To keep the blood in a fluid state that is anticoagulated, the coagulating as well as anticoagulant factors are delicately balanced in the circulating blood. There may occur spontaneous bleeding or intravascular thrombosis due to any disturbance in this delicately balanced system. Blood coagulation means the conversion of blood to a solid gel or clot. The clotting system consists of a cascade of proteolytic enzymes and cofactors which are present in blood as inactive precursors (zymogens). These coagulation factors are:
Factor I (fibrinogen), II (prothrombin), III (thromboplastin or tissue factor; TF), IV (Ca4j, V (accelerator globulin or proaccelerin), VI (proconvertin or serum prothrombin conversion accelertor; SPCA), VIE (antihaemophilic factor-A), VIII (christmas factor or plasma thromboplastin component [PTC] or antihemophilic factor-B), IX (Stuart factor or thrombokinase), X (plasma thromboplastin antecedent [PTA], or antihaemphilic factor-C), XI (hageman factor or contact factor), XII (fibrin stabilizing factor or fibrinase).
Inactive precursors are activated in series. In this process each one gives rise to more of the next. The last enzyme is thrombin which is derived from prothrombin (II). This enzyme converts soluble fibrinogen (I) to an insoluble mesh work of fibrin in which cells are trapped and thus a clot is formed.
There are two pathways in the cascade which result in activation of factor X which then converts prothrombin to thrombin. These pathways are:
• The extrinsic pathway which operates in vivo. It needs a tissue factor (a lipoproteincalled tissue thromboplastin) which is released from damaged tissue into the circulating blood. In this system, factor Xa is formed within seconds due to one step reaction.
• The intrinsic or contact pathway, which operates in vitro. It requires all the factors for coagulation which are present in circulating blood. In this system factor Xa takes several minutes for formation.
Calcium ions and a negatively charged phospholipid (PL) are essential for three steps, namely the action of:
• Factor IXa on X
• Factor Vila on X
• Factor Xa on II
Negatively charged phospholipid (PL) is provided by activated platelets adhering to the damaged vessel. Some factors promote coagulation by binding to PL and a serine protease factor, e.g. factor Va in the activation of II by Xa; Villa in the activation of X by IXa
They are classified as under:
1. Parenteral: Heparin, danaparoid, lepirudin, bivalirudin, and argatroban
a. Coumarin derivatives: Dicoumarol, tromexan, warfarin, phenprocoumon, acenocoumarol and nicoumalone
b. Indandione derivatives: Phenindione, diphenadione, anisindione and bromindione out of all these compounds, warfarin is the most important and most widely used. Other important oral anticoagulants are acenocoumarol and phenindione.
3. In vitro anticoagulants: Sodium citrate, sodium oxalate, and sodium edetate.
Heparin is a mixture of sulphated mucopolysaccharides (MW 3000—40,000). It has strong electronegative charge. It is present in mast cells, intimal layers of blood vessels and granules of basophils. Lungs, liver and intestinal mucosa are the richest sources of heparin. For commercial use, it is extracted from porcine intestinal mucosa and bovine lung. Circulating blood contains no heparin except when the mast cells are disrupted. Its physiological role is to maintain blood in fluid state. It does not affect other organs of the body even in large doses. It also has a lipaemia – clearing effect.
Mechanism of action to keep the blood anticoagulated: Heparin is effective both in vitro and in vivo. It is a powerful immediately acting anticoagulant. Heparin accelerates the action of antithrombin III which prevents the conversion of fibrinogen into fibrin by inhibiting the activated clotting factors. In this process, heparin acts as catalyst. Besides, it also slows down the conversion of prothrombin to thrombin and stabilizes platelets against dumping and disintegrating. Heparin is of two types:
• High molecular weight (HMW) heparin
• Low molecular weight (LMW) heparin.
Former strongly keeps the blood anticoagulated , while the later is a weak anticoagulant.
Pharmacokinetics: Heparin is not effective by oral route because it is precipitated by gastric juice, and digested by enzymes. So it is administered parenterally (i.v. or s.c.). It has a dose dependent action. Since heparin does not cross the placental barrier and also not secreted in mother’s milk it may be given during pregnancy and lactation. It does not affect bleeding time in therapeutic doses. Heparin is metabolized (up to 50%) in the liver by heparinase and the rest of the drug is excreted in urine as unchanged drug.
Haemorrhage, haematuria and gastrointestinal bleeding are common side effects due to keeping the blood anticoagulated for longer times. Prolonged use of heparin (for 6 months) may lead to osteoporosis and spontaneous fractures.
Heparin is contraindicated in:
• Peptic ulcer
• Bacterial endocarditis
• Active tuberculosis
• Threatened abortion
• Other haemorrhagic disorders
Dose: Heparin sodium contains 120 units per mg. A loading dose of 5000 units of heparin is followed by continuous intravenous infusion up to 40,000 units in 24 hours to keep the blood anticoagulated. It may be given by subcutaneous route (5000 units) but intramuscular injections are painful and may have the risk of haematoma formation at the site of injection.
• Deep vein thrombosis
• Intravascular coagulation
• To prevent postoperative thrombosis
Protamine sulphate is used up to a maximum dose of 50 mg i.v. as heparin antagonist to counteract over dosage of heparin. One mg neutralizes 100 units of heparin.
Other Parenteral Anticoagulants
Danaparaid: It is a mixture of heparin-like glycosaminoglycans (84% heparin sulphate, 12% dermatan sulphate, and 4% chondroitin sulphate). Danaparaid is isolated from porcine intestinal mucosa. Danaparaid is effective in keeping the blood anticoagulated. It is used:
• For prophylaxis of deep vein thrombosis (750 antif actor Xa units, s.c. twice daily)
• As anticoagulant for patients with heparin induced thrombocytopenia (750 antifactor Xa units, i.v. twice daily)
• For postoperative deep vein thrombosis following active hip replacement surgery
It acts mainly by promoting inhibition of factor Xa by antithrombin Ill.
Lepirudin: It is recombinant derivative of hirudin. It is a 65-amino acid polypeptide. It directly inhibits thrombin by binding tightly to both catalytic and exosite I sites of thrombin. It is used as anticoagulant in patients with heparin induced thrombocytopenia. It is administered i.v. at a dose adjusted to maintain the prothrombin time at 1.5 to 2.5 times the normal value.
Bivalirudin and argatroban are other direct thrombin inhibitors. Bivalirudin is used in per cutaneous coronary angioplasty as an alternative to heparin. Argatroban is used in patients with heparin-induced thrombocytopenia as an alternative to lepirudin.
Drotrecogin alfa is a human recombinant activated protein-C. It inhibits thrombin effects by inhibiting Va and Villa. It is used as anticoagulant. It is also employed by continuous i.v. infusion to decrease the mortality from severe sepsis (associated with organ dysfunction) in adults at high risk death.
Oral anticoagulants are chemically related to vitamin K. So they act by competitively antagonizing the actions of vitamin K. Thus they inhibit the synthesis of vitamin K dependent clotting factors. It takes about 36— 48 hours for the anticoagulant effect to develop and to make the blood anticoagulated . Unlike heparin, they are not active in vitro.
Warfarin and the other oral anticoagulants are readily absorbed on oral administration. These drugs cross the placental barrier and are also secreted in the mother’s milk. These drugs are extensively bound to plasma albumin. So these drugs have:
• Very low volume distribution
• No urinary excretion
• Long plasma half-life
• Several displacement drug interactions
Warfarin is metabolized in the liver into inactive metabolite which is excreted in the urine.
The main side effect of all oral anticoagulants is haemorrhage (2—4%). Anorexia, nausea, vomiting and diarrhoea are other minor side effects. These are contraindicated in:
• Peptic ulcer
• During first trimester of pregnancy
1. Action of warfarin is potentiated due to:
• Inhibition of its metabolism by cimetidine, metronidazole, cotrimoxazole, erythromycin, ciprofloxacin, disulfiram, chloramphenicol.
• Displacement from plasma protein by phenylbutazone, ethacrynic acid and sulphinpyrazone.
• Inhibition of platelet functions by nonsteroidal anti-inflammatory drugs.
• Inhibition of intestinal vitamin K synthesis by tetracyclines, cephalosporins (3rd generation).
• Enhanced catabolism of clotting factors by d-thyroxin, hyperthyroidism, and fever.
• Decreased synthesis of clotting factors by hepatic disease.
2. Action of warfarin is decreased due to:
• Enzyme induction by barbiturates, rifampicin, carbamazepine.
• Inhibition of intestinal absorption by sucralfate and cholestyramine.
• Increased clotting factors by vitamin K and oestrogen.
• Reduced catabolism of clotting factors by hypothyroidism.
• Hereditary resistance.
Doses are adjusted according to requirements and tests. The doses of commonly used oral anticoagulants are:
Warfarin sodium: 10 mg daily.
Acenocoumarol: 2—10 mg daily.
Phenindione: 50—150 mg daily.
• Deep vein thrombosis
• To prevent development of emboli on the heart valves.
Coagulants promote coagulation. They are indicated in haemorrhagic state. For immediate effects, whole blood or plasma is the best because it supplies all the endogenous coagulating factors. To restore haemostasis, following are the other drugs.
It is a fat soluble coagulation vitamin. It is present in leafy vegetables (as vitamin K1, phytonadione) and intestinal bacterial flora also synthesizes vitamin K (K3, menaquinone). Bile salts are required for the absorption of vitamin K1 and ‘<2 from intestine. However, a water-soluble synthetic vitamin K3 has also been developed which does not require bile salts for its oral absorption. Daily requirement of vitamin K is 50—100 pg/day.
Vitamin K acts as a cofactor in the synthesis of prothrombin, factors VII, IX and X. Deficiency of vitamin K occurs due to obstructive jaundice, liver disease, malabsorption, long-term antimicrobial therapy which alter intestinal flora. It is manifested by bleeding tendency such as haematuria, bleeding from gut, nose and ecchymoses.
Vitamin K is employed:
• In prophylaxis and treatment of bleeding (Vitamin 1<3 orally or K1 parenterally).
• As specific antidote for over dosage of oral anticoagulants. Vitamin K1 oxide is given i.m. due to its fast onset in comparison to vitamin 1(3 because of its delayed onset (24 hrs.).
• To treat vitamin deficiency in adults.
Rapid i.v. injection of emulsified vitamin K produces fall in blood pressure, flushing, breathlessness and a sense of constriction in the chest.
It is a fraction of human plasma. It is used to control bleeding in haemophilia, antihaemophilic globulin (AHG) deficiency and acute afibrinogenemic states. It is given in a dose of 0.5 g by i.v. infusion.
Antihaemophiic factor is a concentrated human antihaemophilic globulin. It is prepared from pooled human plasma. It is used to control bleeding episodes due to haemophilia and AHG deficiency. It is given by i.v. infusion in a dose of 5—10 .tg/kg every 6—12 hours.
Aminocaproic acid and its analogue tranexamic acid: They competitivety inhibit activation of plasminogen and are used in hyperplasminaemic state.
Aprotinin inhibits plasmin, kalllkrein and platelet activation. It is used for hyperplasminaemia caused by fibrinolytic drug overdose and to prevent blood loss during cardiac surgery.
Local haemostatics (styptics) are particularly effective on oozing surfaces, e.g. tooth sockets, open wounds, etc. They act by providing a network of fibrin which promotes coagutation.
The preparations include:
• Human or bovine thrombin: It is applied as dry powder or freshly prepared solution on the oozing surfaces. It is employed in haemophiia, neurosurgery, skin grafting, etc.
• Fibrin foam/sheets: Prepared from human plasma. Dried fibrin sheets or foam are used to cover or pack bleeding surfaces from where it gets absorbed in the body.
• Gelatin sponge: It is used for packing wounds after moistening with saline or thrombin solution.
• Russell’s viper venom: Applied locally to stop external bleeding in haemophiliacs. It acts as a thromboplastin.
• Adrenaline: It is a vasoconstrictor. 1% solution of adrenaline is used for this purpose. Sterile cotton gauze, soaked in this solution, is packed to stop epistaxis or other similar bleeding.
• Adrenochrome monosemicarbazone
• Ethamsylate: It reduces capillary bleeding and improves capillary wall stability. It has antihyaluronidase action. It inhibits PGI production and corrects abnormal platelet function. It is used for the prevention and treatment of capillary bleeding, e.g. epistaxis, after tooth extraction and abortion.
• Tannic acid (20% in glycerine): It is an astringent which is used for bleeding gums and bleeding piles.
Points for Dental Students
1. Topical treatment to stop gingival bleeding includes the use of absorbable gelatin or collagen sponges, topical thrombin or the placement of microfibrillator collagen held in place by packing or splints.
2. Another way of management of gingival bleeding is with oral rinses of antifibrinolytic agents such as tranexamic acid or s-aminocaproic acid.
3, If these local measures are not successful in stopping significantly gingival haemorrhage, platelet transfusions are necessary.
4. Tranexamic acid or s-aminocaproic acid oral rinse is effective in preventing post- extraction bleeding in haemophiliacs A and B with fewer side effects.
5. Fibrin sealants or fibrin glue has been effective as an adjunct with adhesive and haemostatic effects to control bleeding at wound or surgical sites. Its use has allowed reduction in factor concentrate replacement levels in hemophiliacs undergoing dental surgeries when used in combination with antifibrinolytics. Extemporaneous fibrin sealant can be made by combining cryoprecipitate with a combination of 10, 000 units topical thrombin powder diluted in 10 ml saline and 10 ml calcium chloride. When dispensed over the wound simultaneously from separate syringes, the cryoprecipitate and calcium chloride precipitate simultaneously to form a clear gelatinous adhesive.
6. If warfarin anticoagulation is maintained within the therapeutic range currently recommended for prevention of venous thrombosis, arterial fibrillation, or mechanical heart valve, the patients undergoing tooth extraction or alveolar and gingival surgery rarely experience uncontrolled bleeding. While the risk of bleeding is low, embolic complications and death have been reported during subtherapeutic anticoagulation. So therapeutic anticoagulation should be confirmed before and continued through the procedure. Similarly, low dose aspirin (e.g. 81 to 325 mg) can be safely continued. Bleeding is controlled with local pressure (e.g. gauze), suturing, topical thrombin, or tranexamic acid mouth wash.
1. Heparin is a mixture of sulphated mucopolysaccharides and has strong electronegative charge. It exists as high molecular weight (strong anticoagulant) and low molecular weight (weak anticoagulant) heparin. It is effective both in vitro and in vivo.
2. Heparin is a powerful immediately acting anticoagulant which is always administered parenterally.
3. Protamine sulphate is used as heparin antagonist.
4. Oral anticoagulants act by competitively antagonizing the actions of vitamin K and inhibit the synthesis of vitamin K dependent clotting factors. So vitamin K1 is used as oral anticoagulant antagonist.
5. Oral anticoagulants are not effective in vitro and take 36—48 hours for the anticoagulant effect to develop.
6. Coagulants promote coagulation. They are used in haemorrhagic state.
7. Important coagulants are vitamin K, fibrinogen1 antihaemophilic factor1 aminocaproic and tranexamic acids.
8. Vitamin K is employed in prophylaxis and treatment of bleeding.
9. Fibrinogen and antihaemophilic factor are used to control bleeding episodes due to haemophilia and antihaemophiic globulin deficiency.
10. Aminocaproic acid and tranexamic add are fibrinolytic inhibitors and are used in hyperplasminaemic state.
11. Local haemostatics are called styptics and are particularly effective on oozing surfaces. These are used in dental practice to control bleeding during various dental procedures.