Blood Physiology-II; Hemostasis (2024) PDF

Blood Physiology Hemostasis  Cellular Elements of Blood 1.Red Blood Cells 2.White Blood Cells 3.Platelets Platelets (Thrombocytes) Platelets are produced by the bone marrow. They are not whole cells, they are fragments of extraordinarily large bone marrow-bound megakaryocytes. The hormo...

Blood Physiology Hemostasis  Cellular Elements of Blood 1.Red Blood Cells 2.White Blood Cells 3.Platelets Platelets (Thrombocytes) Platelets are produced by the bone marrow. They are not whole cells, they are fragments of extraordinarily large bone marrow-bound megakaryocytes. The hormone THROMBOPOIETIN (produced by liver) increases the # of megakaryocytes in the bone marrow, stimulating them to produce more platelets Function of Platelets; Hemostasis The term hemostasis means prevention of blood loss. Whenever a vessel is ruptured, hemostasis is achieved by several mechanisms: (1) vascular spasm-constriction, (2) formation of a platelet plug, (3) formation of a blood clot as a result of blood coagulation, and (4) eventual growth of fibrous tissue into the blood clot to close the hole in the vessel permanently. Steps in Hemostasis *DAMAGE TO BLOOD VESSEL LEADS TO: 1. Vascular Spasm: Immediate constriction of blood vessel Vessel walls pressed together – become “sticky”/adherent to each other Minimize blood loss Steps in Hemostasis 2. Platelet Plug formation: Platelets will not adhere to normal vascular surfaces, why ? Under normal conditions, the endothelial cells that make up the inner wall of the vessel are electrically negatively charged and repel the negatively charged thrombocytes. Thus, trombocytes do not stick to the vessel wall. Steps in Hemostasis 2. Platelet Plug formation: On the other hand, in response to the damage of the vessel, the collagen fibrils under the endothelium are exposed and thrombocytes adhere to the damaged vessel wall- These granules include platelet aggregation. coagulation factors, ATP, ADP, Binding of platelets causes Thromboxane A2, serotonin, and the release of platelet histamine. granule content out of the cell by exocytosis. Steps in Hemostasis 2. Platelet Plug formation: These factors promotes more platelet aggregation & more ADP and Thromboxane A2 The aggregated platelets become sticky and produce a plug. This is called platelet plug formation.  Steps in Hemostasis 3. Blood Coagulation (clot formation): “Clotting Cascade” a. Transformation of blood from liquid to solid b. Clot reinforces the plug c. Multiple cascade steps in clot formation d. Fibrinogen (plasma protein) is converted to Fibrin Thrombin Mechanism of Blood Coagulation More than 50 important substances that cause or affect blood coagulation have been found in the blood and in the tissues Some of them promote coagulation, called procoagulants, and others that inhibit coagulation, called anticoagulants. Whether blood will coagulate depends on the balance between these two groups of substances. In the blood stream, the anticoagulants normally predominate, so that the blood does not coagulate while it is circulating in the blood vessels. However, when a vessel ruptures, procoagulants from the damaged tissue area are "activated" and the effect of anticoagulants is attenuated, followed by clotting.  Mechanism of Blood Coagulation Blood coagulation takes place in three essential steps: (1) The formation of prothrombin activator. For this, a complex series of chemical reactions involving more than a dozen blood clotting factors take place in the blood.  Mechanism of Blood Coagulation Blood coagulation takes place in three essential steps: (2) Conversion of prothrombin into thrombin. The prothrombin activator catalyzes this (3) Conversion of fibrinogen into fibrin fibers The thrombin acts as an enzyme for this conversion Clotting Cascade Participation of 13 different clotting factors (plasma glycoproteins) Factors are designated by a roman numeral Clotting Cascade is initiated by two ways; Intrinsic pathway / Extrinsic pathway Coagulation is also a good example of positive feedback mechanism.  Clotting Cascade Intrinsic Pathway: It starts when there is an incision within (internal) the vessel or blood contact with a foreign substance (ie: in contact with test tube). It stops bleeding. The intrinsic pathway begins with the activation of Factor XII (Hageman Factor) Extrinsic pathway: It starts when blood escapes into the tissues - perforation of the blood vessel – haemorrhage. Requires tissue factors from outside the blood. The extrinsic pathway begins with the activation of Factor III (Tissue Thromboplastin). Common Pathway leading to the formation of a fibrin clot. Interaction Between the Extrinsic and Intrinsic Pathways After blood vessels rupture, clotting occurs by both pathways simultaneously. Tissue factor initiates the extrinsic pathway, whereas contact of Factor XII and platelets with collagen in the vascular wall initiates the intrinsic pathway. Anticlotting-Anticoagulant Systems However, the clot should not be at a level that will adversely affect blood flow. The body has mechanisms for limiting clot formation itself and for dissolving a clot after it has formed. Systemic antithrombotic (anticoagulant) elements are needed to prevent the coagulation response forming an unwanted thrombosis around the damaged area. The term anticoagulant is used for reactions that are in normal circulation and prevent blood clotting in cases where the vessel wall is not damaged. Anticlotting Systems Intact vessels have anticoagulant property. Under normal conditions, procoagulants and anticoagulants work in balance. The inability to limit of clot formation would be dangerous. A thrombus can forms. A thrombus is a blood clot that forms in a vessel and remains there. Thrombus can rupture and lead to develop embolism. An embolism is a clot that travels from the site where it formed to another location in the body. Embolism may lead to block in blood flow.  Prevention of Blood Clotting in the Normal Vascular System Intravascular Anticoagulants Endothelial Surface Factors; Probably the most important factors for preventing clotting in the normal vascular system are (1) the smoothness of the endothelial cell surface, which prevents contact activation of the intrinsic clotting system; (2) a layer of glycocalyx on the endothelium which repels clotting factors and platelets, thereby preventing activation of clotting; and (3) a protein bound with the endothelial membrane, thrombomodulin, which binds thrombin. Thrombomodulin slows down the clotting process by removing thrombin (4)Endothelial derived nitric oxide (NO) exhibits anticoagulant effects by preventing thrombocyte aggregation and adhesion. When the endothelial wall is damaged, its smoothness and its thrombomodulin layer are lost, and the risk of intravascular coagulation can increase.  Prevention of Blood Clotting in the Normal Vascular System Intravascular Anticoagulants Antithrombin III, Protein C, S, Heparin, TFPI Among the most important anticoagulants in the blood itself are those that remove thrombin from the blood. The most powerful of these are (1) an alpha-globulin called antithrombin III or antithrombin-heparin cofactor. (2) Protein C and S. (3) Heparin. (4) Tissue factor pathway inhibitor (TFPI)  Prevention of Blood Clotting in the Normal Vascular System Intravascular Anticoagulants Heparin is another powerful anticoagulant, but its concentration in the blood is normally low, so that only under special physiologic conditions does it have significant anticoagulant effects. However, heparin is used widely as a pharmacological agent in medical practice in much higher concentrations to prevent intravascular clotting. Anticlotting Systems Defects in any of these natural anticoagulant mechanisms are associated with abnormally high risk of clotting, a condition called hypercoagulability. The Fibrinolytic System In addition to limit clot formation systems, there is a system dissolves a clot after it is formed. This is fibrinolytic system. Because a fibrin clot is not designed to last forever. It is a temporary fix until permanent repair of the vessel occurs. Clot must be removed. The fibrinolytic (or thrombolytic) system is the principal effector of clot removal. It constitutes a plasma proenzyme, plasminogen, Plasminogen can be activated to the active enzyme plasmin by plasminogen activators. Once formed, plasmin digests fibrin, thereby dissolving the clot.  Clot dissolution Clot is slowly dissolved by the “fibrin splitting” enzyme called Plasmin Plasminogen is the inactive precursor of plasmin It is activated by tissue plasminogen activator(t-PA) tPA is used to dissolve the clot in some cases of disease involving a blood clot, such as pulmonary embolism, cerebral hemorrhage. Plasmin breaks down the fibrin network and slowly dissolves the clot Clot formation: Too much or too little Too much: An inappropriate clot, thrombus, forms. This can cause embolism. Also an enlarging thrombus narrows and can occlude vessels Too little: Excessive bleeding occurs. It can result from deficiency of any one of the many blood-clotting factors. There are three particular types of bleeding tendencies; (1) vitamin K deficiency, (2) hemophilia, and (3) thrombocytopenia (platelet deficiency). Decreased Prothrombin, Factor VII, Factor IX, and Factor X Caused by Vitamin K Deficiency Almost all the blood-clotting factors are formed by the liver. Therefore, diseases of the liver such as hepatitis and cirrhosis can sometimes depress the clotting system so greatly that the patient develops a severe tendency to bleed. Another cause of depressed formation of clotting factors by the liver is vitamin K deficiency. Vitamin K is necessary for the formation of five important clotting factors in the liver : prothrombin, Factor VII, Factor IX, Factor X, and protein C. In the absence of vitamin K, subsequent insufficiency of these coagulation factors in the blood can lead to serious bleeding tendencies. Haemophilia Haemophilia is a mostly inherited genetic disorder that impairs the body's ability to make blood clots. This results in people bleeding longer after an injury, easy bruising, and an increased risk of bleeding inside joints or the brain. There are two main types of haemophilia: haemophilia A, 85 %, which occurs due to not enough clotting factor VIII, and haemophilia B, which occurs due to not enough clotting factor IX. Both of these factors are transmitted genetically by way of the female chromosome. Therefore, almost a woman will never have hemophilia Thrombocytopenia Thrombocytopenia means the presence of very low numbers of platelets in the circulating blood. Ordinarily, bleeding will not occur until the number of platelets in the blood falls below 50,000/ml, rather than the normal 150,000 to 300,000. Levels as low as 10,000/ml are frequently lethal.  Coagulation Tests The platelet count is an example in a screening test for primary hemostasis. Screening tests for secondary hemostasis include coagulation proteins, intrinsic system, extrinsic system and members of the common pathway. Clinicians frequently order following coagulation tests to assess blood clotting function in patients; These in vitro tests measure the time elapsed from activation of the coagulation cascade at different points to the formation of fibrin. – Activated partial thromboplastin time (aPTT), – Prothrombin time (PT), – Thrombin time (TT), – Bleeding Time. Warfarin Warfarin is a medication used in the prophylaxis and treatment of venous thrombosis and thromboembolic events. It is in the anticoagulant class of drugs. Warfarin is sold under the brand name Coumadin. Coumadin is a blood-thinning drug. It is commonly used to prevent stroke in people who have atrial fibrillation, valvular heart disease or artificial heart valves. Bleeding Time Definition When a small slit is made in the skin, the hemostatic mechanisms necessary for coagulation are activated. Without the aid of external pressure, bleeding usually stops within 7 to 9 minutes.