Drugs Affecting Coagulation, Bleeding and Thrombosis

 Chapter-44

Drugs Affecting Coagulation, Bleeding and Thrombosis

Haemostasias (arrest of blood loss) and blood coagulation involve complex interactions between the injured vessel wall, platelets and coagulation factors. A cascading series of proteolytic reactions (Fig. 44.1) is started by:

(i) Contact activation of Hageman factor: intrinsic system, in which all factors needed for coagulation are present in plasma. This is slow and takes several minutes to activate factor X.

(ii) Tissue thromboplastin: extrinsic system, needs a tissue factor, but activates factor X in seconds.

The subsequent events are common in the two systems and result in polymerization of fibrinogen to form fibrin strands. Blood cells are trapped in the meshwork of fibrin strands producing clot.

Two in vitro tests ‘activated partial thromboplastin time’ (apt) and ‘prothrombin time’ (PT) are employed for testing integrity of the intrinsic, extrinsic and common pathways of the coagulation cascade. The results are interpreted as:

Most clotting factors are proteins present in plasma in the inactive (zymogen) form. By partial proteolysis they themselves become an active protease and activate the next factor. In addition to its critical role in cleaving and polymerizing fibrinogen, thrombin activates many upstream factors (especially f. XI, VIII and V) of the intrinsic and common pathways—amplifying its own generation and continuation of clot formation. It is also a potent activator of platelets.

On the other hand, factors like antithrombin, protein C, protein S, Anti thromboplastin and the fibrinolysin system tend to oppose coagulation and lyse formed clot. Thus, a check and balance system operates to maintain blood in a fluid state while in circulation and allows rapid haemostasias following injury.

COAGULANTS

These are substances which promote coagulation, and are indicated in hemorrhagic states.

Fresh whole blood or plasma provide all the factors needed for coagulation and are the best therapy for deficiency of any clotting factor; also they act immediately. Other drugs used to restore haemostasias are:

VITAMIN K

decreased concentration of prothrombin in blood and that it could be cured by a fat soluble fraction of hog liver. This factor was called Coagulations vitamin (vit K) and soon its structure was worked out. A similar vitamin was isolated in 1939 from alfalfa grass and labelled vit K1, while that from sardine (sea fish) meal was labelled K2. Synthetic compounds have been produced and labelled K3.

Chemistry and source

Vit K has a basic naphthoquinone structure, with or without a side chain (R) at position 3. The side chain in K1 is phytol, in K2 phenyl, while in K3 there is no side chain.

Daily requirement It is uncertain, because a variable amount of menaquinone (vit K2) produced by colonic bacteria becomes available. Even 3–10 μg/day external source may be sufficient. However, the total requirement of an adult has been estimated to be 50–100 μg/day.

Action

Vit K acts as a cofactor at a late stage in the synthesis by liver of coagulation proteins— prothrombin, factors VII, IX and X. The vit K dependent change (γ carboxylation of glutamate residues of these zymogen proteins; see Fig. 44.2) confers on them the capacity to bind Ca2+ and to get bound to phospholipid surfaces—properties essential for participation in the coagulation cascade.

Utilization

Fat-soluble forms of vit K are absorbed from the intestine via lymph and require bile salts for absorption, while water-soluble forms are absorbed directly into portal blood. An active transport process in the jejunum has been demonstrated for K1, while K2 and K3 are absorbed by simple diffusion. Vit K is only temporarily concentrated in liver, but there are no significant stores in the body. It is metabolized in liver by side chain cleavage and glucuronide conjugation; metabolites are excreted in bile and urine.

Deficiency

Deficiency of vit K occurs due to liver disease, obstructive jaundice, malabsorption, long-term antimicrobial therapy which alters intestinal flora. However, deficient diet is rarely responsible. The most important manifestation is bleeding tendency due to lowering of the levels of prothrombin and other clotting factors in blood. Hematuria is usually first to occur; other common sites of bleeding are g.i.t., nose and under the skin—ecchymoses.

Preparations

• Phytonadione: VITAMIN-K, KENADION 10 mg/ml for i.m. injection.

• Menadione: 0.66 mg in GYNAE CVP with vit C 75 mg, ferrous gluconate 67 mg, Cal. lactate 300 mg and citrus bioflavonoid 150 mg per cap:

• Acetonaphthone: ACETOMENADIONE 5, 10 mg tab; KAPILIN 10 mg tab.

• Menadione sod. bisulfite: 20 mg, in CADISPER-C with vit C 100 mg, adrenochrome monosemicarbazone, 1 mg, ruin 60 mg, methyl hesperidin 40 mg, Cal. phosphate 100 mg per tab. 

• STYPTOCID 10 mg with adrenochrome monosemicarbazone 0.5 mg, rutin 50 mg, vit C 37.5 mg, vit D 200 i.u., Cal. phosphate 260 mg per tab. 

•  Use The only use of vit K is in prophylaxis and treatment of bleeding due to deficiency of clotting factors in the following situations:

Use The only use of vit K is in prophylaxis and treatment of bleeding due to deficiency of clotting factors in the following situations: 

(a) Dietary deficiency: of vit K is very rare in adults. However, when it occurs 5–10 mg/day oral or parenteral vit K rapidly corrects the defects. 

(b) Prolonged antimicrobial therapy: treat in the same way as dietary deficiency of vit K. 

(c) Obstructive jaundice or malabsorption syndromes (sprue, regional ileitis, steatorrhea, etc.): vit K 10 mg i.m./day, or orally along with bile salts. 

(d) Liver disease (cirrhosis, viral hepatitis): associated bleeding responds poorly to vit K. Because of hepatocellular damage, synthesis of clotting factors is inadequate despite the presence of vit K. However, vit K may be of some use if its absorption had been affected due to lack of bile salts. 

Menadione (K3) should not be used for this purpose (see below).(e) Newborns: All newborns have low levels of prothrombin and other clotting factors. Further decrease occurs in the next few days. The cause is both lower capacity to synthesize clotting factors as well as deficiency of vit K. The defect is exaggerated in the premature infant. Vit K 1 mg a.m. soon after birth has been recommended routinely. Some prefer administering 5–10 mg a.m. to the mother 4–12 hours before delivery. Hemorrhagic disease of the newborn can be effectively prevented/treated by such medication.

Menadione (K3) should not be used for this purpose (see below).(f) Overdose of oral anticoagulants: This is the most important indication of vit K. Phytonadione (K1) is the preparation of choice, because it acts most rapidly; dose depends on the severity of hypoprothrombinemia (measured INR) and bleeding. Unnecessary high dose is to be avoided because it will render the patient unresponsive to oral anticoagulants for several days.

Severe: 10 mg a.m. followed by 5 mg 4 hourly; bleeding generally stops in 6–12 hours, but normal levels of coagulation factors are restored only after 24 hr. This dose of vit K will block anticoagulant action for 7–10 days.

Moderate: 10 mg a.m. followed by 5 mg once or twice according to response.

Mild: Just omit a few doses of the anticoagulant.

g) Prolonged high dose salicylate therapy causes hypoprothrombinemia; vit K should be given prophylactically. If bleeding occurs—treat as for oral anticoagulants.

Toxicity

Rapid i.v. injection of emulsified vit K produces flushing, breathlessness, a sense of constriction in the chest, fall in BP; few deaths are on record. It is probably due to emulsion form of the preparation.

Menadione and its water-soluble derivatives can cause hemolysis in a dose-dependent manner. Patients with G-6-PD deficiency and neonates are especially susceptible. In the newborn menadione or its salts can precipitate kernicterus:

(a) by inducing hemolysis and increasing bilirubin load. 

(b) by competitively inhibiting glucuronidation of bilirubin. Glucuronide conjugation is, as such, inadequate in neonates.

Because of poor efficacy and higher toxicity, there is little justification to use menadione and its water soluble salts for any indication.

Fibrinogen

The fibrinogen fraction of human plasma is employed to control bleeding in hemophilia, antihemophilic globulin (AHG) deficiency and acute afibrinogenemic states; 0.5 g is infused i.e.

FIBRINAL 0.5 g/bottle for i.v. infusion.

Antihemophilic factor

It is concentrated human AHG prepared from pooled human plasma. It is indicated (along with human fibrinogen) in hemophilia and AHG deficiency. It is highly effective in controlling bleeding episodes, but action is short-lasting (1 to 2 days). 

Dose: 5–10 U/kg by i.e. infusion, repeated 6–12 hourly. FIBRINAL-H, ANTIHAEMOPHILIC FACTOR: 150 U or 200 U + fibrinogen 0.5 g/bottle for i.e. infusion.

Desmopressin 

It releases factor VIII and von Willebrand’s factor from vascular endothelium and checks bleeding in hemophiliac and von Willebrand’s disease (see p. 577).

Adrenochrome monosemicarbazone 

It is believed to reduce capillary fragility, control oozing from raw surfaces and prevent micro vessel bleeding, e.g. epistaxis, hematuria, retinal hemorrhage, secondary hemorrhage from wounds, etc. Its efficacy is uncertain. 

Dose: 1–5 mg oral, a.m. STYPTOCHROME 3 mg/2 ml inj., STYPTOCID: 2 mg/2 ml inj; in CADISPER-C, STYPTOCID 1 mg, 0.5 mg tab, with other ingredients

Rutina 

It is a plant glycoside claimed to reduce capillary bleeding. It has been used in a dose of 60 mg oral BD–TDS along with vit C which is believed to facilitate its action. Its efficacy is uncertain.

In CADISPER-C 60 mg tab, in KERUTIN-C 100 mg tab, in STYPTOBION 100 mg tab, 200 mg/2 ml inj. 

ETranslate It reduces capillary bleeding when platelets are adequate; probably exerts Anti hyaluronidase action— improves capillary wall stability, but does not stabilize fibrin (not an antifibrinolytic). ETranslate has been used in the prevention and treatment of capillary bleeding in menorrhagia, after abortion, PPH, epistaxis, Malena, hematuria and after tooth extraction, but efficacy is unsubstantiated. Side effects are nausea, rash, headache, and fall in BP (only after i.v. injection).

Dose: 250–500 mg TDS oral/i.v.; ETHAMSYL, DICYNENE, HEMSYL, K. STAT 250, 500 mg tabs; 250 mg/2 ml inj. 

LOCAL HAEMOSTATICS (STYPTICS) 

After injury to arterioles and other smaller blood vessels, normal haemostasias occurs successively by contraction of injured vessel wall (lasting few minutes), adhesion and aggregation of platelets to form a plug, formation of a blood clot, and finally in due course dissolution of the clot by fibrinolysis. External bleeding is usually stopped by manual pressure, cotton-gauze pressure pack or by suturing. Control of bleeding may be aided by local Hemostatics (styptics) that are substances used to stop bleeding from a local and approachable site. They are particularly effective on oozing surfaces, e.g. tooth socket, abrasions, etc. Absorbable materials like fibrin (prepared from human plasma and dried as sheet or foam), gelatin foam, oxidized cellulose (as strips which can be cut and placed in the wound) provide a meshwork which activates the clotting mechanism and checks bleeding. Left in situ these materials are absorbed in 1–4 weeks and generally cause no foreign body reaction. Thrombin obtained from bovine plasma may be applied as dry powder or freshly prepared solution to the bleeding surface in hemophiliacs.

Vasoconstrictors like 0.1% Adr solution may be soaked in sterile cotton-gauze and packed in the bleeding tooth socket or nose in case of epistaxis to check bleeding when spontaneous vasoconstriction is inadequate. Astringents such as tannic acid or metallic salts are occasionally applied for bleeding gums, bleeding piles, etc.

SCLEROSING AGENTS

These are irritants, cause inflammation, coagulation and ultimately fibrosis, when injected into hemorrhoids (piles) or varicose vein mass. They are used only for local injection.

• Phenol (5%) in almond oil or peanut oil: 2–5 ml. 
• Ethanolamine oleate (5% in 25% glycerin and 2% benzyl alcohol): 1–5 ml inj. 
• Sod. tetradecyl sulfate (3% with benzyl alcohol 2%): 0.5–2 ml at each site. SETROL 2 ml inj. 
• Polidocanol (3% inj): 2 ml; ASKLEROL 2 ml inj. 

ANTICOAGULANTS

These are drugs used to reduce the coagulability of blood. They may be classified into:

I. Used in vivo

A. Parenteral anticoagulants

• Heparin, Low molecular weight heparin. 
• Heparinoids—Heparan sulfate, 
• Danaparoid, Leprolin, Ancrod.

B. Oral anticoagulants

1. Coumarin derivatives: Bishydroxycoumarin (dicumarol), Warfarin sod, Acenocoumarin (Coumarone), Ethylbiscoumacetate 
2. Indandione derivative: Phenindione.

HEPARIN

McLean, a medical student, discovered in 1916 that liver contains a powerful anticoagulant. Howell and Holt (1918) named it ‘heparin’ because it was obtained from liver. However, it could be used clinically only in 1937 when sufficient degree of purification was achieved.

Chemistry and occurrence 

Heparin is a nonuniform mixture of straight chain mucopolysaccharides with MW 10,000 to 20,000. It contains polymers of two sulfated disaccharide units:

It carries strong electronegative charges and is the strongest organic acid present in the body. It occurs in mast cells as a much bigger molecule (MW ~75,000) loosely bound to the granular protein. Thus, heparin is present in all tissues containing mast cells; richest sources are lung, liver and intestinal mucosa. Commercially it is produced from ox lung and pig intestinal mucosa.

ACTIONS

1. Anticoagulant

Heparin is a powerful and instantaneously acting anticoagulant, effective both in vivo and in vitro. It acts indirectly by activating plasma antithrombin III (AT III, a serine proteinase inhibitor) and may be other similar cofactors. The heparin-AT III complex then binds to clotting factors of the intrinsic and common pathways (Xa, Iian, Ixta, Xia, Xia and Xiya) and inactivates them but not factor VIIa operative in the extrinsic pathway. At low concentrations of heparin, factor Xa mediated conversion of prothrombin to thrombin is selectively affected. The anticoagulant action is exerted mainly by inhibition of factor Xa as well as thrombin (Iian) mediated conversion of fibrinogen to fibrin.

Low concentrations of heparin prolong apt without significantly prolonging PT. High concentrations prolong both. Thus, low concentration's interfere selectively with the intrinsic pathway, affecting amplification and continuation of clotting, while high concentrations affect the common pathway as well.

Antithrombin III is itself a substrate for the protease clotting factors; binds with the protease to form a stable complex (suicide inhibitor). However, in the absence of heparin, the two interact very slowly. Heparin enhances the action of AT III in two ways:

(a) Long heparin molecule provides a scaffolding for the clotting factors (mainly Xa and Iian) as well as AT III to get bound and interact with each other(b) Heparin induces conformational change in AT III to expose its interactive sites. Recently, it has been shown that a specific Penta saccharide sequence, which is present in only some of the heparin molecules, binds to AT III with high affinity to induce the conformational change needed for rapid interaction with clotting factors.

Inhibition of Iian requires both the mechanisms, but Xa inhibition can occur by mechanism ‘b’ alone. This probably explains why low molecular weight heparin, which is insufficient to provide a long scaffolding, selectively inhibits factor Xa.

Higher doses of heparin given for some time cause reduction in AT-III levels, probably a compensatory phenomenon. Sudden stoppage of conventional-dose therapy may result in rebound increase in coagulability for few days.

2. Antiplatelet

Heparin in higher doses inhibits platelet aggregation and prolongs bleeding time.

3. Lipemia clearing

Injection of heparin clears turbid post-prandial lipemic by releasing a lipoprotein lipase from the vessel wall and tissues, which hydrolyses triglycerides of chylomicron and very low density lipoproteins to free fatty acids; these then pass into tissues and the plasma looks clear. This action requires lower concentration of heparin than that needed for anticoagulation.

Facilitation of fatty acid transport may be the physiological function of heparin; but since, it is not found in circulating blood and its storage form in tissues is much less active, this seems only conjectural.

PHARMACOKINETICS

Heparin is a large, highly ionized molecule; therefore not absorbed orally. Injected i.e. it acts instantaneously, but after such injection anticoagulant effect develops after ~60 min. Bioavailability of such heparin is inconsistent. Heparin does not cross blood-brain barrier or placenta (it is the anticoagulant of choice during pregnancy). It is metabolized in liver by heparinase and fragments are excreted in urine.

Heparin released from mast cells is degraded by tissue macrophages—it is not a physiologically circulating anticoagulant.

After i.e. injection of doses < 100 U/kg, the t½ averages 1 hr. Beyond this, dose-dependent inactivation is seen and t½ is prolonged to 1–4 hrs. The t½ is longer in cirrhotic and kidney failure patients, and shorter in patients with pulmonary embolism.

Unitage and administration  Because of variable molecular size, heparin is standardized only by bioassay:

• 1 U is the amount of heparin that will prevent 1 ml of citrated sheep plasma from clotting for 1 hour after the addition of 0.2 ml of 1% CaCl2 solution. Heparin sod. 1 mg has 120–140 U of activity.

HEPARIN SOD., BEPARINE, NUPARIN 1000 and 5000 U/ml in 5 ml vials for injection.

Heparin should not be mixed with penicillin, tetracyclines, hydrocortisone or NA in the same syringe or infusion bottle. Heparinized blood is not suitable for blood counts (alters the shape of RBCs and WBCs), fragility testing and complement fixation tests.

Dosage 

Heparin is conventionally given i.e. in bolus doses of 5,000–10,000 U (children 50–100 U/kg) every 4– 6 hours, or the initial bolus dose is followed by continuous infusion of 750–1000 U/hr. which may reduce the total dose needed and the incidence of bleeding. The dose and frequency is controlled by apt measurement which is kept at 50–80 sec. or 1.5–2.5 times the patient’s pretreatment value. If this test is not available, whole blood clotting time should be measured and kept at ~2 times the normal value.

Deep such injection of 10,000–20,000 U every 8–12 hrs. can be given if repeated i.e. injection or infusion is not possible. Needle used should be fine and trauma should be minimum to avoid hematoma formation. Hematomas are more common with a.m. injection—this route should not be used.

Low dose (such) regimen

5000 U is injected such every 8– 12 hours, started before surgery and continued for 7–10 days or till the patient starts moving about. This regimen has been found to prevent postoperative deep vein thrombosis without increasing surgical bleeding. It also does not prolong apt or clotting time. However, it should not be used in case of neurosurgery or when spinal anesthesia is to be given. The patients should not be receiving aspirin or oral anticoagulants. It is ineffective in high-risk situations, e.g. hip joint or pelvic surgery.

ADVERSE EFFECTS

Heparin is a large, highly ionized molecule; therefore, not absorbed orally. Injected i.e. it acts instantaneously, but after sac injection anticoagulant effect develops after ~60 min. Bioavailability of sac heparin is inconsistent. Heparin does not cross blood-brain barrier or placenta (it is the anticoagulant of choice during pregnancy). It is metabolized in liver by heparinase, and fragments are excreted in urine.

Heparin released from mast cells is degraded by tissue macrophages—it is not a physiologically circulating anticoagulant.

After i.e. injection of doses < 100 U/kg, the t½ averages 1 hr. Beyond this, dose-dependent inactivation is seen and t½ is prolonged to 1–4 hrs. The t½ is longer in cirrhotic and kidney failure patients, and shorter in patients with pulmonary embolism.

Unitage and administration 

Because of variable molecular size, heparin is standardized only by bioassay: 1 U is the amount of heparin that will prevent 1 ml of citrated sheep plasma from clotting for 1 hour after the addition of 0.2 ml of 1% CaCl2 solution. Heparin sod. 1 mg has 120–140 U of activity.

HEPARIN SOD., BEPARINE, NUPARIN 1000 and 5000 U/ml in 5 ml vials for injection.

Heparin should not be mixed with penicillin, tetracyclines, hydrocortisone or NA in the same syringe or infusion bottle. Heparinized blood is not suitable for blood counts (alters the shape of RBCs and WBCs), fragility testing and complement fixation tests.

Dosage

Heparin is conventionally given i.e. in bolus doses of 5,000–10,000 U (children 50–100 U/kg) every 4– 6 hours, or the initial bolus dose is followed by continuous infusion of 750–1000 U/hr. which may reduce the total dose needed and the incidence of bleeding. The dose and frequency is controlled by Aptt measurement which is kept at 50–80 sec. or 1.5–2.5 times the patient’s pretreatment value. If this test is not available, whole blood clotting time should be measured and kept at ~2 times the normal value.

Deep sic injection of 10,000–20,000 U every 8–12 hrs can be given if repeated i.e. injection or infusion is not possible. Needle used should be fine and trauma should be minimum to avoid hematomas formation. Hamartomas are more common with i.m. injection—this route should not be used.

Low dose (s.c.) regimen

5000 U is injected s.c. every 8– 12 hours, started before surgery and continued for 7–10 days or till the patient starts moving about. This regimen has been found to prevent postoperative deep vein thrombosis without increasing surgical bleeding. It also does not prolong aPTT or clotting time. However, it should not be used in case of neurosurgery or when spinal anaesthesia is to be given. The patients should not be receiving aspirin or oral anticoagulants. It is ineffective in high-risk situations, e.g. hip joint or pelvic surgery.

ADVERSE EFFECTS

• Bleeding due to overdose is the most serious complication of heparin therapy. Haematuria is generally the first sign. With proper monitoring, serious bleeding is reported in 1–3% patients. 

• Thrombocytopenia is another common problem. Generally, it is mild and transient; occurs due to aggregation of platelets. Occasionally serious thromboembolic events result. In some patient's antibodies are formed to the heparin-platelet complex and marked depletion of platelets occurs— heparin should be discontinued. Even LMW heparins are not safe in such patients. 

• Transient and reversible alopecia is infrequent. Serum transaminase levels may rise. 

•  Osteoporosis may develop on long-term use of relatively high doses. 

• Hypersensitivity reactions are rare—urticaria, rigor, fever and anaphylaxis. Patients with allergic diathesis are more liable.

Contraindications

• Bleeding disorders, heparin induced thrombocytopenia. 

• Severe hypertension, (risk of cerebral hemorrhage), threatened abortion, piles, g.i. ulcers (risk of aggravated bleeding). 

• Subacute bacterial endocarditis (risk of embolism), large malignancies (risk of bleeding in the central necrosed area of the tumour), tuberculosis (risk of hemoptysis). 

• Ocular and neurosurgery, lumbar puncture. 

• Chronic alcoholics, cirrhosis, renal failure. 

• Aspirin and other antiplatelet drugs should be used very cautiously during heparin therapy.

Low molecular weight (LMW) heparins

Heparin has been fractionated into LMW forms (MW 3000–7000) by different techniques. LMW heparins have a different anticoagulant profile; selectively inhibit factor Xa with little effect on

IIa. They act only by inducing conformational change in AT III and not by bringing together AT III and thrombin. As a result, LMW heparins have smaller effect on aPTT and whole blood clotting time than unfractionated heparin (UFH) relative to antifactor Xa activity. Also, they appear to have lesser antiplatelet action—less interference with haemostasis. Thrombocytopenia is less frequent. A lower incidence of haemorrhagic complications compared to UFH has been reported in some studies, but not in others. However, major bleeding may be less frequent. The more important advantages of LMW heparins are pharmacokinetic:

• Better subcutaneous bioavailability (70–90%) compared to UFH (20–30%): Variability in response is minimized. 

• Longer and more consistent monoexponentially t½: once daily s.c. administration.

• Since Aptt/clotting times are not prolonged, laboratory monitoring is not needed; dose is calculated on body weight basis.

Most studies have found LMW heparins to be equally efficacious to UFH. Indications of LMW heparins are:

• Prophylaxis of deep vein thrombosis and pulmonary embolism in high-risk patients undergoing surgery; stroke or other immobilized patients. 

• Treatment of established deep vein thrombosis.

•  Unstable angina.

•  To maintain patency of cannula and shunts in dialysis patients, and in extracorporeal circulation.

A number of LMW heparins have been marketed. They differ in composition, pharmacokinetics and dosage.

• differ in composition, pharmacokinetics and dosage. Enoxaparin: CLEXANE 20 mg (0.2 ml) and 40 mg (0.4 ml) prefilled syringes; 20–40 mg OD, s.c. (start 2 hour before surgery).

• Reviparin: CLIVARINE 13.8 mg (eq. to 1432 anti Xa IU) in 0.25 ml prefilled syringe; 0.25 ml s.c. once daily for 5-10 days

• Nadroparin: FRAXIPARINE 3075 IU (0.3 ml) and 4100 IU (0.4 ml) inj., CARDIOPARIN 4000 anti Xa IU/0.4 ml, 6000 anti Xa IU/0.6 ml, 100, 000 anti Xa IU/10 ml inj.

• Dalteparin: 2500 IU OD for prophylaxis; 100 U/Kg 12 hourly or 200 U/Kg 24 hourly for treatment of deep vein thrombosis. FRAGMIN 2500, 5000 IU prefilled syringes.

•  Pamparin: 0.6 ml s.c. OD for unstable angina and prophylaxis of DVT; FLUXUM 3200 IU (0.3 ml), 6400 IU (0.6 ml) inj. 

• Ardeparin: 2500-5000 IU OD; INDEPARIN 2500 IU, 5000 IU prefilled syringes.

Fondaparinux: The pentasaccharide with specific sequence that binds to AT III with high affinity to selectively inactivate factor Xa has been recently produced synthetically and given the name fondaparinux. It has been marketed in USA and some other countries.

HEPARINOIDS

• Heparan sulfate It is a heparin-like natural substance found on cell surface and intercellular matrix in many tissues. It is a less potent anticoagulant than heparin, but may have a more favourable profile of action.

• Danaparoid is a preparation containing mainly heparan sulfate, obtained from pig gut mucosa, which is used in cases with heparin induced thrombocytopenia.

• Lepirudin This recombinant preparation of hirudin (a polypeptide anticoagulant secreted by salivary glands of leech) acts by inhibiting thrombin directly. It is indicated in patients with heparin induced thrombocytopenia.

• Ancrod It is an enzyme obtained from Malayan pit viper venom. It degrades fibrinogen into an unstable form of fibrin which is taken up by RE cells. Thus, fibrinogen gets depleted and an apparent heparin like effect results. It is given only by slow infusion: 2 U/kg over 6 hours for deep vein thrombosis in patients who develop thrombocytopenia or hypersensitivity reactions to heparin and require immediate anticoagulation.

HEPARIN ANTAGONIST

Protamine sulfate 

Protamine is more commonly used when heparin action needs to be terminated rapidly, e.g. after cardiac or vascular surgery.It is a strongly basic, low molecular weight protein obtained from the sperm of certain fish. Given i.v. it neutralises heparin weight for weight, i.e. 1 mg is needed for every 100 U of heparin. For the treatment of heparin induced bleeding, due consideration must be given to the amount of heparin that may have been degraded by the patient’s body in the mean time. However, it is needed infrequently because the action of heparin disappears by itself in a few hours, and whole blood transfusion is indicated to replenish the loss when bleeding occurs.

• In the absence of heparin, protamine itself acts as a weak anticoagulant by interacting with platelets and fibrinogen. Being basic in nature it can release histamine in the body. Hypersensitivity reactions have occurred. Rapid i.v. injection causes flushing and breathing difficulty.

• PROTA, PROTAMINE SULFATE 50 mg in 5 ml inj.

ORAL ANTICOAGULANTS

A haemorrhagic disease was described in cattle in 1924 which was due to feeding them on spoiled sweet clover hay. The disorder was found to be due to prothrombin deficiency and the toxic principle was identified as bishydroxycoumarin in 1939. It was cured by feeding alfalfa grass. First clinical use of bishydroxycoumarin was made in 1941 and many congeners were added later. Warfarin was initially used as rat poison; demonstration of its safety led to clinical trial; it is now a commonly employed oral anticoagulant.

Action and mechanism 

Warfarin and its congeners act as anticoagulants only in vivo, not in vitro. This is so because they act indirectly by interfering with the synthesis of vit K dependent clotting factors in liver. They apparently behave as competitive antagonists of vit K and reduce the plasma levels of functional clotting factors in a dose-dependent manner. In fact, they interfere with regeneration of the active hydroquinone form of vit K (Fig. 44.2) which carries out the final step of γ carboxylating glutamate residues of prothrombin and factors VII, IX and X. This carboxylation is essential for the ability of the clotting factors to bind Ca2+ and to get bound to phospholipid surfaces, necessary for coagulation sequence to proceed.

Factor VII has the shortest plasma t½ (6 hr), its level falls first when warfarin is given, followed by factor IX (t½ 24 hr), factor X (t½ 40 hr) and prothrombin (t½ 60 hr). Though the synthesis of clotting factors diminishes within 2–4 hours of warfarin administration, anticoagulant effect develops gradually over the next 1–3 days as the levels of the clotting factors already present in

 plasma decline progressively. Thus, there is always a delay between administration of the drug and the anticoagulant effect. Larger initial doses hasten the effect only slightly.

Therapeutic effect occurs when synthesis of clotting factors is reduced by 40–50%.

• Protein C, protein S, osteocalcin and some other proteins contain glutamate residues that require vit. K dependent γ carboxylation. These are also inhibited by oral anticoagulants, but density of adult bone is not affected, though new bone formation may be depressed.

• The differences between different oral anticoagulants are primarily pharmacokinetic and in the adverse side effects produced by them. These are summarized in Table 44.1

Recemic Warfarin sod.

• It is the most popular oral anticoagulant. The commercial preparation of warfarin is a mixture of R (dextrorotatory) and S (levorotatory) enantiomers. The S form is more potent and is metabolized relatively faster by ring oxidation, while R form is less potent and degraded by side chain reduction. Both are partially conjugated with glucuronic acid and undergo some enterohepatic circulation; finally excreted in urine.

• Warfarin is rapidly and completely absorbed from intestines and is 99% plasma protein bound. It crosses placenta and is secreted in milk; however, quantity of active form is generally insufficient to affect the suckling infant.

• UNIWARFIN 1, 2, 5 mg tabs; WARF-5: 5 mg tab.

• Bishydroxycoumarin (Dicumarol) It is slowly and unpredictably absorbed orally. Its metabolism is dose dependent—t½ is prolonged at higher doses. Has poor g.i. tolerance. 

• DICOUMAROL 50 mg tab.

Acenocoumarol (Nicoumalone) The t½ of acenocoumarol as such is 8 hours, but an active Table 44.1: Pharmacokinetic and adverse effect profile of oral anticoagulants Drug t½ Duration Dose (mg) Adverse side effects (hour) of action (other than bleeding) (days) Loading Maintenance* 1. Bishydroxycoumarin 25–100 4–7 200 for 50–100 Frequent g.i.t. disturbances (dose dependent) 2 days 2. Warfarin sod. 36–48 3–6 10–15 2–10£ Alopecia, dermatitis, diarrhoea 3. Acenocoumarol 18–24 2–3 8–12 2–8 Oral ulceration, g.i.t. distur- (Nicoumalone) bances, dermatitis, urticaria, alopecia 4. Ethylbiscoumacetate 2 1–3 900 300–600 Alopecia, bad taste 5. Phenindione 5 1–3 200 50–100 Orange urine, rashes, fever, leukopenia, hepatitis, nephropathy, agranulocytosis * Daily maintenance dose: to be adjusted by measurement of prothrombin time (INR). £ To be taken in a single dose at the same hour (usually bed time) each day. Chapter 44 Anticoagulants 601 602 Drugs Affecting Blood and Blood Formation Section 10 metabolite is produced so that overall t½ is about 24 hours. Acts more rapidly.

ACITROM, 1, 2, 4 mg tabs.

Ethyl biscoumacetate 

It has a rapid and brief action; occasionally used to initiate therapy, but difficult to maintain.

Phenindione

It produces more serious nonhaemorrhagic toxic effects: should not be used.

DINDEVAN 50 mg tab.

Factors enhancing effect 

• Pregnancy: plasma level of clotting factors is higher. 

• Nephrotic syndrome: drug bound to plasma protein is lost in urine. 

• Genetic warfarin resistance: the affinity of warfarin (as well as of vit K epoxide) to bind to the     reductase enzyme, which generates the active vit K hydroquinone, is low. Dose of oral anticoagulant     is   4–5 times higher.

Contraindications 

All contraindications to heparin (p. 599) apply to these drugs as well. Factors which enhance the effect of oral anticoagulants (see above) should also be taken into consideration.

during pregnancy. Warfarin given in early pregnancy increases birth defects, especially skeletal abnormalities: fetal warfarin syndrome—hypoplasia of nose, eye socket, hand bones, and growth retardation. Given later in pregnancy, it can cause CNS defects, fontal hemorrhaged, fontal death and accentuates neonatal hypoprothrombinemia.

Drug interactions

A large number of drugs interact with oral anticoagulants at pharmacokinetic or pharmacodynamic level, and either enhance or depress their effect. These interactions are clinically important (may be fatal if bleeding occurs) and may involve more than one mechanism; the exact mechanism of an interaction is not always definable.

A. Enhanced anticoagulant action

• Broad-spectrum antibiotics, inhibit gut flora and reduce vit K production. 

• Newer cephalosporins (cefamandole, moxalactam, etoperidone) cause hypoprothrombinemia by the same mechanism as warfarin —additive action. 

• Aspirin: inhibits platelet aggregation and causes g.i. bleeding—this may be hazardous in anticoagulated patients. High doses of salicylates have synergistic hypoprothrombinemic action and also displace warfarin from protein binding site. 

• Long acting sulfonamides, indomethacin, phenytoin and probenecid: displace warfarin from plasma protein binding. 

• Chloramphenicol, erythromycin, celecoxib, cimetidine, allopurinol, amiodarone and metronidazole: inhibit warfarin metabolism. 

• Tolbutamide and phenytoin: inhibit warfarin metabolism and vice versa. 

• Liquid paraffin (habitual use): reduces vit K absorption.

 B. Reduced anticoagulant action

• Barbiturates (but not benzodiazepines), rifampin and griseofulvin induce the metabolism of oral anticoagulants. The dose of anticoagulant determined during therapy with these drugs would be higher: if the same is continued after withdrawing the inducer— marked hypoprothrombinemia can occur— fatal bleeding is on record.

• Oral contraceptives: increase blood levels of clotting factors.

USES OF ANTICOAGULANTS

• The aim of using anticoagulants is to prevent thrombus extension and embolic complications by reducing the rate of fibrin formation. They do not dissolve already formed clot, but prevent recurrences. Heparin is utilized for rapid and short-lived action, while oral anticoagulants are suitable for maintenance therapy. Generally, the two are started together; heparin is discontinued after 4–7 days when warfarin has taken effect.

• The important features of heparin and oral anticoagulants are compared in Table 44.2.

• 1. Deep vein thrombosis and pulmonary embolism Because venous thrombi are mainly fibrin thrombi, anticoagulants are expected to be highly effective. The best evidence of efficacy of anticoagulants comes from treatment and prevention of venous thrombosis and pulmonary embolism. Prophylaxis is recommended for all high risk patients including bedridden, old, postoperative, postpartum, poststroke and leg fracture patients. When deep vein thrombosis/ pulmonary embolism has occurred, immediate heparin followed by warfarin therapy should be instituted. Three months anticoagulant therapy (continued further if risk factor persists) has been recommended by American College of Chest Physicians (2001).

• Introduction of low dose heparin prophylaxis for patients undergoing elective surgery has considerably reduced the incidence of leg vein thrombosis and pulmonary embolism in the postoperative period. It has been extended to other situations needing prolonged immobilization. It is based on the premise that inhibition of small amount of activated factor X prevents further amplification of active products—particularly thrombin. This is the regimen of choice: does not need laboratory monitoring; spontaneous bleeding does not occur. LMW heparin is being preferred for this purpose.

Anticoagulants are of little value in chronic peripheral vascular diseases.

• Myocardial infarction (MI) Arterial thrombi are mainly platelet thrombi; anticoagulants are of questionable value. Their use in acute MI has declined. They do not alter immediate mortality of MI. It was hoped that anticoagulants will prevent extension of the thrombus and ward off a recurrent attack. This has not been supported by the collected statistics. They may benefit by preventing mural thrombi at the site of infarction and venous thrombi in leg veins. Thus, anticoagulants may be given for a short period till patient becomes ambulatory. For secondary prophylaxis against a subsequent attack— anticoagulants are inferior to antiplatelet drugs. Heparin (i.v.) for 2–8 days followed by oral anticoagulants for 3 months or low dose s.c. heparin are generally given after recanalization of coronary artery by fibrinolytic therapy. Heparin is also used during coronary angioplasty and stent placement.

• Unstable angina Short-term use of heparin has reduced the occurrence of MI in unstable angina patients; aspirin is equally effective. Current recommendation is to use aspirin + heparin followed by warfarin.

• Rheumatic heart disease: Atrial fibrillation (AF) Warfarin/low dose heparin/low dose aspirin are effective in preventing stroke (due to embolism from fibrillating atria). The ‘Stroke prevention in Atrial Fibrillation’ trial and a metanalysis have shown warfarin to be more effective than aspirin. Current guideline is to give warfarin to a target INR of 2–3 in AF patients with high risk for stroke (elderly, heart failure, etc.), and to reserve aspirin for low-risk patients or for those unable to take warfarin. Anticoagulants are given for 3–4 weeks before and after attempting conversion of AF to sinus rhythm.

• Cerebrovascular disease Anticoagulants are of little value in cerebral thrombosis. They have been used with the aim of preventing clot propagation, but all the trials conducted, including International Stroke Trial (IST), have failed to demonstrate significant benefit. Neurological sequelae are similar whether they are used or not. Moreover, in the initial stages it is difficult to rule out cerebral hemorrhage (unless CAT scan

`

• is done) in which they can be devastating. They may be used in cerebral embolism, because showers of emboli are often recurrent and can be prevented by anticoagulants. A late start (after one week) anticoagulant therapy is advocated by many in case of large embolic stroke. Oral anticoagulants may be beneficial in transient ischemic attacks (TIAs), but antiplatelet drugs are simpler to use and probably better.

• Vascular surgery, prosthetic heart valves, retinal vessel thrombosis, extracorporeal circulation, hemodialysis Anticoagulants are indicated along with antiplatelet drugs for prevention of thromboembolism.

• Heparin flushes (200 U in 2 ml) every 4–8 hr. are used to keep patent long-term intravascular cannula/catheters.

• Defibration syndrome or ‘disseminated intravascular coagulation’ occurs in abruptio placentae and other obstetric conditions, certain malignancies and infections. The coagulation factors get consumed for the formation of intravascular microplots and blood is incoagulable. Heparin paradoxically checks bleeding in such patients by preserving the clotting factors. However, in some cases heparin may aggravate bleeding.

FIBRINOLYTICS (Thrombolytics)

• These are drugs used to lyse thrombi/clot to recanalize occluded blood vessels (mainly coronary artery). They are curative rather than prophylactic; work by activating the natural fibrinolytic system (Fig. 44.3).

• Haemostatic plug of platelets formed at the site of injury to blood vessels is reinforced by fibrin deposition to form a thrombus. Once repair is over, the fibrinolytic system is activated to remove fibrin. The enzyme responsible for digesting fibrin is a serine protease Plasmin generated from plasminogen by tissue plasminogen activator (t-PA), which is produced primarily by vascular endothelium. Plasminogen circulates in plasma as well as remains bound to fibrin. The t-PA selectively activates fibrin bound plasminogen within the thrombus, and any plasmin that leaks is inactivated by circulating antiplasmins. Fibrin bound plasmin is not inactivated by antiplasmins because of common binding site for both fibrin and antiplasmin.

• When excessive amounts of plasminogen are activated (by administered fibrinolytics), the α2 antiplasmin is exhausted and active plasmin persists in plasma. Plasmin is a rather nonspecific protease: degrades coagulation factors (including fibrinogen) and some other plasma proteins as well. Thus, activation of circulating plasminogen induces a lytic state whose major complication is haemorrhage. Even selective activation of thrombus bound plasmin can cause bleeding by dissolving physiological thrombi.

• In general, venous thrombi are lysed more easily than arterial, and recent thrombi respond better: little effect on thrombi > 3 days old. The clinically important fibrinolytics are:

Streptokinase (Stk)

• It is obtained from β hemolytic Streptococci group C. It is inactive as such: combines with circulating plasminogen to form an activator complex which then causes limited proteolysis of other plasminogen molecules to plasmin. Antistreptococcal antibodies present due to past infections inactivate considerable fraction of the initial dose of Stik: a loading dose is necessary in the beginning. Its t½ is estimated to be 30–80 min. 

• Streptokinase is antigenic; can cause hypersensitivity reactions and anaphylaxis, especially when used second time in a patient. Repeat doses are also less effective due to neutralization by antibodies. Fever is common, hypotension and arrhythmias are reported. 

• For MI: 2.5 lac IU i.v. over 10 min followed by 5 lac IU over next 60 min (stop in between if full recanalization occurs) or 6000 IU/min for upto 2 hr.Because of the availability of newer fibrinolytics which do not pose some of the above problems, Stk is infrequently used now in developed countries. However, being the least expensive, it is still widely used in India and other developing countries.

• STREPTASE, (freeze dried powder in vials) 2.5 lac, 7.5 lac and 15 lac IU/vial, ESKINASE, CARDIOSTREP 7.5 lac, 15 lac IU/vial.

• For MI: 7.5–15 lac IU infused i.e. over 1 hr. For deep vein thrombosis and pulmonary embolism: 2.5 lac IU loading dose over ½-1 hr., followed by 1 lac IU/hr for 24 hr.

Urokinase 

• It is an enzyme isolated from human urine; now prepared from cultured human kidney cells, which activates plasminogen directly and has a plasma t½ of 10–15 min. It is nonantigenic. Fever occurs during treatment, but hypotension and allergic phenomena are rare. Indicated in patients in whom streptokinase has been used for an earlier episode, use has now declined due to introduction of newer fibrinolytics. 

• UROKINASE, KD-UNASE, 2.5 lac, 5 lac, 10 lac IU per vial inj.

•  For MI: 2.5 lac IU i.v. over 10 min followed by 5 lac IU over next 60 min (stop in between if full recanalization occurs) or 6000 IU/min for up to 2 hr.

• For venous thrombosis and pulmonary embolism: 4400 IU/kg over 10 min i.v. followed by 4400 IU/kg/hr for 12 hr.

Alteplase

• (recombinant tissue plasminogen activator (rt-PA) Produced by recombinant DNA technology from human tissue culture, it specifically activates gel phase plasminogen already bound to fibrin, and has little action on circulating plasminogen. It is rapidly cleared by liver and has a plasma t½ of 4–8 min. Because of the short t½, it needs to be given by slow i.v. infusion and often requires heparin coadministration. It is nonantigenic, but nausea, mild hypotension and fever may occur. It is expensive. 

• ACTILYSE 50 mg vial with 50 ml solvent water.

• ACTILYSE 50 mg vial with 50 ml solvent water.For MI: 15 mg i.v. bolus injection followed by 50 mg over 30 min, then 35 mg over the next 1 hr.

• For pulmonary embolism: 100 mg i.v. infused over 2 hr.

• Retelles It is a modified form of rt-PA that is longer acting, but somewhat less specific for fibrin bound plasminogen. The longer duration of action enables bolus dose administration (10 mg over 10 min repeated after 30 min). 

• Tenecteplase It is a mutant variant of rt-PA with higher fibrin selectivity and longer duration of action. A single i.v. bolus dose (0.5 mg/kg) or split into two doses 30 min apart is given.

• The clinical efficacy and risk of bleeding with reteplase and tenecteplase are similar to alteplase.

Uses of fibrinolytics

 1. Acute myocardial infarction 

• is the chief indication. Fibrinolytics are an alternative first line approach to emergency percutaneous coronary intervention (PCI) with stent placement. Recanalization of thrombosed coronary artery has been achieved in 50–90% cases. Time lag in starting the infusion is critical for reducing area of necrosis, preserving ventricular function and reducing mortality. The benefits of i.v. thrombolytic therapy have been established by large randomised studies. Aspirin with or without heparin is generally started concurrently or soon after thrombolysis to prevent reocclusion.

• Alteplase has advantages over streptokinase, including higher thrombolytic efficacy. However, incidence of haemorrhage is not lower; may even be higher. Its stronger lytic effect on physiological haemostatic plugs may compensate for the lesser systemic fibrinolytic state.

• Fibrinolytic therapy has also been used in unstable angina, because many such patients have coronary thrombi. 

• Deep vein thrombosis

in leg, pelvis, shoulder etc.; up to 60% patients can be successfully treated. Thrombolytics can decrease subsequent pain and swelling, but the main advantage is preservation of venous valves and may be a reduced risk of pulmonary embolism, though at the risk of haemorrhage. Comparable results have been obtained with Stk, urokinase and rt-PA.

• Pulmonary embolism

Fibrinolytic therapy is indicated in large, life-threatening pulmonary embolism. The lung function may be better preserved, but reduction in mortality is not established.

1. Acute myocardial infarction

• is the chief indication. Fibrinolytics are an alternative first line approach to emergency percutaneous coronary intervention (PCI) with stent placement. Recanalization of thrombosed coronary artery has been achieved in 50–90% cases. Time lag in starting the infusion is critical for reducing area of necrosis, preserving ventricular function and reducing mortality. The benefits of i.v. thrombolytic therapy have been established by large randomised studies. Aspirin with or without heparin is generally started concurrently or soon after thrombolysis to prevent reocclusion.

• Alteplase has advantages over streptokinase, including higher thrombolytic efficacy. However, incidence of hemorrhage is not lower; may even be higher. Its stronger lytic effect on physiological hemostatic plugs may compensate for the lesser systemic fibrinolytic state.

• Fibrinolytic therapy has also been used in unstable angina, because many such patients have coronary thrombi.

2. Deep vein thrombosis

• in leg, pelvis, shoulder etc.; up to 60% patients can be successfully treated. Thrombolytics can decrease subsequent pain and swelling, but the main advantage is preservation of venous valves and may be a reduced risk of pulmonary embolism, though at the risk of haemorrhage. Comparable results have been obtained with Stk, urokinase and rt-PA

3. Pulmonary embolism

• Fibrinolytic therapy is indicated in large, life-threatening pulmonary embolism. The lung function may be better preserved, but reduction in mortality is not established.

4. Peripheral arterial occlusion

• Fibrinolytics recanalise ~40% limb artery occlusions, especially those treated within 72 hr. However, it is indicated only when surgical thrombectomy is not possible. Regional intraarterial fibrinolytics have been used for limb arteries with greater success. Peripheral arterial thrombolysis is followed by short-term heparin and long-term aspirin therapy.

• Fibrinolytics have no role in chronic peripheral vascular disease.

5. Stroke:

• Thrombolytic therapy of ischemic stroke is controversial. Trials showing improved neurological outcome with no change in mortality, as well as those finding significant risk of intracranial hemorrhage and increased mortality are on record. No net benefit was concluded by the ATLANTIS trial in patients treated at 3–5 hours of stroke onset. However, rt-PA is approved for use in ischemic stroke, and current opinion supports use of i.v. alteplase in carefully selected patients who can be treated

• within 3 hours of onset, and in whom intracranial hemorrhage is ruled out along with all risk factors for bleeding.

Evaluation

• All patients with ST segment elevation myocardial infarction (STEMI) are candidates for reperfusion therapy. Both short-term and long-term outcome is determined by early restoration of flow in the occluded artery, regardless of whether it is achieved by thrombolysis or by PCI. Best results are obtained if perfusion can be restored within the first hour (the golden hour). While the efficacy of fibrinolytics in dissolving the thrombus diminishes with passage of time (little benefit after 6 hours of MI onset), reperfusion by PCI is not as much affected by the time lapse. Thrombolysis may be favoured if it can be started within 1–2 hours of onset. After 3 hours, PCI is favoured. Moreover, PCI has the advantage of lower bleeding risk, higher grade of flow in the reperfused artery and reduction in the rate of nonfatal recurrent MI compared to thrombolysis. As such, wherever available, PCI is being used in preference. Presence of risk factors for bleeding also favour PCI. However, the overall 6-month mortality has not been found to differ between either mode of reperfusion.

• erization, should be avoided in patients who are to be given thrombolytics, because risk of bleeding is increased. With concurrent use of heparin, major bleeding (including intracranial hemorrhage) occurs in 2–4% patients. The incidence of bleeding is almost similar with Stk, urokinase and rt-PA. Analysis of recent trials has shown that exclusion of heparin reduces bleeding, and that heparin affords no extra benefit over fibrinolytic + aspirin. Another analysis has shown that efficacy of Stk and rt-PA in MI is similar, but certain other features favour the newer thrombolytics

• Thrombolytic therapy requires careful patient selection. It is contraindicated in all situations where the risk of bleeding is increased, such as— recent trauma, surgery, biopsies, haemorrhagic Chapter 44 Fibrinolytics 607 608 Drugs Affecting Blood and Blood Formation Section 10 stroke or peptic ulcer, severe hypertension, aneurysms, bleeding disorders, diabetes, acute pancreatitis, etc. Its use in retinal vessel occlusion has been abandoned.

ANTIFIBRINOLYTICS

• These are drugs which inhibit plasminogen activation and dissolution of clot.

Epsilon amino-caproic acid (EACA)

• It is an analogue of the amino acid lysine combines with the lysine binding sites of plasminogen and plasmin so that the latter is not able to bind to fibrin and lyse it. It is a specific antidote for fibrinolytic agents and has been used in many hyperlacticaemia states associated with excessive intravascular fibrinolysis resulting in bleeding, e.g.:

• Overdose of streptokinase/urokinase/alteplase.

• To prevent recurrence of subarachnoid and g.i. hemorrhage. 

• Certain traumatic and surgical bleedings (prostatectomy, tooth extraction in hemophiliacs). 

• Abruptio placentae, PPH and certain cases of menorrhagia.

•  However, the usefulness of EACA in most of the above conditions is equivocal, except in overdose of fibrinolytics. In haematuria it can cause ureteric obstruction by the unlysed clots. Therefore, fibrinolysis must be established firmly before using it. It can cause intravascular thrombosis. Rapid i.v. injection results in hypotension, bradycardia and may be arrhythmias. It should be used cautiously when renal function is impaired. Myopathy occurs rarely.

• Initial priming dose is 5 g oral/i.v., followed by 1 g hourly till bleeding stops (max. 30 g in 24 hrs)

• AMICAR, HEMOCID, HAMOSTAT 0.5 g tab., 1.25 g/5 ml syr., 5 g/20 ml inj. 

Tranexamic acid

Like EACA, it binds to the lysine binding site on plasminogen and prevents its combination with fibrin and is 7 times more potent. It has been used for prevention of excessive bleeding in: 

•  Overdose of fibrinolytics 

• After cardio-pulmonary bypass surgery. 

• After tonsillectomy, prostatic surgery, tooth extraction in hemophiliacs. 

• Menorrhagia, especially due to IUCD. 

• Recurrent epistaxis, ocular trauma, bleeding peptic ulcer.

• Main side effects are nausea and diarrhoea. Headache, giddiness and thrombophlebitis of injected vein are other adverse effects.

• Dose: 10–15 mg/kg 2–3 times a day or 1–1.5 g TDS oral, 0.5–1 g TDS by slow i.v. infusion.

• CYCLOKAPRON 500 mg tab, 100 mg/ml inj.

Aprotinin

• It is a polypeptide isolated from bovine tissues with polyvalent serine protease inhibitory activity: trypsin, chymotrypsin, kallikrein and plasmin are inhibited. It can be administered only i.v. and has a t½ of 2 hr. It has been employed in selected situations:

• Administered at the beginning of cardiopulmonary bypass surgery—it reduces blood loss.

• Traumatic, haemorrhagic and endotoxic shock—has adjuvant value.

• Acute pancreatitis (trypsin may be released in circulation which may be fatal).

• Fibrinolytic states, prostatic surgery, carcinoid: may afford symptomatic relief.

• Renal toxicity and ischaemic events like MI and stroke are the possible adverse effects.

• Dose: 5 lac KIU (Kallikrein inactivator unit) initially, followed by 2 lac KIU every 4 hr, all as slow i.v. infusion;

• TRASYLOL INF 5 lac KIU in 50 ml inj; APROGEN 1 lac KIU (10 ml) and 5 lac KIU (50 ml) inj.

ANTIPLATELET DRUGS (Antithrombotic drugs)

• These are drugs which interfere with platelet function and are useful in the prophylaxis of thromboembolic disorders.

• Platelets express several glycoprotein (GP) integrin receptors on their surface. Reactive proteins like collagen and von Willebrand factor (vWF) are exposed when there is damage to vascular endothelium, and they react respectively with platelet GPIa and GPIb receptors. This results in platelet activation and release of proaggregatory and vasoconstrictor mediators like TXA2, ADP and 5-HT. The platelet GPIIb/IIIa receptor undergoes a conformational change favouring binding of fibrinogen that cross links platelets inducing aggregation. Thus, a ‘platelet plug’ is formed. In veins, due to sluggish blood flow, a fibrinous tail is formed which traps RBCs ‘the red tail’. In arteries, platelet mass is the main constituent of the thrombus. Antiplatelet drugs are, therefore, more useful in arterial thrombosis, while anticoagulants are more effective in venous thrombosis.

• Prostacyclin (PGI2), synthesized in the intima of blood vessels, is a strong inhibitor of platelet aggregation. A balance between TXA2 released from platelets and PGI2 released from vessel wall appears to control intravascular thrombus formation. Platelets also play a role in atherogenesis.

• In the above scheme, various drugs act on different targets to interfere with platelet function. The clinically important antiplatelet drugs are:

Aspirin

• n It acetylates and inhibits the enzyme COX1 and TX-synthase—inactivating them irreversibly. Because platelets are exposed to aspirin in the portal circulation before it is deacetylated during first pass in the liver and because platelets cannot synthesize fresh enzyme (have no nuclei) TXA2 formation is suppressed at very low doses and till fresh platelets are formed. Thus, aspirin induced prolongation of bleeding time lasts for 5–7 days. Effect of daily doses cumulates and it has now been shown that doses as low as 40 mg/ day have an effect on platelet aggregation. Maximal inhibition of platelet function occurs at ~160 mg aspirin per day.

• Aspirin also inhibits COX1 and PGI2 synthesis in vessel wall. However, since intimal cells can synthesize fresh enzyme, activity returns rapidly. It is possible that at low doses (75–150 mg/day or 300 mg twice weekly), TXA2 formation by platelets is selectively suppressed, whereas higher doses (> 900 mg/day) may decrease both TXA2 and PGI2 production.

• Aspirin inhibits the release of ADP from platelets and their sticking to each other. However, it has no effect on platelet survival time and their adhesion to damaged vessel wall.

• ASA 50 mg tab., COLSPRIN, DISPRIN CV-100: aspirin 100 mg soluble tab, LOPRIN 75 mg tab, ASPICOT 80 mg tab, ECOSPRIN 75, 150 mg tab.

• Other NSAIDs are reversible inhibitors of COX, produce short-lasting inhibition of platelet function—are not clinically useful.

Dipyridamole 

• It is a vasodilator which was introduced for angina pectoris (see Ch. 39). It inhibits phosphodiesterase and blocks uptake of adenosine to increase platelet cAMP which potentiates PGI2 and interferes with aggregation. Levels of TXA2 or PGI2, are not altered, but platelet survival time reduced by disease is normalized.

• Dipyridamole alone has little clinically significant effect, but improves the response to warfarin, along with which it is used to decrease the incidence of thromboembolism in patients with prosthetic heart valves.

• Dipyridamole has also been used to enhance the antiplatelet action of aspirin, but trials have failed to demonstrate additional benefit in prophylaxis of MI. Risk of stroke in patients with transient ischaemic attacks (TIAs) may be additively reduced.

• Dose: 150–300 mg/day. PERSANTIN 25, 100 mg tabs, THROMBONIL 75, 100 mg tabs, DYNASPRIN: dipyridamole 75 mg + aspirin 60 mg e.c. tab.

Ticlopidine 

• It is the first thienopyridine which alters surface receptors on platelets and inhibits ADP as well as fibrinogen-induced platelet aggregation. The Gi coupled P2YAC (also labelled P2Y12) type of purinergic receptors which mediate adenylyl cyclase inhibition by ADP are blocked irreversibly by ticlopidine. As a result, activation of platelets is interfered. It prevents fibrinogen binding to platelets without modifying GPIIb/IIIa receptor. There is no effect on platelet TXA2, but bleeding time is prolonged and platelet survival in extra-corporeal circulation is increased. Because of different mechanism of action, it has synergistic effect on platelets with aspirin: combination is a potent platelet inhibitor.

• Ticlopidine is well absorbed orally, is converted in liver to an active metabolite, cumulates in the body—peak antiplatelet effect is produced after 8–10 days therapy. The plasma t½ after single dose is 8 hr, but after multiple doses it is 8 days.

• Ticlopidine has produced beneficial effects in stroke prevention, TIAs, intermittent claudication, unstable angina, PCI, coronary artery bypass Chapter 44 Antiplatelet Drugs 609 610 Drugs Affecting Blood and Blood Formation Section 10 grafts and secondary prophylaxis of MI. Combined with aspirin, it has markedly lowered incidence of restenosis after PCI and stent thrombosis. Because of its potential for serious adverse reactions, use of ticlopidine is restricted to supplementing aspirin or when aspirin is contraindicated.

• Side effects: Diarrhea, vomiting, abdominal pain, headache, tinnitus, skin rash. Serious adverse effects are bleeding, neutropenia, thrombocytopenia and jaundice. Several fatalities have occurred.

• Dose: 250 mg BD with meals; effect persists several days after discontinuation; TYKLID, TICLOVAS, TICLOP, 250 mg tab; ASTIC ticlopidine 250 mg + aspirin 100 mg tab.

Clopidogrel 

• This newer congener of ticlopidine has similar mechanism of action, ability to inhibit platelet function and therapeutic efficacy, but appears to be safer and better tolerated (CLASSICS study). The clopidogrel vs aspirin in patients at risk of ischemic events (CAPRIE) trial has found clopidogrel recipients to have a slightly lower annual risk of primary ischemic events than aspirin recipients. The most important adverse effect is bleeding. Addition of aspirin to clopidogrel has been found to double the incidence of serious bleeding among high-risk stroke patients (MATCH study). A lower frequency of neutropenia, thrombocytopenia and other bone marrow toxicity compared to ticlopidine has been recorded. Side effects are diarrhea, epigastric pain and rashes.

•  Clopidogrel + aspirin is as effective in stented patients as ticlopidine + aspirin. Clopidogrel is 50% absorbed orally and like ticlopidine, it is a prodrug; action lasts for upto 7 days.

• Dose: 75 mg OD; CLODREL, CLOPILET, DEPLATT 75 mg tab.

Glycoprotein (GP) IIb/IIIa receptor antagonists

• GP IIb/IIIa antagonists are a new class of potent platelet aggregation inhibitors which act by blocking the key receptor involved in platelet aggregation. The GP IIb/IIIa is an adhesive receptor (integrin) for fibrinogen and Awf through which agonists like collagen, thrombin, TXA2, ADP, etc. induce platelet aggregation. Thus, GP IIb/IIIa antagonists block aggregation induced by all platelet agonists. 

Abciximab

• It is the Fab fragment of a chimeric monoclonal antibody against GP IIb/IIIa. Given along with aspirin + heparin during PCI it has markedly reduced the incidence of restenosis, subsequent MI and death. After a bolus dose platelet aggregation remains inhibited for 12–24 hr, while the remaining antibody is cleared from blood with a t½ of 10–30 min.

• Dose: 0.25 mg/kg i.v. 10–60 min before PCI, followed by 10 μg/min for 12 hr. REOPRO 2 mg/ml inj.

• Abciximab is nonantigenic. The main risk is haemorrhage, incidence of which can be reduced by carefully managing the concomitant heparin therapy. Thrombocytopenia is another complication. Constipation, ileus and arrhythmias can occur. It is very expensive, but is being used in unstable angina and as adjuvant to coronary thrombolysis/PCI with stent placement.

• Eptifibatide and Tirofiban respectively are peptide and nonpeptide GP IIb/IIIa receptor antagonists, developed as alternatives to abciximab. 

 

Uses of antiplatelet drugs

• For certain indications like maintenance of vascular recanalization, stent placement, vessel grafting, etc. potent inhibition of platelet function is required. This is achieved by combining antiplatelet drugs which act by different mechanisms.

1. coronary artery disease

• Coronary artery disease MI: Low dose aspirin started immediately after MI has been found to reduce mortality and prevent reinfarction. It also improves survival when used along with thrombolytic therapy. Ticlopidine and clopidogrel are alternatives.

• Aspirin is now routinely used to prevent reocclusion after thrombolytic therapy. It is also given along with heparin to cover PCI, and then continued indefinitely. Ticlopidine, clopidogrel or abciximab used along with aspirin have markedly improved the outcome of PCI and stent procedures.

• Unstable angina Aspirin reduces the risk of MI and sudden death in patients with unstable angina. For maximum benefit aspirin (100–150 mg/day) is given along with heparin—followed by warfarin. Ticlopidine or clopidogrel can be used as alternatives or adjuvant to aspirin.

• The Clopidogrel in unstable angina to prevent recurrent events (CURE) trial has found that addition of clopidogrel to aspirin further reduced cardiovascular mortality, nonfatal MI and stroke by 20%.

• Primary and secondary prevention of MI On the basis of trials in post-MI as well as in those with no such history, it has been recommended that aspirin 75–150 mg/day be given to all individuals with evidence of coronary artery disease and in those with risk factors for the same, but routine use in the whole population is not warranted. Aspirin reduces the incidence of fatal as well as nonfatal MI but increases the risk of cerebral hemorrhage; overall mortality is marginally reduced.

2. Cerebrovascular disease

• Antiplatelet drugs do not alter the course of stroke due to cerebral thrombosis. However, aspirin has reduced the incidence of TIAs, of stroke in patients with TIAs or persistent atrial fibrillation and in those with history of stroke in the past. It is recommended in all such individuals. The European stroke prevention study-2 (ESPS) has found combination of dipyridamole with low dose aspirin to be synergistic in secondary prevention of stroke. Ticlopidine and clopidogrel also reduce TIAs and stroke.

3. Coronary angioplasty, stents, bypass implants

• The patency of recanalized coronary artery or implanted bypass vessel is improved and incidence of reclusion is reduced by aspirin alone and in combination with ticlopidine/ clopidogrel. Abciximab used along with aspirin and heparin has markedly reduced restenosis and subsequent MI after coronary angioplasty.

4. Prosthetic heart valves and arteriovenous shunts

• Antiplatelet drugs, used with warfarin reduce formation of microthrombi on artificial heart valves and the incidence of embolism. Aspirin is clearly effective but increases risk of bleeding due to warfarin. Dipyridamole does not increase bleeding risk, but incidence of thromboembolism is reduced when it is combined with an oral anticoagulant. Antiplatelet drugs also prolong the patency of chronic arteriovenous shunts implanted for hemodialysis and of vascular grafts.

5. Venous thromboembolism

• Anticoagulants are routinely used. Trials have shown antiplatelet drugs also to have a prophylactic effect, but their relative value in comparison to or in addition to anticoagulants is not known.

6. Peripheral vascular disease

• Aspirin/ ‘ticlopidine/clopidogrel may produce some improvement in intermittent claudication and reduce the incidence of thromboembolism.