Anticoagulant Antiplatelet and Thrombolytic Drugs A few terms

Anticoagulant, Antiplatelet, and Thrombolytic Drugs

A few terms to know… Ø Coagulation- the physiologic process by which the blood clots to form solid masses, or clots. (Over 30 types of cells and substances in blood affect clotting. ) Ø A blood clot is a thick mass of coagulated blood, platelets and other materials stuck together Ø A thrombus (pl, thrombi) is an intravascular clot. (A thrombus can break into smaller pieces, dislodge from the location where it was initially formed. ) Ø An embolus is a blood clot, piece/globule of fatty deposit, or other object that is carried through the bloodstream. Ø An embolism refers to the obstruction of a blood vessel by a foreign substance or a blood clot that travels through the bloodstream, lodges in a smaller blood vessel, and plugs it. Ø Substances that can cause embolisms include: blood clots; piece/ globule of fatty deposit; clumps of bacteria, ‘vegetation’ or ‘debris’ on a heart valve; amniotic fluid; air bubble, chemicals and drugs (mainly illegal ones). Ø Blood clots are the most common cause of embolisms.

Formation of intravascular clots ► Protective when injury to blood vessel would lead to hemorrhage and blood loss ● Insults to blood vessels occur in normal physiology ► Problematic, dangerous and even life-threatening, for example: ● Certain hypercoaguable states ‒ Genetic; iatrogenic; diseases such as leukemia ● Prosthetics ‒ artificial heart valves ● Impaired mobility ‒ Post-operative bed-rest; long airplane flights ● Emergency situations ‒ Ischemic stroke; myocardial infarction; massive pulmonary embolus ● Other ►Therefore, drugs are commonly used to reduce risk of clot, or to treat a clot that has formed

Physiology and Pathophysiology of Coagulation ● Thrombosis‒ may result in severe consequences, due to reduction or cessation of blood flow to a tissue by the thrombus itself, or by rupture and release of thrombi ● Arterial thrombosis • Platelet adhesion (often ruptured atherosclerotic plaque) • Release of ADP & TXA 2 • Causes decreased/ absent perfusion distally -medical emergency • Depending on source of embolus, the clot may embolise to lower extremities, brain, heart, kidney, spleen, bowel ● Venous thrombosis • Stagnation of blood in lower extremities – Fibrin formation • Typically embolise to right side of heart then lungs (safety net) • Paradoxical emboli (cross from venous circulation through a septal defect between the right and left sides of the heart, thereby entering the arterial circulation)

Complications of intravascular clots: short and long-term Arterial vs venous clots

Ischemic cerebrovascular accident (CVA, stroke, “brain attack”) and Myocardial Infarct (MI, “heart attack”) are two of the most feared events

Ex: Arterial blockage in lower extremities

Ex: Venous blockage in lower extremities

Ex: Venous blockage in lower extremities

Lower extremity DVT can embolise to the lungs

Animations of hemostasis (blood coagulation cascade) Hemostasis, Coagulation and Fibrinolysis https: //www. youtube. com/watch? v=9 QVTHDM 90 io The Coagulation Cascade http: //www. allaboutbleeding. com/includes/videos/Coag. Cascade. mp 4

Clot formation begins with tissue injury, which then activates platelets. When activated, platelets induce fibrin strand formation from platelet to platelet, thereby forming a fibrin mesh (clot) Figure 52 -1 B Mechanism of platelet aggregation and actions of antiplatelet drugs.

Physiology of clot formation: • Stage One of Hemostasis: Formation of a “platelet plug” – Injury: Endothelial cells that line the blood vessel wall, and the sub-endothelial tissues, get injured » Components in the blood (eg platelets, clotting factors) are exposed to molecules from the injured endothelial cells and sub-endothelial tissues (eg tissue factor, collagen) » Note: Clotting factors, platelets and other molecules are inactive under normal conditions, but become activated sequentially – Platelets adhere to damaged tissue, become activated, amplify the clotting cascade, and aggregate at the site of injury – Vasoconstriction triggered by Injury to the blood vessel wall: smooth muscles in blood vessel wall immediately vasoconstrict the vessel, which reduces blood loss from the ruptured vessel

Physiology of clot formation, cont’d: • Stage Two of Hemostasis: Coagulation leads to fibrin formation via ‒ Intrinsic pathway (aka contact activation pathway, turned on by contact with sub-endothelial collagen) ‒ Extrinsic pathway (aka tissue factor pathway, turned on by release of tissue factor from damaged cells) ‒ The intrinsic and extrinsic pathways have the common step of activating Factor X: this begins the “common pathway”. o Activation of factor X o Conversion of prothrombin to thrombin o Production of fibrin o Then, later, clot contraction • Hemostasis is kept under control by ANTITHROMBIN • Physiologic dissolution of clots (fibrinolysis) after tissue repair. • Release of Tissue Plasminogen Activator (t-PA) converts plasminogen to PLASMIN

INJURY Exposed collagen Damaged tissue Thrombolytics Lehne, Figure 52 -2, page 596

Drugs used to treat Thromboembolic Disorders Three major classifications of drugs: • Anticoagulants: − Suppress the coagulation cascade − Heparin, warfarin • Antiplatelets: − Inhibit platelet aggregation − Aspirin, clopidogrel • Thrombolytics: − Promote lysis of fibrin strands, causing dissolution of thrombi − tissue plasminogen activator ie t-PA (alteplase) 19

N A L U G A O N A C I T : S T • Reduce the formation of fibrin • Two mechanisms of action • Inhibit the synthesis of clotting factors • Inhibit the activity of clotting factors

HEPARIN AND HEPARIN DERIVATIVES

Heparin (unfractionated, UFH) • Heparin (unfractionated) is not a single molecule, but a mixture of long polysaccharide chains, with molecular weights that vary from 3000 to 30, 000 (units? k. D? ) – Active region is a unique penta-saccharide (five carbon sugar) – used for decades for prevention & treatment of thrombosis – Highly polar, cannot readily cross membranes – Mechanism: suppresses coagulation by helping antithrombin to inactivate clotting factors, primarily thrombin (factor II) & factor Xa, and thereby suppresses formation of fibrin • Particularly effective for prophylaxis of venous thromboses – BUT: variable anticoagulant effects, pharmacological properties, limited bioavailability, and highly variable anticoagulant response – Very rapid-acting anticoagulant (onset within minutes of IV administration) – Half-life only 1. 5 hours, unless hepatic or renal disease – Hepatic metabolism, renal excretion 23

Heparin (Unfractionated, UFH) • Therapeutic uses – Preferred anticoagulant during pregnancy and when rapid anticoagulation is required • Does not enter breast milk – Pulmonary embolism (PE) – Ischemic stroke, evolving (t-PA may be preferred if given within 2 hours of symptoms) – Massive deep vein thrombosis (DVT) – For anticoagulation during extracorporeal procedures when blood flows through machine • Open heart surgery • Renal dialysis – Low-dose therapy postoperatively (DVT prophy) – Disseminated intravascular coagulation (DIC) – Adjunct to thrombolytic therapy (eg MI) 24

Heparin (Unfractionated, UFH) • Intensive lab monitoring required – Activated partial thromboplastin time (a. PTT) (p 601) – Follow protocol • Draw blood Q 4 -6 hours for continuous infusion. • Adjust dose based on lab results • During short-term, low-dose prophylactic tx, labs aren’t usually required • Units, Route & preparations • Dosed in units • Administered only by IV or subcut • IV- – Most commonly, a bolus dose (based on weight) is administered, followed by continuous infusion (based on weight. Lab is checked after 4 – 6 hours to titrate infusion rate up or down. – Or intermittent infusion (not common) • Deep subcutaneous (sub. Q) (BID or TID) • Several formulations and concentrations available – Dilute vs concentrated; single dose vs multi-dose vials – Read labels carefully. – Check IV bag and infusion pump carefully. • Antidote for overdose: Protamine sulfate

Heparin (Unfractionated, UFH) • Adverse effects- reduce risk of bleeding by screening pts for risk factors, monitor closely and avoid antiplatelet drugs – Hemorrhage – Heparin-induced thrombocytopenia (HIT) • antibodies form against heparin-platelet protein complexes • Increases thrombotic events • Uses up all the platelets (↓platelet level) • Is an absolute contraindication to giving heparin again – Hypersensitivity reactions commercial preparations derived from animal sources • Contraindicated – Thrombocytopenia – Uncontrollable bleeding – During and immediately after surgery of the eye, brain, or spinal cord

Nursing Implications r/t Monitoring for, and Teaching, S/S of Bleeding • • ↓BP, ↑Heart Rate Headache, faintness Petechiae, bruises, hematoma Red or black stools Cloudy or discolored urine Pelvic pain (possible ovarian hemorrhage) Lumbar pain (possible adrenal hemorrhage) 27

Nursing Implications r/t Minimizing the Risk of Bleedingteach to patient/family prn • Screen for risk factors • Follow requirements for therapeutic drug monitoring • Beware drug or food interactions. Monitor blood levels carefully any time a new drug is added, or a current drug is discontinued from the drug regimen. • Minimize physical manipulation of the patient • Minimize invasive procedures (eg foley catheter) • Avoid subcut and IM injections • Minimize concurrent use of anticoagulants – for example, heparin, warfarin, dabigatran) • Minimize concurrent use of antiplatelet drugs – for example, aspirin, clopidogrel • Use in caution in those with CPR or surgery within previous 3 weeks • Avoid noncompressable vascular puncture sites • Wear identification for emergency personnel 28

Question- which lab is used to monitor effects of heparin? A patient is receiving an intravenous infusion of heparin to treat a pulmonary embolism. What laboratory value will the nurse monitor to evaluate treatment with this medication? A. Activated partial thromboplastin time (a. PTT) B. Prothrombin time (PT) C. Platelet count D. Hemoglobin and hematocrit 29

Question: antidote for heparin overdose? What is the antidote for heparin? A. Ferrous sulfate B. Atropine sulfate C. Protamine sulfate D. Magnesium sulfate 30

Low-Molecular-Weight Heparins • Heparin preparations composed of molecules that are shorter than those found in unfractionated heparin • LMWH as effective as UFH • Mechanism: inactivates Factor Xa – not effective to inactivate thrombin • Administered subcut • Dosage based on body weight (fixed dose) Advantages: fixed dose, no lab, highly predictable plasma levels Cost: considerably more expensive But, does not require labs/ monitoring; can be given at home Pharmacokinetics Higher bioavailability Longer half-life- permits once or twice a day dosing • Antidote for toxicity: Protamine sulfate

• Low-Molecular-Weight Heparins Adverse effects – Bleeding (but less than with unfractionated heparin) – Heparin-induced thrombocytopenia (HIT) – Severe neurologic injury for patients undergoing spinal puncture or spinal epidural anesthesia • Therapeutic uses – First-line therapy for prevention and tx of DVT – Prevention of DVT following surgery • abdomen; hip or knee replacement – Off label use for DVT prophylaxis • in multi-trauma, or spinal surgery – Prevention of ischemic complications in pts with unstable angina, non Q-wave MI, and ST-elevation MI (STEMI) Three on market: ü Enoxaparin (Lovenox)- used in >80% of hospitals ü Dalteparin (Fragmin) ü Tinzaparin (Innohep)

All anticoagulants • Pose a risk of spinal or epidural hematoma in patients undergoing spinal puncture or spinal/ epidural anesthesia • Pressure of hematoma on spinal cord can result in prolonged or permanent paralysis • See Lehne text, p 599

RECOMMENDATION: Health care professionals and institutions involved in performing spinal/epidural anesthesia or spinal punctures should determine, as part of a pre-procedure checklist, whether a patient is receiving anticoagulants and identify the appropriate timing of enoxaparin dosing in relation to catheter placement or removal. To reduce the potential risk of bleeding, consider both the dose and the elimination half-life of the anticoagulant: For enoxaparin, placement or removal of a spinal catheter should be delayed for at least 12 hours after administration of prophylactic doses such as those used for prevention of deep vein thrombosis. Longer delays (24 hours) are appropriate to consider for patients receiving higher therapeutic doses of enoxaparin (1 mg/kg twice daily or 1. 5 mg/kg once daily). A postprocedure dose of enoxaparin should usually be given no sooner than 4 hours after catheter removal. In all cases, a benefit-risk assessment should consider both the risk for thrombosis and the risk for bleeding in the context of the procedure and patient risk factors. Medwatch 11/2013

WARFARIN

Warfarin, the first oral anticoagulant • Originally discovered when a farmer observed that his cattle began bleeding after ingesting spoiled clover silage – Deemed too risky for humans used as rat poison – A failed suicide attempt with large dose brought renewed clinical interest • Used to prevent thrombosis • Mechanism: suppresses coagulation by decreasing production of four clotting factors (VII, IX, X and prothrombin, all of which are dependent on vitamin K) • PK: only administered orally, well absorbed; 99% bound to albumin; unbound warfarin readily crosses into placenta and breast milk; hepatic metabolism by CYP 2 C 9; metabolites excreted in urine & feces • Clinical considerations – Initial onset 6 – 12 hours after first dose; peak effect takes several days to develop. (Not useful in emergencies) – Effect persists 2 – 5 days after discontinuing – Drug therapy typically initiated with heparin (which has immediate onset) until warfarin is at therapeutic levels – Warfarin may need to be temporarily DC’d for elective surgery (Heparin is re-instituted during interim until safe to go back on warfarin) 36

Warfarin, the first oral anticoagulant • Lab monitoring ESSENTIAL! – Never does a person “not need” monitoring, although frequency of labs are somewhat individualized – Prothrombin time (PT)/ International normalized ratio (INR) ‒ Normal PT/INR is 1. 0 ‒ Patient’s “Goal PT/INR” depends on condition being treated ‒ Longest reasonable amount of time between labs 2 – 4 weeks ‒ Patients titrate daily dose of warfarin based on PT/INR values • Antidote Vitamin K 1 (phytonadione) • • oral preferred (IV has risk of allergy or anaphylaxis) Useful in emergencies (eg sudden trauma) • Therapeutic use: long-term prophylaxis of thrombosis • Prevention of venous thrombosis and associated risk of pulmonary embolism • Prevention of thromboembolism – Eg in patients with prosthetic heart valves • Prevention of thrombosis in patients with atrial fibrillation • Reduce recurrent Transient Ischemic Attacks and MI

Warfarin, the first oral anticoagulant • Adverse effects – Bleeding – Hemorrhage – Fetal hemorrhage and teratogenesis • Pregnancy Category X • Contraindicated during lactation – Other adverse effects • Patient Teaching – S/S of bleeding; monitoring plan- schedule of labs; drug and food interactions; must tell all providers of all drugs; wear “Medic. Alert”-type identification; stop warfarin (use another method) until after an elective surgery – Take at same time every day – Warfarin has perhaps the most drug or food interactions of any medication!

Warfarin, the first oral anticoagulant • Drug interactions (p 606 - 607) – Warfarin has perhaps the most drug and food interactions of any medication! – Worrisome due to increased bleeding or loss of protection – Drugs that increase anticoagulant effects • Heparin, aspirin, acetaminophen – Drugs that promote bleeding • Drugs that compete for binding with plasma proteins • Drugs that induce or inhibit the drug-metabolizing enzymes (CYP 2 C 9) – Drugs that decrease anticoagulant effects • Contraindicated: very large list (p 607) • severe thrombocytopenia and others at high risk of bleeding • Patients undergoing a variety of procedures or surgeries • Liver disease, alcoholism- conditions that can disrupt production of clotting factors • Pregnancy and lactation 39

Warfarin, the first oral anticoagulant • Teach pt to ingest the same amount of dietary Vitamin K each day • Dietary vitamin K: Mayonnaise, canola oil, soybean oil, and green leafy vegetables 40

Question: warfarin and drug interactions Which patient does the nurse identify as most likely needing an increased dose of warfarin [Coumadin] to have the same anticoagulant effect? A. Patient taking acetaminophen [Tylenol] for back pain B. Patient taking cimetidine [Tagamet] to prevent gastric ulcers C. Patient taking oral contraceptives to prevent pregnancy D. Patient taking prednisone [Deltasone] for rheumatoid arthritis 41

HEPARIN VS. WARFARIN

Comparison between Heparin & Warfarin MOA Route Onset Heparin Warfarin Inactivates thrombin & factor Xa injection SQ, IV Effects begin rapidly Inhibits synthesis of clotting factors oral Begin slowly

Comparison between Heparin & Warfarin Duration Monitoring Antidote Heparin Warfarin Effects fade quickly Effects persist for days a. PTT PT Protamine Sulfate Vitamin K

Direct Thrombin Inhibitors • Dabigatran etexilate (Pradaxa) • Oral prodrug that undergoes conversion to dabigatran • Advantages: • Doesn’t require monitoring of anticoagulation • little risk of adverse interactions • same dose can be used for all patients regardless of age or weight • Therapeutic uses • Atrial fibrillation • Knee or hip replacement • Adverse effects • Bleeding • No specific antidote to reverse dabigatran-related bleeding • Gastrointestinal (GI) disturbances • Clinical considerations • Plasma levels peak about 1 – 3 hours after oral dosing. Not metabolized by liver, excreted by kidneys. Half-life 13 hours. Take dose at same time every day. No antidote

Direct Factor Xa Inhibitors • Rivaroxaban [Xarelto] – Binds directly with factor Xa to cause inactivation – Prevention of DVT and PE after total hip or knee replacement surgery – Prevention of stroke in patients with atrial fibrillation – Treatment of DVT and PE unrelated to orthopedic surgery – Oral – No lab test – No antidote – Dosing at same time every day is required 46

T E L E T : A L S P G I U T R N A D

Antiplatelet Drugs • Aspirin (ASA) – Inhibition of cyclooxygenase – Adverse effect • Increases risk for GI bleeding • Ticlopidine [Ticlid] – Inhibits ADP-mediated aggregation – Adverse effects • Hematologic effects • Clopidogrel [Plavix] – ADP receptor antagonist 48

Figure 52 -1 A Mechanism of platelet aggregation and actions of antiplatelet drugs.

ASPIRIN

Antiplatelet Drugs: ASPIRIN • Aspirin (ASA) – Irreversible Inhibition of cyclooxygenase • Effects last ___ days? • Indications for use – Transient ischemic attack (TIA) – Primary prevention of Ischemic Stroke • Secondary prevention of Ischemic stroke ‒ Primary prevention of MI ‒ Secondary prevention of MI – Acute MI – Chronic stable angina – Unstable angina – Coronary stenting • Adverse effect – Bleeding; GI bleeding; Hemorrhagic stroke – Enteric-coated tablets may not reduce the risk of GI bleeding

CLOPIDOGREL

Antiplatelet Drugs: Clopidogrel • Clopidogrel [Plavix] – ADP receptor antagonist; Blocks P 2 Y 12 ADP receptors on the platelet surface, preventing ADP-stimulated aggregation • Adverse effects: similar to aspirin • Bleeding • TTP (thrombotic thrombocytopenia purpura) • Drug Interactions: PPI’s, CYP 2 C 19 inhibitors • Therapeutic uses – Prevents blockage of coronary artery stents – Reduces thrombotic events in patients with acute coronary syndromes • Prevents stenosis of coronary stents; also for secondary prevention of MI, ischemic stroke, and other vascular events • Use with caution in combination with other drugs that promote bleeding

Antiplatelet Drugs: glycoprotein IIb/IIIa receptor antagonists • Glycoprotein (GP) IIb/IIIa receptor antagonists – Most effective antiplatelet drugs – “Super aspirins” – Reversible blockade of platelet GP IIb/IIIa receptors – Therapeutic use • Acute coronary syndromes • Percutaneous coronary interventions

S C I O B M H T O R L T Y

Thrombolytic Drugs • Alteplase [t. PA] – Binds plasminogen Breaks down fibrin strands in the blood clot • Uses – Ischemic stroke- emergency management; must be administered within 2 hours of the onset of symptoms, preferably ASAP • Risk of bleeding increases as time passes after clot occurred – Massive pulmonary emboli – Acute coronary thrombosis (acute MI) – Deep venous thrombosis (DVT) – Clearing clogged central catheters • Adverse effects – Bleeding: Risk for intracranial bleeding higher than with streptokinase – If bleeding begins, treat with whole blood or blood products (packed red blood cells, fresh-frozen plasma) – Aminocaproic acid [Amicar] is last resort –Fever • Advantages – Does not cause allergic reactions – Does not induce hypotension

Question During administration of alteplase [Activase], the patient’s IV site starts to ooze blood around the catheter. Which action by the nurse is most appropriate? A. Discontinue the infusion of alteplase. B. Assess the patient’s vital signs. C. Apply direct pressure over the puncture site. D. Administer aminocaproic acid [Amicar]. 57