Hemostasis and Blood Coagulation PDF

 The term hemostasis means prevention of blood loss.  Whenever a vessel is severed or ruptured, hemostasis is achieved by several mechanisms:  vascular constriction,  formation of a platelet plug,  formation of a blood clot as a result of blood coagulation, and  eventual growth of fibrous t...

 The term hemostasis means prevention of blood loss.  Whenever a vessel is severed or ruptured, hemostasis is achieved by several mechanisms:  vascular constriction,  formation of a platelet plug,  formation of a blood clot as a result of blood coagulation, and  eventual growth of fibrous tissue into the blood clot to close the hole in the vessel permanently Vascular Constriction  Immediately after a blood vessel has been cut or ruptured, the trauma to the vessel wall itself causes the smooth muscle in the wall to contract;  This instantaneously reduces the flow of blood from the ruptured vessel.  The contraction results from  local myogenic spasm,  local autacoid factors from the traumatized tissues and blood platelets, and  nervous reflexes  The nervous reflexes are initiated by pain nerve impulses or other sensory impulses that originate from the traumatized vessel or nearby tissues.  However, even more vasoconstriction probably results from local myogenic contraction of the blood vessels initiated by direct damage to the vascular wall.  And, for the smaller vessels, the platelets are responsible for much of the vasoconstriction by releasing a vasoconstrictor substance, thromboxane A2. Formation of the Platelet Plug  If the cut in the blood vessel is very small—indeed, many very small vascular holes do develop throughout the body each day—the cut is often sealed by a platelet plug, rather than by a blood clot.  Platelets have many functional characteristics of whole cells, even though they do not have nuclei and cannot reproduce.  In their cytoplasm are such active factors as  actin and myosin molecules, which are contractile proteins similar to those found in muscle cells, and still another contractile protein, thrombosthenin, that can cause the platelets to contract;  residuals of both the endoplasmic reticulum and the Golgi apparatus that synthesize various enzymes and especially store large quantities of calcium ions;  mitochondria and enzyme systems that are capable of forming adenosine triphosphate (ATP) and adenosine diphosphate (ADP);  enzyme systems that synthesize prostaglandins, which are local hormones that cause many vascular and other local tissue reactions;  an important protein called fibrin-stabilizing factor (Factor XIII)  a growth factor that causes vascular endothelial cells, vascular smooth muscle cells, and fibroblasts to multiply and grow, thus causing cellular growth that eventually helps repair damaged vascular walls. Mechanism of the Platelet Plug  When platelets come in contact with a damaged vascular surface, especially with collagen fibers 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 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 and to a protein called von Willebrand factor that leaks into the traumatized tissue from the plasma  They secrete large quantities of ADP;  Their enzymes form thromboxane A2.  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.  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  This is at first a loose plug, but it is usually successful in blocking blood loss if the vascular opening is small.  The platelet-plugging mechanism is extremely important for closing minute ruptures in very small blood vessels that occur many thousands of times daily.  Indeed, multiple small holes through the endothelial cells themselves are often closed by platelets actually fusing with the endothelial cells to form additional endothelial cell membrane Blood Coagulation in the Ruptured Vessel  The clot begins to develop in 15 to 20 seconds if the trauma to the vascular wall has been severe, and in 1 to 2 minutes if the trauma has been minor.  Within 3 to 6 minutes after rupture of a vessel, if the vessel opening is not too large, the entire opening or broken end of the vessel is filled with clot.  After 20 minutes to an hour, the clot retracts; Mechanism of Blood Coagulation  Prothrombin activator is generally considered to be formed in two ways, although, in reality, the two ways interact constantly with each other:  by the extrinsic pathway that begins with trauma to the vascular wall and surrounding tissues and  by the intrinsic pathway that begins in the blood itself. Prevention of Blood Clotting in the Normal Vascular System  Probably the most important factors for preventing clotting in the normal vascular system are  the smoothness of the endothelial cell surface, which prevents contact activation of the intrinsic clotting system;  a layer of glycocalyx on the endothelium (glycocalyx is a mucopolysaccharide adsorbed to the surfaces of the endothelial cells), which repels clotting factors and platelets, thereby preventing activation of clotting;  a protein bound with the endothelial membrane, thrombomodulin, which binds thrombin.  The thrombomodulin-thrombin complex also activates a plasma protein, protein C, that acts as an anticoagulant by inactivating activated Factors V and VIII.  When the endothelial wall is damaged, its smoothness and its glycocalyx-thrombomodulin layer are lost, which activates both Factor XII and the platelets, thus setting off the intrinsic pathway of clotting.  If Factor XII and platelets come in contact with the subendothelial collagen, the activation is even more powerful.  Among the most important anticoagulants in the blood itself are those that remove thrombin from the blood.  The most powerful of these are  the fibrin fibers that themselves are formed during the process of clotting and  an alpha-globulin called antithrombin III or antithrombin-heparin cofactor.  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.  Heparin is produced by many different cells of the body, but especially large quantities are formed by the basophilic mast cells located in the pericapillary connective tissue throughout the body. Lysis of Blood Clots—Plasmin  When a clot is formed, a large amount of plasminogen is trapped in the clot along with other plasma proteins.  This will not become plasmin or cause lysis of the clot until it is activated.  The injured tissues and vascular endothelium very slowly release a powerful activator called tissue plasminogen activator (t-PA) that a few days later, after the clot has stopped the bleeding, eventually converts plasminogen to plasmin, which in turn removes the remaining unnecessary blood clot  Excessive bleeding can result from deficiency of any one of the many blood-clotting factors.  Three particular types of bleeding tendencies  vitamin K deficiency,  hemophilia, and  thrombocytopenia (platelet deficiency).  Almost all the blood-clotting factors are formed by the liver!!!  Therefore, diseases of the liver such as hepatitis, cirrhosis, and acute yellow atrophy 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 liver formation of five of the important clotting factors:      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.  Vitamin K is continually synthesized in the intestinal tract by bacteria, so that vitamin K deficiency seldom occurs in the normal person  In gastrointestinal disease, vitamin K deficiency often occurs as a result of poor absorption of fats from the gastrointestinal tract.  The reason is that vitamin K is fat-soluble and ordinarily is absorbed into the blood along with the fats.  One of the most prevalent causes of vitamin K deficiency is failure of the liver to secrete bile into the gastrointestinal tract (which occurs either as a result of obstruction of the bile ducts or as a result of liver disease).  Lack of bile prevents adequate fat digestion and absorption and, therefore, depresses vitamin K absorption as well.  Thus, liver disease often causes decreased production of prothrombin and some other clotting factors both because of poor vitamin K absorption and because of the diseased liver cells Hemophilia  Hemophilia is a bleeding disease that occurs almost exclusively in males.  In 85 per cent of cases, it is caused by an abnormality or deficiency of Factor VIII;  This type of hemophilia is called hemophilia A or classic hemophilia.  About 1 of every 10,000 males in the United States has classic hemophilia.  In the other 15 per cent of hemophilia patients, the bleeding tendency is caused by deficiency of Factor IX.  Both of these factors are transmitted genetically by way of the female chromosome  When a person with classic hemophilia experiences severe prolonged bleeding, almost the only therapy that is truly effective is injection of purified Factor VIII. Thrombocytopenia  Thrombocytopenia means the presence of very low numbers of platelets in the circulating blood  The bleeding is usually from many small venules or capillaries, rather than from larger vessels as in hemophilia.  As a result, small punctate hemorrhages occur throughout all the body tissues.  The skin of such a person displays many small, purplish blotches, giving the disease the name thrombocytopenic purpura Thromboembolic Conditions  An abnormal clot that develops in a blood vessel is called a thrombus.  Once a clot has developed, continued flow of blood past the clot is likely to break it away from its attachment and cause the clot to flow with the blood;  Such freely flowing clots are known as emboli.  Also, emboli that originate in large arteries or in the left side of the heart can flow peripherally and plug arteries or arterioles in the brain, kidneys, or elsewhere.  Emboli that originate in the venous system or in the right side of the heart generally flow into the lungs to cause pulmonary arterial embolism.  The causes of thromboembolic conditions in the human being are usually twofold: 1. Any roughened endothelial surface of a vessel—as may be caused by arteriosclerosis, infection, or trauma—is likely to initiate the clotting process. 2. Blood often clots when it flows very slowly through blood vessels, where small quantities of thrombin and other procoagulants are always being formed. Use of t-PA in Treating Intravascular Clots  Genetically engineered t-PA (tissue plasminogen activator) is available.  When delivered directly to a thrombosed area through a catheter, it is effective in activating plasminogen to plasmin, which in turn can dissolve some intravascular clots. Disseminated Intravascular Coagulation  Occasionally the clotting mechanism becomes activated in widespread areas of the circulation, giving rise to the condition called disseminated intravascular coagulation.  This often results from the presence of large amounts of traumatized or dying tissue in the body that releases great quantities of tissue factor into the blood.  Frequently, the clots are small but numerous, and they plug a large share of the small peripheral blood vessels.  This occurs especially in patients with widespread septicemia, in which either circulating bacteria or bacterial toxins—especially endotoxins— activate the clotting mechanisms  Plugging of small peripheral vessels greatly diminishes delivery of oxygen and other nutrients to the tissues— a situation that leads to or exacerbates circulatory shock.  It is partly for this reason that septicemic shock is lethal in 85 per cent or more of patients. Blood Coagulation Tests  When a sharp-pointed knife is used to pierce the tip of the finger or lobe of the ear, bleeding ordinarily lasts for 1 to 6 minutes.  The time depends largely on the depth of the wound and the degree of hyperemia in the finger or ear lobe at the time of the test.  Lack of any one of several of the clotting factors can prolong the bleeding time, but it is especially prolonged by lack of platelets Prothrombin Time  Prothrombin time gives an indication of the concentration of prothrombin in the blood  Blood removed from the patient is immediately oxalated so that none of the prothrombin can change into thrombin.  Then, a large excess of calcium ion and tissue factor is quickly mixed with the oxalated blood.  The excess calcium nullifies the effect of the oxalate, and the tissue factor activates the prothrombin to thrombin reaction by means of the extrinsic clotting pathway.  The time required for coagulation to take place is known as the prothrombin time