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Lecture

Hemostasis

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Department
Physiology
Course
PSL201Y1
Professor
Christopher Perumalla
Semester
Summer

Description
Lumen of blood vessel (a) Damaged blood vessel endothelium Rupture in the blood vessel Exposed collagen fibers Lumen of blood vessel Endothelium Subendothelium Smooth muscle Interstitial fluid Lumen of blood vessel (a) Damaged blood vessel endothelium Rupture in the blood vessel Exposed collagen fibers Lumen of blood vessel Endothelium Subendothelium Smooth muscle Interstitial fluidLecture 31 Hemostasis For bleeding to occur from a blood vessel, two things need to happen. Firstly, there needs to be damage done to the blood vessel. The second thing that needs to happen is that the pressure in the blood vessel (in the lumen) must be greater then the pressure outside the blood vessel (the pressure in the interstitial fluid). When the blood vessel is damaged, a number of physical and physiological mechanisms are activated that promote hemostasis. Smaller blood vessels are frequently ruptured by minor traumas of everyday life. Hemostasis seals these defects and stops loss of blood so we are not even aware of the damage to these small blood vessels. When there is damage to the blood vessel, the endothelial lining is disrupted and the underlining collagen protein from the subendothelium tissue is exposed. This initiates two separate but overlapping hemostatic mechanisms. These hemostatic mechanisms include vascular spasm, platelet plug formation and blood coagulation (clotting).1. Vascular spasm Vascular spasm is a physical response resulting from the constriction of the blood vessel. This constriction minimizes blood loss. The vascular spasm is an intrinsic vascular response and is sympathetically mediated. Vascular spasm reduces blood loss but does not stop the bleeding completely. 2. Platelet plug The formation of the plug is a physical response. The plug forms around the site of vessel damage and thereby decreases blood loss. Platelets are chief players in the formation of the platelet plug. They are the fragments of large cells called megakaryocytes that are released from the stem cell in the bone marrow. Platelets have granules that contain certain secretory products. Both the formation of the platelet plug and the subsequent blood clot require the presence of platelet and a fairly large set of specific proteins. These platelet proteins and other clogging proteins are floating around the plasma inside the blood vessel.Megakaryocyte Platelets Megakaryocyte PlateletsIn platelet plug formation, the key protein is von Willebrand factor (vWf). This factor is secreted by megakaryocytes, platelets as well as endothelial cell lining in the blood vessel. The vWf is present in the plasma at all times but only accumulates at the site of vessel damage when the vessel is damaged. When the tissue is damaged and the blood comes into contact with the subendothelium tissue, vWF binds to collagen fibers in the subendothelial layer, thereby triggering the binding of platelets that are flowing in the blood vessel to the vWf. This anchors platelets in the area of damaged blood vessel. Contact between the platelets and the vWf changes the metabolism and the surface properties of platelets, making them sticky and at the same time stimulating secretion of certain chemicals. These secretory products include ADP that stimulates morphological changes in the platelets, causing them to adhere to each other and to form a mass at the site of the injured vessel. This mass of platelets secrete more ADP which stimulates further adhesion of platelets, thereby providing a positive feedback loop that increases the rate of platelet plug formation. Furthermore, the adheredTXA2 ADP Platelet Platelet aggregation adhesion Exposed collagen fibers (a) Damaged blood vessel endothelium Lumen of blood vessel Endothelium Subendothelium Smooth muscle Interstitial fluid TXA2 ADP Platelet Platelet aggregation adhesion Exposed collagen fibers (a) Damaged blood vessel endothelium Lumen of blood vessel Endothelium Subendothelium Smooth muscle Interstitial fluidplatelets also secrete another chemical called thromboxin A2 (TXA2). TXA2 further supports platelet adhesion by stimulating ADP secretion. In addition to secretion of ADP and AXA2 which aid in the platelet adhesion, activated platelets also secrete powerful vasoconstrictives (increases resistance to bloodflow and reduces blood loss) that include serotonin and epinephrine. TXA2 also acts as a very potent vasoconstrictive.  Role of arachidonic acid in platelet adhesion (collection) Arachidonic acid is a phospholipid located in the membrane of the platelets and serves as a precursor for TXA2. Adhered platelets convert arachidonic acid to TXA2 which stimulates platelet aggregation and ADP secretion. However, in healthy intact endothelial cells, arachidonic acid is converted to prostacyclin (prostaglandin I2) which inhibits platelet plug formation in intact blood vessels. Nitric oxide is also released and with prostacyclin assure that unnecessary platelet plugs are not formed in intact blood vessels and that there is a free flow of blood in uninjured blood vessels.Lumen of blood vessel Endothelium Subendothelium Smooth muscle Interstitial fluid No platelet aggregation Prostacyclin Nitric oxide Collagen fibers (b) Normal blood vessel endothelium Lumen of blood vessel Endothelium Subendothelium Smooth muscle Interstitial fluid No platelet aggregation Prostacyclin Nitric oxide Collagen fibers (b) Normal blood vessel endothelium. 3. Blood coagulation (physiological response) Injured blood vessel along with the formation of platelet plug and the release of vasoconstrictives, also release factors that initiate a series of reactions known as coagulation. Formation of a clot on top of a platelet plug strengthens and supports the plug. Many proteins are involved in the process of coagulation. The proteins involved are called clogging factors and are present in the plasma in inactive form. Only when the first clotting factor is activated, the next factor is activated in turn and so on. This is so that no unwanted clots are formed in intact blood vessels. Most of these clotting factors in the plasma are formed in the liver. The ultimate step for the formation of a clot is the conversion of the plasma protein fibrinogen to fibrin. Fibrin is insoluble and possesses thread like molecules in which red blood cells are trapped. This thereby forms a clot. This conversion is initiated by an enzyme called thrombin. Thrombin itself is present in the plasma in an inactive form called prothrombin. Prothrombin is converted to thrombin by an activated factor called factor 10 (Fxa). Fxa can be activated in two ways: either by extrinsic pathway or int
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