Understanding Anticoagulants

• Anticoagulants are drugs that prevent blood coagulation via inhibitory action on clotting factors.

Lecture Objectives

• To understand and discuss coagulation and anticoagulation
• To review the normal physiology of coagulation.
• To classify anticoagulant drugs.
• To understand the kinetics and dynamics of the main drugs of different classes

Definitions

• Thrombosis is the formation of a clot within a blood vessel during life.
• Embolus is a dislodged piece of thrombus circulating in the blood.
• Thromboembolism is the occlusion of a blood vessel due to a dislodged piece of thrombus.

Defective Haemostasis

• Normal blood clotting is essential for survival to maintain the integrity of the circulatory system.
• Inadequate coagulation leads to excessive bleeding.
• Excessive coagulation leads to thrombus/thrombi formation, obstructing blood flow.
• Anticoagulants are used in patients with excessive coagulation.

Introduction to Haemostasis

• Haemostasis is the normal physiological response to prevent significant blood loss following vascular injury.
• Haemostasis prevents blood loss through vasoconstriction, coagulation, and platelet plugging.
• Coagulation involves physiological and biochemical reactions with coagulation proteins forming an insoluble fibrin clot.
• Fibrinolysis dissolves the clot via plasmin (formed from plasminogen), restoring blood flow.

Coagulation Cascade

• The coagulation cascade has two distinct initiation points: extrinsic and intrinsic pathways.
• The intrinsic pathway is initiated by internal injury to the vessel wall causing damage to the endothelial lining, vessel wall defects or bacterial contact.
• The extrinsic pathway is initiated by external injury (trauma) to the vessel and nearby tissues.
• Activated Factor X (Factor Xa) plays a central role where the intrinsic and extrinsic pathways converge.

Anticoagulant Drugs

• Indirect thrombin inhibitors: Heparin (UFH), LMWHs (dalteparin, nadroparin calcium, enoxaparin sodium, reviparin, parnaparin, certoparin), Fondaparinux
• Direct thrombin inhibitors (Parenteral): Bivalent DTIs (Hirudin, Lepirudin, Desirudin, Bivalirudin), Univalent DTIs (Argatroban, Malagatran)
• Direct thrombin inhibitors (Oral): Dabigatran etexilate mesylate
• Oral anticoagulants: Coumarin Derivatives (Warfarin, Dicumarol, Acenocoumarol, Phenindione)
• Direct Factor Xa Inhibitors: Rivaroxaban, Apixaban

Anticoagulant Classes, Routes & Targets

• Anticoagulants can be administered parenterally or orally.
• Parenteral administration targets indirect thrombin inhibitors (UFH, LMWH, Fondaparinux, Danaparoid) and direct thrombin inhibitors (Argatroban, Hirudin, Bivalirudin, Lepirudin, Desirudin).
• Oral administration targets coumarin derivatives like Warfarin, Acenocoumarol, Bishydroxycoumarin (Dicumarol); direct factor Xa inhibitors like Rivaroxaban and Apixaban and direct thrombin inhibitor Dabigatran-etexilate.

Indications of Anticoagulants

• Drugs are used for blood storage for transfusion or hematological testing.
• Used to treat strokes, myocardial infarctions, pulmonary embolisms, disseminated intravascular coagulation (DIC), deep vein thrombosis (DVT), coronary artery bypass grafting, artificial heart valves, and cerebral thrombosis.

Clinical Conditions Associated with Venous Thrombosis

• Malignancy
• Inflammation
• Immobility
• Surgery
• Trauma
• Lupus anticoagulant
• Sickle cell disease
• Childbirth
• Obesity

Indirect Thrombin Inhibitors

• They exert antithrombotic effects by binding with antithrombin.
• Unfractionated heparin (UFH), low molecular-weight heparins (LMWH), and fondaparinux bind to antithrombin and enhance inactivation of factor Xa.
• Unfractionated heparin and LMWH enhance inactivation of thrombin (by antithrombin).
• Antithrombin III inhibits Factor X and thrombin.
• Unfractionated Heparin inhibits Factor X and thrombin.
• LMWHs inhibit Factor X only.
• Fondaparinux inhibits Factor X only.

Unfractionated Heparin (UFH)

• UFH is a highly acidic mucopolysaccharide (negatively charged).
• Its molecular weight ranges from 5,000 to 30,000.
• UFH is normally present on endothelial cell surfaces as heparan sulfate.
• UFH binds to Antithrombin III (AT-III), increasing its activity 1,000 times.
• AT-III inhibits clotting factors, mainly thrombin (IIa), IXa, and Xa.
• Heparin is a fast-acting anticoagulant.
• Major sources of heparin include porcine intestines and beef lungs.

Heparin Pharmacokinetics

• Heparin is not absorbed orally due to its large size and high ionization.
• Intravenous administration provides instant action via bolus or continuous infusion.
• Subcutaneous administration is inconsistent, requiring administration every 8-12 hours.
• Heparin does not cross the blood-brain barrier or placenta.
• Metabolized in the liver (heparinise).
• Excreted in urine.

Heparin Mechanism

• Heparin inactivates thrombin by binding both ATIII and thrombin.
• Binding to ATIII is mediated by a unique pentasaccharide sequence on heparin.
• Binding to thrombin occurs through the heparin-binding domain on the enzyme.
• Inactivation of factor Xa requires heparin to bind to ATIII through its pentasaccharide sequence.

Administration

• Unfractionated heparin is given continuously via IV, intermittently at a full dose, or subcutaneously at a low dose.

Lab Monitoring of Heparin

• Close monitoring of activated partial thromboplastin time (aPTT or PTT) is required when receiving UFH.
• Therapeutic range is based on 0.2 to 0.4 units/ml heparin.
• Monitoring aims to measure the drug's effect.
• Can be reversed with protamine sulfate.

Adverse Effects of Heparin

• Bleeding is a common adverse effect.
• HIT (Heparin-induced Thrombocytopenia)
• Osteoporosis
• Hypersensitivity reactions
• Skin necrosis

Contraindications of Heparin

• HIT.
• Hypersensitivity to the drug.
• Active bleeding.
• Hemophilia.
• Significant thrombocytopenia.
• Purpura.
• Severe hypertension.
• Intracranial hemorrhage.
• Infective endocarditis.
• Active tuberculosis.
• Ulcerative lesions of the GIT.
• Threatened abortion.
• Visceral carcinoma.
• Advanced hepatic or renal disease.

Low Molecular Weight Heparins (LMWHs)

• Shorter chain fractions of heparin.
• LMWHs inhibit activated factor X but have less effect on thrombin.
• Enoxaparin, dalteparin, and tinzaparin are effective in prophylaxis or treatment of several thromboembolic conditions.
• They have longer half-lives (2-4 hours).
• LMWH do not cross the placenta.
• LMW heparin levels do not need laboratory monitoring due to predictable pharmacokinetics and plasma levels, except in renal insufficiency, obesity, and pregnancy.

Advantages of LMWH

• LMWHs have replaced UFH for clinical indications.
• LMWHs are as effective as UFH but are safer.
• Less frequent dosing is required.
• Administered subcutaneously.
• No need for laboratory monitoring.
• Less likely to cause thrombocytopenia.
• Less incidence of hemorrhage as a side effect.

Fondaparinux

• The synthetic pentasaccharide molecule avidly binds antithrombin with high specific activity, leading to efficient inactivation of factor Xa.
• The long half-life of 15 hours allows for once-daily subcutaneous administration.
• It is effective in preventing and treating venous thromboembolism.
• Does not cross-react with HIT antibodies.

Parenteral Direct Thrombin Inhibitors

• Hirudin is a specific, irreversible thrombin inhibitor from leech saliva that is now available in recombinant form as lepirudin.
• It is independent of antithrombin.
• It can reach and inactivate fibrin-bound thrombin in thrombi.
• It must be administered parenterally and needs monitoring by aPTT.
• Lepirudin is a good alternative for thrombosis related to heparin-induced thrombocytopenia (HIT).
• Lepirudin is excreted by the kidney and should be used cautiously in patients with renal insufficiency as no antidote exists.

Bivalirudin and Argatroban

• Bivalirudin is administered I/V and inhibits platelet activation, and it has rapid onset of action and short half life.
• Argatroban is a thrombin inhibitor approved for use in patients with HIT with or without thrombosis and coronary angioplasty in patients with HIT.
• Argatroban has a short half-life and is given by continuous intravenous infusion.
• Argatroban's effects are monitored by aPTT.
• Argatroban clearance is not affected by renal disease but is dependent on liver function, and dose reduction is required in patients with liver disease.

Oral Direct Thrombin Inhibitors

• Dabigatran and its metabolites are oral agents.
• Dabigatran etexilate mesylate is the first oral direct thrombin inhibitor approved.
• Dabigatran reduces the risk of stroke and systemic embolism with nonvalvular atrial fibrillation.
• It is approved for prevention of venous thromboembolism in patients who have undergone hip or knee replacement surgery.
• Has rapid onset and offset of action.
• Routine coagulation monitoring is unnecessary.
• Renal impairment results in delayed drug clearance and may require dose adjustment.
• Primary toxicity of dabigatran is bleeding.
• It has no antidote.

Oral Direct Xa Inhibitors

• Apixaban and rivaroxaban are available.
• Oral direct Xa inhibitors and oral direct thrombin inhibitors show advantages over warfarin.
• Warfarin has a narrow therapeutic window, is affected by diet and many drugs, and requires monitoring for dosage adjustment.

Warfarin and Other Coumarin Anticoagulants

• Warfarin (Coumadin) is a coumarin derivative.
• Coumarin, Dicumarol and Acenocumarol are other coumarin anticoagulants.

Warfarin Properties

• Introduced as an antithrombotic agent in the 1950s.
• One of the most commonly prescribed drugs.
• Administered as the sodium salt with 100% bioavailability.
• Over 99% is bound to plasma albumin.
• It has a small volume of distribution and a long half-life in plasma (36 hours).
• It is metabolized in the liver and excreted via the renal route.
• Urinary excretion doesn't involve unchanged drug.

Warfarin MOA

• Warfarin and other vitamin K antagonists (VKA) block the regeneration of active form of vitamin K.
• They inhibit the enzyme vitamin K1-2,3 epoxide reductase.
• Vitamin K is required in the liver to activate vitamin K-dependent coagulation factors (II, VII, IX, X) and anticoagulant proteins C and S, via γ-carboxylation.
• Without vitamin K, coagulation factors remain inactive.

Clinical Uses of Warfarin

• Mainly for long-term anticoagulation in patients at risk for thromboembolic events.
• Venous thrombosis, Pulmonary embolism
• Thromboembolic complications associated with AF, hip replacement surgery, and cardiac valve replacement
• Post MI, recurrent MI, and thromboembolic events like stroke or systemic embolization
• Cardiac embolism

Warfarin Toxicity

• Warfarin crosses the placenta and causes hemorrhagic disorders in the fetus.
• It affects fetal proteins in bone and blood, causing birth defects characterized by abnormal bone formation, so it should not be used during pregnancy.
• Warfarin shows a coagulative effect in the first few days of administration due to the inhibition of the synthesis of anticoagulant protein C.
• Can cause cutaneous necrosis and frank infarction of the breast, fatty tissues, intestine, and extremities.
• Heparin is co-administered for a bridging effect in the initial four days of warfarin therapy.

Reversal of Warfarin Action

• Excessive anticoagulant effect and bleeding can be reversed by stopping the drug.
• Give oral or parenteral vitamin K1 (phytonadione), fresh-frozen plasma, prothrombin complex concentrates (e.g., Bebulin and Proplex T), and recombinant factor VIIa (rFVIIa).

Warfarin Efficacy & Safety

• Warfarin has a narrow therapeutic index.
• Peak antithrombotic effect takes 96 hours (four days).
• Effectiveness is monitored by lab testing PT/INR.
• Efficacy diminishes below INR 2.0,.
• Below INR 1.5, there is no efficacy.
• High dose treatment safety is compromised above INR 4.
• Coadministered heparin is discontinued when the INR reaches the desired therapeutic range.

Drug Interactions of Warfarin

• Drugs inhibiting warfarin metabolism (increase warfarin effects): Omeprazole, disulfiam, cimetidine, amiodarone, metronidazole, and trimethoprim-sulfamethoxazole.
• Drugs inducing enzymes metabolizing warfarin (decrease warfarin effects): Barbiturates, rifampin, carbamazepine.
• Cholestyramine binds warfarin in the intestine and reduces its absorption and bioavailability.
• Pharmacodynamic interactions reducing anticoagulant effect of warfarin occur with vitamin K (increases synthesis of clotting factors) and hypothyroidism (decreases turnover of clotting factors).

Sources of Vitamin K

• Sources include fat-soluble vitamins.
• Absorption requires pancreatic and bile secretions
• Sources include leafy green vegetables, bacteria in intestinal tract.
• No significant body stores

Vitamin K Content in Foods

• Green tea: 712 µg
• Avocado: 634 µg
• Turnip greens: 408 µg
• Brussels sprouts: 317 µg
• Chickpeas: 220 µg

Differences Between Heparin and Warfarin

• Heparin affects intrinsic pathway, Warfarin affects extrinsic pathways.
• Heparin inactivates thrombin and factor Xa, Warfarin inhibits synthesis of clotting factors.
• Heparin can be administered IV or subQ, Warfarin given via PO.
• Heparin does not cross placenta or into breast milk, Warfarin crosses placenta (teratogenic).
• Onset of Heparin is rapid (minutes), Warfarin is slow (hours).
• Duration of Heparin is brief (hours), Warfarin is Prolonged (days).
• Heparin has few drug interactions compared to Warfarin.
• Heparin is eliminated renally, Warfarin is eliminated hepatically.
• aPTT for Heparin monitoring, PT for Warfarin monitoring.
• Protamine is the antidote for Heparin, Phytomenadione (Vitamin K) for Warfarin.