Anticoagulants Mechanism of Action Clinical

Guide to Diagnostic Tests, 7e >DDx Diana Nicoll, Chuanyi Mark Lu, Stephen J. McPhee+ TABLE 8–4.ANTICOAGULANTS: MECHANISM OF ACTION, CLINICAL INDICATIONS, AND LABORATORY MONITORING. Anticoagulant Route of Administration Warfarin Oral Mechanism of Action Warfarin inhibits vitamin K epoxide reductase (VKOR) (specifically the VKORC1 subunit) and thereby diminishes available vitamin K in the tissues. As a result, warfarin inhibits the vitamin K-dependent synthesis of coagulation factors II, VII, IX and X, as well as the regulatory factors, protein C and protein S. Route of Elimination Clinical Indications and Usage Long-term prophylaxis or treatment of venous thrombosis and systemic embolism in patients with: Metabolized in the liver (CYP2C9); Excreted via the urine and feces T1/2: 20–60 hours (mean 40 hours) Warfarin is slow-acting and has a long half-life. Its activity is determined partially by genetic factors (eg, polymorphisms in the VKORC1 and CYP2C9 genes). •Atrial fibrillation or artificial heart valves •Deep venous thrombosis (DVT) and/or pulmonary embolism (PE) •Antiphospholipid antibody syndrome Heparin, unfractionated (UFH) Intravenous (infusion); Subcutaneous (injection) •PT/INR (most commonly used) •Factor assays (e.g., FVII, FX) •Chromogenic factor Xa assay The chromogenic factor Xa assay is useful if patients have documented lupus anticoagulant (LAC) interference. Warfarin is contraindicated in pregnant women. Short-term anticoagulation use (prophylaxis and treatment) in hospitalized patients with: Heparin is a glycosaminoglycan composed of chains of alternating residues of D-glucosamine and iduronic acid. Heparin binds to antithrombin (AT) and enhances its function of inactivating coagulation factors including thrombin and factor Xa. For inhibition of thrombin, heparin must bind to both the coagulation enzyme and AT, whereas binding to the enzyme factor is not required for inhibition of FXa. Laboratory Monitoring Metabolized in the liver; may be partially metabolized in the reticuloendothelial system T1/2: 1–2 hours •Acute coronary syndrome (eg, unstable angina/non-STEMI) •Venous thromboembolic disorders (DVT and/or PE) •Cardiopulmonary bypass for open heart surgery •Hemodialysis procedure •Atrial fibrillation •Stroke (ischemic) •ECMO circuit for extracorporeal life support •Indwelling central or peripheral venous catheters (to maintain •aPTT (most commonly used) •Chromogenic anti-Xa assay Institutional aPTT-based heparin therapeutic interval must be used. The chromogenic anti-Xa assay should be used if aPTT is unreliable (eg, LAC interference, FXII deficiency, acute illness with elevated FVIII and/or fibrinogen, liver dysfunction, consumptive coagulopathy). patency) •Prophylaxis of DVT and thromboembolism in hospitalized patients who undergo abdominal surgery, hip or knee replacement Heparin, low-molecular weight (LMWH) (eg, Enoxaparin, Dalteparin) Subcutaneous (injection), occasionally intravenous (bolus) LMWH consists of heparin-derived fragments (about one-third of the size of heparin), which mainly inactivate FXa via AT. It has reduced ability to inactivate thrombin because the smaller fragments cannot bind simultaneously to both AT and thrombin. surgery and acutely ill patients with severely restricted mobility Metabolized in the liver (60–90%); excreted via urine (10–40%) T1/2: 4–7 hours •Inpatient treatment of acute DVT with or without PE •Outpatient treatment of acute DVT with or without PE •Prophylaxis of ischemic complications in unstable angina and non-Q-wave MI •Treatment of acute STEMI, with or without subsequent percutaneous coronary intervention (PCI) •Chromogenic anti-Xa assay (4 hours after subcutaneous administration) Monitoring is only required for patients with weight extremes (morbid obesity or cachexia), pregnancy, old age, neonates, renal insufficiency, bleeding, or thrombosis while receiving therapy. •Prophylaxis of DVT in patients who have had orthopedic surgery (hip fracture, hip or knee replacement), or abdominal surgery Fondaparinux Subcutaneous (injection) Fondaparinux is a synthetic pentasaccharide which is identical to a sequence of five monomeric sugar units in heparin. Like LMWH, fondaparinux inactivates FXa via AT. It does not inactivate thrombin. •Treatment of acute DVT and PE when administered in conjunction Excreted unchanged via urine T1/2: 17–21 hours with warfarin •Treatment of acute heparin-induced thrombocytopenia (HIT) (off label usage) Fondaparinux is contraindicated in patients with severe renal impairment or body weight less than 50 kilograms. Argatroban Intravenous (infusion) Bivalirudin Intravenous (injection and infusion) Dabigatran Oral Argatroban is a small molecule direct thrombin inhibitor (DTI). It interacts with the active site of thrombin, but does not make contact with the exosites I or II of thrombin. Bivalirudin is a synthetic hirudin analog, which acts as a specific and reversible DTI. It binds to thrombin via direct interactions with the active site and the exosite of thrombin. It inhibits both circulating and clot-bound thrombin. Dabigatran is an orally active DTI. Dabigatran etexilate is a prodrug, which needs to be converted in the liver to the active compound that binds directly to thrombin with high affinity and specificity. Metabolized in the liver T1/2: 40–50 minutes. Because of its hepatic metabolism, it may be used in patients with renal dysfunction Predominantly proteolysis (non-organ elimination), plus renal excretion T1/2: approximately 25 minutes Rivaroxaban Oral •Anticoagulation use in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA) •Anticoagulation use in patients with or at risk of HIT undergoing PCI •Prophylaxis and treatment of thrombosis in patients with HIT (offlabel usage) after subcutaneous administration) Monitoring is only required for patients with weight extremes (morbid obesity or cachexia), pregnancy, old age, neonates, renal insufficiency, bleeding, or thrombosis while receiving therapy. •aPTT Obtain baseline aPTT, monitor aPTT every 2 hours until therapeutic range of 1.5–3.0 times baseline aPTT achieved. •ACT The ACT should be used in patients with renal impairment. ACT >300 seconds indicate adequate anticoagulation. Excreted unchanged via kidney •Prophylaxis of stroke in patients with non-valvular atrial fibrillation •Long-term treatment of DVT with or without PE to reduce risk of recurrence •Acute treatment of DVT with or level of the drug. T1/2: 12–17 hours. (The drug is not recommended for use in patients with a GFR less than 15 mL/min or in patients who are without PE (only after an initial 5-day treatment with a parenteral anticoagulant) •Prophylaxis of thromboembolic The aPTT is insensitive to dabigatran at higher drug levels. The TT is very sensitive to dabigatran, and a normal TT excludes significant dabigatran hemodialysis-dependent.) Rivaroxaban is an oxazolidinone derivat Ωive optimized for inhibiting both free FXa and FXa bound in the prothrombinase complex. It is a highly selective direct FXa inhibitor with oral bioavailability and rapid onset of action. It blocks the active site of FXa and does not require a cofactor. •Prophylaxis and treatment of thrombosis in patients with HIT •Anticoagulation use during PCI in patients who have HIT or are at risk for developing HIT •Chromogenic anti-Xa assay (3 hours disease following hip or knee replacement surgery (European Union and Canada only) Monitoring is not usually required. If monitoring is indicated, obtain plasma effect but is not useful for monitoring or dose adjustment. •Prophylaxis of stroke and systemic embolism in non-valvular atrial •Chromogenic anti-Xa assay About two-thirds metabolized in liver fibrillation •Treatment of acute DVT with or Routine monitoring is not required. and one-third excreted unchanged via kidney without PE •Long-term treatment of DVT with or Monitoring may be helpful under certain conditions (e.g., renal failure, T1/2: 5–9 hours without PE to reduce risk of recurrence •Prophylaxis of DVT following hip or older age, acute illness, during bleeding or thrombotic episodes, or to verify adherence to therapy). knee replacement surgery Apixaban Oral Apixaban is an oral, reversible, and selective active site inhibitor of FXa. It does not require a cofactor. Apixaban inhibits both free and clot-bound FXa, as well as prothrombinase activity. Metabolized in the liver. About 75% of metabolites are eliminated in feces (biliary and direct intestinal excretion) and about 25% through urinary excretion. •Prophylaxis of stroke and systemic embolism in non-valvular atrial fibrillation •Venous thromboembolism treatment •Prophylaxis of DVT following hip or •Chromogenic anti-Xa assay Routine monitoring is not required. knee replacement surgery T1/2: 12 hours Edoxaban Oral Edoxaban is an oral, direct and selective FXa inhibitor. It inhibits free FXa and prothrombinase activity. It also inhibits thrombin-induced platelet aggregation. Eliminated as unchanged drug in urine. Renal clearance accounts for ~50% of total clearance, and hepatic metabolism and biliary excretion account for the remainder. T1/2: 10–14 hours •Prophylaxis of stroke and systemic embolism in non-valvular atrial fibrillation •Acute treatment of DVT with or without PE (only after an initial 5-day treatment with a parenteral anticoagulant) •Chromogenic anti-Xa assay Routine monitoring is not required. aPTT = activated partial thromboplastin time; AT = antithrombin; DTI = direct thrombin inhibitor; DVT = deep vein thrombosis; ECMO = extracorporeal membrane oxygenation; FXa = factor Xa; GFR = glomerular filtration rate; HIT = heparin-induced thrombocytopenia; INR = International Normalized Ratio; LMWH = low-molecular-weight heparin; PCI = percutaneous coronary intervention; PE = pulmonary embolism; PT = prothrombin time; PTCA = percutaneous transluminal coronary angioplasty; STEMI = ST elevation myocardial infarction; T1/2 = half-life; TT = thrombin time; UFH = unfractionated heparin. Adapted from respective package inserts. 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