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Essay on Blood Coagulation
Essay Contents:
- Essay on the Introduction to Blood Coagulation
- Essay on the Methods Determining Blood Coagulation
- Essay on the Importance of Blood Coagulation
- Essay on the Mechanism of Blood Coagulation
- Essay on the Factors Effecting Blood Coagulation
- Essay on the Diseases Occurring Due to Blood Coagulation
- Essay on the Natural Inhibitors of Blood Coagulation
- Essay on the Factors Preventing and Hastening Blood Coagulation
Essay # 1. Introduction to Blood Coagulation:
When blood is shed, it loses its fluidity in a few minutes and sets into a semisolid jelly. This phenomenon is called blood coagulation or clotting. On further keeping, the clot retracts to a smaller volume and presses out a clear straw-coloured fluid, called the serum. Serum will not clot any more.
When the process of blood coagulation is studied under the ultra-microscope, it is seen that, minute granules appear at first, often near a clump of disintegrating platelets. These granules join together to form needles, which again unite with one another to form long threads across the whole bulk of blood. These threads cross one another and form a sort of network, into the meshes of which the red and white cells become entangled. The clot gradually retracts and serum separates out.
It is to be noted that blood coagulation is the property of plasma alone. The red and white cells do not take part in it. They only become caught up in the meshes of the clot and are thereby removed. It is due to this fact that the clot has a red colour, and the serum is a clear non-cellular fluid. Blood platelets take some part in the process.
Normal Coagulation Time:
Measured according to the method of Lee and White it is 6 to 17 minutes in glass tube and 19 to 60 minutes in siliconised tube.
Essay # 2. Methods Determining Blood Coagulation:
i. Capillary Glass Tube Method:
This method is usually adopted as a bed side procedure. The finger is pricked and the blood is made to flow into a capillary glass tube about 15 cm (6 inches) long. A small bit of the glass tube is carefully broken off every fifteen seconds until a fine thread of clotted blood appears while the tube is being broken. The period between the appearance of blood in the finger and the formation of this thread is taken as the blood coagulation time. The average time, by this method, is 3-4 minutes.
ii. Wright’s Coagulometer:
The principle is same as above. Blood is allowed to flow into a dozen capillary tubes of equal calibre. The tubes are sealed on both sides and placed in water bath at 37°C. After 4 minutes, the first tube (the tube which was first filled with blood) is removed from the water bath, the ends are broken and the blood inside is expelled into water. The same procedure is repeated with all the other tubes at intervals of 30 seconds. When the blood expelled from a particular tube has the form of a worm-like clot, the end point is reached.
iii. Method of Lee and White:
1 ml of blood is drawn from a vein by a dry syringe and placed in two clean test-tubes, 8 mm in diameter. The tubes are closed by a rubber cork. At 5 minutes after withdrawal of the blood in the manner described, the first tube is gently tilted 45 degrees at one minute intervals until it can be inverted 180 degrees without blood flowing.
This time is recorded and the same procedure is repeated with the second tube. As handling favours coagulation, the time for the second tube is taken as the true blood coagulation time since it was tilted less than first tube.
Bleeding Time:
Normal average is 3.25 minutes, the range being 2-5 minutes. It is usually determined by Duke’s method. The lobule of the ear is punctured and the time is noted. The blood oozing out is mopped up with a piece of filter paper every half a minute until bleeding stops. This indicates the end point.
Prothrombin Time (Quick):
An approximate prothrombin time is generally 11 to 16 seconds. When tissue extract (thromboplastin) and calcium chloride are mixed (added) in an optimum amount to blood of normal fibrinogen content, the only factor which has an inadequate concentration of prothrombin, can vary the coagulation time.
If the prothrombin is diminished the blood coagulation time increases. This test is a quantitative one for prothrombin in blood based on the blood coagulation time of oxalated blood plasma in the presence of tissue extract (thromboplastin) and calcium chloride.
In each laboratory a curve of prothrombin concentration in the blood to the prothrombin time is usually drawn for the evaluation of the prothrombin time. The only precaution is that blood removed from the patient is immediately oxalated so that none of the prothrombin can be converted into thrombin.
Method:
In a test-tube 0.2 ml of commercial thromboplastin containing calcium is kept at 37°C. After 30 seconds, 0.1 ml plasma is quickly added from a pipette, and a stop-watch is started simultaneously. The tube is kept in the water bath and is shaken constantly but gently for 10 seconds. Then in bright direct illumination the tube is tilted continually from vertical to almost horizontal position once per second until a gel appears.
This is the end point. A value of 11 to 16 seconds is satisfactory, but the test should always be performed in duplicate.
Essay # 3. Importance of Blood Coagulation:
The phenomenon of coagulation is of enormous physiological importance. Its purpose is to stop further haemorrhage. When bleeding occurs, the shed blood coagulates and the bleeding vessels become plugged off by the clot.
The retraction of the clot compresses the ruptured vessels further and in this way bleeding is stopped.
Essay # 4. Mechanism of Blood Coagulation:
As early as 1904 Morawitz described the basic facts about the mechanism of blood clotting in the following manner. When blood is shed, the platelets (by coming in contact with rough water-wet-table surface), disintegrate and liberate thromboplastin.
Certain amount of thromboplastin is also derived from the damaged tissues of the injured locality. Thromboplastin converts prothrombin into thrombin with the help of calcium ions and thrombin interacts -with fibrinogen forming fibrin.
This is the clot. This theory can be summarised in the following steps:
Normally:
Prothrombin + Calcium ion + Fibrinogen → Nil
After shedding of blood:
1. Thromboplastin + Prothrombin + Calcium ion → Thrombin
2. Thrombin + Fibrinogen → Fibrin (Clot).
Since 1940, research work has indicated that the clotting mechanism is a complex process. In 1954 an International Committee was established. The committee suggested an international system of nomenclature time to time with the appearance of new factors.
Essay # 5. Factors Effecting Blood Coagulation:
Factor I or Fibrinogen:
It is globulin in nature but has a much bigger molecule than serum globulin. The molecular weight is about 330,000. It is coagulated at about 56°C and precipitated by one-fifth saturation with ammonium sulphate and saturation with NaCl. It is distinguished from other plasma proteins by its property of clotting, during which fibrinogen is converted into fibrin.
Factor II or Prothrombins:
It is protein in nature and present in normal plasma. It has a molecular weight of about 62,700. It is very labile in aqueous solution and is inactivated by acids at pH 4.8, by alkali at pH 10.0 and by heat at 60°C; but is stable indefinitely when dried from the frozen state. In oxalated plasma, two forms of prothrombin are found ‘A’ and ‘B’.
The A’ form is destroyed by oxygen and is heat labile. The ‘B’ form is removable by aluminium hydroxide. In normal plasma the two forms remain united as calcium compound. When oxalate is added, calcium is removed and the two components become separate.
It can be isolated as follows:
If the pH of plasma is adjusted at 5.3, both prothrombin and globulin are precipitated. Prothrombin is dissolved by treating the precipitate with dilute calcium bicarbonate. After filtration the pH of the filtrate is again adjusted to 5.3 when prothrombin separates out. In this form it is a white powder, insoluble in water and remains combined with a protein. 100 ml of plasma contains 40 mgm of this substance.
The prothrombin activity of blood is measured by the clotting time of recalcified oxalated plasma, to which tissue emulsion has been added. In human subject, the average ‘prothrombin time’ is 12 seconds. Prothrombin time will be longer in deficiency of factor V or factor VII or Stuart factor. Prothrombin is manufactured in the liver. Vitamin K is essential for the formation of prothrombin. During clotting, prothrombin is converted into thrombin.
Factor III or Thromboplastin:
It is derived from two sources:
1. Intrinsic in the Plasma:
Intrinsic thromboplastin is formed in the plasma due to interaction between different plasma factors, e.g., Hageman factor or factor XII, PTA or factor XI, Christmas factor or factor IX, antihaemophilic globulin or factor VIII, calcium ions, factor V and factor X.
Prothrombin is converted into thrombin with the help of intrinsic thromboplastin in presence of calcium ions. It should be noted that blood flowing normally through the circulatory system will not clot. But if the surface of the blood vessel becomes rough due to any reason, blood will clot even without the addition of tissue extract (extrinsic thromboplastin).
2. Extrinsic or Tissue Thromboplastin:
It is formed from different tissues, e.g., extracts of brain, lungs, etc., as result of injury. So long it was known that prothrombin was converted into thrombin with the help of calcium ions and thromboplastin liberated from damaged tissues. But recently it has been found that various plasma factors, e.g., factor VII or proconvertin, are required for such conversion and the process is called extrinsic thromboplastin formation.
Factor IV or Calcium:
Ionic calcium greatly helps in blood clotting; by acting as a cofactor in the blood coagulation process. It is essential for the formation of both intrinsic and extrinsic thromboplastins and also in the conversion of prothrombin into thrombin.
Factor V or Labile Factor Accelerator Globulin or Proaccelerin:
This factor is necessary for the complete conversion of prothrombin into thrombin by the extrinsic or intrinsic thromboplastin. It is a protein, heat-labile and is activated within half an hour at 56°C or by increasing the pH to 10.5. It is present in plasma but is used up during clotting.
Factor VI or Accelerin:
This factor is a hypothetical activation product of proaccelerin (factor V).
Factor VII or Stable Factor or Proconvertin:
This factor is present in plasma and is not used up during clotting. It is heat-stable and can withstand temperature up to 56°C. It is a protein and remains associated with prothrombin. It accelerates extrinsic or tissue thromboplastin formation, being activated by extract released from damaged tissue. Its formation is retarded after administration of Dicoumarin and in deficiency of vitamin K. During blood clotting proconvertin is changed into converting.
Factor VIII or Antihaemophilic Factor (AHF) or Antihaemophilic Globulin (AHG) or Platelet Cofactor I:
This factor helps in the formation of intrinsic thromboplastin and intrinsic prothrombin conversion. It is present in the plasma and disappears when the blood clots. It is protein in nature and remains in close association with fibrinogen. This factor is antihaemophilic. In Haemophilia (bleeder’s disease) the defect is not in the platelets but it is due to the absence of this factor which helps in the breakdown of platelets and liberation of platelet cofactor I or thromboplastin factor.
The deficiency of AHG resulting in classical haemophilia in the male is transmitted as a sex-linked recessive trait. The body fails to synthesise this essential globulin due to the absence of the specific enzyme which is controlled by the mutant gene. It is adsorbed on barium sulphate and has a molecular weight greater than 200,000.
Factor IX or Christmas Factor or Plasma Thromboplastin Component (PTC) or Platelet Cofactor II:
This factor is necessary for intrinsic thromboplastin formation. Absence of this factor leads to a disease stimulating Haemophilia known as Haemophilia C and is transmitted as a sex-linked recessive in the male. It is adsorbed by aluminium hydroxide, is labile to heat but is relatively stable on storage. It is precipitated by 59 percent ammonium sulphate. This type of disease was first found in a patient named Christmas and hence the name Christmas factor. This factor is not used up during clotting.
Factor X or Stuart Factor:
In 1959 the international nomenclature has been given to this factor. Chemically it has many of the properties similar to that of factor VII. Its synthesis is also retarded after administration of Dicoumarin. Absence of this factor leads to mild haemorrhagic diathesis. It is stable in room temperature, but destroyed rapidly at 56°C in serum.
Factor XI or Plasma Thromboplastin Antecedent (PTA):
This is activated by active Hageman factor, and ultimately leads to formation of thrombin. Deficiency of this causes mild bleeding tendencies of haemophiloid D type and is transmitted as a sex-linked dominant to both sexes.
Factor XII or Hageman or Surface Factor:
This is protein in nature. Inactive form is activated on surface contact. This in turn activates the protein- splitting enzyme kallikrein to produce plasma kinins. The resulting effects are increased vascular permeability and dilatation of blood vessels.
Factor XIII or Fibrin-Stabilising or Laki-Lorand factor (LLF):
The active form along with Ca++ converts soft fibrin clot to a solid, fibrous one. Its action also decreases the solubility of the clot in urea sol. Persons having congenital malformation of LLF suffer from poor wound healing.
Role of Thrombin:
Thrombin is a homogeneous glycoprotein of molecular weight 40,000 acting as a proteinase. It autocatalyses its own formation by converting plasma Ac-globulin into the active serum Ac-globulin and by labilising platelets to accelerate thromboplastin generation and liberates vasoconstrictors. It splits only four peptide bonds in the conversion of fibrinogen to fibrin and these are all bonds between arginine and glycine residues.
Role of Phospholipid:
Phospholipid kephalin (cephalin) helps in the formation of prothrombinase. In the intrinsic system it is in the platelet factor 3 and in the extrinsic one in tissue thromboplastin.
Role of Protein:
Blood clotting factors, from V to XII, are plasma proteins mostly β-globulins. A few of them are however either α-globulin or ϒ-globulin.
The needs for contribution of many clotting factors are involved in the blood coagulation process. But the plasma protein clotting factors usually interact in pairs. Due to this interaction each of the clotting factors is in turn converted from an inactive form to an active one.
Since all the clotting factors are not supposed to possess enzyme actions, yet this conversion of enzymes from an inactive form to an active one is initiated in the sequence of action of clotting factors. The process of intrinsic and extrinsic systems has been shown schematically in Fig. 4.3.
Davie and Ratnoff (1965) have proposed what has been termed a ‘waterfall sequence hypothesis’ to explain the succession of events taking place in the blood coagulation. Each protein coagulation factor exists in the plasma in an inactive (proenzyme) form and is activated sequentially until finally thrombin is formed which then converts fibrinogen into fibrin.
Macfarlane has suggested a scheme of blood coagulation called an enzyme cascade which is very similar to the ‘waterfall’ scheme (Fig. 4.4) of Davie and Ratnoff.
Clot Retraction:
Usually blood clot retracts to about half its initial volume within 20 to 24 hours. When blood is shed, fibrins form a network like structure. The platelets adhere to these fibrin networks and form knots. The fibrin framework then becomes twisted and shortened, and clot retraction occurs.
Essay # 6. Diseases Occurring Due to Defects in Blood Coagulation:
Lack of Fibrinogen or Factor I:
Afibrinogenaemia or fibrinogenopenia is a rare congenital disease due to lack of fibrinogen. Sometimes it is found during abnormal pregnancy.
Due to Diminution of Prothrombin or Factor II:
Vitamin K helps in the formation of prothrombin in the liver. Vitamin K is a naphthoquinone derivative. It is absorbed from the small intestine in the presence of bile salts. In the liver it helps in the synthesis of prothrombin and factor VII or stable factor or proconvertin.
In the liver disease, e.g., Cirrhosis of liver, malignant disease of the liver, etc., there is diminution of synthesis of prothrombin in the liver. In Obstructive jaundice due to absence of bile salts, vitamin K is not absorbed. Due to lack of vitamin K, synthesis of prothrombin and factor VII is decreased. Prothrombin time is prolonged and haemorrhages often occur.
Due to Lack of AHG or Factor VIII-Haemophilia:
It is a disease which occurs in males but is transmitted through females. The blood coagulation-time is abnormally prolonged. There is a tendency to bleed severely after trivial injuries. The knee or elbow joint may be distended with blood. The platelet count remains normal. There is lack of factor VIII or antihaemophilic globulin (AHG). Blood transfusion temporarily supplies AHG and stops bleeding.
Sometimes it has been observed that if bloods taken from two subjects are mixed together, coagulation time is normal although the blood coagulation time of each individual subject has got prolonged blood coagulation time. From this it has been assumed that there are two types of haemophilic subjects, one lacking in AHG and another lacking factor IX or Christmas factor or PTC.
Due to Diminution of Factors V, VII and IX-Psedohaemophilia:
In this disease there is congenital deficiency of factors V, VII and IX. The haemorrhagic condition stimulates haemophilia.
Essay # 7. Natural Inhibitors of Blood Coagulation:
To maintain blood in a fluid state in the normal condition, retarding influences coexist with positive coagulation-inducing -factors in the circulating blood.
Some of the ingrained safeguards against intravascular clotting are:
(a) The relative slowness of thrombin production,
(b) The unbroken continuity of the vascular endothelium and
(c) Removal of clotting intermediates by the R. E. cells. Besides these, other definite inhibitors of coagulation are present.
Antithrombin activities remove thrombin from blood. Antithrombin I is the thrombin-adsorbing effect of fibrin but whether it plays a role in normal blood coagulation is unknown. Antithrombin II is a factor which acts jointly with heparin. Antithrombin III is the so-called physiological antithrombin because it is present naturally and inactivates thrombin progressively. Heparin is described separately below. Antithromboplastins are present in normal blood, and one or more circulating antithromboplastins are claimed to be present.
Intravascular Clotting or Thrombosis:
i. Thrombus:
It is a clot formed inside the blood vessels. Thrombus is formed due to slowing of circulation and damage of the vascular endothelium. Atheromatous patches occur in blood vessels and the vascular endothelium is damaged in some abnormal conditions. Masses of platelets are deposited in the damaged endothelium. Filaments of fibrin form also a network in this region. The platelets liberate thromboplastin.
The fibrin, entangled in the lamellae of platelets, forms the thrombus or clot. Intravascular thrombosis sometimes occurs in coronary and cerebral vessels which are called coronary thrombosis and cerebral thrombosis respectively. After surgical operations, etc., thrombosis may occur in big veins.
ii. Heparin:
At first it was isolated from liver by McLean in Howell’s laboratory, hence the name. Subsequently, it has been extracted from many tissues in the body. It is anticoagulant, in vivo and in vitro. One unit of heparin is defined as the quantity of material which will prevent the clotting of 1ml of cat’s blood for 24 hours when kept in cold. Chemically it is mucoitin polysulphuric acid.
Mucoitin is a polysaccharide, composed of glucosamine, glucuronic acid and esterified sulphuric acid forming an ester with molecular weight of about 17,000. It has been shown that any substance with a high molecular weight, and being composed of polysaccharides and several SO4 groups, can act as an anticoagulant. Hirudin, found in cervical glands of the common medicinal leech (Hirudo), is a compound of this nature. Heparin is normally secreted by the mast cells.
These cells are found in blood to about 1%. They remain scattered throughout the reticulo-endothelial system and found abundantly along the course of many blood vessels, such as those of liver. Sometimes they replace the intima of the blood vessels. These cells are found to contain granules which are supposed to be the precursors of heparin.
It is doubtful whether heparin is present in normal blood in any appreciable amount and as such it probably takes no part in preventing intravascular clotting normally. Heparin helps to maintain the normal fluidity of the blood within the vascular bed. It inhibits the transformation of prothrombin to thrombin when accompanied by a plasma cofactor albumin X and neutralises the action of thrombin on fibrinogen.
iii. Fibrinolysis:
Clotted blood if kept sterile remains intact for several weeks. But if it is not kept sterile the clot breaks up. This fibrin breakdown in the clot is known as fibrinolysis and is brought about by a proteolytic enzyme in the plasma known as plasmin or fibrinolysin.
The precursor of the enzyme plasminogen (also known as profibrinolysin) is activated to plasmin by activators present in tissues, serum, urine and some bacteria. Normally fibrinolysis is prevented by the presence of another substance in the blood known as antiplasmin which remains attached to the plasma albumin.
Essay # 8. Factors Preventing and Hastening Blood Coagulation:
i. By lowering temperature, blood coagulation can be prevented.
ii. By avoiding contact with water-wettable surface and injured tissues. This prevents thrombokinase action. When blood is collected in a tube coated with paraffin, the surface not being water-wettable, the platelets will not break down and coagulation will not take place.
iii. Removal of calcium ions:
(a) By Precipitation:
This is the commonest practice in clinical laboratories. This is done by adding citrates or oxalates of Na or K. Sodium fluoride (0.3% solution) is also used,
(b) By Formation of a Complex Compound:
The substances used are di- and trisodium citrate and ethylene diamine tetra acetate (EDTA).
iv. Precipitation of Fibrinogen:
By adding various salt solutions in adequate amounts. When blood is mixed with one quarter of its volume of magnesium sulphate or with an equal volume of half saturated sodium sulphate solution, clotting is prevented.
v. By the Addition of Substances of Biological Origin:
a. Protamines:
Simple proteins found in some fish.
b. Peptone:
When it is injected into the veins, the coagulability of blood is reduced. [But peptone does not prevent the blood coagulation of a sample of blood in vitro]. Extracts of cray fish and nussels act in somewhat similar manner. They act by increasing secretion of heparin by the mast cells.
c. Heparin:
Mucoitin-polysulphuric acid produced by mast cells.
d. Hirudin:
Hirudin (Leech extract) and the venom of certain snake. Heparin, hirudin and venom inhibit blood coagulation by inhibiting activation of prothrombin and thrombin fibrinogen reaction.
e. Cystein:
Same as heparin and hirudin.
f. Dicoitmarin or Dicoumarol:
It is chemically related to the naphthoquinone derivative. It is antagonist to vitamin K. It inhibits the synthesis of prothrombin in the liver by preventing the action of vitamin K. Dicoumarol lowers the plasma prothrombin level and depresses the activity of factor VII.
g. Phenindione:
Action similar to that of dicoumarol. Its action is quick and depresses the activity of factor VII more than prothrombin.
vi. By adding azo dyes and synthetic products:
Chicago blue, trypan red, trypan blue act as anticoagulants both in vivo and in vitro.
Factors Hastening Blood Coagulation:
i. Warmth.
ii. Contact with water-wet table surface and contact with rough surface.
iii. Additions of foreign bodies into, a sample of blood (vide ‘Defibrinated blood’).
iv. Addition of thrombin.
v. Addition of thromboplastin.
vi. Vitamin K injection or oral administration in high doses increases the prothrombin content of blood and increases the coagulability.
vii. Addition of calcium chloride, both in vivo and in vitro.
viii. Adrenaline injection produces constriction of blood vessels and helps in haemostatis mechanism.