Anticoagulant therapy Presented by : Saeed Bani Saleh and Marwa Alqerenawi Dr. Mohammad Alani

Revision for coagulation cascade Intrinsic pathway Extrinsic pathway ………………………………….. XII Tissue injury Tissue factor XI IX Partial thromboplastin time Prothombin time (10_14s) VII VIII X Ca+2 V lipids Prothrombin (II) thrombin fibrinogen fibrin XIII Stabilized clot

Anticoagulant drugs Drugs that inhibit the action of the coagulation factors(ex. heparin). Drugs that interfere with the synthesis of coagulation factors (ex. warfarin). New oral anticoagulant.

Low molecular weight heparin(LMWH) Injectable , rapidly acting AC that interfere with the formation of thrombus . Naturally it is complexed with histamine in mast cells. Acidic in nature Extracted from porcine intestinal mucosa Low molecular weight heparin(LMWH) Anionic glycosamino glycans produced from enzymatic depolymerization of unfractionated heparin . Like enoxaparin , dalteparin , tinzaparin.

Activated thrombin (factor aII) Antithrombin III fast Activated factor (aX) Slow …….………………….. heparin

Activated factor (aX) Antithrombin III fast LMWH

pharmacokinetic LMWH (sc) Heparin : therapeutic dose (IV) bolus of (5000 U) continuous IV (20 U per kg per hr) prophylactic dose (SC) 5000 U every 12 hr Need continuous monitoring of the anti coagulant effect by monitoring aPTT (1,5_2.5x control ) just in IV injections after 6 hr and now it is monitored by antifactor (X) levels. LMWH (sc) therapeutic dose: given as a weight _ adjusted dose No need for monitoring excreted via kidneys

Acute venous thromboembolism (DVT or PE) and prophylaxis. Prophylaxis of postoperative venous thrombosis in patient undergoing surgery In pregnant women Acute coronary syndromes : MI, unstable angina After vascular bypass grafting AF in acute setting LMWH used in outpatient clinics Indications for use

Adverse effects of heparin Bleeding : we should stop the heparin and give protamine sulfate. Thrombosis : with chronic use due to reduction of antithrombin. Because it is extracted from porcine it may act as antigen and cause urticaria or anaphylactic shock. Transient alopecia Osteoporosis: dose related. Heparin induced thrombocytopenia

Heparin induced thrombocytopenia : With higher doses , more common in surgical than medical patients. Type 1: common , mild due to non immunologic factor , early(within 5 days) Type 2: rare , more serious (within 5_14 d) due to autoantibody against heparin and platelet factor 4 , causing platelet activation and aggregation lead to life threatening venous and arterial thrombosis even in the setting of thrombocytopenia.

Management: DIAGNOSIS: 4Ts scoing system: Thrombocytopenia Timing of the fall of the platete count Presence of new thrombosis the likelihood of another cause of thrombocytopenia Management: Discontinue the drug and give an alternative like lepirudin (not LMWH ,the Ab may be cross reactive).

Contraindications of heparin Hypersensitivity to heparin Previous HIT Bleeding disorders (thrombocytopenia , hemophilia) Alcoholics Recent surgery of brain, eye or spinal cord Severe HTN Active bleeding (GI , intracranial)

Cause osteoporosis and HIT LMWH Heparin X II , X Longer duration (3_24hr) Short duration (1_4hr) Does not Cause osteoporosis and HIT SC IV , SC Does not need Need monitoring

Warfarin

Warfarin is an oral anticoagulant widely used to control and prevent thromboembolic disorders and it’s the most widely used oral anticoagulant. Warfarin is clinically available as a racemic mixture of R- and S-warfarin. The S-warfarin has 4 times greater anticoagulation potency than R-warfarin.

Mechanism of Action - Clotting factors II, VII, IX, X need vitamin K as a cofactor for their synthesis in liver - Warfarin inhibits vitamin K epoxide reductase and vitamin K reductase

Pharmacokinetic - Oral, rapidly absorbed with high (100%) bioavailability - 99% bound to plasma albumin (displaced by sulphonamides) - Crosses placenta to foetus - Actions terminated by metabolism in liver - Metabolites excreted in urine and stool - Warfarin (t ½ 36 h)

Indications -Prophylaxis and/or treatment of venous thrombosis and arterial embolism. -Prophylaxis and/or treatment of the thromboembolic complications associated with atrial fibrillation , cardiac valve replacement and dilated cardiomyopathy. To reduce the risk of death, recurrent myocardial infarction, and thromboembolic events such as stroke or systemic embolization after myocardial infarction. After vascular bypass grafting

Contraindications to warfarin therapy include - Bleeding disorders - Poor compliance - Alcoholism - Recent stroke (3 weeks) - Recent surgery to brain or eye - Active peptic ulcer, active inflammatory bowel disease, or oesophageal varices - Severe hypertension - Severe renal impairment - Pregnancy.

Warfarin Monitoring The level of anticoagulation is monitord by the INR. International Normalized Ratio (INR) —  a standardized test based on measurment of the prothrombin time. In most cases, an INR of 2 to 3 is therapeutic. How ever, the patient with mechanical heart valves need coagulation with goal INR of 2.5 to 3.5. ** Heparin is initiated first As soon as PTT is theraputic, initiate warfarin. Continue heparine for at lest 4 days after starting warfarin. Once INR is therapeutic on warfarin, we stop heparin

Dosage There is much inter-individual variation in dose requirements - initiate dose: 10 mg for 2 days in healthy individuals -we check INR after 2 days and adjust dose according to results. -Patient with risk factors requiring prophylactic anticoagulants can have warfarin introduced slowly using lower doses. -The duration of warfarin therapy depends on the clinical indication.

Adverse effects Bleeding: from GIT, renal tracts, and in brain Cardiovascular: hypotension, syncope, vasculitis. CNS: dizziness, fatigue, headache, lethargy. Hepatic: elevated liver enzymes, hepatitis, jaundice. hypersensitivity reactions, rash, Teratogenicity during pregnancy Skin : skin necrosis (rare but serious)

Next generation anticoagulants

In the last few years , The new oral anticoagulants are rapidly replacing warfarin for several indications . The new agents are direct anticoagulants that target a single clotting enzyme, either: factor Xa and thrombin -dirict factor Xa inhibitor: rivaroxaban, apixaban, edoxaban. -Dirict thrombin inhibitor: lepirudin, argatroban, dabigatran.

Dabigatran -direct thrombin inhibitor reversibly which inhibits: -Conversion of fibrinogen to fibrin -Activation of factors V, VIII, XI, and XIII -Thrombin-induced platelet aggregation Dose: 150 mg orally twice a day Dabigatran: avoid if creatinine clearance <15ml/min 25

- Rapid absorption - Metabolism: on liver; rapidly and completely hydrolyzed to active form by plasma and hepatic esterases - Excretion: Renal (80%) Half-life:14-17 hours Onset: 1-2 hour  Adverse effect : -Bleeding -Diarrhea; heartburn; mild stomach pain ; nausea, dyspepsia. -Severe allergic reactions -Anemia

Apixaban Half-life : 8 to 14 hours oral direct Xa inhibitor Dose: 5mg twice daily AVOID in creatinine Clearance <15 ml/min - Rapid absorption - Metabolism:15% liver metabolism - Excretion: Fecal (46-56%), Renal (27%) Half-life : 8 to 14 hours Onset: 3-4 hours SE : -Bleeding- -Anemia Nausea 27

New agent versus Warfarin 1- All new oral anticoagulants have same effect for prevention of stroke or systemic embolism and more effect than warfarin. 2- Dabigatran is less effective to prevention of myocardial infarction, More gastrointestinal bleeding than warfarin 3- approximately 10% reduction in mortality with the new oral anticoagulants compared with warfarin. 4- The cost of new drugs are more than wafarin . 5- Clinicians now discover antidote for over doses of new drugs which are Aripazine , Andexanet , Idarucizumab. 6- New drugs don’t need INR for monitoring .

References Davidson’s principles and practice of medicine. http://search.medscape.com/search/?q=warfarin clinical pharmacology made incredibly easy!_ 3rd edition uptodate.com>Patient information: Warfarin https://www.health.qld.gov.au/publications/clinica l-practice/guidelines- procedures/medicines/warfarin-guidelines.pdf

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