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Haemostasis Coagulation Dvt Pe Notes

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Semester 2 Case 8: The Grocer

* What is the structure & function of platelets?
[1] Platelets

(AKA: Thrombocytes) are minute discs that are formed in the bone marrow from megakaryocytes - extremely large calls of the haematopoietic series in the marrow. Platelets have many functional characteristics of whole cells, even though they do not have nuclei &
cannot reproduce. In their cytoplasm are such active factors as:

* Actin & myosin molecules, which are contractile proteins similar to those found in muscle cells, and another contractile protein, thrombosthenin, that can cause the platelets to contract

* Residuals of both the endoplasmic reticulum & the Golgi apparatus that synthesise various enzymes and especially store large quantities of calcium ions

* Mitochondria & enzyme systems that are capable of forming ATP & ADP

* Enzyme systems that synthesise prostaglandins, which are local hormones that cause many vascular & other local tissue reactions

* A protein called fibrin-stabilising factor

* A growth factor that causes vascular endothelial cells, vascular smooth muscle cells, and fibroblasts to multiply & grow, thus causing cellular growth that eventually helps repair damaged vascular walls. The cell membrane of the platelets is also important. On its surface is a coat of glycoproteins that repulses adherence to normal endothelium and yet causes adherence to injured areas of the vessel wall, especially to injured endothelial cells and even more so to any exposed collagen from deep within the vessel wall. The membrane also contains large amounts of phospholipids that activate multiple stages in the blood-clotting process. Thus, the platelet is an active structure. It has a half-life in the blood of 8-12 days, so that over several weeks its functional processes run out. Then it is eliminated from the circulation mainly by the tissue macrophage system. >50% of the platelets are removed by macrophages in the spleen, where the blood passes through a latticework of tight trabeculae. Under an electron microscope, activated platelets appear green, and inactive platelets appear blue.

* How does haemostasis & blood coagulation work?
Haemostasis = Prevention of blood loss. Whenever a vessel is severed or ruptured, haemostasis is achieved by several mechanisms: Vascular constriction ? Formation of a platelet plug ? Formation of a blood clot as a result of blood coagulation ? Eventual growth of fibrous tissue into the blood clot to close the hole in the vessel permanently Vascular Constriction Blood vessel cut or ruptured.

Trauma to the vessel wall itself causes the smooth muscle to contract

Local myogenic spasm Local autacoid factors from lasting minutes or hours the traumatised tissues &
blood platelets (e.g. Thromboxane A2, serotonin) Direct damage to vascular wall

Instantly reduces flow of blood from ruptured vessel

Nervous reflexes

Pain nerve impulses or other sensory impulses that originate from the traumatised vessel or nearby tissues

Formation of the Platelet Plug If the cut in a blood vessel is very small, then it is often sealed by a platelet plug, rather than by a blood clot. When platelets come in contact with a damaged vascular surface, especially with collagen fibres in the vascular wall, the platelets themselves immediately change their own characteristics drastically:
- They begin to swell
- They assume irregular forms with numerous irradiating pseudopods (temporary projections of the cytoplasm) protruding from their surfaces
- Their contractile proteins contract forcefully and cause the release of granules that contain multiple active factors
- They become sticky so that they adhere to collagen in the tissues via GP1b & to a protein called von Wille-brand factor that leaks into the traumatised tissue from the plasma
- They secrete large quantities of ADP, which attracts more platelets &stimulates their degranulation (positive feedback)
- Their enzymes form thromboxane A, which promotes platelet aggregation, degranulation, & vasoconstriction (positive feedback) The ADP and thromboxane in turn act on nearby platelets to activate them as well, and the stickiness of these additional platelets causes them to adhere to the original activated platelets. Therefore, at the site of any opening in a blood vessel wall, the damaged vascular wall activates successively increasing numbers of platelets that themselves attract more and more additional platelets, thus forming a platelet plug. At first this is a loose plug, but it is usually successful in blocking blood loss if the vascular opening is small. Then, during the subsequent process of blood coagulation, fibrin threads form. These attach tightly to the platelets, thus constructing an unyielding plug. Blood Coagulation in the Ruptured Vessel Severe trauma to vascular wall ? Clot begins to develop within 15-20seconds. Minor trauma to vascular wall ? Clot begins to develop within 1-2minutes. Activator substances (clotting factors) from the traumatised vascular wall, from platelets, and from blood proteins adhering to the traumatised vascular wall initiate the clotting process. Within 3-6minutes after vessel rupture, if the opening isn't too large, the entire opening or broken end of the vessel is filled with clot. After 20-60minutes, the clot retracts; this closes the vessel still further. Growth of Fibrous Tissue into the Blood Clot Once a blood clot has formed, it can follow one of two courses:

* It can become invaded by fibroblasts, which subsequently form connective tissue all through the clot - Usual in a clot that forms due to a small hole. Begins within a few hours after the clot is formed, which is promoted at least partially by growth factor secreted by platelets. This continues to complete organisation of the clot into fibrous tissue within about 1-2weeks.

* Or, it can dissolve - When excess blood has leaked into the tissues and tissue clots have occurred where they aren't needed, special substances within the clot itself usually become activated. These function as enzymes to dissolve the clot.

Mechanism of Blood Coagulation Procoagulants promote coagulation. Anticoagulants inhibit coagulation. Whether blood will coagulate depends on the balance between these 2 groups of substances. In the bloodstream, the anticoagulants normally predominate, so that the blood doesn't coagulate whilst it is circulating in the blood vessels. When a vessel is ruptured, procoagulants from the area of tissue damage become "activated" and override the anticoagulants, and then a clot does develop. Clotting takes place in 3 essential steps: 1) In response to rupture of the vessel or damage to the blood itself, a complex cascade of chemical reactions occurs in the blood involving more than a dozen blood coagulation factors ? Formation of a complex of activated substances collectively called PROTHROMBIN ACTIVATOR. 2) This prothrombin activator catalyses conversion of prothrombin into thrombin. 3) The thrombin acts as an enzyme to convert fibrinogen into fibrin fibers that enmesh platelets, blood cells, and plasma to form the clot. Conversion of Prothrombin to Thrombin
- Once the prothrombin activator has formed (as explained above), in the presence of sufficient amounts of ionic Ca2+, it causes conversion of prothrombin to thrombin.
- The thrombin causes polymerisation of fibrinogen molecules into fibrin fibres within another 10-15seconds. Thus, the rate-limiting factor in causing blood coagulation is usually the formation of prothrombin activator and NOT the subsequent reactions beyond that point, because these terminal steps normally occur rapidly to form the clot itself. Platelets also play an important role in the conversion of prothrombin to thrombin because much of the prothrombin first attaches to prothrombin receptors on the platelets already bound to the damaged tissue.

Prothrombin & Thrombin: Prothrombin = An a2-globulin plasma protein, which is unstable and can split easily into smaller compounds, one of which is thrombin. Prothrombin is formed continually by the liver, and it is continually being used throughout the body for blood clotting. If the liver fails to produce prothrombin for a day or more, its concentration in the plasma falls too low to provide normal blood coagulation. Vitamin K is required by the liver for normal formation of prothrombin as well as for formation of a few other clotting factors. Therefore, either lack of vitamin K or the presence of liver disease that prevents normal prothrombin formation can decrease the prothrombin level so low that a bleeding tendency results.

Fibrinogen: Fibrinogen = A high-molecular-weight protein that occurs in the plasma. It is formed in the liver, and liver disease can decrease the concentration of circulating fibrinogen. Due to its large size, little fibrinogen normally leaks from the blood vessels into the interstitial fluids, and so interstitial fluids don't normally coagulate. Yet, when permeability of capillaries pathologically increases, fibrinogen leaks and causes clotting in the same way that blood can clot. Conversion of Fibrinogen to Fibrin

Thrombin is a protein enzyme with weak proteolytic capabilities. It acts on fibrinogen to remove 4 low-molecular-weight peptides from each molecule of fibrinogen, forming 1 molecule of fibrin monomer. This has the automatic ability to polymerise with other fibrin monomer molecules to form fibrin fibers. These long fibrin fibers constitute the reticulum of the blood clot. In the early stages of polymerisation, the fibrin monomer molecules are held together by weak hydrogen bonding, and the newly-forming fibers aren't cross-linked with one another. Therefore, the resultant clot is weak & can be broken apart with ease. Another process occurs in the following few minutes that greatly strengthens the fibrin reticulum. This involves a substance called fibrin-stabilising factor that is present in small The blood clot is composed of a meshwork of fibrin fibers running in all directions and entrapping blood cells, platelets, & plasma. The fibers also adhere to damaged surfaces of blood vessels; therefore, the blood clot becomes adherent to any vascular opening and thereby prevents further blood loss.

amounts in normal plasma globulins, but is also released from platelets entrapped in the clot. Fibrin-stabilising factor must itself be activated by thrombin before it can have an effect. Once activated, it acts as an enzyme to cause covalent bonds between more & more of the fibrin monomer molecules, as well as multiple cross-linkages between adjacent fibrin fibers.

Clot Retraction - Serum A few minutes after a clot is formed, it begins to contract & usually expresses most of the fluid from the clot within 20-60minutes. The fluid expressed is called serum because all its fibrinogen and most of the other clotting factors have been removed; in this way, serum differs from plasma. Serum cannot clot because it lacks these factors. Platelets are necessary for clot retraction to occur!!! Therefore, failure of clot retraction is an indication that the number of platelets in the circulating blood might be low.

* Platelets in blood clots become attached to the fibrin fibers in such a way that they actually bond different fibers together.

* Also, platelets entrapped in the clot continue to release procoagulants, one of the most important of which is fibrin-stabilising factor (Factor XIII), which causes more and more cross-linking bonds between adjacent fibrin fibers.

* In addition, the platelets themselves contribute directly to clot contraction by activating platelet thrombosthenin, actin, & myosin molecules, which are all contractile proteins in the platelets & cause strong contraction of the platelet spicules attached to the fibrin. This also helps compress the fibrin meshwork into a smaller mass. The contraction is activated & accelerated by thrombin as well as by calcium ions released from calcium stores in the mitochondria, endoplasmic reticulum, and Golgi apparatus of the platelets. As the clot retracts, the edges of the broken blood vessel are pulled together, thus contributing still further to the ultimate state of haemostasis. Vicious Circle of Clot Formation Once a blood clot has started to develop, it normally extends within minutes into the surrounding blood. The clot itself initiates positive feedback to promote more clotting. One of the most important causes of this is the fact that the proteolytic action of thrombin allows it to act on many of the other blood-clotting factors in addition to fibrinogen. For instance, thrombin has a direct proteolytic effect on prothrombin itself, tending to convert this into still more thrombin, and it acts on some of the blood-clotting factors responsible for formation of prothrombin-activator. Blood clot continues to form until blood leakage ceases.

* How is haemostasis initiated & inhibited?
Initiating mechanisms are set into play by:
- Trauma to the vascular wall & adjacent tissues
- Trauma to the blood

-

Contact of the blood with damaged endothelial cells or with collagen & other tissue elements outside the blood vessel In each instance, this leads to the formation of prothrombin activator, which then causes prothrombin conversion to thrombin and all the subsequent clotting steps. PROTHROMBIN ACTIVATOR is formed in 2 ways, and these 2 ways interact with each other constantly:

* The extrinsic pathway that begins with trauma to the vascular wall & surrounding tissues

* The intrinsic pathway that begins in the blood itself Most of the blood-clotting factors that are involved in these pathways are inactive forms of proteolytic enzymes. When they are converted to their active forms, their enzymatic actions cause the successive, cascading reactions of the clotting process. A small letter 'a' in the name of a clotting factor shows that it is in its active form - e.g. Factor VIII = inactive, Factor VIIIa = active. Extrinsic Pathway Initiation: The traumatised vascular wall or traumatised extravascular tissues come in contact with the blood. This leads to:
-Release of TISSUE FACTOR (composed especially of phospholipids from the membranes of the tissue plus a lipoprotein complex that functions mainly as a proteolytic enzyme).
-Tissue factor complexes with blood clotting factor VII to form a TF-VIIa complex, which in the presence of Ca2+, acts as an enzyme on Factor X to form Factor Xa. Tf-VIIa plus Factor X = EXTRINSIC TENASE COMPLEX.
-Factor Xa combines immediately with tissue phospholipids that are part of tissue factor or with additional phospholipids released from platelets. It also combines with Factor V. This forms a complex called PROTHROMBIN ACTIVATOR.
-Within a few seconds, in the presence of Ca2+, prothrombin activator splits prothrombin to form thrombin. Amplification: Once thrombin forms, the proteolytic action of some of the thrombin converts Factor V to Factor Va. This then becomes an additional strong accelerator of prothrombin activation. Therefore, thrombin causes positive feedback through Factor V to accelerate the entire process once it begins.
[2] Some of the thrombin also activates Factor VIII and platelets. This causes large scale thrombin generation, which is sufficient for fibrin clots. Coagulation moves to the surface of activated platelets, which gives a burst of thrombin via the intrinsic pathway.

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