Discuss the physiological processes involved in hemostasis.

Outline:

·        Vascular spasm

·        Formation of a platelet plug

·        Formation of a blood clot:

- conversion of prothrombin to thrombin

- conversion of fibrinogen to fibrin

·        Eventual growth of fibrous tissue

Essay:

            When a small blood vessel is transected or damaged, the injury initiates a series of events that leads to the formation of a clot. This seals off the damaged region and prevents further blood loss, the process being termed hemostasis. The initial event is constriction of the vessel and formation of a temporary hemostatic plug of platelets that is triggered when platelets bind to collagen. This is followed by conversion of the plug into the definitive clot.

            Immediately after a blood vessel is cut or ruptured, the stimulus of the trauma to the vessel causes the wall of the vessel to contract, which instantaneously reduces the flow of blood from the vessel rupture. The contraction results from nervous reflexes, local myogenic spasm, and local humoral factors from the traumatized tissues and blood platelets. The nervous reflexes are initiated by pain or other impulses that originate from the traumatized vessel or from nearby tissues. The vasoconstriction is due to serotonin, thromboxane A₂ and other substances liberated from the platelets that adhere to the walls of the damaged vessels. This local vascular spasm can last for many minutes during which time the ensuing processes of platelet plugging and blood coagulation can take place.

            If the rent in the blood vessel is very small – and many small vascular holes do develop throughout the body each day – it is often sealed by a platelet plug. Platelets are minute round or oval discs 2 to 4 micrometers in diameter. They are formed in the bone marrow from megakaryocytes that fragment into platelets either in the bone marrow or soon after entering the blood. When platelets come into contact with a damaged vascular surface, such as the collagen fibers in the vascular wall or even damaged endothelial cells, they swell and release active factors from their granules, such as ADP and thromboxane A₂, which in turn act on nearby platelets to activate them as well, and the stickiness of these additional platelets causes them to adhere to the originally activated platelets. This forms a fairly loose plug that is usually successful in blocking blood loss if the vascular opening is small. Then, during the subsequent process of blood coagulation, fibrin threads form that attach to the platelets, thus constricting a tight and unyielding plug.

            The loose aggregation of platelets in the temporary plug is bound together and converted into the definitive clot by fibrin. The clotting mechanism responsible for the formation of the fibrin involves a cascade of reactions in which inactive enzymes are activated, and the activated enzymes in turn activate other inactive enzymes. The net result is the formation of a complex of activated substances collectively called prothrombin activator which catalyzes the conversion of prothrombin into thrombin. The thrombin acts as an enzyme to convert fibrinogen to fibrin fibers that enmesh platelets, blood cells, and plasma to form the clot.

            Thrombin is a serine protease that is formed from its circulating precursor, prothrombin, by the action of activated factor X. Factor X can be activated by reactions in either of 2 systems, an intrinsic and an extrinsic pathway. The initial reaction in the intrinsic system is conversion of inactive factor XII to active factor XII. Active factor XII then activates factor XI, and active factor XI activates factor IX. Activated factor IX forms a complex with factor VIII, activating factor X. Phospholipids from aggregated platelets and Ca²⁺ are necessary for full activation of factor X. The extrinsic system is triggered by the release of tissue thromboplastin, a protein-phospholipid mixture that activates factor VII. The tissue thromboplastin and factor VII activate factors IX and X. In the presence of platelets, Ca²⁺, and factor V, activated factor X catalyzes the conversion of prothrombin to thrombin. Platelets play an important role in the conversion of prothrombin to thrombin because much of the prothrombin first attaches to prothrombin receptors on the platelets that have already bound to the damaged tissue. Then this binding accelerates the formation of thrombin from the prothrombin.

            Thrombin acts on fibrinogen to remove 2 pairs of polypeptides from each molecule, forming a molecule of fibrin monomer that has the automatic capability of polymerizing with other fibrin monomer molecules. Therefore, many fibrin monomer molecules polymerize within seconds into long fibrin fibers that form the reticulum of the clot. The fibrin is initially a loose mesh of interlacing strands. It is converted by the formation of covalent cross-linkages to a dense, tight aggregate. This latter reaction is catalyzed by factor III, the fibrin-stabilizing factor, and requires Ca²⁺. The blood clot is composed of fibrin fibers running in all directions and entrapping blood cells, platelets, and plasma. The fibrin fibers also adhere to damaged surfaces of blood vessel. Once a blood clot has started to develop, it normally extends within minutes into the surrounding blood, initiating a vicious cycle to promote more clotting.

            Within a few minutes after a clot is formed, it begins to contract and usually expresses most of the fluid from the clot within 20 to 60 minutes. Platelets are necessary for clot retraction to occur. As the clot retracts, the edges of the broken blood vessel are pulled together, thus contributing to the ultimate state of hemostasis. Eventually, after the formation of a clot, it can become invaded by fibroblasts, which subsequently form connective tissue all through the clot, or it can dissolve.