HOMEOSTASIS AND COAGULATION

The principle function of blood is to keep the internal environment of the body tissues constant and in this way to maintain homeostasis. Homeostasis is a term used to describe normal body functions, which include blood pressure, heart rate, body temperature, respiration and blood composition. In order to perform the processes involved in homeostasis, blood must be fluid. A mechanism known as hemostasis keeps the body fluid within the confines of the circulatory system.

Table of Contents
Hemostasis
Abnormal Hemostasis
Mechanisms Involved in hemostasis
Clotting Factors
Plasmatic Coagulation
Inhibitors
Extrinsic Pathway
Intrinsic Pathway
Intrinsic and Extrinsic Pathway
Antithrombin III

Normal Hemostasis
Blood normally is a fluid tissue as it circulates through out the body via the blood vessels. When vessels are injured, blood escapes and bleeding continues for a period of time but then slowly subsides. Several biologic systems play a role in stopping the flow of blood from an injured vessel. In addition to the vessels themselves, platelets and clotting factors interact to form a haemostatic clot. The formation of a haemostatic clot is a temporary measure and as the wound heals the clot slowly dissolves

Abnormal Hemostasis
There are two forms of abnormal hemostasis, which are described as follows:
a. Prolonged Bleeding: Following an injury bleeding may not stop in the same length of time it normally should. This may be the result of an abnormality involving the blood vessels, the platelets, clotting factors or increased activity of the fibrinolytic system. Hemophilia A is an example of prolonged bleeding directly related to an abnormal form of factor VIII, where the coagulant portion of the factor VIII molecule is deficient.
b. Thrombosis:
A thrombus or a clot in a blood vessel is formed by the coagulation of the blood. The formation of this clot is abnormal because its presence in a blood vessel obstructs the flow of blood to the tissues in that area, resulting in cellular changes. A heart attack can be one of the consequence of abnormal clot formation.

Mechanism Involved In Hemostasis
In the case of healthy subjects there exists a equilibrium between the coagulation potential on the one side and fibrinolytic potential + coagulation inhibitors on the other. In the fibrinolytic potential outweighs the coagulation potential or the coagulation factors are diminished then there is a risk of hemorrhage. If the coagulation potential outweighs the fibrinolytic potential or the inhibitors are diminished, there is a risk of thrombosis.
A delicate balance of components on both sides of the scale is required to maintain hemostasis.
1. Blood vessels:
The vascular system is composed of arteries, veins and the microcirculatory system. The blood vessels provide a non-thrombogenic surface allowing the blood to circulate in a closed vascular system. The nonthrombogenic surface is attributed to properties of the vessel walls and activities of platelets.
2. Platelets:
Platelets or thrombocytes are produced in the bone marrow by large cells called megakarycocytes. The normal numbers of platelets circulating are 150,000 to 450,ooo per cubic millimeter blood. To aid in hemostasis, platelets must be present in adequate number and must be functioning normally.
Platelets have Three major Functions:
a. Support Vascular integrity
Platelets support vascular integrity in two ways,
i. They help the blood vessels to maintain vascular integrity by donating membrane materials to the endothelial cells lining the vessel walls.
ii. Platelets also fill gaps that may occur between endothelial cells because of minimal damage or vasodilatation. By filling the gap a non trombogenic surface is maintained.
If a gap were allowed to remain and became larger, sub endothelial structures which are foreign to platelets and clotting factors would initiate fibrin formation.
b. Adhesion/Aggregation:
Platelets are considered to be first kind of defense in a haemostatic response to an injury. Following injury to a vessel wall, platelets adhere to the injured surface and quickly form a platelet plug. This activity keeps the blood within a closed vascular system. In the formation of the plug, platelets change as they aggregate irreversibly.
Irreversible aggregation causes platelet constituent to be released. Many of the constituent have an immediate effect upon the haemostatic response. One platelet constituent, known as platelet factor 3, becomes available on the surface of the platelets. Platelet factor 3 is a phospholipid and participates with certain clotting factors to produce thrombin with the ultimate formation of fibrin.

Clotting Factors
The clotting factors designations with some of the commonly used synonyms are as follows:
Factor I Fibrinogen
Factor II Prothrombin
Factor III Tissue thromboplastin
Factor IV Calcium
Factor V Plasma AcGLOB, Proaccelerin Labile factor
Factor VI Not assigned
Factor VII Proconvertin, Stable factor
Factor VIII Anti-hemophilic Globulin Hemophilia-A
Factor IX Christmas factor, Plasma Thromboplastin component
Factor X Stuart prower factor
Factor XI Plasma thromboplastin Antecendant (PTA)
Factor XII Hageman factor
Factor XIII Fibrin stabilizing factor, Prekallikrein, Fletcher factor, HMWK, Fitzgerald.
The clotting factors with the exception of factor III and factor IV are plasma proteins. Factor III is found in all tissues and is released when cells are damaged. factor IV is needed fro several interactions between clotting factors to occur in the production of fibrin.
Each clotting factor is designated by a Roman numeral and its most common synonym. Roman numerals are used most often referring to the clotting factors.
Notice that factor VI is missing. A plasma protein was given a Roman numeral but later studies showed it did not fulfill all the criteria established by the international nomenclature committee to qualify as a factor.
Prekallikrein, also known as Fletcher factor, and kininogen are plasma proteins. Although they are members of the kinin system, they are required for the complete activation of factor XII.
T simplify and for easy remembrance of clotting factors, they are separated into three major groups and each group shares certain characteristics. These three groups are:
a. Fibrinogen Group:
Factor I, V and XIII are produced in the liver. A portion of factor VIII molecule is produced in the liver and another portion by the endothelial cells. These factors are present in fresh normal plasma and adsorbed plasma.
They are not present in serum because they are consumed during the clotting process.
Coumarin, which is an oral anti-coagulant, has no effect upon their production, therefore, these factors are present in plasma obtained from individuals taking oral anticoagulants.
Factors VI and VIII are labile and their activity is rapidly lost in stored plasma. this is an important consideration in coagulation testing and in therapy.
b. Prothrombin Group:
Members in this group includes Factor II, VII, IX and X.
These clotting factors are produced in the Liver and Vitamin K is required for their synthesis.
These clotting factors are present in stored plasma. With the exception of Factor II, they are not totally consumed during the clotting process, therefore they are present in serum.
Because of the antogonistic action on Vitamin K by Coumarin medication, the concentration of these factors is reduced in plasma obtained from individuals taking oral anticoagulants.
c. Contact Group:
Members in this group include Factors XII, XI Prekallikrein and kininogen.
Factor XII, XI prekallikrein and Kininogen are synthesized in the liver.
Factor XII and XI are fairly stable and may be found in stored plasma and adsorbed plasma. they are not consumed during the clotting process, therefore, they are also present in serum.

Plasmatic Coagulation
About 20 factors (proteins) are involved which circulate in blood as inactive precursors (A substance that precedes the formation of another substance).
Activation signifies conversion to an enzyme which in its turn activates the subsequent factor.
Distinction is to be made between two activation pathways Namely:
a. Intrinsic pathway: in which only intravascular plasmatic factors and those released by platelets are involved.
b. Extrinsic Pathway: in which what are known as tissue thromboplastine are released from the surrounding tissue by injury and initiate the coagulation process.
Both pathways lead to the conversion of prothrombin to thrombin, which converts ion of fibrin webs provides the basis for measurements of coagulation times.
Activation Process:
Coagulation factors are present in the blood as inactive precursors awaiting activation together with calcium and phospholipids by their activated antecedent factor. Activation means consumption, and hence a transitory fall in concentrating.

Inhibitors
The achievable coagulation system conceals potential risk for the individual. Hyper and hypo function disturb the equilibrium. It must be adaptable enough to maintain the theological (flow) properties of the blood the one hand, and on the other hand to prevent the passage of blood into the tissue by sealing the capillaries. Activation of the system has therefore to remain limited to the extent and location of the need. This task is performed by inhibitors which block the enzymatic activity. The most important inhibitor is antithrombin III. Others include alpha-macro-globulin and alpha-antitrypsin.
Fibrinolysis:
After the fibrin has fulfilled its function, it must be catabolised in a process known as fibrinolysis. Two possible activation pathways lead finally to conversion of the protein plasminogen into the enzyme plasmin, which in its turn cleaves fibrin into even smaller, and hence soluble, degradation products.
Extrinsic Pathway
In the case of injury, tissue thromboplastin passes into the blood and activates Factor VII to Factor VII a, which in turn activates Factor X. Here begins the section of the cascade common to both activation pathways. Namely, Factor X a- with Factor V as accelerator- activates the prothrombin (Factor II) to thrombin (Factor II a). Thrombin cleaves fibrinogen, thereby initiating the formation of fibrin.
The extrinsic pathway is monitored with the aid of the prothrombin time test. In the test, we create the same conditions as in vitro in order to launch this part of the cascade. The time required for the formation of first fibrin web is the prothrombin time which is measured in terms of seconds. This test measures the collective activity of clotting factors I, II, VII and X.
Use of Prothrombine Time Test:
1. The test is most often used to monitor oral anticoagulation therapy.
2. It is also used as a sensitive indicator for dysfunction of the liver.
Intrinsic Pathway
Contact with a foreign surface effects the activation of Factor XII. This triggers a regular cascade of activity namely via Factor XI, IX and VII to the common end pathway and hence the formation of fibrin. The intrinsic pathway is monitored with the aid of a Partial thromboplastin time.
Uses of activated partial thromboplastin time:
1. It is used as screening procedure to detect clotting factors.
2. It is used to monitor heparin therapy.
3. It is used to monitor replacement therapy in individuals with a clotting factor deficiency.
Extrinsic and Intrinsic Pathway
The inactive coagulation factors present in the plasma are to some extent assigned to two different activation pathways. From factor X onwards the cascade then proceeds jointly upto fibrin. This fibrin clot is initially of a loose structure. In the presence of activated factor XII it is stabilized to a mechanically firm clot which makes the haemostasis permanent. Since Factor XII does not act on the fibrin until the latter is formed, determination of this factor requires a separate test system.
Screening for Coagulation Disorders:
The activated partial thromboplastin time in conjunction with prothrombin time frequently permits a crude localization of a coagulation defect is probably to be found in Factor XII, is prolonged, the defect is probably it could well be matter of a factor VII deficiency. If, however, both screening tests are pathological, then the deficiency is more likely to have arisen in the joint end pathway of factors X, V, II and I.
Thrombin Time:
The end point of plasmatic coagulation is the activation of Prothrombin (factor II) to Thrombin(II a). Thrombin rapidly converts fibrinogen into fibrin. Antithrombins as the name implies are counteractive.
Thrombin normally converts fibrinogen into fibrin. This reaction is inhibited by fibrin, FDP and by antithrombins. If such products are present in the plasma to an increased extent, then the TT is prolonged.
The same occurs when the fibrinogen level is lowered, as in the case of augmented fibrinolysis or during a fibrinolytic therapy. One of the uses of this test is therefore in the monitoring of fibrinolytic (Strepto Kinase) or thrombolytic (Heparin) therapy.

Antithrombin III
Antithrombin III is a plasma protein. It is a naturally occurring inhibitor to the coagulation system. It is also the cofactor for heparin. Adequate levels of Antithrombin III must be present in plasma for heparin to exert its anticoagulant effect. Antithrombin III slowly inhibits the activity of activated clotting factors XII a, XI a, IX a and X a. It also neutralizes the active enzyme thrombin.
In order for heparin to exert the its anticoagulant effect, it must form a complex with antithrombin III. Once heparin is given, it complexes with antithrombin III and immediately the AT III heparin complex increases the speed of inhibitory activity.