Coagulation & Anticoagulation

• By the end of the class, students will be able to understand and discuss:
  • Introduction to coagulation and anticoagulation.
  • Review of normal physiology of coagulation.
  • Classification of anticoagulant drugs.
  • Kinetics and dynamics of main drugs of different classes.

Definitions

• Thrombosis is the formation of a clot within a blood vessel during life, derived from the Greek words for clot, curd, and congeal.
• An embolus is a dislodged piece of thrombus that circulates in the blood.
• Thromboembolism is the occlusion of a blood vessel due to a dislodged piece of thrombus.
• An anticoagulant is a substance that prevents coagulation or clotting of blood by its inhibitory action on clotting factors.

Defective Haemostasis

• Normal blood clotting is essential for survival because It maintains the integrity of the circulatory system.
• Inadequate coagulation due to lack of coagulation factors leads to excessive bleeding, as seen in Hemophilia and von Willebrand's disease.
• Excessive coagulation leads to the formation of thrombi, potentially obstructing blood flow, which is common in hospitalized or immobilized patients, or after abdominal/orthopedic surgery, where anticoagulants are used.

Introduction to Haemostasis

• Haemostasis is the normal physiological response that prevents significant blood loss following vascular injury.
• Haemostasis prevents blood loss through vasoconstriction, coagulation, and platelet plugging. Platelet plugging precedes coagulation.
• Coagulation involves a series of physiological and biochemical reactions of coagulation proteins. This series of reactions results in formation of an insoluble fibrin clot.
• Fibrinolysis is the process where the clot is dissolved following tissue repair. Plasmin, formed from plasminogen, facilitates this process.

The Coagulation Cascade

• The coagulation cascade is believed to have two distinct initiation points: extrinsic and intrinsic pathways.
• The intrinsic pathway initiates with internal injury to the vessel wall, which damages the endothelial lining. It can also be activated by defective vessel walls or endothelial contact with bacteria.
• The extrinsic pathway initiates with external injury (trauma) to the vessel and nearby tissues.
• Activated Factor X (Factor Xa) is central to the coagulation cascade, as it is the point where the intrinsic and extrinsic pathways converge.

Anticoagulant Drugs

• Indirect thrombin inhibitors in parenteral form are: Heparin (UFH), LMWHs consisting of: dalteparin, nadroparin calcium, enoxaparin sodium, reviparin, parnaparin, and certoparin, Fondaparinux.
• Direct thrombin inhibitors could be parenteral or oral.
  • Parenteral include bivalent DTIs: Hirudin, Lepirudin, Desirudin, Bivalirudin, and univalent DTIs: Argatroban, Malagatran.
  • Oral: Dabigatran etexilate mesylate.
• Oral anticoagulants such as coumarin derivatives: Warfarin, Dicumarol, Acenocoumarol, Phenindione.
• Direct Factor Xa Inhibitors such as: Rivaroxaban and Apixaban.
• Anticoagulants classes and routes of administration:
  • Parenteral: Indirect thrombin inhibitors such as UFH, LMWH, Fondaparinux, Danaparoid, direct thrombin inhibitors such as Argatroban, Hirudin, Bivalirudin, Lapirudin, Desirudin.
  • Oral: Coumarin derivatives such as Warfarin, Acenocoumarol, Bishydroxycoumarin (Dicumarol), direct factor Xa inhibitors such as Rivaroxaban, Apixaban, and direct thrombin inhibitor: Dabigatran-etexilate.

Indications of Anticoagulants

• Anticoagulants are used for blood storage for transfusion or hematological testing and 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 and Inflammation
• Immobility and Surgery
• Trauma
• Lupus anticoagulant
• Sickle cell disease
• Childbirth
• Obesity

Indirect Thrombin Inhibitors

• They are named so because their antithrombotic effect is exerted by binding with antithrombin, a separate protein.
• Unfractionated heparin (UFH), low molecular-weight heparins (LMWH), and fondaparinux bind to antithrombin and enhance its ability to inactivate factor Xa.
• Unfractionated heparin, and to a lesser extent LMWH, also enhance inactivation of thrombin, by antithrombin.
• This means inhibition can be summarised as:
  • Antithrombin III -> Factor X and thrombin.
  • Unfractionated Heparin -> Factor X and thrombin.
  • LMWHs -> Factor X only.
  • Fondaparinux -> Factor X only.

Unfractionated Heparin (UFH)

• It's a highly acidic mucopolysaccharide. Its molecules are negatively charged.
• The molecular weight is between 5,000-30,000.
• It's normally present on the endothelial cell surfaces as heparan sulfate.
• It binds to Antithrombin III (AT-III) and potentiates its activity 1,000 times. AT-III is a natural anticoagulant, inhibiting mainly thrombin (IIa), IXa, and Xa.
• Heparin is a fast-acting anticoagulant.
• Major sources of heparin are porcine intestines and beef lungs.

Heparin: Pharmacokinetics

• Absorption:
  • Oral: Not absorbed due to being large and highly ionized.
  • Intravenous: Immediate action (bolus or continuous infusion).
  • Subcutaneous: inconsistent absorption (every 8-12 hours).
• Distribution: Does not cross blood-brain barrier or placenta.
• Metabolism: Occurs in the liver (heparinise).
• Excretion: Via urine.
• To inactivate thrombin, heparin serves as a template and binds both anti-thrombin III (ATIII) and thrombin.
  • Binding to ATIII is mediated by the unique penta-saccharide sequence on heparin.
  • Binding to thrombin occurs through the heparin-binding domain on the enzyme.
• To inactivate factor Xa, heparin needs only to bind to ATIII through its pentasaccharide sequence.

Heparin Administration

• Unfractionated heparin is given:
  • Continuous IV.
  • Intermittent full dose.
  • Subcutaneous low dose.

Lab Monitoring of Heparin Effect and Overdose

• Close monitoring of the activated partial thromboplastin time (aPTT or PTT) is necessary for patients receiving UFH.
• The PTT therapeutic range is between 0.2 and 0.4 units/ml heparin.
• The purpose is to measure the effect of the drug, not the drug concentration.
• Heparin overdose can be reversed with protamine sulfate.

Adverse Effects and Contraindications of Heparin

• Adverse effects: Bleeding is common, HIT, osteoporosis, hypersensitivity reactions, and skin necrosis.
• Heparin is contraindicated in patients with 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, or advanced hepatic or renal disease.

Low Molecular Weight Heparins (LMWHs)

• LMWHs inhibit activated factor X, but have less effect on thrombin- they are the shorter chain, low-molecular-weight (LMW) fractions of heparin.
• LMW heparins like enoxaparin, dalteparin, and tinzaparin are effective in preventing or treating several thromboembolic conditions.
• They have longer half-lives, around 2-4 hours.
• LMWH does not cross the placenta, similar to UFH.
• LMW heparin levels don't require lab monitoring because of their predictable pharmacokinetics and plasma levels, aside from those with renal insufficiency, obesity, or pregnancy.

LMWHs Replacement of UFH

• LMWHs have replaced UHF for most clinical indications for the following reasons:
  • LMWHs are as effective and safer than UFH.
  • Less frequent dosing is required and administered in BD or OD doses.
  • Administered subcutaneously.
  • There is less likelihood to cause thrombocytopenia.
  • There is less incidence of hemorrhage as a side effect.

Fondaparinux

• Fondaparinux is a synthetic pentasaccharide molecule that binds antithrombin with high specific activity, leading to efficient inactivation of factor Xa.
• Fondaparinux has a long half-life of 15 hours, allowing for once-daily subcutaneous administration.
• Fondaparinux is effective in the prevention and treatment of venous thromboembolism and does not cross-react with pathologic HIT antibodies in most individuals.

Parenteral Direct Thrombin Inhibitors

• Hirudin is a specific, irreversible thrombin inhibitor from leech saliva, now available in recombinant form as lepirudin.
• Its action is independent of antithrombin and can reach and inactivate fibrin-bound thrombin in thrombi.
• Lepirudin is administered parenterally and is monitored by aPTT.
• Lepirudin is a good alternative in HIT-related thrombosis.
• As lepirudin is excreted by the kidney, it must be used cautiously in patients with renal insufficiency, as there is no antidote.
• Bivalirudin is administered intravenously. It also inhibits platelet activation with a rapid onset of action and a short half life.
• Argatroban is a thrombin inhibitor approved for use in patients with HIT (thrombosis) and coronary angioplasty in patients with HIT (it also has a short half-life, it's given via continuous intravenous infusion, its monitored by aPTT).
  • Its clearance is not affected by renal disease but on liver function, dose reduction is required in liver disease.

Oral Direct Thrombin Inhibitors

• Dabigatran and its metabolites are examples of these.
• Dabigatran etexilate mesylate. It's the first approved oral direct thrombin inhibitor.
• Dabigatran reduces the risk of stroke and systemic embolism, and is approved for prevention of venous thromboembolism in patients, after hip/knee replacement surgery.
• The agents have rapid onset and offset of action, thus, routine coagulation monitoring is unnecessary. However, renal impairment results in delayed drug clearance and dose adjustment may be required.
• Primary toxicity of dabigatran is bleeding, and it has no antidote.

Oral Direct Xa Inhibitors

• Apixaban and rivaroxaban are drugs that are available oral direct factor Xa inhibitors.
• Compared to warfarin, oral direct Xa/thrombin inhibitors show significant advantages due to diet and narrow therapeutic window.

Warfarin and Other Coumarin Anticoagulants

• Warfarin is derived from Coumarin and is a brand name (Coumadin).
• Dicumarol and Acenocumarol are included in this group.
• Warfarin (under the trade name Coumadin) went on the market in humans as an antithrombotic drug in the 1950s. It remains among the most often administered medications.
• Warfarin is usually given as a salt with sodium and has complete bioavailability.
• More than 99% of racemic warfarin binds to albumin in plasma, which might explain its limited plasma volume and extended plasma half-life (36 hours).
• It is eliminated via the renal system after being processed in the liver. Drug that has not been metabolized and renally excreted.

Warfarin MOA

• Warfarin is considered a Vitamin K antagonist and blocks the active form of Vitamin K.
• Vitamin K is required in the liver to activate coagulation factors 2, 7, 9, and 10 and antiprocoagulant proteins C and S.
• When the carboxylation process is finished, the proteins will be functional. Warfarin prevents the regeneration of Vitamin K, keeping K-dependent coagulation factors in an inactive state (native state).

Clinical Uses of Warfarin

• It is mainly used for long-term anticoagulation in patients who are at risk for thromboembolic events.
• Can be used for Prophylaxis and/or treatment of: Venous thrombosis, Pulmonary embolism, Thromboembolic complications associated with, hip replacement surgery, cardiac valve replacement and AF. In addition, post MI, recurrent MI, stroke or systemic embolization.
• Cardiac Embolism.

Warfarin Toxicity

• Warfarin readily crosses the placenta and can cause a hemorrhagic disorder in the fetus.
• Warfarin can affect fetal proteins with Y carboxyglutamate residues (bone/blood), causing abnormal bone formation. Warfarin it is not used during pregnancy.
• Due to inhibition of anticoagulant protein C and S, warfarin has coagulative effects and causes necrosis (frank infarction of the breast, fatty tissues, intestine, and extremities. The lesion in such hemorrhagic infarction is venous thrombosis).
• Therefore, heparin is coadministered for four days of warfarin therapy.

Reversal of Warfarin Action

• The excessive anticoagulant effect and bleeding can be reversed by stopping the drug and administering oral or parenteral vitamin K1 (phytonadione), fresh-frozen plasma, prothrombin complex concentrates, and recombinant factor VIIa (rFVIIa).
• Warfarin has a therapeutic index.
• The peak anthrombotic effects may achieve in 9 days.
• Monitored by lab testing PT/INR.
• Warfarin efficacy is diminished if less than 2.
• Avoid compromising on the effectiveness if there is a low dosage given.
• Discontinue heparin (coadministered).

Drug Interactions of Warfarin

• Warfarin's anticoagulant effects can be amplified when taken with drugs that impede its metabolism
• Examples: omeprazole, disulfiram, cimetidine, amiodarone, metronidazole, and trimethoprim-sulfamethoxazole.
• Warfarin's anticoagulant effects can be greatly diminished when taken with medicines that induce enzymes that metabolize it (barbiturates, rifampin, carbamazepine)
• Warfarin absorption and bioavailability are decreased by cholestyramine.
• Pharmacodynamic interactions that lower a medicine’s impact include vitamin K (which boosts the production of clotting factors) and hypothyroidism lowering the turnover rate of clotting factors.

Sources of Vitamin K

• Fat-soluble vitamin.
• Absorption requires pancreatic and bile secretions.
• Sources include leafy green vegetables, and bacteria in the intestinal tract.

Differences Between Heparin and Warfarin

• Pathway:
  • Heparin affects the intrinsic pathway.
  • Warfarin affects the extrinsic pathway.
• MOA:
  • Heparin inactivates thrombin and factor Xa.
  • Warfarin inhibits synthesis of clotting factors.
• Route:
  • Heparin is IV or subQ.
  • Warfarin is PO.
• Teratogenic:
  • Heparin does not cross the placenta or into breast milk.
  • Warfarin crosses the placenta (teratogenic).
• Onset:
  • Heparin is rapid (minutes).
  • Warfarin is slow (hours).
• Duration:
  • Heparin is brief (hours).
  • Warfarin is prolonged (days).
• Drug interactions:
  • Heparin has few.
  • Warfarin has many.
• Elimination:
  • Heparin is eliminated renally.
  • Warfarin is eliminated hepatically.
• Monitoring:
  • aPTT with Heparin
  • PT with Warfarin
• Antidote:
  • Protamine for Heparin
  • Phytomenadione (Vitamin K) for Watfarin