High Yield Coagulation

http://droualb.faculty.mjc.edu/Course%20Materials/Physiology%20101/Chapter%20Notes/Fall%202007/chapter_15%20Fall%202007%20Phy%20101.htm Platelets and Hemostasis      The process of hemostasis occurs in three steps: vascular spasm, formation of platelet plug and formation of a blood clot, or thrombus.    Vascular Spasm      Vascular spasm occurs as the result of mechanisms within blood vessels themselves that are set off by the damage to the vessel. Activation of the sympathetic nervous system causes further vasoconstriction.   Platelet Plug      Platelets (thrombocytes) are non-nucleated fragments of megakaryocytes which become "sticky" under certain circumstances and adhere to damaged blood vessels. Platelet plug formation requires platelets and specific plasma proteins. The key protein is von Willebrand factor (vWf) secreted by megakaryocytes, platelets and endothelial cells. vWf accumulates at the site of vessel damage.       The platelet plug begins when vessel damage exposes subendothelial tissue. vWf binds to collagen fibers and this changes vWf to make it bind and anchor platelets. The platelets undergo a change in metabolism and surface properties that causes them to become more "sticky" and to secrete certain products.       Two of the secreted products, serotonin and epinephrine, cause vasoconstriction. ADP, another secreted product, causes platelet aggregation by a positive feedback loop. ADP also stimulates thromboxane A2production which further increases platelet aggregation.       Thromboxane A2 forms from arachidonic acid derived from the plasma membrane of the platelet and stimulates ADP secretion, platelet aggregation and vasoconstriction. Healthy endothelial cells prevent platelet aggregation by converting arachidonic acid to prostacyclin and releasing it and nitric oxide (NO). Both prostacyclin and NO inhibit platelet plug formation.       Platelets also have a high concentration of actin and myosin which enables them to contract and increase the tightness of the platelet plug.

Formation of a Blood Clot      The protein fibrin is essential for clot formation. Fibrin clot formation is secondary to platelet plug formation. Fibrin clot formation requires coagulation factors which cause a sequence of reactions called a coagulation cascade.      The ultimate result of the coagulation cascade is the conversion of fibrinogen into fibrin. This conversion is catalyzed by thrombin, the active form of  prothrombin. The fibrin that forms consists of a meshwork of strands that is further stabilized by the formation of covalent bonds between strands. The formation of bonds is catalyzed by factor XIIIa (the subscript a indicates the activated form of factor XIII).     Thrombin plays a central role in the formation of the fibrin clot by: 1. Catalyzing the conversion of fibrinogen to fibrin. 2. Catalyzing the conversion of  Factor XIII to XIIIa. 3. Positive feed back on the intrinsic pathway and the conversion of X to Xa.                 Two pathways lead to the activation of thrombin: 1. Intrinsic pathway that involves coagulation factors already present in the plasma. 2. Extrinsic pathway involving coagulation factors present in damaged tissue.   Intrinsic Pathway      This pathway begins when Factor XII is activated by contact with collagen and phospholipids in subendothelial tissue. This starts a cascade of reactions that lead to the activation of thrombin.      Also part of the intrinsic pathway is platelet factor 3, a phospholipid located on the surface of activated platelets. The calcium ion (factor IV) also plays an important role in both intrinsic and extrinsic pathways.

	Extrinsic Pathway      This pathway begins when tissue factor (factor III) comes in contact with factor VII in the plasma and activates it to VIIa . The complex then activates factor X which in turn activates the conversion of prothrombin into thrombin.

Factors Limiting Clot Formation      Tissue factor pathway inhibitor inhibits the extrinsic factor and is secreted by healthy endothelial cells.      Thrombomodulin, also secreted by endothelial cells, forms a complex with thrombin. This complex activates protein C. Activated protein C inhibits both the intrinsic and extrinsic pathways.       Plasmin, a protein derived from plasminogen, eventually dissolves clots. Plasminogen itself is activated by plasminogen activators such as tissue plasminogen activator secreted by endothelial cells during clot formation and activated by fibrin.

Coagulation Factors in Clot Formation Disorders      Deficiency of factor VIII most common factor deficient in hemophilia causes excessive bleeding.      von Willebrand Disease is due to a deficiency of von Willebrand factor which is important for platelet plug formation. vWf is also a plasma carrier of factor VIII. The absence of von Willebrand factor causes factor VIII to be less stable and means less factor VIII is available in the plasma for the intrinsic pathway.      Vitamin K deficiency causes less clotting factors  to be synthesized by the liver. Aspirin as an Anticoagulant      Aspirin at low dosages acts as an anticoagulant by inhibiting thromboxane formation. However, at high doses aspirin inhibits the formation of prostacyclin and increases the likelihood of clot formation. Labs:  PTT or aPTT - more letters so measures longer pathway ie intrinsic pathway. An activator such as silica, kaolin is added to plasma and the time it takes to clot is measured. PT - fewer letters measures shorter pathway ie extrinsic pathway. Tissue Factor is added to plasma and the time it takes to clot is measured.  INR - is a standardized way of reporting PT lab values.  Replaces PT clinically.