calcium ions (Ca 2+ )(which is why blood banks use a chelating agent to bind the calcium in donated blood so the blood will not clot in the bag). y   about a dozen other protein clotting factors . Most of these circulate in the blood as inactive precursors. They areactivated by proteolytic cleavage becoming, in turn, active p roteases for other factors in the system. Initiating the Clotting Process There are two processes that can initiate clotting: y   A very rapid process the so-called extrinsic pathway (upper right) and y   a slower but larger intrinsic pathway (upper left). T he Extrinsic Pathway y   D amaged cells display a surface protein called tissue factor ( TF ) y   Tissue factor binds to activated Factor 7 . y   The TF- 7 heterodimer is a protease with two substrates: o   Factor 9 and o   Factor 10   T he Intrinsic Pathway y   Factor 12 (also called the Hageman factor) circulates in the blood. y   I f blood escapes into tissue spaces (e.g., as a result of an injury), contact with collagens in the tissue spaceactivates Factor 12. y   A ctivated Factor 12 is a serine protease that activates Factor 11 which, in turn, activates y   Factor 9 which, in turn, activates y   Factor 10 .  T he T wo Pathways Converge y   Factor 10  produced by either or, more likely, both pathways  binds and activates Factor 5 . This heterodimeris called p rothrombinase because it is a protease that converts p rothrombin (also known as Factor II ) to thrombin . y   Thrombin has several different activities. Two of them are: o   proteolytic cleavage of  fibrinogen (aka Factor I ) to form:    soluble molecules of  fibrin and a collection of small    fibrino p e p tides   o   activation of Factor 13 which forms covalent bonds between the soluble fibrin molecules converting them into aninsoluble meshwork  the clot .(Thrombin and activated Factors 10 ( Xa ) and 11 ( X I a ) are also serine p roteases . Link to discussion.)  Amp lifying the Clotting Process The clotting process also has several p ositive feedback loo p s which quickly magnify a tiny initial event into whatmay well be a lifesaving plug to stop bleeding. y   The TF-7 complex (which started the process) also activates Factor 9 . o   Factor 9 binds to Factor 8 , a protein that circulates in the blood stabilized by another protein, von WillebrandFactor ( vWF ). o   This complex activates more Factor 10 . y   A s thrombin is generated, it activates more o   Factor 5   o   Factor 8 , and o   Factor 11 (all shown above with green arrows). y   Factor 11 amplifies the production of activated Factor 9 .Thus what may have begun as a tiny, localized event rapidly expands into a cascade of activity. Platelets Platelets are cell fragments produced from megakaryocytes . B lood normally contains 150,000 to 400,000 per microliter (µl). I f this value should drop much below 20,000/µl,there is a danger of uncontrolled bleeding. This is because of the essential role of platelets y   in maintaining the integrity of the adherens junctions that provide a tight seal between the endothelial cells thatline the blood vessels; y   in forming a clot where blood vessels have been broken.When blood vessels are damaged, fibrils of collagen in the extracellular matrix (ECM) are exposed. Platelets thenbegin to adhere to the collagen through the action of  y   specific receptors for collagen present on their plasma membrane y   von Willebrand factor which links the platelets to the collagen.  These actions cause a plug of platelets to form at the site.The bound platelets release y   AD P and thromboxane A 2 , which recruit and activate still more platelets circulating in the blood. (This role of thromboxane accounts for the beneficial effect of low doses of aspirin  a cyclooxygenase inhibitor  inavoiding heart attacks.) y   tissue factor y   serotonin, which enhances their clumping and promotes constriction of the blood vessel. B leeding Disorders A deficiency of a clotting factor can lead to uncontrolled bleeding. The deficiency may arise because y   not enough of the factor is produced or y   a mutant version of the factor fails to perform properly.Examples: y   von Willebrand disease (the most common) y   hemo p hilia A for factor 8 deficiency y   hemo p hilia B for factor 9 deficiency. y   hemo p hilia C for factor 11 deficiency I n some cases of von Willebrand disease, either a d eficient level or a mutant version of the factor eliminates its protective effect on factor 8. The resulting low level of factor 8 mimics hemophilia A. Why do all the human bleeding disorders involve factors in amplification pathways? Probably because they arethe only deficiencies that can be tolerated. Loss of the genes for y   tissue factor or y   factor 7   H e m o p hilia  A and B   The genes encoding factors 8 and 9 are on the X chromosome. Thus their inheritance is X-linked.Like other X-linked disorders, hemophilia A and B are found almost exclusively in males because they inherit justa single X chromosome, and if the gene for factor 8 (or 9) on it is defective, they will suffer from the disease.Queen Victoria of the UK was a carrier of a mutant factor 9 gene and passed it on to several of her descendants.Link to a discussion and pedigree.There are many different mutant versions of the genes for factors 8 and 9 . Although some produce only a minor effect on the function of their protein, others fail to produce any functioning clotting factor.  T reating H e m o p hilia  A and B   What can be done? F actor  8 and 9 can be extracted from donated blood, usually pooled from several thousand donors, and purified. I njections of this material can halt episodes of bleeding in hemophiliacs and have allowed countless young men tolive relatively normal lives.However, in the early 1980s, blood contaminated with the human immunodeficiency virus ( HIV ) wasunknowingly used to manufacture preparations of factors 8 and 9. I n some areas, 90% or more of the hemophiliacs became infected by these contaminated preparations. Many have since died of  AIDS . The future now looks brighter because: y   all donated blood is now tested to see if the donor has been infected with H IV (as well as hepatitis B and C); y   plasma-derived preparations of factors 8 and 9 are now treated with heat and/or solvents to destroy any virusesthat might be present; y   recombinant factor 8 and recombinant factor 9 made by genetic engineering are now available. These recombinant factors are made by inserting the DNA encoding the human protein into mammalian cellsgrown in culture. E. coli cannot be used because these factors are glycoproteins, and E. coli lacks the machinery toattach carbohydrate properly.And the team that brought us Dolly reported in the 19 December 1997 issue of  S cience that they have succeeded incloning female sheep transgenic for the human factor 9 gene. The human gene is coupled to the promoter for theovine (sheep) milk protein beta-lactoglobulin. When the lambs mature, it is hoped that they will secrete largeamounts of human factor 9 in their milk, which can then be purified for human therapy.Several attempts have also been made to try to cure hemophilia by gene thera p y . I t is difficult to see how even the most worried critics of genetic engineering can fail to approve its potential tosave the lives of thousands of hemophiliacs in the years to come. L iver T rans p lants People with liver failure can be cured with a liver transplant. On the rare occasions when the patient hashappened to be a hemophiliac ( A , B or C), the transplant cured not only the patient's liver disease but cured hishemophilia as well! Controlling Clotting While the ability to clot is essential to life, the process must be carefully regulated. I nappropriate clot formation,especially in the brain or lungs, can be life-threatening.  A ntithro mb in III A s its name suggests, this plasma protein (a serpin) inhibits the formation of thrombin. I t does so by binding to and thus in activating: y   prothrombin

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