Pathophysiology and Pharmacology of Hemostasis 2023-2024 PDF

PATHOPHYSIOLOGY AND PHARMACOLOGY OF HEMOSTASIS Krystal Riccio, PharmD, BCACP, CDCE Professor of Pharmacy Practice Roseman University, College of Pharmacy  Learning Objectives: Part 1 1. Recognize the roles of the following in hemostasis: nitric oxide, prostacyclin, e...

PATHOPHYSIOLOGY AND PHARMACOLOGY OF HEMOSTASIS Krystal Riccio, PharmD, BCACP, CDCE Professor of Pharmacy Practice Roseman University, College of Pharmacy  Learning Objectives: Part 1 1. Recognize the roles of the following in hemostasis: nitric oxide, prostacyclin, endothelin, collagen, tissue factor, adenosine diphosphatase (ADPase), heparin, antithrombin III, thrombomodulin, thrombin, protein C, protein S, tissue plasminogen activator (tPA), plasminogen activator inhibitors (PAI), plasmin, thrombin activatable fibrinolysis inhibitor (TAFI), and alpha2-antiplasmin. 2. Explain the steps of platelet adhesion, activation, and aggregation by recognizing the roles of the following: von Willebrand’s factor (vWF), thrombin, ADP, thromboxane A2, serotonin, and fibrinogen. 3. Identify each of the glycoprotein receptors on the platelet and its function in platelet adhesion, activation, and aggregation.  Learning Objectives: Part 2 6. Recognize the advantage of using the international normalized ratio (INR) over a standard PT in monitoring anticoagulation therapy. 7. Given a particular drug therapy or genetic disorder, determine how bleeding time, clotting time, prothrombin time (PT), thrombin time (TT) and activated partial thromboplastin time (aPTT) will be affected. 8. List the common coagulation disorders and briefly describe the pathophysiology of each. 9. Identify the role of vitamin K in hemostasis. 10. Describe the specific mechanism of action, indication, major adverse effects, pharmacokinetics and important drug interactions (if any) for the medications presented. 11. Identify common interactions with warfarin and the expected changes in INR, clotting, or bleeding risk. 12. Classify the medications presented as: anticoagulant,  Introduction 4  Hemostasis  A balance of coagulation, anticoagulation, thrombotic, and fibrinolytic functions within the body  Maintaining blood flow, while maintaining the integrity of blood vessels fibrin thrombotic olyti c u latio anticoagu c oag lation n  Introduction 5  Process of hemostasis (at site of injury) 1. Vasoconstriction 2. Platelet adhesion, activation, & aggregation = plug 3. Clotting cascade activation = fibrin clot 4. Dissolution of clot, fibrinolysis  Imbalance within the process can result in excessive clotting or increased bleeding  Genetic and/or environmental factors can contribute to imbalance within hemostasis  Outline 6  Vessel Wall  Platelet Activity  Clotting Cascade  Fibrinolysis  Laboratory Values  Coagulation/Bleeding disorders  Medication Therapies  Anti-platelets  Anticoagulants  Fibrinolytics  Procoagulants  Summary 1. Vasoconstriction  Vessel Wall 8  Healthy vessel wall  Endothelial lining cells Nitric oxide (NO) Prostacyclin Adenosine diphosphatase (ADPase)  Injured vessel wall  Subendothelial matrix Endothelin Evgenov et al. Nature Reviews Drug Exposed collagen Discovery 5, 755–768 (September 2006) | von Willebrand factor (vWF) doi:10.1038/nrd2038 Fibrinogen Tissue factor 2. Platelet plug formation ADHESION, ACTIVATION, AGGREGATION  Platelets 10  Non-nucleated cell fragments created from megakaryocytes in bone marrow  normal blood platelet count  150,000 – 450,000 per microliter  Circulate throughout the body  lifespan about 7-10 days  Smooth surface until activated → exposed receptors  Platelets house granules, which contain substances that potentiate platelet activity and coagulation  Platelets 11  In response to vascular injury Adhesion Activation Aggregati (secretion on )  Platelets – Adhesion 12 Smith C, Marks AD, Lieberman M. Marks’ Basic Medical Biochemistry, 2nd Ed. Lippincott Williams & Wilkins, Baltimore, MD, 2005.  Platelets – Adhesion 13  Vascular injury exposes collagen and von Willebrand factor (vWF) 1. GPIa  collagen 2. GPIb  vWF  collagen 3. GPIIbIIIa  vWF  collagen or GPIIbIIIa  fibrinogen (aggregation)  Platelets – Activation 14  With the binding of these receptors, platelet receptors undergo conformational changes, which further exposes GPIIb-IIIa receptors  GPIIb-IIIa receptors are the most abundant receptors on platelets  The binding of GPIIb-IIIa to vWF and/or fibrinogen induces the platelets to secrete thromboxane A2, thereby causing degranulation and further expression of GPIIb-IIIa Adenosine diphosphate (ADP) Thromboxane A2 (TXA2) degranulation Von Willebrand factor Calcium Serotonin Platelet-derived growth factor (PDGF)  Recruitment of surrounding platelets  Platelet – Activation 15 aggregation  Platelet – Aggregation 16  Exposed GPIIb-IIIa receptors bind to vWF or fibrinogen  vWF binding increases adhesion and aggregation  Fibrinogen binding increases aggregation Integrationof the fibrin mesh (from the clotting cascade) within the platelet plug  Additional platelets are recruited from circulating blood to further enhance the rapid formation of the platelet plug  Platelet – Aggregation 17 atio gre g Ag n  Platelet – Aggregation 18 Platelet Platelet http://gripsdb.dimdi.de/rochelexikon/pics/THROMBOZYTENADHAESION$1.gif, Review: Platelet Plug Formation 19 t i a tiv ivat i Ac on Ac t gat on ggre A ion va ti Activation Acti on Adhesion 3. Fibrin clot formation CLOTTING CASCADE, FIBRIN CROSS- LINKING, INTEGRATION WITHIN PLATELET PLUG (SOLIDIFICATION)  Clotting Factors 21  The majority of clotting factors are manufactured in the liver, with the exception of  Factors V & VIII are produced by endothelial cells  Factor XIII is produced by platelets  In the event of severe liver disease or damage, clotting factor production may be affected  Genetic variations may also cause clotting factors to be less or more effective within the clotting cascade  Clotting Factor Formation Liver Factors I, II, VII, IX, X, XI, XII Protein C Protein S Platele ts Factor XIII Endothelial Lining Cells Factors V, VIII  Blood Coagulation Factors 23 Facto Common Name Half-life Grouping r (h) I/Ia Fibrinogen/Fibrin 100 – Thrombin- 150 sensative II/IIa Prothrombin/Thrombin 50 – 80 vitamin K- dependent III Tissue Factor 0.75 – 1 extrinsic V Proaccelerin (Labile factor) 12 – 36 Thrombin- sensative VII Proconvertin (Stable factor) 4–6 vitamin K- dependent VIII Antihemophilic factor A 12 – 15 Thrombin- sensative IX Antihemophilic factor B, 18 – 30 vitamin K- Christmas factor dependent X Stuart-Power factor 25 – 60 vitamin K-  The Clotting Cascade 24  Inactive clotting factors circulate throughout plasma as zymogens.  A cascading series of proteolytic reactions convert zymogens into active proteases.  These reactions are initiated by the exposure of negatively charged collagen (intrinsic pathway) or release of tissue factor from subendothelial matrix (extrinsic pathway) secondary to vascular injury.  Cell-Based Model 25 Clotting IntrinsicCascade Extrinsic Pathway Pathway Collagen Subendotheli Kallikrein Prekallikrein al Matrix XII XIIa Tissue Factor Exposure XI XIa (III) IX IXa + VII + vW VIIIa VIIa f II I- f X X Xa+Va V V W Xa v II I I I XIIIa X IIa 26 Fibrinogen Common Fibrin cross-linked Pathway Clotting IntrinsicCascade Extrinsic Pathway Pathway Collagen Subendotheli Kallikrein Prekallikrein al XII XIIa Matrix Tissue Factor Exposure XI XIa Ca + Ca + + + VII Ca++ IX + IXa VIIa +Ca + vW VIIIa + f Ca++ II I- f X +Va V V W v Xa II XIIIa X I I I IIa Fibrinogen Common Fibrin 27 cross-linked Pathway  Fibrin Mesh  Solid Clot 28  Fibrinogen (I) is converted to Fibrin (Ia) monomers by Thrombin (IIa).  Factor XIIIa (activated by IIa) catalyzes covalent cross- linking of fibrin to form insoluble fibrin polymers. soluble partially soluble XIIIa insoluble  Regulation 29  Potentiate clotting cascade  Thrombin  Xa  Inhibit clotting cascade  Thrombin  Thrombomodulin  Protein C  Protein S  SERine Protease INhibitorS (SERPINS) Antithrombin III  Lipoprotein-associated Coagulation Inhibitor (LACI)  Regulation 30  Positive Feedback Mechanisms  Thrombin, Low Concentrations allosteric activation of FV, FVII, FVIII, FXI, and FXIII  FXa feedback activates FVII 31  Regulation 32  Inhibition of the Clotting Cascade  Thrombin, High Concentrations Complexes with thrombomodulin, to activate Protein C Activated Protein C Protein S Ca++ Complexes (APC Complex) Inactivates FVa and FVIIIa  Antithrombin III Irreversibly binds FIIa, FIXa, FXa, FXIa, and FXIIa Endogenous heparans enhance binding  Lipoprotein-associated Coagulation Inhibitor (LACI) Binds to TF-FVIIa Complex  Inhibition 33 LACI Protein C + Protein S + Ca++ thrombomoduli n 4. Fibrinolysis DEGRADATION OF THE FIBRIN CLOT  Fibrinolysis 35  As clots are formed, fibrinolysis is triggered to maintain hemostasis  Once the injured vasculature has healed, fibrinolysis will remove the clot in order to restore normal blood flow  Plasminogen, a circulating zymogen, binds to fibrin with high affinity, which causes plasminogen to be incorporated within the fibrin clot.  Fibrinolysis 36  Plasminogen activators (tissue plasminogen activator, t-PA, and urokinase) are released in response to injury, venous stasis, or stress, but remain inactive until bound to fibrin.  t-PA release from endothelial cells is promoted by the APC Complex (activated when thrombin concentration is high)  Prourokinase is produced by epithelial cells and activated by plasmin or kallikrein  Fibrinolysis 37 1. Plasminogen is activated to plasmin, a serine protease, by plasminogen activators in the presence of fibrin 2. Plasmin cleaves fibrin polymers into fibrin degradation products (FDPs) 3. Plasmin is released from FDPs and inactivated by circulating α2-antiplasmin 4. Plasminogen Activator Inhibitors type 1 and 2 (PAI-1, PAI-2) block unbound tissue plasminogen activator (t-PA) and urokinase  Regulation – Fibrinolysis 38  Fibrinolysis Regulation 39  Thrombin-activatable fibrinolysis inhibitor (TAFI)  Activated by thrombin  Inhibits fibrinolysis during clot formation 40 41 Laboratory studies MEASURES OF COAGULATION  Utility of Laboratory Studies 43  Distinguish defects within the clotting cascade  intrinsic, extrinsic, and common pathways  Determine the quantity of functional platelets  Monitor medication therapies  PT (Prothrombin Time) 44  In Vitro Study: Detects the time required for fibrin strands to form following the addition of Ca++ and tissue thromboplastin (tissue factor) to the plasma.  Indicator of extrinsic & common pathways  VII, X, V, II, I  Varies from lab to lab, depending on reagent used  Normal: 12 – 15 seconds  Monitoring warfarin effects, screening for liver function  INR (International Normalized Ratio) 45  Standardized calculation using PT  Normalizes laboratory PT values based on reagent (tissue thromboplastin) used by lab  ISI = International Sensitivity Index  Normal: 0.8 – 1.2  ISI Monitoring for therapeutic warfarin effects  INR (International Normalized Ratio) 46 Blood from a single patient Patient Mean Thromboplastin PT Normal PTR ISI INR Reagent (Seconds) (Seconds) A 16 12 1.3 3.2 2.6 B 18 12 1.5 2.4 2.6 C 21 13 1.6 2.0 2.6 D 24 11 2.2 1.2 2.6 E 38 14.5 2.6 1.0 2.6  aPTT (activated Partial Thromboplastin Time) 47  In Vitro Study: Detects the time required for a fibrin clot to form following the addition of Ca++ and partial thromboplastin plus an activator (kaolin or silica)  Utilizing plasma  Indicator of the intrinsic and common pathways  I, II, V, VIII, IX, X, XI, XII, and prekallikrein  Normal: 24 – 38 seconds  Monitoring heparin effects  ACT (Activated Clotting Time) 48  In Vitro Study: Detects the time required for a fibrin clot to form following the addition of Ca++ and partial thromboplastin plus an activator (kaolin or silica)  Utilizing Whole blood  Indicator of the intrinsic and common pathways  I, II, V, VIII, IX, X, XI, XII, and prekallikrein  Normal: 70 – 180 seconds  By using whole blood, test to be performed at bedside or during surgery more quickly than aPTT  Monitoring bivalirudin effects  Thrombin Time (TT) 49  In Vitro Study: Detects the time required for fibrin strands to form when thrombin is added to a plasma sample  Indicator of the final steps in the common pathway  Delayed TT indicates hypofibrinogenemia  Normal: 15 seconds 50  Bleeding Time 51  In Vivo Study: Time to stop bleeding following a standardized cut/incision on the patient’s forearm.  Blood removed every 30 seconds with blotting paper until bleeding stops  Indicator of capillary and platelet function  Normal: 8 – 10 minutes  Highly subjective and rarely performed  Poor sensitivity and specificity 52 Coagulation disorders Thrombosis Excess Clot Formation  Virchow’s Triad 55  Coagulopathy  Primary: genetic disorders  Secondary: cancer, pregnancy, medications (OC/HRT)  Vascular Injury  Trauma, surgery, atherosclerosis  Impaired Blood Flow  Venous stasis  Turbulent blood flow  Thrombotic Risk Example 56 (vascular injury) hy ) at gu lop c oa imary (pr  Thrombosis 57  Fibrin rich clots  Platelets < fibrin  Erythrocytes trapped in extensive fibrin mesh  Platelet rich clots  Platelets > fibrin  Less erythrocytes trapped in fibrin mesh  Anticipated clot type often drives selection of drug therapy  Atherothrombosis – within arteries 58  http://medsurfer.com/2009/07/01/predicting-risk-of-heart-disease/ 59 Circulation 104:365, 2001  Coronary Atherothrombosis 60 A, Plaque rupture without superimposed thrombus. B, Acute coronary thrombosis superimposed on an atherosclerotic plaque with focal disruption of the fibrous cap, triggering fatal myocardial infarction. Schoen FJ: Interventional and Surgical Cardiovascular pathology: Clinical Correlations and Basic Principles. Philadelphia, WB Saunders, 1989, p 61.  Atherothrombosis 61  Coronary: angina or myocardial infarction  Cerebral: transient ischemic attacks or stroke  Peripheral: peripheral artery disease (PAD)  Venous Thromboembolism 62 (VTE)  Deep Vein Thrombosis (DVT)  Occurring in the deep veins of the upper or lower extremities  Unilateral pain, erythema, and edema  Possible gangrene or amputation  Can embolize and move into a pulmonary system  Pulmonary Embolism (PE)  Embolus from DVT lodging into pulmonary artery  Sudden onset dyspnea and chest pain  Possible death 63 http://img.medscape.com/pi/emed/ckb/emergency_medicine/756148-756734-759765- Bleeding disorders Congenital & Acquired  Congenital Bleeding 65 Disorders  Hemophilia A  Deficiency of clotting factor VIII  Approximately 1 in 5,000 live male births (40% spontaneous)  Hemophilia B  Deficiency of clotting factor IX  Approximately 1 in 30,000 live male births  von Willebrand Disease  Deficiency of vWF (quantitative or qualitative)  Factor VIII activity may also be affected  Most common inheritable bleeding disorder 0.1 % of the general population 70 – 80% partial quantitative deficiency  Acquired Bleeding Disorders 66  Disseminated Intravascular Coagulation (DIC)  May be the result of sepsis, trauma, obstetric complications (recent birth/abortion), burn, malignancies  Tissue Factor released into circulation  Uncontrolled thrombosis  Overactive thrombolysis  Diffuse bleeding, multiple organ dysfunction, multiple thrombi  Liver Disease  Deficiency in clotting factor production  Malnutrition  Vitamin K deficiency (chronic alcoholics, neonates) 67  68 PHARMACOLOG Y Antiplatelet medications Prevent Platelet Activation &/or Aggregation  Antiplatelet Medications 70  Anti-Thromboxane  Phosphodiesterase  Aspirin Inhibitors   ADP Receptor Dipyridamole Antagonist (Persantine®)   Ticlopidine (Ticlid®) Cilostazol  Clopidogrel (Plavix®) (Pletal®)  Prasugrel (Effient®)   Ticagrelor (Brilinta®) Combination  GPIIb/IIIa Antagonists Agent   Abciximab (ReoPro®) Dipyridamole  Eptifibatide ER/Aspirin (Integrilin®) (Aggrenox®)  Tirofiban (Aggrastat®)  Antiplatelet Agent Activities 71  Anti-Thromboxane Class 72  Aspirin (Ecotrin®- enteric coated)  Acetyl salicylic acid (ASA)  Mechanism of action (MOA) Irreversible cyclooxygenase (COX) inhibitor Selective for COX-1 at antiplatelet dosing (50- 325mg) Life of the platelet (7 – 10 days) Prevent thromboxane formation, reducing platelet activation Also inhibits PGI2 (preventing platelet adhesion & aggregation) at higher doses, therefore, lower antiplatelet dosing is recommended  Anti-Thromboxane Class – 73 Aspirin Phospholipids in Cell Membrane Phospholipa se Arachidonic Acid Lipoxygenas Cyclooxygena e se Leukotriene Prostaglandi Prostaglandins s ns & Thromboxane Aspirin  Anti-Thromboxane Class - 74 Aspirin  Indications  Atrial Fibrillation  Coronary Arterial Disease (CAD)  Acute Coronary Syndrome (ACS)  Cerebrovascular accident (CVA), TIA/Ischemic stroke  Antipyretic  Analgesic  Anti-inflammatory  Drug-induced flushing (niacin)  Drug Interactions (DIs)  Non-Steroidal Anti-Inflammatory Drugs  Anticoagulant & Anti-thrombotic Medications  ADP-Receptor Antagonists 75  Ticlopidine (Ticlid®)  Clopidogrel (Plavix®) Prasugrel  Prasugrel (Effient®) Ticagrelor  Ticagrelor (Brilinta®)  ADP-Receptor Antagonists 76  ADP Receptor Subtypes: P2Y1, P2Y12  ADP binding to P2Y1 results in conformational changes of GPIIb/IIIa to promote platelet aggregation  ADP binding to P2Y12 results in lower levels of cyclic AMP, thereby, promoting platelet activation  ADP-Receptor Antagonists 77  Blocking either purinergic receptor, P2Y 1 or P2Y12, will block activation and/or aggregation of platelets 12 Arterioscler Thromb Vasc Biol. 1999;19:2281-2285.  ADP-Receptor Antagonists Ticlopidine (Ticlid®) 78  Discontinued from US Market 2021  MOA  Irreversibly binds P2Y12 receptor, blocking platelet activation  ADME:  Prodrug: requires activation by CYP 3A4  Black Box Warning: neutropenia/agranulocytosis, thrombotic thrombocytopenic purpura (TTP) and aplastic anemia  ADP-Receptor Antagonists 79 Clopidogrel (Plavix®)  MOA  Irreversibly binds P2Y12 receptor, blocking platelet activation  ADME:  Prodrug: requires activation by CYP450 isoenzymes 2C19 major  Usual dose: 75mg orally once daily  Loading dose may or may not be given (300mg orally once)  ADP-Receptor Antagonists 80 Clopidogrel (Plavix®)  Indication  ACS/CAD  CVA/TIA/Ischemic stroke  Established peripheral arterial disease (PAD)  ADRs  Black Box Warning: Consider alternative treatment or treatment strategies in CYP2C19 poor metabolizers  Gastrointestinal discomfort  DIs  Anticoagulants & antiplatelets  Proton pump inhibitors (omeprazole, esomeprazole)  ADP-Receptor Antagonists 81 Clopidogrel (Plavix®)  Not shown to have clinically significant outcomes Clopidogrel CYP1A2 PPI Inhibition Esterase CYP2C19 CYP2B6 SR26334 (inactive) 2-Oxo-Clopidogrel CYP3A4 CYP2C9 PPI Inhibition CYP2C19 CYP2B6 R-130964 (active)  ADP-Receptor Antagonists 82 Prasugrel (Effient®)  MOA  Irreversibly binds P2Y12 receptor, blocking platelet activation  ADME:  Prodrug: requires activation by CYP450 isoenzymes 3A and 2B6  Food delays absorption, but no effect on AUC  Usual dose: 60mg orally once, then 10mg orally daily  Consider reducing dose to 5mg orally daily in < 60kg patient  Concurrent therapy with aspirin 75 – 325mg orally daily  ADP-Receptor Antagonists 83 Prasugrel (Effient®)  Indication  ACS  ADRs: Hypertension, arrhythmias, hyperlipidemia, leukopenia  Black Box Warning  Prasugrel can cause significant, sometimes fatal, bleeding in patients with active pathological bleeding or a propensity to bleed, a history of transient ischemic attack or stroke, a body weight of less than 60 kg, or concomitant use of medications that increase the risk of bleeding (eg, warfarin, heparin, fibrinolytics, chronic use of NSAIDs). Prasugrel is not recommended in patients 75 years of age and older, except for high-risk situations (diabetes, history of prior myocardial infarction). Do not start prasugrel in patients likely to undergo urgent CABG and discontinue at least 7 days prior to any surgery. If possible, manage bleeding without discontinuing prasugrel, as discontinuation in the first few weeks after acute coronary syndrome may increase risk for subsequent cardiovascular events.  ADP-Receptor Antagonists 84 Ticagrelor (Brilinta®)  MOA  Reversibly binds P2Y12 receptor, reducing platelet activation  ADME:  Active drug and active metabolite through CYP 3A4  Take with or without food  Usual dose: 180mg orally once, then 90mg orally daily  Concomitant aspirin dosing: Loading dose of 325mg, maintenance 75-100mg orally once daily  ADP-Receptor Antagonists 85 Ticagrelor (Brilinta®)  Indication  ACS, CAD, CVA: TIA/ischemic stroke  ADRs: Dyspnea, bradycardia, hyperuricemia  Black Box Warning  Bleeding Risk Ticagrelor, like other antiplatelet agents, can cause significant, sometimes fatal, bleeding. Do not use ticagrelor in patients with active pathological bleeding or a history of intracranial hemorrhage. Do not start ticagrelor in patients planned to undergo urgent coronary artery bypass graft surgery (CABG). When possible, discontinue ticagrelor at least 5 days prior to any surgery. Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, percutaneous coronary intervention (PCI), CABG, or other surgical procedures in the setting of ticagrelor. If possible, manage bleeding without discontinuing ticagrelor. Stopping ticagrelor increases the risk of subsequent cardiovascular events.  Aspirin Dose and Reduced Ticagrelor Effectiveness Maintenance doses of aspirin above 100 mg reduce the effectiveness of ticagrelor and should be avoided. After any initial dose, use with aspirin 75 to 100 mg daily  GPIIb/IIIa Antagonists 86  Glycoprotein αIIbβIIIa is a receptor on the platelet membrane, which binds vWF and fibrinogen  Platelet adhesion & aggregation  Blocking GPIIb/IIIa receptors, therefore, decreases platelet aggregation  Abciximab (Reopro®)  Eptifibatide (Integrilin®)  Tirofiban (Aggrastat®)  GPIIb/IIIa Antagonists 87 Abciximab (Reopro®)  Humanized monoclonal antibody Fab fragment that binds GPIIb/IIIa receptor  Indication: ACS (myocardial infarction [MI], unstable angina [UA], percutaneous coronary intervention [PCI])  ADRs: bleeding, hypotension, thrombocytopenia  Dosing: 0.25 mg/kg IV bolus (over 5 min), followed by 0.125 mcg/kg/min (maximum 10 mcg/min) IV infusion for ≥ 12 hours  GPIIb/IIIa Antagonists 88 Eptifibatide (Integrilin®)  Cyclic peptide that blocks GPIIb/IIIa fibrinogen binding site  Indication: ACS  ADRs: bleeding, hypotension, thrombocytopenia  Dosing: IV bolus 180 mcg/kg actual body weight (maximum 22.6 mg), followed by 2 mcg/kg/min (maximum 15 mg/hr) IV infusion for up to 72 hr  GPIIb/IIIa Antagonists 89 Tirofiban (Aggrastat®)  Non-peptide that blocks GPIIb/IIIa fibrinogen binding site  Indication: ACS (UA/NSTEMI)  ADRs: bleeding, thrombocytopenia, bradycardia  Dosing: 25 mcg/kg IV bolus, then 0.15 mcg/kg/min continuous IV infusion up to 18 hr  Phosphodiesterase Inhibitors Dipyridamole (Persantine®, Aggrenox®) 90  MOA 1. Block adenosine uptake by platelets  vasodilation 2. Decreasing phosphodiesterase activity within the platelet  increasing cAMP  decreasing platelet activation  Not recommended as monotherapy  Combination therapy for secondary stroke/TIA prevention Aggrenox® (dipyridamole ER 200mg/aspirin 25mg) one capsule orally twice daily  Adjunct to warfarin therapy for prophylaxis of thromboemboli in prosthetic heart valve patients Persantine® (dipyridamole) 75 – 100mg orally four times daily  Phosphodiesterase Inhibitors Cilostazol (Pletal®) 91  MOA: Decreasing phosphodiesterase activity within the platelet  increasing cAMP  decreasing platelet activation  Indication: Intermittent Claudication (PAD)  ADRs: Headache, Dizziness, Upper Respiratory Infections, Gastrointestinal Discomfort, Atrial Fibrillation  DIs: reduce dosing when used in along with diltiazem, ketoconazole, itraconazole, erythromycin, or omeprazole  Dosing: 100mg orally twice daily Anticoagulant medications Prevent Fibrin Formation Oppose the Clotting Cascade  Anticoagulant Medications 93  Drug Classes  Heparin Products UnfractionatedHeparin (UFH) Low Molecular Weight Heparin (LMWH)  Synthetic Pentasaccharide  Direct Anti-Factor Xa  Direct Thrombin Inhibitors  Vitamin K Antagonist  Heparin Products 94  Found in secretory granules of mast cells; commercially extracted from porcine intestinal mucosa or bovine lung  MOA: potentiate activity of antithrombin  Conformational change makes reactive site more accessible  Catalyzes thrombin-antithrombin reaction rate by ≥ 1000- fold  Measured in units not weight  USP unit = quantity of heparin that prevents 1ml of sheep plasma from clotting for 1 hr  heterogeneous commercial preparations maintain similar biological activity, although careful monitoring is still required  Heparin Products 95  Antithrombin has activity against multiple clotting factors: IIa, IXa, Xa, XIa, XIIa  Specific portions of heparin polysaccharide polymer are responsible for different mechanisms of heparin activity A particular pentasaccharide sequence is responsible for high affinity binding to antithrombin III; Another larger monomeric segment of the polymer is required to inhibit thrombin; Only the pentasaccharide sequence is necessary for anti-factor Xa activity  Heparin Products 96  Pentasaccharide component of heparin products responsible for binding antithrombin III (ATIII)  Heparin – UFH 97  Unfractionated Heparin (UFH)  Mean size 12,000 daltons or 40 monosaccharide units  Binds ATIII = Major activity against IIa and Xa  Indications  Treatment & Prophylaxis of VTE (DVT/PE)  Unstable angina  MI  During coronary angioplasty & stent placement  During cardiopulmonary bypass surgery  Atrial Fibrillation  Disseminated Intravascular Coagulation (DIC)  Heparin – UFH 98  Routes of Administration  IV Push, Continuous IV Infusion (CIVI), Subcutaneous  ADRs  Bleeding  Injection site reactions  Heparin-Induced Thrombocytopenia (HIT) 5 – 10 days after initiation of heparin (in heparin naïve patients) Platelet count < 150,000 or 50% drop from baseline IgG antibodies against heparin-platelet factor 4 complexes  thrombosis  Heparin – LMWH 99  Low Molecular Weight Heparin (LMWH)  Enoxaparin (Lovenox®) for subcutaneous administration  Dalteparin (Fragmin®) for subcutaneous administration  Mean size 4,500 daltons or 15 monosaccharide units  Binds ATIII = Major activity against Xa > IIa  Indications  Prophylaxis of DVT (post-surgical, immobility, cancer)  Unstable angina  MI  Heparin – LMWH 10 0  ADRs  Black Box Warning: Epidural or spinal hematomas, which may result in long-term or permanent paralysis, may occur in patients who are anticoagulated with low molecular weight heparins or heparinoids and are receiving neuraxial anesthesia or undergoing spinal puncture.  Local Hematoma  Bleeding  HIT (less common compared to UFH)  Heparin Product Reversal 10 1  Protamine  Mixture of basic polypeptides  MOA Binds heparin tightly, forming an inactive complex Partially effective with reversing LMWH  Dosing based on amount of UFH or LMWH to be reversed Lowest dose is recommended to prevent inherent anticoagulant activity of protamine About 1mg protamine : 100 units of heparin About 1mg protamine : 1mg enoxaparin Up to 50mg protamine IV over 10 minutes  Synthetic Pentasaccharide Fondaparinux (Arixtra®) 10 2  MOA: Designed to bind antithrombin III in such a way as to potentiate inactivation of factor Xa exclusively  Indication: VTE, Prophylaxis and Treatment  ADRs *HIT not reported  Black Box Warning: Epidural or spinal hematomas, which may result in long-term or permanent paralysis, may occur in patients who are anticoagulated with low molecular weight heparins, heparinoids, or fondaparinux sodium and are receiving neuraxial anesthesia or undergoing spinal puncture.  Injection site rash, fever, bleeding, anemia  Dosing: 2.5 – 10mg subcutaneous daily (weight-based dosing)  Comparison of Heparin Products & Synthetic Pentasaccharide Agents 10 3  A. Heparin binds to antithrombin via its pentasaccharide sequence. This induces a conformational change in the reactive center loop of antithrombin that accelerates its interaction with factor Xa. To potentiate thrombin inhibition, heparin must simultaneously bind to antithrombin and thrombin. Only heparin chains composed of at least 18 saccharide units or 5400 daltons, are of sufficient length to perform this bridging function. All of the heparin chains are long enough to do this. B. LMWH has greater capacity to potentiate factor Xa inhibition by antithrombin than thrombin because, with a mean molecular weight of 4500–5000, at least half of the LMWH chains are too short to bridge antithrombin to thrombin. C. The synthetic pentasaccharide only accelerates factor Xa inhibition by antithrombin because the pentasaccharide is too short to bridge antithrombin to 10 thrombin. 4  http://www.multivu.com/mnr/52349-janssen-xarelto- Anti-Factor Xa rivaroxaban Rivaroxaban (Xarelto®) 10 5  MOA: direct binding = factor Xa inhibitor  Indication/Dosing  Non-valvular Atrial Fibrillation 20mg orally once daily with the evening meal CrCl 15 to 50 mL/min, 1 mg daily with the evening meal  DVT/PE treatment or recurrent episode prophylaxis 15mg orally twice daily for 21 days, then 20mg orally once daily thereafter. Take with food. CrCl < 30 mL/min, avoid use  Prophylaxis of DVT following orthopedic surgery 10mg orally once daily with or without food Knee replacement = 12 days, hip replacement = 35 days CrCl < 30 mL/min, avoid use  Chronic Coronary or Peripheral Artery Disease (CAD or PAD)  Anti-Factor Xa Rivaroxaban (Xarelto®) 10 6  ADRs: bleeding, elevated liver enzymes, nausea, anemia  Black Box Warning: Discontinuing rivaroxaban in patients with nonvalvular atrial fibrillation increases risk of thrombotic events. If anticoagulation with rivaroxaban must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant. Spinal/epidural hematoma risk in patients also receiving neuraxial anesthesia or undergoing spinal puncture  http://www.cxvascular.com/ Anti-Factor Xa Apixaban (Eliquis®) 10 7  MOA: Direct factor Xa inhibitor  Indication/Dosing  Non-valvular Atrial Fibrillation 5mg orally twice daily 2.5mg orally twice daily If 2 OUT OF 3: Age ≥ 80years, weight ≤ 60kg, Scr ≥ 1.5mg/dL  DVT/PE treatment or recurrent episode prophylaxis 10mg orally twice daily for 7 days, then 5mg orally twice daily thereafter  Prophylaxis of DVT following orthopedic surgery 2.5mg orally twice daily Hip replacement surgery: 35 days Knee replacement surgery: 12 days  Anti-Factor Xa Apixaban (Eliquis®) 10 8  ADRs: bleeding  Black Box Warning: Discontinuing apixaban in patients with nonvalvular atrial fibrillation increases risk of thrombotic events. If anticoagulation with apixaban must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant. Spinal/epidural hematoma risk in patients also receiving neuraxial anesthesia or undergoing spinal puncture  Anti-Factor Xa Reversal 10 Agent 9  Rivaroxaban and apixaban ONLY  Andexanet alfa (Andexxa®) Low dose: 400mg IV bolus, then 4mg/min CIVI up to 120min High dose: 800mg IV bolus, then 8mg/min CIVI up to 120min  Anti-Factor Xa Edoxaban (SavaysaTM) 11 0  MOA: Direct Factor Xa inhibitor  Indication/Dosing  Non-valvular Atrial Fibrillation 60mg orally once daily CrCl > 95 ml/min: Do NOT Use CrCl 15 – 50 ml/min: 30mg once daily  Treatment of DVT and PE Following 5 – 10 days parenteral treatment 60mg orally once daily Adjusted dose based on renal clearance, body weight, and pgp-drug interactions; 30mg once daily  Anti-Factor Xa Edoxaban (SavaysaTM) 11 1  ADRs: bleeding, anemia, abnormal liver enzymes  Black Box Warning: Reduced efficacy in patients with CrCl > 95 ml/min. Discontinuing edoxaban in patients with nonvalvular atrial fibrillation increases risk of thrombotic events. If anticoagulation with edoxaban must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant. Spinal/epidural hematoma risk in patients also receiving neuraxial anesthesia or undergoing spinal puncture  Direct Thrombin Inhibitors 11 (DTI) 2  Bind directly to thrombin (factor IIa) to render it inactive  Derived from Hirudo medicinalis (natural anticoagulant found in leeches) http://www.abc.net.au/reslib/200704/  DTI Binding Comparison 11 3  DTI – Bivalirudin 11 (Angiomax®) 4  MOA  Synthetic polypeptide that binds directly to catalytic and substrate binding sites of free and clot-bound thrombin  Also exhibits some anti-platelet activity  Thrombin slowly cleaves this bond to regain activity  Rapid onset and rapid offset  Indication: percutaneous coronary angioplasty  ADRs  Hypotension, Nausea, Bleeding, Back Ache, Pain  Dosing: bolus IV dosing adjusted by ACT results during procedure; may be followed by CIVI for up to 20 hr  DTI – Argatroban 11 5  MOA: competitive, reversible inhibitor of thrombin binding directly to the catalytic site of both free and clot-associated thrombin  Indications: HIT positive patients needing immediate anticoagulation, PCI  ADRs  Bleeding, chest pain, GI discomfort, fever, pain  Dosage adjustment required in liver disease  Dosing: CIVI; adjusted based on aPTT  Bolus prior to CIVI for PCI  DTI – Dabigatran (Pradaxa®) 11 6  MOA: dabigatran and its active metabolites inhibit both free and clot-bound thrombin http://www.prweb.com/  Indication/Dosing  Non-valvular atrial fibrillation 150mg orally every 12hours CrCl 15-30mL/min, 75mg orally every12hours  VTE treatment & prevention of recurrent VTE Following 5-10 days of parenteral anticoagulation 150mg orally every 12 hours CrCl