Coagulation Physiology, Antithrombotics PDF

4/8/2024 COAGULATION PHYSIOLOGY, ANTICOAGULATION, ANTIPLATELETS AND ANTITHROMBOTICS Brent Gravelle, PhD, MD Appalachian College of Pharmacy Office Hours: 4-5pm, call or email or by appointment OBJECTIVES Physiology, Pathophysiology, Pharmacology, Therapeutics Overview hemostasis Describe parenteral...

4/8/2024 COAGULATION PHYSIOLOGY, ANTICOAGULATION, ANTIPLATELETS AND ANTITHROMBOTICS Brent Gravelle, PhD, MD Appalachian College of Pharmacy Office Hours: 4-5pm, call or email or by appointment OBJECTIVES Physiology, Pathophysiology, Pharmacology, Therapeutics Overview hemostasis Describe parenteral anticoagulants, their mechanism of action, pharmacokinetics, application and toxicity Describe oral anticoagulants, their mechanism of action, pharmacokinetics, clinical uses, and toxicity Describe antiplatelets, their mechanism of action, uses, and toxicity 1 4/8/2024 DEFINITIONS Normal Hemostasis: 1. The maintenance of blood in a fluid, clot-free state in normal vessels 2. Induction of a rapid and localized hemostatic plug at a site of vascular injury Thrombosis: pathologic opposite of hemostasis, an inappropriate activation of normal hemostatic processes, such as the formation of a clot (thrombus) in uninjured or minimally injured vasculature DEFINITIONS Coagulation: Conversion of fluid blood into a solid gel or clot Arterial thrombus: usually associated with atherosclerosis and causes ischemia in the downstream or watershed area Venous thrombus: in venous vasculature 2 4/8/2024 DEFINITIONS Embolism: distal occlusion formed by the fragmentation of a thrombus Types: Arterial: leading to stroke, ulceration, gangrene Venous: deep vein thrombosis (DVT), pulmonary embolism (PE) COAGULATION PRO- VS ANTITHROMBOTIC PROPERTIES 3 4/8/2024 Plasma Coagulation Factors ANTITHROMBOTIC PROPERTIES Antiplatelet effects: Endothelial Prostacyclin (PGI2) Nitric Oxide (NO) Adenosine diphosphatase (ADPase/CD39) which degrades ADP → ↓ platelet aggregation Membrane-associated heparin-like molecules which are cofactors which interact with antithrombin III to inactivate thrombin, factor IXa, Xa, XIa and XII 4 4/8/2024 Antithrombotic Properties ADPase/CD39 ANTITHROMBOTIC PROPERTIES (CONTINUED) Thrombomodulin - a thrombin receptor Binding of thrombin converts it to an anticoagulant capable of activating Protein C Protein C inhibits clotting by proteolytic cleavage of factors Va and VIIIa. Requires protein S as a cofactor “Tissue factor pathway inhibitor” inhibits factor VIIa – tissue factor(factor III) complex which prevents the activation of additional factors IX and X. Tissue-type plasminogen activator (t-PA)* 5 4/8/2024 Coagulation Pro- VS Antithrombotic Properties Protein S ase PROTHROMBOTIC PROPERTIES Platelet effects: endothelial injury leads to exposure of the ECM (subendothelial collagen) which platelets adhere to via GpIb & von Willebrand factor (vWF) or GpVI directly. Procoagulant effects: endothelial cells are induced by bacterial endotoxin or by cytokines (TNF or IL-1) to synthesize tissue factor (factor III) which activates the extrinsic clotting cascade. Endothelial cells also bind IXa & Xa. Antifibrinolytic effects: Endothelial cells secrete plasminogen activator inhibitors (PAI) 6 4/8/2024 Coagulation Pro- VS Antithrombotic Properties Protein S ase Thrombus Formation 7 4/8/2024 NORMAL HEMOSTASIS 8 4/8/2024 9 4/8/2024 PLATELET EVENTS Platelets adhere to ECM at sites of endothelial injury and become activated Activation causes secretion of granule products and exposure of phospholipid complexes that are important in the intrinsic coagulation pathway Released ADP stimulates the formation of a primary hemostatic plug by causing a conformational change on the platelet surface GpIIb-IIIa receptors so they can bind fibrinogen 10 4/8/2024 11 4/8/2024 PLATELET EVENTS (CONTINUED) Thromboxane A2 (TxA2) is an important platelet aggregator along with ADP and thrombin binding to platelet surface receptors (PARs=Protease – activated receptors) Platelet contraction – fused mass of platelets called secondary hemostatic plug Fibrin deposition stabilizes & anchors the aggregated platelets SECONDARY HEMOSTATIC PLUG 12 4/8/2024 QUESTION 1 What do the main platelet granules consist of? TXA2 ADP 5HT QUESTION 2 Which of the following are responsible for normal anticoagulation? Check all that apply A. ADP B. PGF2 C. TFPI D. Nitrous oxide E. PGI2 F. ADPase G. TXA2 H. Factor X I. Antithrombin III J. thrombomodulin 13 4/8/2024 QUESTION 3 Which factor do platelets adhere to? A. GPIIbIIIa B. Tissue factor C. GPIb D. VwF E. Factor IV F. GPVI 14 4/8/2024 TWO COAGULATION PATHWAYS Intrinsic Surface contact Extrinsic Tissue injury Tissue factor (III) or thromboplastin Plasma Coagulation Factors 15 4/8/2024 HMWK, KAL/PK Tissue factor (III) Coagulation Pathways Coagulation Pathways 16 4/8/2024 ANTICOAGULATION Natural anticoagulants: Antithrombin III Inhibits activation of thrombin (II) & serine proteases (IXa, Xa, XIa, XIIa) Activated by binding to heparin-like molecules on endothelial cells Protein C and Protein S Activated by thrombomodulin Inhibit factors Va and VIIIa Tissue factor pathway inhibitor (TFPI) Inhibits tissue factor (III)/VIIa which ↓IXa/Xa complexes 17 4/8/2024 ase FIBRINOLYTIC CASCADE Limits size of final clot Plasmin derived from plasminogen Activated by: factor XIIa/kallikrein, urokinase-like PA (u-PA) or tissuetype PA (t-PA) 18 4/8/2024 Fibrinolytic Cascade FIBRINOLYTIC CASCADE (CONTINUED) t-PA most active when attached to fibrin Forms fibrin split products or fibrin degradation products Measured clinically by D-dimer Free plasmin is inactivated by α2 antiplasmin 19 4/8/2024 FIBRINOLYTIC CASCADE Thrombin-activatable fibrinolysis inhibitor (TAFI) cleaves N-terminal lysine residues of fibrin—aids antiplasmin QUESTION What is the purpose of the clotting cascade? To make fibrin 20 4/8/2024 LOVE=HEMOSTASIS Everybody talks about it, nobody understands it. JH Levy 2000 VIRCHOW’S TRIAD 21 4/8/2024 HYPERCOAGULABILITY HYPERCOAGULABILITY Mutations in factor V gene 2-15% of Caucasians carry the Leiden mutation 1-2% of the population has a prothrombin mutation leading to elevated prothrombin levels – 3-fold increased risk of venous thrombosis Elevated homocysteine which inhibits antithrombin III or thrombomodulin 22 4/8/2024 Acquired Thrombosis Risk Factors 23 4/8/2024 24 4/8/2024 POTENTIAL OUTCOMES OF VENOUS THROMBOSIS PULMONARY EMBOLISM (PE) 25 4/8/2024 PULMONARY EMBOLISM DIAGNOSIS Doppler ultrasound, venography for DVT, D-Dimer Contrast enhanced Spiral CT, MRI for PE or other vascular abnormalities, ventilation/ perfusion scan, Oxygen saturation (PO2) MRA for brain PT/aPTT, TT, BT INR Platelet count, factor testing 26 4/8/2024 LABORATORY TESTS: ANTI-XA LEVEL For monitoring of UFH and LMWHs. Checked 6 hrs after intiation for UFH and 4 hrs for LMWHs. Therapeutic ranges of heparin are as follows: LMWH: 0.5-1.2 IU/mL [1, 2] UH: 0.3-0.7 IU/mL [3, 2] 1.Weitz JI. Antithrombotic Drugs. In: Hoffman F, Benz EJ, Shattil SJ, eds. Hematology: Basic Principles and Practice. 5th ed. Philadelpha, PA: Churchill Livingstone; 2009: Chapter 137. 2.Pagana KD, Pagana TJ, Pagana TN. Mosby's Diagnostic & Laboratory Test Reference. 14th ed. St. Louis, Mo: Elsevier; 2019. 3.Lehman CM, Frank EL. Laboratory Monitoring of Heparin Therapy: Partial Thromboplastin Time or Anti-Xa Assay? LabMedicine. 2009; Volume 40, Number 1. LABORATORY TESTS 27 4/8/2024 LABORATORY TESTS The PT is responsive to depression of three of the four Vitamin K-dependent factors (II,VII, X) 28 4/8/2024 NORMAL NUMBERS From the Washington Manual of Therapeutics 32st edition: aPTT = 24 to 34 seconds, ACCP 25-40 PT = 10.5 to 14.5 seconds, ACCP 10-13 INR =.78 to 1.22 or ACCP 0.9-1.1 TT = 11.3 to 18.5 sec Platelets = 140,000 to 440,000/µl, ACCP 150-350 Bleeding time = 2.5-9.5 minutes SEE HANDOUT 29 4/8/2024 PHARMACOLOGY OF ANTIPLATELET AGENTS AND ANTICOAGULANTS 30 4/8/2024 DRUGS Antiplatelets Anticoagulants Parenteral Oral ANTIPLATELET AGENTS Aspirin (Ecotrin®) Cangrelor (Kengreal) Prasugrel (Effient®) Clopidogrel (Plavix®) Ticagrelor (Brilinta®) Aspirin-dipyridamole (Aggrenox®) 31 4/8/2024 ASPIRIN (ASA, ECOTRIN®, DURLAZA-162.5 MG ER CAP) ASA=ACETYLSALICYLIC ACID Aspirin:ADME pKa = 3.5 pKa = 2.9  Aspirin is very rapidly absorbed from the gastrointestinal tract  Aspirin appears in the blood within 10 min and achieves a peak plasma concentration within 30–40 min  It is rapidly hydrolyzed in the body to salicylic acid (t1/2 = 3-6 h).  Salicyluric acid and salicyl phenolic glucuronide, are two major metabolic pathways 32 4/8/2024 Aspirin (ASA, Ecotrin®,Durlaza) ADVERSE EFFECTS 33 4/8/2024 ADVERSE EFFECTS Main concern is gastric upset & Gastric & duodenal ulcers as other adverse effects (ie.intracranial bleeding) are rare at antithrombotic doses! Aspirin inhibits PGE2 and PGF2α that protects stomach lining. PPIs and VitC may protect stomach Reye’s syndrome: hepatic injury & encephalopathy in children treated for influenza B… should not be given to children less than 12-16 yrs old. Tinnitis with higher doses 4-19% of asthmatics allergic ASPIRIN (ASA, ECOTRIN®, DURLAZA) Drug-drug interactions Increased bleeding with other antiplatelet drugs & Wafarin ACEI: might block effectiveness & may exacerbate hyperkalemia causing bradycardia leading to syncope… SSRI’s and corticosteroids: increased frequency & severity of GI problems Increase levels of lithium, sulfonlyureas and methotrexate Mg-Aluminum hydroxide antiacids can alkalize urine enough to increase salicylate clearance significantly Caution with other ototoxic drugs 34 4/8/2024 ASPIRIN (ASA, ECOTRIN®, DURLAZA) Platelets play important role in arterial thrombi formation: Stroke Transient ischemic attack (TIA) Coronary heart disease Angina pectoris Myocardial infarction (MI) Peripheral vascular disease Early atherosclerotic lesions ASPIRIN (ASA, ECOTRIN®, DURLAZA) Therapeutic Uses: Secondary prevention of coronary or cerebral vascular events, such as stroke and MI Primary prevention of vascular disease in individuals at risk of coronary events (10-year CHD risk > 6-10% based on Framingham risk scoring) Post MI, PCI, Coronary artery bypass grafting (CABG) chronic Afib/flutter, < 75 yo w/ no risk factors but > 55 if ♀ or 45 ♂ Adjuvant to thrombolytic therapy Prevention of thromboembolic complications in individuals with valvular heart disease or prosthetics 35 4/8/2024 Ann Intern Med. 2016;164(12):836-845. 36 4/8/2024 NEWEST ASA INFO C D 37 4/8/2024 MORE ASA INFO February 2024 by the Canadian Cardiovascular Society and Canadian Association of Interventional Cardiology (CCS/CAIC) in Canadian Journal of Cardiology. In the absence of atherosclerotic cardiovascular (CV) disease (ASCVD), the routine use of aspirin (ASA) is not recommended for primary prevention of ASCVD regardless of sex, age, or diabetes (strong recommendation). Question: A 20 yo varsity hockey player is referred to you by his coach. The young athlete has excessive bruising after a very physical match 2 days before where he got checked hard into the boards several times. His knee was bothering him, so he took two 325 mg aspirin tablets several hrs before the contest. As you ponder the etiology, you order several blood tests. Which test or finding do you most likely expect to be abnormal as a result of the prior aspirin use? A. APTT B. Bleeding time C. INR D. Platelet count E. PT 38 4/8/2024 ANTIPLATELET AGENTS: P2Y12 INHIBITORS Prasugrel (Effient®)* Clopidogrel (Plavix®)* Ticagrelor (Brilinta®) Cangrelor (Kengreal) *Thienopyridines P2Y12 INHIBITORS MOA: as a class they inhibit platelet aggregation by inhibiting the ADP pathway of platelets starting with P2Y1/P2Y12 receptor which reduces the inhibition of adenylate cyclase which ↑cAMP → ↓ platelet activation (32-1 G&G) 39 4/8/2024 CLOPIDOGREL (PLAVIX®) Pro drug that 15% is activated & inhibits ADP receptor Fewer side effects: less(TTP ), pts report fever, paleness, weakness, purple skin patches or jaundice Adverse effects: Black box warning from the FDA on March 12, 2010: estimated 2-14% of the US population that have low levels of the CYP 2C19 liver enzyme needed to activate clopidogrel & may not get the full effect. Tests are available to predict susceptiblity to this problem or not. Others? HA, chest pain, GI issues, dizziness, itching Peaks 3-7 days w/ 80% of plts inhibited at 5 hrs, last 5 days Metabolized in the liver but 50/50 kidney-liver excretion 40 4/8/2024 CLOPIDOGREL (PLAVIX®) Drug-drug interactions: Concurrent use of PPI’s (mainly omeprazole or esomeprazole) will decrease action on platelets by blocking conversion from prodrug to active metabolite! Others? Other anticoagulants, and CYP2C19 inhibitors such as cimetidine, fluconazole, ketoconazole, voriconazole, and SSRIs Atorvastatin(Lipitor), fish-oil, gingko Therapeutic uses: Approved for prevention of stroke, MI, death in patients with recent MI or stroke, established PAD or acute coronary syndrome(ACS) or prevention of thrombic events after TIA Main use is with ASA after angioplasty or MI For secondary prevention only if ASA allergy PRASUGREL (EFFIENT®) Pro drug that also inhibits the P2Y12 receptor but does it irreversibly prolonging effect after discontinuation! Quicker onset & more stable than others in class. Adverse effects: BBW: May cause significant, fatal bleeding, avoid in those w/cerebrovascular disease or > 75 yo. Caution in those 10%), ↑ Cr and Uric acid, bradyarrhythmias and decreased hepatic function. 100mg reduce effectiveness. Avoid use with strong CYP3A inhibitors and inducers…such as simvastatin and lovastatin in > 40 mg doses, monitor digoxin levels when initiating treatment or changing dose. Therapeutic uses: indicated for patients with ACS to reduce thrombotic events. BBW avoid use when CABG likely & stop 5 days before surgery BENTRACIMAB (TICAGRELOR REVERSAL AGENT) Experimental monoclonal antibody which binds free ticagrelor preventing it from binding to P2Y12 receptor. Currently in Phase 3 trials (REVERSE-IT) Ticagrelor Bentracimab 43 4/8/2024 CANGRELOR (KENGREAL) adenosine triphosphate analog that selectively and specifically blocks P2Y12 receptor-mediated platelet activation. Only IV P2Y12 receptor inhibitor Effects last for one hr after discontinuation Adjunct for PCI in patients who have not been treated with other P2Y12 inhibitors or GPIIbIIIa inhibitors Transition to ORAL P2Y12 inhibitor after PCI DIPYRIDAMOLE (PERSANTINE®) Vasodilator by inhibiting phosphodiesterase that breaks down cAMP, blocks adenosine reuptake It acts as a thromboxane synthase inhibitor, lowering the levels of TXA2 Mainly used for prevention of thrombotic complications of heart valve replacement in combination with warfarin or aspirin Main side effect is…? 44 4/8/2024 Phosphodiesterase Inhibitor: Dipyridamole Increase in cAMP: 1. Activation of Adenylate cyclase 2. Inhibition of phosphodiesterase (PDE)  Reuptake: DP block reuptake mechanism of Adenosine so that increased build-up adenosine can stimulate A2-receptors to increase the production of cAMP  Increased cAMP level facilitate the influx of free Ca2+ ion back into storage granules. Free Ca ions are needed for GPIIb, Thromboxane A2 activation and degranulation. 45 4/8/2024 ASPIRIN-DIPYRIDAMOLE (AGGRENOX®) For prevention of CVA after stroke/TIA 25mg ASA/200 mg Dipyridamole May be used for myocardial stress testing as an alternative to exercise-induced stress methods such as treadmills May cause chest pain if used for CAD Aminophylline may reverse effects of over dosage Do not crush or chew Don’t use if CrCl is less tha 10mL/min MORE ANTIPLATELETS: GP IIB/IIIA RECEPTOR ANTAGONISTS Abciximab (ReoPro), discontinued Aug15, 2019 Tirofiban (Aggrastat), Eptifibatide (Integrilin) MOA: Bind platelet glycoprotein receptor IIbIIIa (alphaIIbBeta3) which blocks binding of fibrinogen preventing aggregation. 46 4/8/2024 TABLE 30.4 2ND ED. G&G MANUAL OF P&T OR 32.4 13 ED PBT Because of their short half lives, they must be given by continuous infusion. 47 4/8/2024 ABCIXIMAB (REOPRO) Fab fragement of human monoclonal antibody the half life of unbound antibody is approx. 30 min Because the duration of action is long (18-24 hrs), if major bleeding occurs, platelet transfusion may reverse the aggregation defect because free antibody concentrations fall rapidly after cessation of infusion. Used for PCI and when used with heparin and ASA prevents restenosis, recurrent MI(ACS) or death. AE: Bleeding and thrombocytopenia CI:< 100,000 EPTIFIBATIDE (INTEGRILIN) Cyclic peptide Same indications as Abciximab, discontinue infusion prior to CABG Used with ASA and heparin Same side effects Platelet aggregation is restored within 4-6-8-12 hrs after cessation of infusion. 48 4/8/2024 TIROFIBAN (AGGRASTAT) Nonpeptide Used in conjunction with heparin Efficacy for non Q wave, Non STEMI and unstable angina Administered for 30 min before and 12-24 hrs after angioplasty or atherectomy Similar side effects QUESTION It is estimated that 2-14% of the US population that have low levels of which liver enzyme needed to activate clopidogrel? A. CYP 2C19 B. CYP 3A4 C. CYP 2C9 D. CYP 2Y12 49 4/8/2024 QUESTION Which of the following drugs is a IIbIIIa inhibitor? A. Dipyridamole B. Brilanta C. Clopidogrel D. Tirofiban E. Ecotrin SUMMARY 50 4/8/2024 ANTICOAGULANTS Unfractionated heparin (UFH) Low molecular weight heparins (LMWH) Vitamin K antagonist (Warfarin, Coumadin®) Direct Thrombin inhibitors (DTIs) Factor Xa inhibitors INDICATIONS FOR ANTICOAGULATION Venous thromboembolic disease Valvular heart disease Heart valve replacement Atrial fibrillation _______________________________________ Cerebral vascular disease Peripheral vascular disease Ischemic heart disease 51 4/8/2024 CONTRAINDICATIONS TO ANTICOAGULATION Risk of hemorrhage > benefits of therapy Hemorrhagic tendencies or blood dyscrasias Traumatic surgery with large open areas, recent or contemplated surgery of CNS or eye Active ulceration or overt bleeding Spinal puncture and procedures (epidural anesthesia) with potential for long-term complications (“black-box” warning LMWH) Inadequate laboratory facilities UNFRACTIONATED HEPARIN (UFH) Typically isolated from bovine lung or porcine intestinal mucosa. MOA: catalyzes the inactivation of thrombin (IIa), factor Xa and factor IXa by antithrombin III (also factors XIa, XIIa & plasmin & conversion of fibrinogen to fibrin) Not absorbed by GI mucosa, therefore given IV or SQ Monitor using aPTT or Anti X level q6hrs until therapeutic.(1.5-2.5 X control, 0.3-0.7 units/mL Peaks in 2-4 hrs, t1/2 90 min. Cleared by the reticuloendothelial or mononuclear phagocytic system (rapid phase) & a gradual renal phase which is best explained by a combination of saturable & nonsaturable first-order kinetic models 52 4/8/2024 Heparin: Molecular Mass Distribution Standard unfractioned Heparin is a heterogenous mixture of polysaccharide chains of varying length and mean molecular weight of 15,000 Da (3000-30,000) 53 4/8/2024 Unfractionated Heparin (UFH) UNFRACTIONATED HEPARIN (UFH) Adverse effects: Bleeding, monitor Hb & HCT, platelets Hypersensitivity: fever, chills, urticaria Hyperkalemia and/or osteoporosis with long term use Heparin-induced thrombocytopenia (HIT) – rare Bronchospasm, nausea, vomiting, and shock Type II (IgG-mediated) reaction Heparin antibody complexes bind to platelets causing aggregation and clots 54 4/8/2024 HEPARIN INDUCED THROMBOCYTOPENIA (HIT) Heparin Induced Thrombocytopenia (HIT) 55 4/8/2024 Unfractionated Heparin (UFH) Fatal errors can occur (esp in neonates) when Heparin injection@ 10,000 units/mL vs flushes @ 10 or 100 units/mL is given. Antidote: Protamine sulfate within 30 min of overdose 1 mg will reverse or neutralize 100 units of heparin Max dose 50 mg over 30 min. UNFRACTIONATED HEPARIN (UFH) Therapeutic uses: Surgery Hemodialysis DVT prophylaxis Venous thromboembolic disease Arterial thromboembolic disease Acute phase of unstable angina In stroke-in evolution Following MI Used in arterial embolism of end organs Was anticoagulant of choice in pregnancy as it does not cross placenta, can be reversed and could discontinued only 24 hrs before delivery 56 4/8/2024 LOW MOLECULAR WEIGHT HEPARINS (LMWH) Fragments of UFH which are approximately 1/3 the molecular weight of UFH (mean 40005000 Da) range 1000-10,000 Da) Weights differ resulting in differences in their activity against Xa, thrombin, affinity for plasma proteins, propensity to release TFPI and duration of activity LOW MOLECULAR WEIGHT HEPARINS (LMWH) Enoxaparin (Lovenox®) Dalteparin (Fragmin®) Tinzaparin (Innohep®) not available in U.S. Stored at room temperture 57 4/8/2024 Factor Xa antithrombin LOW MOLECULAR WEIGHT HEPARINS (LMWH) MOA: binds to antithrombin III and enhances its ability to inactivate factor IIa (Thrombin) and Xa (XIa,XIIa) Bind less avidly to heparin binding proteins than heparin, ↑ bioavailability and makes a more predictable anticoagulation effect Do not bind to endothelial cells which could account for longer plasma half-lives and dose-independent clearance Principally renal route of clearance Monitor Hb, platelets and FOBT (Guiac) 58 4/8/2024 LOW MOLECULAR WEIGHT HEPARINS (LMWH) Advantages over UFH: 1. Predictable anticoagulation dose response 2. Improved subcutaneous bioavailability 3. Dose-independent clearance 4. Longer biologic half-life 5. Lower incidence of thrombocytopenia 6. Reduced need for routine lab monitoring 7. Lower risk of osteoporosis LOW MOLECULAR WEIGHT HEPARINS (LMWH) Contraindications: Pork allergy Previous HIT Active or major bleed Sulfite allergy (tinzaparin) Caution with morbid obese, underweight, or in renal/liver failure Black box warning: pts receiving neuraxial anesthesia (spinal epidural) or spinal puncture are at risk for hematoma and paralysis Partially reversed with protamine 59 4/8/2024 LOW MOLECULAR WEIGHT HEPARINS (LMWH) Therapeutic uses: DVT prophylaxis in acute medical illness with restricted mobility, abdominal surgery, hip replacement Treatment of DVT or PE in cancer Unstable angina or non-Q-wave MI Unapproved therapeutic anticoagulation for DVT in pregnancy. “Now Drug of Choice in Pregnancy” FROM PHARMACOPOEIA 60 4/8/2024 WARFARIN (COUMADIN®) Jantoven 61 4/8/2024 WARFARIN (COUMADIN®) Generic agents: Various manufacturers Bioavailability differences between products? Conflicting data http://www.coumadin.com/html/atpharmacy.htm 62 4/8/2024 A: WARFARIN: PHARMACOKINETICS Oral bioavailability > 90% D: High plasma protein binding Albumin M: Predominantly hepatic R-warfarin: CYP1A2, CYP3A4 S-warfarin: CYP2C9, CYP2C19 E: Mainly renal http://www.perkinelmer.com/catalog/category/id/adme%20pk Pharmacotherapy, 2014. 63 4/8/2024 WARFARIN: PHARMACOKINETICS Factor Onset: VII t50 (hours) 4-6 Protein C 8 IX 24 Protein S 30 Depletion of circulating factors X 36-48 Decreased production of active factors II 50-72 Depends on t50 of vitamin K clotting factors Generally occurs within 24 hours of first dose Steady state: May take 3-5 days Duration: Single dose: 2-5 days MECHANISM OF ACTION 64 4/8/2024 INTERFERING WITH THE CYCLIC INTERCONVERSION OF VIT K & ITS 2,3 EPOXIDE (VIT K EPOXIDE) → DEPLETION OF VITAMIN KH2 RESULTS IN THE PRODUCTION OF HEMOSTATICALLY DEFECTIVE VIT K DEPENDENT FACTORS WARFARIN: PHARMACOGENOMICS Vitamin K epoxide reductase complex 1 (VKORC1): Variety of mutations Decreased doses required in individuals with variant alleles Higher doses required in individuals with mutation causing warfarin resistance Mutations cause warfarin resistance Haplotype A associated with smaller doses (Asian) Haplotype B or NonA associated with larger doses (white, African American) Pharmacotherapy, 2014. 65 4/8/2024 WARFARIN: PHARMACOGENOMICS Cytochrome P450 2C9 (CYP2C9) > 12 polymorphisms Two most common alleles (*2 and *3) decreased the clearance of S-warfarin 14 – 49% Associated with increased bleed risk Require significantly lower warfarin doses Warfarin: Pharmacogenomics 66 4/8/2024 Warfarin: Drug-Food Interactions Warfarin: Drug-Drug Interactions Carbamazepine Cholestyramine cephalosporins w/ NMTTside chain 67 4/8/2024 THERAPEUTIC INR WARFARIN: CONTRAINDICATIONS Risk of hemorrhage is greater than benefits of therapy Pregnancy Hemorrhagic tendencies or blood dyscrasias Traumatic surgery with large open areas, recent or contemplated surgery of CNS or eye Bleeding tendencies with active ulceration or overt bleeding(1) gastro-intestinal, genitourinary or respiratory tracts; (2) cerebrovascular hemorrhage; (3) aneurysms-cerebral, dissecting aorta; (4) pericarditis and pericardial effusions; or bacterial endocarditis 68 4/8/2024 Warfarin: Contraindications Senility, alcoholism, psychosis or other lack of patient cooperation Spinal puncture and procedures with potential for uncontrollable bleeding Inadequate laboratory facilities Threatened abortion, eclampsia and preeclampsia Miscellaneous: major regional, lumbar block anesthesia, malignant hypertension and known hypersensitivity to warfarin or to any other components of this product WARFARIN: ADVERSE EFFECTS Fatal or non-fatal hemorrhage from any tissue or organ Necrosis of skin and other tissues Thrombosis within subcutaneous fat Deficiency of protein C or S Other adverse reactions reported less frequently include: Systemic cholesterol microembolization Alopecia Purple toe syndrome, urticaria, dermatitis including bullous eruptions GI intolerance 69 4/8/2024 70 4/8/2024 WARFARIN: THERAPEUTIC USES Prophylaxis and/or treatment of: Venous thrombosis and its extension Pulmonary embolism Thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement Reduce risk of death, recurrent MI, and thromboembolic events such as stroke or systemic embolization after MI 71 4/8/2024 WARFARIN REVERSAL Vitamin K (Mephyton) PO or IV only, Risk of Anaphylaxis Four Factor Prothrombin Complex Concentrate (Kcentra) IV of factors II, VII, IX, X, Protein C, Protein S, administer with vitamin K. Three Factor Prothrombin Complex Concentrate (Bebulin or Profilnine) IV of Factors II, IX and X. Given with FFP or Factor VIIa and vitamin K. Factor VIIa Recombinant (NovoSeven RT) DIRECT THROMBIN (FACTOR IIA) INHIBITORS (DTIS) Bivalirudin (Angiomax®) - injectable Argatroban (Novastan®) - injectable Desirudin (Iprivask®) discontinued 2019 Dabigatran (Pradaxa®) – oral 72 4/8/2024 BIVALIRUDIN (ANGIOMAX®) t1/2 is only 25 min! Bolus injection after reconstitution and dilution…weight based 0.75 mg /kg then infusion at 1.75 mg/kg/hr Monitor aPTT and ACT, platelets, H & H For CrCl 4 on combined therapy Adverse effects: Hypotension Fever Diarrhea Therapeutic uses: DOC for prophylaxis or treatment of thrombosis in HIT For prophylaxis during PCI. Target ACT is 300 - 450 sec. or monitor aPTT 1.5-3Xs normal or 50mL/min or 3-5 days if < 50 mL/min. Dabigatran will come down to low level in 12h with normal functioning kidney. Till then, diuresis to remove drug quickly Activated charcoal to adsorb the lipophilic drug Hemodialysis But alas, now there is an antidote… PRAXBIND (IDARUCIZUMAB) FDA approved in October, 2015 For reversal of Pradaxa Half life of 47 min Complete anticoagulation reversal in 4 hrs Intravenously administer the dose of 5 g (2 vials, each contains 2.5 g—figure 1) as Two consecutive infusions (figure 2) or Bolus injection by injecting both vials consecutively one after another via syringe (figure 3) 77 4/8/2024 PRAXBIND ADMINISTRATION ADVERSE REACTIONS Headache Thromboembolic Risk Hypersensitivity Risks of Serious Adverse Reactions in Patients with Hereditary Fructose Intolerance due to Sorbitol Excipient hypokalemia (9/123, 7%), delirium (9/123, 7%), constipation (8/123, 7%), pyrexia (7/123, 6%), pneumonia (7/123, 6%). 78 4/8/2024 THROMBIN RECEPTOR OR PAR-1 INHIBITOR Vorapaxar (Zontivity) May 2014 A competitive antagonist of PAR-1 which inhibits thrombin (factor IIa) induced platelet aggregation rapid onset of action and a circulating half-life of 3 or 4 days. Effect on receptor can persist for up to 4 weeks after the drug is stopped. for the reduction of thrombotic cardiovascular events in patients with a history of MI or peripheral artery disease CI in pts with hx of intracranial bleeds, stroke or TIAs Potent CYP3A4 inducers, such as rifampin, reduce drug exposure, while strong CYP3A4 inhibitors, such as ketoconazole, increase drug exposure. Antacids and pantoprazole reduce drug exposure. 79 4/8/2024 FACTOR XA INHIBITORS Rivaroxaban (Xarelto®) Apixaban (Eliquis®) Edoxaban (Savaysa®) Betrixaban (Bevyxxa) 80 4/8/2024 Rivaroxaban (Xarelto)  XARELTO® is a prescription medicine used to reduce the risk of stroke and blood clots in people with atrial fibrillation  XARELTO® is also a prescription medicine used to treat deep vein thrombosis and pulmonary embolism, and to help reduce the risk of these conditions occurring again.  XARELTO® is also a prescription medicine used to reduce the risk of forming a blood clot in the legs and lungs of people who have just had knee or hip replacement surgery.  t1/2 = 7-11 hr, Cmax = 2-4 hr, Bioavailability is dose and food dependent (for 10 mg dose: 80-100% without regard to food but doses> 15 mg- must take with food.), 30% drug is eliminated intact in urine, 70% metabolized drug is excreted in urine and feces. RIVAROXABAN (XARELTO®) Oral direct factor Xa inhibitor Substrate of CYP3A4/5 or P-gp system Does not require blood tests, nor does it require a special diet or limiting alcohol. Requires renal adjustment, don’t use when CrCl< 30 ml/min for DVT prophylaxis, 15 mg must be taken with food. If missed dose: if 15 mg taken bid then take immediately. Take other dose as scheduled. If taking 10,15 or 20 mg once daily; take immediately on same day, if next day already then skip dose. APIXABAN (ELIQUIS®) Approved December 28, 2012 Oral direct factor Xa inhibitor Requires dose reduction if any 2 of the following: >80 yo, 1.5 Avoid 24 to 48 hrs before surgery Adverse effects: Bleeding Therapeutic uses Postoperative DVT prophylaxis Stroke prevention in nonvalvular atrial fibrillation VTE and PE prophylaxis and treatment 83 4/8/2024 Apixaban (Eliquis)  reduce the risk of stroke and blood clots in people with atrial fibrillation  reduce the risk of forming a blood clot in the legs and lungs of people who have just had knee or hip replacement surgery.  t1/2 = 12 hr, Cmax = 3-4 hr, BioAvai 50%, protein binding 87%, 25% metabolized rest excreted unchanged, excretion: renal (27%) biliary (73%),  Substrate for CYP3A4 and P-gp: Strong dual inhibitors increase blood levels of apixaban, while inducer will reduce the blood level. Eg. ketoconazole, itraconazole, ritonavir, clarithromycin  Caution with, other blood thinner, Aspirin, NSAID, warfarin, Heparin, Clopidogrel NOW HAS AN ANTIDOTE: Andexxa Disnontinue 48 hrs before elective surgery EDOXABAN (SAVAYSA®) Approved Jan, 2015 Oral direct factor Xa inhibitor Adverse Effects: bleeding, increased incidence of vaginal bleeding vs warfarin May have higher incidence abnormal LFTs(7.8%), rash or anemia 84 4/8/2024 EDOXABAN (SAVAYSA®) Therapeutics uses: treatment of DVT or PE after 5-10 days of parenteral treatment. Reduce incidence of stroke in nonvalular atrial fibrillation (NVAF) pts who have CrCl < 95ml/min. BBW: Do not use when CrCl >95 ml/min because of increased chance of stroke compared to warfarin. Drug-drug interactions: other anticoagulants and Rifampin. May increase Cmax for P-gp inhibitors such as quinidine, verapamil, amiodarone, ketoconazole, erythromycin and cyclosporine (reduce dose!) Antidote: Andexxa (off lable) yes yes Calvin H. Yeh “Oral Direct Factor Xa Inhibitors” circulation research, Circ Res. 2012;111:1069-1078 85 4/8/2024 BETRIXABAN (BEVYXXA) New June 23, 2017 For DVT prophylaxis in adults hospitalized for acute medical illness only…not nonvalvular afib!! Similar side effects (18%) to enoxaparin 17% with a bleeding incidence of 2.4% vs 1.2%. Though pkg insert lists it at >5% Reduce dose with renal impairment , avoid with liver impairment Recommended duration of 35-42 days with an effective half life of 19-27 hrs! FACTOR XA INHIBITOR ANTIDOTE Andexanet alfa (Andexxa) (approved May, 2018) (coagulation factor Xa (recombinant), inactivated-zhzo) Lyophilized Powder for Solution and Intravenous Injection Must be reconstituted w/ NS and infused w/ in line filter indicated for patients treated with rivaroxaban, apixaban, and edoxaban (and probably Betrixaban) when reversal of anticoagulation is needed The most common adverse reactions (≥ 5%) in patients receiving ANDEXXA were urinary tract infections and pneumonia and > 3% infusion related disorders. 86 4/8/2024 FON DAP A RIN UX (ARIXTRA®) MOA: selective, indirect factor Xa Inhibitor via AT III No direct effect on thrombin activity Administered subcutaneously! NOT intramuscularly Bioavailability: 100% Peak plasma concentration in ~2 – 3 hours Not metabolized, active form appears in urine Renal elimination Half-life: 15 – 18 hours Anticoagulant effect lasts ~2 – 4 days Monitor platelets, H&H daily Protamine is ineffective as an antidote Fondaparinux  A synthetic, highly sulfonated pentasaccharide.  Its composition will not change, which results in improved pharmacokinetics and a more selective anticoagulant action  It is the first selective factor Xa inhibitor. 87 4/8/2024 FONDAPARINUX (ARIXTRA®) Contraindications: BBW—spinal anesthesia Renal impairment CrCl < 30 ml/min Weight < 50 kg when used for prophylaxis Active major bleeding (spinal/epidural hematoma) Bacterial endocarditis Thrombocytopenia Monitor antiXa levels 3 hrs post dose FONDAPARINUX (ARIXTRA®) Therapeutic uses: comes in (2.5,5,7.5,10 mg prefilled syringes) do not expel air bubble before injection. Thromboprophylaxis after: Hip fracture surgery, Hip or knee replacement surgery, Abdominal surgery Treatment of acute DVT or PE Off Label use: Unstable angina or MI & HIT 88 4/8/2024 SWITCHING FROM WARFARIN TO NOAC For factor Xa inhibitors, STOP warfarin and add: Rivaroxaban when INR < 3 Edoxaban when INR < 2.5 Apixaban when INR