Anticoagulant Therapy for Venous Thrombosis Flashcards Preview

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Flashcards in Anticoagulant Therapy for Venous Thrombosis Deck (22):

What is the definition of anticoagulants?

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


What is the mechanism of warfarin?

  • Warfarin (Coumadin) - a vitamin K antagonist that inhibits the enzymatic reduction of vitamin K epoxide
    • 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
  • Reductase (vitamin K epoxide reductase or VKORC1) is the principal modulator of warfarin response
    • Mutations either increase sensitivity to warfarin or cause hereditary warfarin resistance
      • Homozygosity for a missense mutation is the cause of combined deficiency of prothrombin and factors VII, IX, and X (quite rare)


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

  • Warfarin is rapidly absorbed from the GI tract and has a half-life of 36-42 hours
  • 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)
    • 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
    • These factors must be at 20% before anticoagulation is effective
      • So, warfarin is a slow-acting anticoagulant
  • The effect of warfarin is monitored with the prothrombin time, which is sensitive to factors II, VII, and X
    • Although factor IX is not measured, it is usually reduced in parallel with factor X, and therefore does not have to be separately quantitated
  • 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
    • The International Normalized Ratio(INR) refers to the ratio of patient to control prothrombin time raised to a power-the International Sensitivity Index(ISI)
      • With a ratio of 1.5 and an ISI of 2, the INR is 2.25
      • Values of 2 to 3 are considered therapeutic
      • Therefore, the dose of warfarin is titrated to give an INR in this range


What are some factors that affect the response to warfarin?

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


What are some factors that antagonize warfarin?

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


What is warfarin necrosis?

  • 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
    • This is due to a disproportionate decline in Protein C or S as compared to factors IX, X, and prothrombin


What are the indications and contraindications of warfarin?

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


What are some ways of reversing the warfarin effect?

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


What is the mechanism and pharmacokinetics of heparin?

  • Since preparations are not chemically homogeneous, assayed by biologic activity; must be a minimum of 120 biologic units per mg of material
    • Besides anticoagulant action, releases lipoprotein lipase and inhibits smooth muscle cell proliferation
  • Molecular weight ranges from 3-30,000 (mean, 15,000)
    • Lower MW predominantly inhibits Xa, higher MW inhibits thrombin and binds to platelets
    • All enhance the activity of antithrombin
  • Poor GI absorption - given I.V. or subcutaneously
  • Half-life is dose-dependent
    • 56 min after 100 U/kg and 156 min after 400 U/kg
    • T 1/2 reduced in patients with extensive thrombotic disease, and thrombin bound to fibrin is protected from heparin-antithrombin complex
  • Catabolism - binds to endothelium, taken up by macrophages
    • 30% inactivated by liver heparinase
    • 70% excreted as uroheparin
    • Neutralized by platelet factor 4


What are the therapeutic uses of heparin?

  • In the acute treatment of:
    • deep vein thrombosis
    • pulmonary thromboembolism
    • sudden arterial occlusion
    • consumption coagulopathy (DIC) associated with malignancy
    • prevent clotting in extracorporeal circuits (renal dialysis, heart-lung machine, etc.)
      • 80 U/kg as an I.V. bolus, followed by 18U/kg per hour as a continuous I.V. infusion
  • 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
    • 5000 u or more subcut every 12 hrs
  • 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


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

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


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

  • Prepared by the depolymerization of heparin
    • A third of fragments have the pentasaccharide sequence that binds antithrombin
    • Since each process is patented, FDA considers each LMWH to be a distinct drug
    • Three are approved in US:
      • dalteparin
      • enoxaparin
      • tinzaparin
  • Better bioavailability (90%) and a longer half-life (3-4 hrs: once or twice daily subcutaneous injections) than unfractionated heparin
    • Importantly, much less protein binding so that there is an excellent correlation between dose and biologic effect
      • therefore, monitoring with clotting tests is usually not required except in special circumstances (see below)
  • 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)
    • 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
  • Major advantage is reduced frequency of heparin-induced thrombocytopenia
    • Also, heparin stimulates osteoclasts and inhibits osteoblasts promoting osteoporosis
    • LMWH do not inhibit osteoblasts and have less effect on osteoclasts, causing less osteoporosis
  • Protamine sulfate reverses the effect of heparin, but has only limited effect on LMWHs


What is the clinical use of LMWH?

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


What is the definition of bridging?

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


What are the major adverse events of LMWH?

  • Bleeding
    • in the epidural space after epidural catheter placement for anesthesia
    • in wounds
    • from other sites
  • To be used safely, they should not be given to patients with potential bleeding lesions or too soon after invasive procedures
  • They may accumulate in patients with renal disease (the major route of elimination)
  • 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


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

  • 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.
    • Measurement of anti-Xa levels also suggested for children (kinetics differ from adults), and possibly for pregnant women (expanding plasma volume)
    • 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
  • Cost-considerations: LMWH are currently more expensive than heparin
    • 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
    • Furthermore, because they are often more effective than heparin, there are fewer thrombotic complications of surgery, and less bleeding
    • Finally, heparin-induced thrombocytopenia is a life-threatening disease with considerable morbidity
      • the less frequent occurrence of this complication increases cost-effectiveness


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

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


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

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


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.

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


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

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


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

  • Advantages
    • Directly inhibit thrombin and do not require antithrombin for their efficacy
    • They also are able to penetrate the fibrin clot and inhibit clot-bound thrombin-heparin and LMWHs lack this capability
  • Disadvantages
    • 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>
    • No specific antidotes should a patient have bleeding
      • the short half-life of bivalirudin is an advantage in this respect
    • A definite drawback is that they prolong the prothrombin time, making it difficult to monitor concurrent warfarin treatment


What are the major features of tissue plasminogen activators?

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