Anticoagulant Therapy for Venous Thrombosis Flashcards

Question 1

Q

What is the definition of anticoagulants?

Answer

A

<ul>
<li>Anticoagulants are drugs that target molecules required for the generation of thrombin and thrombin itself</li>
<li>These agents may:
<ul>
<li>affect the synthesis of the procoagulants (warfarin)</li>
<li>potentiate anticoagulants such as antithrombin (heparin & low molecular weight heparins-LMWH)</li>
<li>block the active site of factor Xa or thrombin (direct inhibitors-DI’s, DTI’s)</li>
</ul>
</li>
<li>The diagram shows the locus of action of these drugs:</li>
</ul>

Question 2

Q

What is the mechanism of warfarin?

Answer

A

<ul>
<li>Warfarin (Coumadin) - a vitamin K antagonist that inhibits the enzymatic reduction of vitamin K epoxide

<ul>
<li>Vitamin K (in the reduced state) is the coenzyme of a carboxylase responsible for the carboxylation of glutamic acid residues on factors II, VII, IX, X, and proteins C, S, and Z</li>
</ul>
</li>
<li>Reductase (vitamin K epoxide reductase or VKORC1) is the principal modulator of warfarin response
<ul>
<li>Mutations either increase sensitivity to warfarin or cause hereditary warfarin resistance
<ul>
<li>Homozygosity for a missense mutation is the cause of combined deficiency of prothrombin and factors VII, IX, and X (quite rare)</li>
</ul>
</li>
</ul>
</li>
</ul>

Question 3

Q

What are the pharmacokinetics of warfarin, and how is it monitored?

Answer

A

<ul>
<li>Warfarin is rapidly absorbed from the GI tract and has a half-life of 36-42 hours</li>
<li>Effective anticoagulation requires a decrease in clotting factors to 20% of normal and is a function of their half-life (factor VII and protein C: 6-7 hrs; factors IX and X: 24 hrs; prothrombin: 90 hrs)
<ul>
<li>Thus, after a dose of Warfarin, factor VII and protein C will be 20% of normal at 48 hrs, but factors IX and X require 3-5 days</li>
<li>These factors must be at 20% before anticoagulation is effective
<ul>
<li>So, warfarin is a slow-acting anticoagulant</li>
</ul>
</li>
</ul>
</li>
<li>The effect of warfarin is monitored with the prothrombin time, which is sensitive to factors II, VII, and X
<ul>
<li>Although factor IX is not measured, it is usually reduced in parallel with factor X, and therefore does not have to be separately quantitated</li>
</ul>
</li>
<li>Clinical and laboratory studies suggest that prolongation of the prothrombin time to 1 1/2 to 2 times normal prevents the growth of a thrombus
<ul>
<li>The International Normalized Ratio(INR) refers to the ratio of patient to control prothrombin time raised to a power-the International Sensitivity Index(ISI)
<ul>
<li>With a ratio of 1.5 and an ISI of 2, the INR is 2.25</li>
<li>Values of 2 to 3 are considered therapeutic</li>
<li>Therefore, the dose of warfarin is titrated to give an INR in this range</li>
</ul>
</li>
</ul>
</li>
</ul>

Question 4

Q

What are some factors that affect the response to warfarin?

Answer

A

<ul>
<li>Poor oral intake of vitamin K

<ul>
<li>patients on restricted diets, anorexic, diarrhea, destruction of bowel flora (a source of vitamin K)</li>
</ul>
</li>
<li>Polymorphisms in VKORC1 (increase resistance) and CYP2C9 (decrease clearance)
<ul>
<li>explain some of the variability in responses to warfarin</li>
</ul>
</li>
<li>Drugs inhibiting metabolic clearance (CYP 2C9) such as:
<ul>
<li>erythromycin</li>
<li>fluconazole</li>
<li>anti-inflammatory agents</li>
<li>H2-blockers</li>
</ul>
</li>
<li>Liver disease augments impaired clotting factor synthesis</li>
<li>Unknown mechanism - other antibiotics, anti-arrhythmic drugs such as amiodarone, some herbals like Ginkgo and garlic</li>
</ul>

Question 5

Q

What are some factors that antagonize warfarin?

Answer

A

<ul>
<li>Recent vitamin K therapy</li>
<li>Anticonvulsants</li>
<li>St John’s Wort</li>
<li>Antibiotics (enhance CYP 2C9)</li>
<li>Foods (broccoli, greens, etc.) rich in vitamin K have minimal effect and need not be restricted from the diet</li>
</ul>

Question 6

Q

What is warfarin necrosis?

Answer

A

<ul>
<li>Heterozygotes for Protein C or S deficiency, or persons with low levels of Protein C/S due to poor diet and relative deficiency of vitamin K, may suffer massive skin and subcutaneous fat necrosis if suddenly exposed to full doses of warfarin

<ul>
<li>This is due to a disproportionate decline in Protein C or S as compared to factors IX, X, and prothrombin</li>
</ul>
</li>
</ul>

Question 7

Q

What are the indications and contraindications of warfarin?

Answer

A

<ul>
<li>Indications for warfarin therapy:

<ul>
<li>chronic anticoagulation of patients with thromboses</li>
<li>artificial heart valves</li>
<li>atrial fibrillation (to prevent embolization)</li>
<li>other conditions predisposing to thrombosis (deficiencies of antithrombin, Protein C or S).</li>
</ul>
</li>
<li>Contraindications:
<ul>
<li>pregnancy - especially 1st trimester (teratogenic) and 3rd trimester (neonatal hemorrhage)</li>
</ul>
</li>
</ul>

Question 8

Q

What are some ways of reversing the warfarin effect?

Answer

A

<ul>
<li>Prorhrombin time returns toward normal within 24-48 hrs of stopping warfarin (depends on how prolonged INR is).</li>
<li>clotting factors may be immediately replenished by giving Prothrombin Complex Concentrate or plasma transfusion (25-35 ml/Kg).</li>
<li>Oral vitamin K in a single dose of 1 mg to 5 mg will return prothrombin time to normal in 24 hrs
<ul>
<li>Subcutaneous or intravenous vitamin K (Aquamephyton) available for those unable to use oral route</li>
<li>However, if INR fully corrected, patient will be at risk of having new thrombotic event & will be refractory to warfarin for several days</li>
</ul>
</li>
</ul>

Question 9

Q

What is the mechanism and pharmacokinetics of heparin?

Answer

A

<ul>
<li>Since preparations are not chemically homogeneous, assayed by biologic activity; must be a minimum of 120 biologic units per mg of material

<ul>
<li>Besides anticoagulant action, releases lipoprotein lipase and inhibits smooth muscle cell proliferation</li>
</ul>
</li>
<li>Molecular weight ranges from 3-30,000 (mean, 15,000)
<ul>
<li>Lower MW predominantly inhibits Xa, higher MW inhibits thrombin and binds to platelets</li>
<li>All enhance the activity of antithrombin</li>
</ul>
</li>
<li>Poor GI absorption - given I.V. or subcutaneously</li>
<li>Half-life is dose-dependent
<ul>
<li>56 min after 100 U/kg and 156 min after 400 U/kg</li>
<li>T 1/2 reduced in patients with extensive thrombotic disease, and thrombin bound to fibrin is protected from heparin-antithrombin complex</li>
</ul>
</li>
<li>Catabolism - binds to endothelium, taken up by macrophages
<ul>
<li>30% inactivated by liver heparinase</li>
<li>70% excreted as uroheparin</li>
<li>Neutralized by platelet factor 4</li>
</ul>
</li>
</ul>

Question 10

Q

What are the therapeutic uses of heparin?

Answer

A

<ul>
<li>In the acute treatment of:

<ul>
<li>deep vein thrombosis</li>
<li>pulmonary thromboembolism</li>
<li>sudden arterial occlusion</li>
<li>consumption coagulopathy (DIC) associated with malignancy</li>
<li>prevent clotting in extracorporeal circuits (renal dialysis, heart-lung machine, etc.)
<ul>
<li>80 U/kg as an I.V. bolus, followed by 18U/kg per hour as a continuous I.V. infusion</li>
</ul>
</li>
</ul>
</li>
<li>Prophylaxis to prevent deep vein thrombosis and pulmonary embolism in patients on prolonged bed rest (post-operative, after myocardial infarction, etc.), or for chronic intravascular coagulation syndromes
<ul>
<li>5000 u or more subcut every 12 hrs</li>
</ul>
</li>
<li>In patients in whom warfarin is not appropriate (pregnant, non-compliant, etc.), heparin may be administered subcutaneously in doses up to 10,000 u every 12 hrs</li>
</ul>

Question 11

Q

How is heparin monitored? What are some complications and contraindications? What is the antagonist for heparin?

Answer

A

<ul>
<li>Monitor with aPTT test

<ul>
<li>should be twice the control value (generally 50-70 sec)</li>
</ul>
</li>
<li>Complications
<ul>
<li>bleeding in approximately 20% of patients, especially women > 60</li>
<li>osteoporosis and vertebral collapse when given for > 6 months</li>
</ul>
</li>
<li>Contraindications (all relative):
<ul>
<li>thrombocytopenia (platelet factor 4 neutralizes heparin)</li>
<li>peptic ulcer</li>
<li>liver and renal disease</li>
</ul>
</li>
<li>Antagonist: protamine sulfate - 5 mg for each 1000 u of heparin given</li>
<li>Heparin-induced thrombocytopenia:
<ul>
<li>Antibodies develop to neoepitopes on platelet factor 4 induced by heparin-binding</li>
<li>Associated with paradoxical thromboses</li>
<li>When recognized, heparin must be discontinued immediately, and alternative anticoagulants started
<ul>
<li>but NOT warfarin - decreases protein C provoking major thromboses</li>
</ul>
</li>
</ul>
</li>
</ul>

Question 12

Q

What is low molecular weight heparin (LMWH) and what are the advantages over heparin?

Answer

A

<ul>
<li>Prepared by the depolymerization of heparin

<ul>
<li>A third of fragments have the pentasaccharide sequence that binds antithrombin</li>
<li>Since each process is patented, FDA considers each LMWH to be a distinct drug</li>
<li>Three are approved in US:
<ul>
<li>dalteparin</li>
<li>enoxaparin</li>
<li>tinzaparin</li>
</ul>
</li>
</ul>
</li>
<li>Better bioavailability (90%) and a longer half-life (3-4 hrs: once or twice daily subcutaneous injections) than unfractionated heparin
<ul>
<li>Importantly, much less protein binding so that there is an excellent correlation between dose and biologic effect
<ul>
<li>therefore, monitoring with clotting tests is usually not required except in special circumstances (see below)</li>
</ul>
</li>
</ul>
</li>
<li>Because the heparin molecule is truncated (18 saccharide units as compared with 30-50 for heparin), most LMWH are unable to bind thrombin(factor IIa)
<ul>
<li>However, they enhance the inactivation of activated factor X (Xa) by antithrombin, so that the ratio of anti-Xa to anti-IIa is much higher than for heparin</li>
</ul>
</li>
<li>Major advantage is reduced frequency of heparin-induced thrombocytopenia
<ul>
<li>Also, heparin stimulates osteoclasts and inhibits osteoblasts promoting osteoporosis</li>
<li>LMWH do not inhibit osteoblasts and have less effect on osteoclasts, causing less osteoporosis</li>
</ul>
</li>
<li>
Protamine sulfate reverses the effect of heparin, but has only limited effect on LMWHs
</li>
</ul>

Question 13

Q

What is the clinical use of LMWH?

Answer

A

<ul>
<li>LMWH have proven to be better than heparin for the prevention of thrombosis in patients having:

<ul>
<li>joint replacements</li>
<li>neurosurgery</li>
<li>spinal cord injury</li>
</ul>
</li>
<li>They are superior to heparin in the treatment of:
<ul>
<li>deep vein thrombosis/pulmonary embolism</li>
<li>unstable angina</li>
<li>prevention of recurrent thromboses in patients with cancer</li>
</ul>
</li>
<li>LMWH may be used in pregnancy as it does not cross placenta or appear in breast milk.</li>
</ul>

Question 14

Q

What is the definition of bridging?

Answer

A

<ul>
<li>Providing anticoagulation in the perioperative period to patients at risk for thrombosis when warfarin is held, usually 3-5 days before invasive procedures</li>
<li>LMWH is started and continued until 24 hrs preoperatively
<ul>
<li>INR should be <1.5 at time of surgery</li>
<li>LMWH and warfarin are resumed 24 hrs postoperatively if hemostasis is adequate</li>
<li>LMWH is stopped when the INR has been in the therapeutic range for 48 hours</li>
</ul>
</li>
</ul>

Question 15

Q

What are the major adverse events of LMWH?

Answer

A

<ul>
<li>Bleeding

<ul>
<li>in the epidural space after epidural catheter placement for anesthesia</li>
<li>in wounds</li>
<li>from other sites</li>
</ul>
</li>
<li>To be used safely, they should not be given to patients with potential bleeding lesions or too soon after invasive procedures</li>
<li>They may accumulate in patients with renal disease (the major route of elimination)</li>
<li>It is recommended to give 2/3 the dose of LMWH in those with creatinine clearance <30 ml/min, and perform factor Xa assays 4-6 hours after a dose</li>
</ul>

Question 16

Q

What is involved in the monitoring in the LMWH and what are the cost considerations of using this drug?

Answer

A

<ul>
<li>If it is decided to monitor, the anti-Xa levels needed for prophylaxis are 0.1-0.3 units, and for treatment, 0.5-1.2 units.

<ul>
<li>Measurement of anti-Xa levels also suggested for children (kinetics differ from adults), and possibly for pregnant women (expanding plasma volume)</li>
<li>Although LMWH infrequently causes heparin-induced thrombocytopenia, it is unsafe to use in this condition as it cross-reacts with the antibodies to the heparin-PF4 complex</li>
</ul>
</li>
<li>Cost-considerations: LMWH are currently more expensive than heparin
<ul>
<li>However, because LMWH may be self-administered by the patient, home treatment is feasible for most persons with deep vein thrombosis, leading to large cost savings</li>
<li>Furthermore, because they are often more effective than heparin, there are fewer thrombotic complications of surgery, and less bleeding</li>
<li>Finally, heparin-induced thrombocytopenia is a life-threatening disease with considerable morbidity
<ul>
<li>the less frequent occurrence of this complication increases cost-effectiveness</li>
</ul>
</li>
</ul>
</li>
</ul>

Question 17

Q

What is fondaparinux and what is its use compared to the heparins?

Answer

A

<ul>
<li>Totally synthetic molecule consisting of the pentasaccharide sequence that serves as the binding site for antithrombin

<ul>
<li>Enhances the ability of antithrombin to inhibit factor Xa, but has no anti-thrombin activity</li>
</ul>
</li>
<li>Greater than 90% absorption from subcutaneous depots, and very little binding to plasma proteins
<ul>
<li>Half-life of 17-21 hours after subcutaneous injection</li>
</ul>
</li>
<li>Entirely excreted by the kidney; avoid use in patients with renal failure
<ul>
<li>Does not form complexes with platelet factor 4 (thus, no heparin-induced thrombocytopenia)</li>
<li>Safely given to some patients with this disorder</li>
</ul>
</li>
<li>Somewhat more effective than LMWH for the prevention of thromboembolism, and safe and effective for the treatment of thromboembolism</li>
<li>However, there is no reversal agent</li>
</ul>

Question 18

Q

What are the direct factor Xa inhibitors? What are some important features of each?

Answer

A

<ul>
<li>Small molecule inhibitors of Factor Xa (free & bound)

<ul>
<li>oral, monitoring not required</li>
<li>no specific reversal agents (Prothrombin Complex Concentrates might be effective)</li>
</ul>
</li>
<li>Rivaroxaban (Xarelto®):
<ul>
<li>60-80% oral bioavailability, peaks at 2.5-4 hrs, T/2 9 hrs
<ul>
<li>excreted by kidney (66%) & in bile (33%)</li>
<li>potentiated by strong dual inhibitors of P-gp and CYP 3A4</li>
</ul>
</li>
<li>Indications:
<ul>
<li>nonvalvular atrial fibrillation: 20 mg with evening meal (15 mg if renal function impaired)</li>
<li>treatment of DVT, PE, and preventing recurrences: 15 mg twice daily for 21 days, then 20 mg once daily (give with food)</li>
<li>prevention of DVT/PE after hip or knee replacement: 10 mg daily.</li>
</ul>
</li>
<li>Not indicated for patients with prosthetic heart valves, and use cautiously in pregnancy</li>
<li>Risk of rebound thrombosis when drug is stopped</li>
</ul>
</li>
<li>Apixiban (Eliquis®):
<ul>
<li>1.80% oral bioavailability, peaks at 3 hrs, T/2 8-15 hrs</li>
<li>excreted in bile (75%) and kidney (25%)</li>
<li>Potentiated by strong dual inhibitors of P-gp and CYP 3A4.</li>
<li>Indications:
<ul>
<li>nonvalvular atrial fibrillation: 5 mg twice daily - 2.5 mg twice daily if age ≥80, weight ≤60kg, or creatinine ≥1.5 mg/dl</li>
<li>treatment of DVT/PE and prevention of recurrences</li>
</ul>
</li>
<li>Not recommended in pregnancy, nursing mothers, severe liver disease</li>
<li>Risk of rebound thrombosis when drug is stopped.</li>
</ul>
</li>
<li>Edoxaban (pending FDA-approval):
<ul>
<li>1.62% oral bioavailability, peaks within 1-2 hrs</li>
<li>Excreted by the kidney (50%)</li>
<li>Effective in nonvalvular atrial fibrillation & treatment of DVT/PE
<ul>
<li>Dose 30-60 mg - lower dose for low body weight, renal failure, P-gp & CYP 3A4 use</li>
</ul>
</li>
</ul>
</li>
<li>*Cytochrome P450 3A4 and P-glycoprotein inhibitors are ketoconazole, itraconazole, ritonavir, clarithromycin</li>
</ul>

Question 19

Q

Compare the direct Factor Xa inhibitors to warfarin in terms of monitoring, onset and offset of action, effect on diet, drug interactions, intercranial bleeding, reversal, and cost.

Answer

A

<ul>
<li>Monitoring

<ul>
<li>DI's - no</li>
<li>Warfarin - yes</li>
</ul>
</li>
<li>Onset and offset of action
<ul>
<li>DI's - hours</li>
<li>Warfarin - days</li>
</ul>
</li>
<li>Effect of diet
<ul>
<li>DI's - minimal</li>
<li>Warfarin - moderate</li>
</ul>
</li>
<li>Drug interactions
<ul>
<li>DI's - infrequent</li>
<li>Warfarin - frequent</li>
</ul>
</li>
<li>Intercranial bleeding (%/yr)
<ul>
<li>DI's - less often (0.41)</li>
<li>Warfarin - more often (0.79)</li>
</ul>
</li>
<li>Reversal
<ul>
<li>DI's - no specific agent</li>
<li>Warfarin - vitamin K</li>
</ul>
</li>
<li>Cost
<ul>
<li>DI's - high</li>
<li>Warfarin - low</li>
</ul>
</li>
</ul>

Question 20

Q

What are the direct thrombin inhibitors? What are some important features of each?

Answer

A

<ul>
<li>Thrombin has an exosite that binds to fibrinogen, and a catalytic site that cleaves fibrinogen to fibrin

<ul>
<li>Direct thrombin inhibitors bind to one or both of these sites and prolong both the aPTT and PT tests</li>
<li>The ability of thrombin to activate platelets, factors V, VIII, and XI is also impaired</li>
</ul>
</li>
<li>Hirudin was originally extracted from leeches and is currently made by recombinant DNA technology); it binds to both sites</li>
<li>Desirudin (similar to hirudin) is given in a dose of 15 mg twice daily subcutaneously for prevention of thrombosis after hip replacement surgery</li>
<li>Bivalirudin (hirulog) is given intravenously for prevention of thrombosis in patients undergoing coronary artery angioplasty
<ul>
<li>Half-life is only 25 min</li>
</ul>
</li>
<li>Argatroban is approved for patients with heparin-induced thrombocytopenia
<ul>
<li>It is given intravenously and binds reversibly to the active site of thrombin</li>
<li>The dose is adjusted to prolong the aPTT to 1.5-3x baseline.</li>
</ul>
</li>
<li>Argatroban is safe in patients with renal failure but avoid in those with liver disease</li>
<li>Dabigatran etexilate (Pradaxa®) is a prodrug, converted to dabigatran after absorption from the gut
<ul>
<li>Although its oral bioavailability is only 6-7%, it is not affected by food and there is no requirement for monitoring</li>
<li>Peak blood levels are reached in 2 hrs and the T/2 is 14-17 hrs</li>
<li>Excretion is 80% renal and 20% biliary</li>
<li>It is approved for atrial fibrillation in a dose of 150 mg twice daily
<ul>
<li>if impaired renal function, 75 mg twice daily</li>
</ul>
</li>
<li>It is also approved for the treatment of DVT and PE following 5-10 days of a parenteral agent</li>
<li>No specific reversal agent
<ul>
<li>in emergency, activated prothrombin complex concentrate might be effective</li>
</ul>
</li>
</ul>
</li>
</ul>

Question 21

Q

What are the advantages of the direct thrombin inhibitors? What are the disadvantages?

Answer

A

<ul>
<li>Advantages

<ul>
<li>Directly inhibit thrombin and do not require antithrombin for their efficacy</li>
<li>They also are able to penetrate the fibrin clot and inhibit clot-bound thrombin-heparin and LMWHs lack this capability</li>
</ul>
</li>
<li>Disadvantages
<ul>
<li>Excessive bleeding because they are such effective anticoagulants, although this has not been the case in some trials, and there was less intracranial bleeding with dabigatran than with warfarin (%/yr: 0.3 vs 0.74, P<.001)</li>
<li>No specific antidotes should a patient have bleeding
<ul>
<li>the short half-life of bivalirudin is an advantage in this respect</li>
</ul>
</li>
<li>A definite drawback is that they prolong the prothrombin time, making it difficult to monitor concurrent warfarin treatment</li>
</ul>
</li>
</ul>

Question 22

Q

What are the major features of tissue plasminogen activators?

Answer

A

<ul>
<li>Given intravenously either by bolus injection, continuous infusion, or directly into a thrombus through a catheter</li>
<li>Indications:
<ul>
<li>Acute cerebral thrombosis (within 6 hours of onset)</li>
<li>Lysis of thrombi in the coronary and pulmonary arteries when these are life-threatening</li>
<li>Used experimentally in venous thrombosis to prevent post-thrombotic syndrome</li>
</ul>
</li>
<li>Main adverse effect is bleeding
<ul>
<li>when given systemically, 1-2% incidence of intracranial hemorrhage with residual neurologic disability</li>
</ul>
</li>
</ul>

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Anticoagulant Therapy for Venous Thrombosis Flashcards

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