events in hemostasis

Physiology

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Events in Hemostasis

The term hemostasis means prevention of blood loss. Whenever a vessel is severed or ruptured,
hemostasis is achieved by several mechanisms: (1) vascular 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.

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;. The contraction results from (1) local myogenic spasm, (2) local autacoid factors from the traumatized tissues and blood platelets, and (3) nervous reflexes. The nervous reflexes are initiated by pain nerve impulses or other sensory impulses that originate from the traumatized vessel or nearby tissues. .

Formation of the Platelet Plug

If the cut in the blood vessel is very smallindeed, many very small vascular holes do develop throughout the body each daythe cut is often sealed by a platelet plug, rather than by a blood clot..

Physical and Chemical Characteristics of Platelets

Platelets (also called thrombocytes) are minute discs 1 to 4 micrometers in diameter. They are formed in the bone marrow from megakaryocytes, . The normal concentration of platelets in the blood is between 150,000 and 300,000 per microliter. 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 (1) 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; (2) residuals of both the endoplasmic reticulum and the Golgi apparatus that synthesize various enzymes and especially store large quantities of calcium ions; (3) mitochondria and enzyme systems that are capable of forming adenosine triphosphate (ATP) and adenosine diphosphate (ADP); (4) enzyme systems that synthesize prostaglandins, which are local hormones that cause many vascular and other local tissue reactions; (5) an important protein called fibrin-stabilizing factor, (6) 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; 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; and their enzymes form thromboxane A2. The ADP and thromboxane in turn act on nearby platelets to activate them .. This is first a loose plug, but it is usually successful in blocking blood loss if the vascular opening is small. Then, during the subsequent process of blood coagulation, fibrin threads form. These attach tightly to the platelets, thus constructing an unyielding plug.


Blood Coagulation in the Ruptured Vessel
The third mechanism for hemostasis is formation of the blood clot. 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. Activator substances from the traumatized vascular wall, from platelets, and from blood proteins adhering to the traumatized vascular wall initiate the clotting process.

Fibrous Organization or Dissolution of the Blood Clot

Once a blood clot has formed, it can follow one of two courses: (1) It can become invaded by fibroblasts, which subsequently form connective tissue all through the clot, or (2) it can dissolve. The usual course for a clot that forms in a small hole of a vessel wall is invasion by fibroblasts, beginning within a few hours after the clot is formed . This continues to complete organization of the clot into fibrous tissue
within about 1 to 2 weeks. Conversely, when excess blood has leaked into the tissues and tissue clots have occurred where they are not needed, special substances within the clot itself usually become activated. These function as enzymes to dissolve the clot,

Mechanism of Blood Coagulation

Basic Theory. More than 50 important substances that cause or affect blood coagulation have been found in the blood and in the tissuessome that 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. But when a vessel is ruptured, procoagulants from the area of tissue damage become activated and override the anticoagulants, and then a clot does
develop.
General Mechanism. All research workers in the field of blood coagulation agree that clotting takes place in three essential steps: (1) In response to rupture of the vessel or damage to the blood itself, a complex cascade of chemical reactions occurs in the blood involving more than a dozen blood coagulation factors. The net result is formation of a complex of activated substances
collectively called prothrombin activator. (2) The prothrombin activator catalyzes conversion of
prothrombin into thrombin. (3) The thrombin acts as an enzyme to convert fibrinogen into fibrin fibers that enmesh platelets, blood cells, and plasma to form the clot

Clotting Factors in Blood and Their Synonyms

Clotting Factor Synonyms
Fibrinogen Factor I

Prothrombin Factor II

Tissue factor Factor III; tissue thromboplastin

Calcium Factor IV

FactorV Proaccelerin; labile factor; Ac-globulin

Factor VII Serum prothrombin conversion

; proconvertin;
stable factor
Factor VIII Antihemophilic factor (AHF);
antihemophilic factor A
Factor IX Christmas factor;
antihemophilic factor B
Factor X Stuart factor; Stuart-Prower factor

FactorXI antihemophilic factor C

Factor XII Hageman factor

Factor XIII Fibrin-stabilizing factor

Prekallikrein Fletcher factor
High-molecular-weight Fitzgerald factor; HMWK
kininogen (high-molecular-weight) kininogen
Plateletsactivator.



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Blood Clot. The clot is composed of a meshwork of fibrin fibers running in all directions and entrapping blood cells, platelets, and plasma.The fibrin fibers also adhere to damaged surfaces of blood vessels; therefore, the blood clot becomes adherent to any vascular opening and thereby prevents further blood loss.

Clot RetractionSerum. 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.The fluid expressed is called serum because all its fibrinogen and most of the other clotting factors have been removed; in this way, serum differs from plasma. Serum cannot clot because it lacks these factors. Platelets are necessary for clot retraction to occur. Therefore, failure of clot retraction is an indication that the number of platelets in the circulating blood might be low. .

Extrinsic Pathway for Initiating Clotting

The extrinsic pathway for initiating the formation of prothrombin activator begins with a traumatized vascular wall or traumatized extravascular tissues that come in contact with the blood. This leads to the following steps
1. Release of tissue factor. Traumatized tissue releases a complex of several factors called tissue factor or tissue thromboplastin. This factor is composed especially of phospholipids from the membranes of the tissue plus a lipoprotein complex that functions mainly as a proteolytic enzyme.

2. Activation of Factor Xrole of Factor VII and tissue factor. The lipoprotein complex of tissue factor further complexes with blood coagulation Factor VII and, in the presence of calcium ions, acts enzymatically on Factor X to form activated Factor X (Xa).

3. Effect of activated Factor X (Xa) to form prothrombin activatorrole of Factor V. The activated Factor X combines immediately with tissue phospholipids that are part of tissue factor
or with additional phospholipids released from platelets as well as with Factor V to form the complex called prothrombin activator.Within a few seconds, in the presence of calcium ions (Ca++), this splits prothrombin to form thrombin




Intrinsic Pathway for Initiating Clotting
The second mechanism for initiating formation of prothrombin activator, and therefore for initiating clotting, begins with trauma to the blood itself or exposure of the blood to collagen from a traumatized blood vessel wall. Then the process continues through the series of cascading reactions shown in Figure
Intrinsic Pathway for Initiating Clotting
The second mechanism for initiating formation of prothrombin activator, and therefore for initiating clotting, begins with trauma to the blood itself or exposure of the blood to collagen from a traumatized blood vessel wall
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1. Blood trauma causes (1) activation of Factor XII and (2) release of platelet phospholipids. Trauma to the blood or exposure of the blood to vascular wall collagen alters two important clotting factors in the blood: Factor XII and the platelets.When Factor XII is disturbed, such as by coming into contact with collagen or with a wettable surface such as glass, it takes on a new molecular
configuration that converts it into a proteolytic enzyme called activated Factor XII.
Simultaneously, the blood trauma also damages the platelets because of adherence to either collagen or a wettable surface (or by damage in other ways), and this releases platelet phospholipids that contain the lipoprotein called platelet factor 3, which also plays a role in subsequent clotting reactions.
2. Activation of Factor XI. The activated Factor XII acts enzymatically on Factor XI to activate this
factor as well, which is the second step in the intrinsic pathway. This reaction also requires
HMW (high-molecular-weight) kininogen and is accelerated by prekallikrein.
3. Activation of Factor IX by activated Factor XI.
The activated Factor XI then acts enzymatically on Factor IX to activate this factor also.
4. Activation of Factor Xrole of Factor VIII.
The activated Factor IX, acting in concert with activated Factor VIII and with the platelet
phospholipids and factor 3 from the traumatized platelets, activates Factor X. It is clear that when
either Factor VIII or platelets are in short supply, this step is deficient. Factor VIII is the factor that is missing in a person who has classic hemophilia, for which reason it is called antihemophilic factor.
Platelets are the clotting factor that is lacking in the bleeding disease called thrombocytopenia.
5. Action of activated Factor X to form prothrombin activatorrole of Factor V. This step in the intrinsic pathway is the same as the last step in the extrinsic pathway. That is, activated Factor X combines with Factor V and platelet or tissue phospholipids to form the complex called prothrombin activator. The prothrombin activator in turn initiates within seconds the cleavage of prothrombin to form thrombin, thereby setting into motion the final clotting process, as described earlier.




Role of Calcium Ions in the Intrinsic and Extrinsic Pathways

Except for the first two steps in the intrinsic pathway, calcium ions are required for promotion or acceleration of all the blood-clotting reactions. Therefore, in the absence of calcium ions, blood clotting by either pathway does not occur. In the living body, the calcium ion concentration
seldom falls low enough to significantly affect the kinetics of blood clotting. But, when blood is removed from a person, it can be prevented from clotting by reducing the calcium ion concentration below the threshold level for clotting, either by deionizing the calcium by causing it to react with substances such as citrate ion or by precipitating the calcium with substances such as oxalate ion.

Difference Between the Extrinsic and Intrinsic Pathways

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An especially important difference between the extrinsic and intrinsic pathways is that the extrinsic
pathway can be explosive; once initiated, its speed of completion to the final clot is limited only by the amount of tissue factor released from the traumatized tissues and by the quantities of Factors X, VII, and V in the blood. With severe tissue trauma, clotting can occur in as little as 15 seconds. The intrinsic pathway is much slower to proceed, usually requiring 1 to 6 minutes to cause clotting.

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 (glycocalyx is a mucopolysaccharide adsorbed to the surfaces of the endothelial cells), which repels clotting factors and platelets, thereby preventing activation of clotting; and (3) a protein bound with the endothelial membrane, thrombomodulin, which binds thrombin. Not only does the binding of thrombin with thrombomodulin slow the clotting process by removing thrombin, but 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.
Antithrombin Action of Fibrin and Antithrombin III. Among the most important anticoagulants in the blood itself are those that remove thrombin from the blood. The most powerful of these are (1) the fibrin fibers that themselves are formed during the process of clotting and (2) an alpha-globulin called antithrombin III . While a clot is forming, about 85 to 90 per cent of the thrombin formed from the prothrombin becomes adsorbed to the fibrin fibers as they develop.This helps prevent the spread of thrombin into the remaining blood and, therefore, prevents excessive spread of theclot. The thrombin that does not adsorb to the fibrin fibers soon combines with antithrombin III, which further blocks the effect of the thrombin on the fibrinogen and then also inactivates the thrombin itself during the next 12 to 20 minutes.
Heparin. 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,
The heparin molecule is a highly negatively charged conjugated polysaccharide. By itself, it has little or no anticoagulant properties, but when it combines with antithrombin III, the effectiveness of antithrombin III for removing thrombin increases by a hundredfold to a thousandfold, and thus it acts as an anticoagulant. Therefore, in the presence of excess heparin, removal of free thrombin from the circulating blood by antithrombin III is almost instantaneous. .

Lysis of Blood ClotsPlasmin

Plasmin digests fibrin fibers and some other protein coagulants such as fibrinogen, Factor V, Factor VIII, prothrombin, and Factor XII. Therefore, whenever plasmin is formed, it can cause lysis of a clot by destroying many of the clotting factors, thereby sometimes even causing hypocoagulability
of the blood.
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Conditions That Cause Excessive Bleeding in
Human Beings
bleeding caused by (1) vitamin K deficiency, (2) hemophilia, and
(3) thrombocytopenia (platelet deficiency)


Vitamin K Deficiency
With few exceptions, 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 tobleed. 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. .
vitamin K is injected into all surgical patients with liver disease or with obstructed bile ducts before performing the surgical procedure. Ordinarily, if vitamin K is given to a deficient patient 4 to 8 hours

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. Therefore, almost never will a woman have hemophilia because at least one of her two X chromosomes will have the appropriate genes.. For instance, bleeding can often last for days after extraction of a tooth.
severe prolonged bleeding, almost the only therapy that is truly effective is injection of purified Factor VIII. The cost of Factor VIII is high, and its availability is limited because it can be gathered only from
human blood and only in extremely small quantities.

Thrombocytopenia

Thrombocytopenia means the presence of very low numbers of platelets in the circulating blood. People with thrombocytopenia have a tendency to bleed, as do hemophiliacs, except that 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. As stated earlier, platelets are especially important for repair of minute breaks in capillaries and other small vessels. 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 leth










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