ANTICOAGULANT THERAPY MONITORING Mail Email this article
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Warfarin (Coumadin®)
Standard Unfractionated Heparin (UFH)
Heparin-induced Thrombocytopenia with Thrombosis (HIT)
Low Molecular Weight Heparin (LMWH)
Fondaparinux (Arixtra®, pentasaccharide)
Direct Thrombin Inhibitors (DTIs)
Monitoring Using Anti-Xa (download PDF)


Warfarin (CoumadinÒ)


Indications for warfarin

  • Treatment of arterial and venous thrombosis to prevent clot propagation
  • Prevention of thromboembolic disease in thrombophilia, atrial fibrillation, mechanical heart valves, and high-risk surgery
Mechanism of action for warfarin

  • Prevents the vitamin K dependent  gamma-carboxylation of factors II, VII, IX, and X, proteins C and S, slowing thrombin production
Dosage of warfarin

  • 5-10 mg/day with no loading dose. Must be monitored due to unpredictable half-life.
    Affected by many drugs and dietary variation
  • Requires 2-7 days to reach therapeutic levels. To achieve immediate anticoagulation, begin with heparin.
Laboratory monitoring: The INR

  • PT generates the international normalized ratio (INR) by this formula:

INR = (Patient PT/MRI PT) ISI

Where…


PT = prothrombin time in seconds

MRI = geometric mean of reference interval

ISI = international sensitivity index supplied by reagent manufacturer

Target INRs

  • Post-myocardial infarction, most therapy and prophylaxis: INR 2.0-3.0

  • Mechanical heart valves: INR 2.5-3.5

Laboratory monitoring sequence

  • Daily until INR is therapeutic twice at least 24 hours apart

  • Twice a week for 2 weeks, then once a month until therapy is complete

Managing warfarin overdose

No bleeding

Warfarin dosage

INR 3.5-5

Decrease, do not stop drug

INR 5-8

Decrease, consider 1 mg K PO

INR 5-8, bleeding risk high

Decrease, give 2.5-5 mg K PO or1 mg SQ

INR > 8

Stop drug, give 2.5-5 mg K PO or 2-3 mg SQ

INR > 8, bleeding risk high

·          Stop drug, give 5 mg K PO or 3-5 mg SQ

·          Consider 10 mL/kg FFP or 25 U/kg PCCs (p. 36)

Minor bleeding

Warfarin dosage

INR 2-3.5

Decrease, look for site

INR 3.5-5

Stop drug, reinstitute at lower dose

INR 5-8

Stop drug, give 2.5 mg K PO or 1 mg SQ

INR 5-8, thrombotic risk high

Stop drug, do not give K

INR > 8

·          Stop drug, give 5 mg K PO or 2-5 SQ

·          Consider 10 mL/kg FFP or 25 U/kg PCCs (p. 36)

Major bleeding

Warfarin dosage

INR 2-3.5

Stop drug, give 5 mg SQ K or IV, repeat as necessary, look for bleeding site

INR 3.5-5

·          Stop drug, give 5-10 mg K SQ or IV, repeat

·          Consider 10-15 mL/kg FFP or 25-50 U/kg PCCs (p. 36)

INR 5-8

·          Stop drug, give 5-10 mg K SQ or IV, repeat

·          Give 15 mL/kg FFP or 25-50 U/kg PCCs (p. 36)

INR >8

·          Stop drug, give10 mg K SQ or IV, repeat 6h

·          Give 15 mL/kg FFP or 25-50 U/kg PCCs (p. 36)



 

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Standard Unfractionated Heparin (UFH)


Indications for UFH

  • Treatment of arterial and venous thrombosis to prevent clot propagation

Mechanism of action

  • Increases the inhibitory effect of antithrombin on the serine proteases thrombin, IXa, Xa, XIa, and XIIa with greatest effect upon thrombin
  • UFH clearance varies by individual and requires routine monitoring
Usual dosage

  • 80 IU/kg bolus, 8 IU/kg/h IV started concurrently with warfarin
  • Discontinue after 5 days if the INR has been therapeutic for at least 24 hours
Laboratory monitoring: PTT

  • Assay 4-6 hours after bolus dosage and every 24 hours thereafter; if dose adjustment is needed, 6 hours after changing IV infusion
  • UAB target for prophylaxis: 51 - 70 s; based upon anti-Xa of 0.1 to 0.4 U/mL
  • UAB target for therapy: 71 - 105 s; based upon anti-Xa of 0.3 to 0.7 U/mL
  • Target PTT interval varies with reagent lot; last updated 10/26/12. Contact UAB special coagulation laboratory for current values.
Laboratory monitoring: platelet count

  • Check PLT count daily to detect heparin induced thrombocytopenia (HIT)
  • If count drops 30-50%, consider HIT, withdraw heparin, start alternative anticoagulant, order confirmatory test for HIT
Overdose of UFH

  • Stop heparin and monitor PTT. Heparin half-life is approximately 30 minutes. If bleeding is severe, consider protamine sulfate (1 mg/100 units heparin)
  • FFP does not reverse heparin effect
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Heparin-induced Thrombocytopenia with Thrombosis (HIT)


From 1-5% of patients receiving unfractionated heparin develop HIT. An antibody to heparin-bound platelet factor 4 (PF4) that activates platelets causes HIT. HIT is a major source of morbidity and mortality, and must be rigorously guarded against. Daily platelet counts throughout and following heparin therapy are the primary defense. A 30-50% decrease, even when the count remains within the normal range, may signal the onset of HIT. Laboratory confirmation consists of an immunoassay for the anti-heparin-PF4 antibody. This assay requires several hours and yields a relatively high false positive rate, thus is considered confirmatory but not diagnostic. When the clinical suspicion is high, heparin should be replaced with one of the direct thrombin inhibitors Lepirudin or Argatroban, until the clinical situation is elucidated.

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Low Molecular Weight Heparin (LMWH)




Enoxaparin, Tinzaparin (Lovenox)

 

Indications for LMWH

  • Prevention or treatment of thromboembolic disease

Mechanism of action

  • Increases the inhibitory effect of antithrombin on the serine proteases thrombin and Xa with greatest effect upon Xa
  • LMWH clearance is predictable and requires little monitoring in uncomplicated thrombosis; enoxaparin accumulates in renal insufficiency
Dosage for Enoxaparin

  • Prophylaxis: 40 mg SQ once a day (for morbidly obese, may need 60 mg)
  • Therapeutic: 1 mg/kg q12h (maximum of 150 mg)
Laboratory monitoring of Enoxaparin

 

  • Use chromogenic anti-Xa heparin assay; PTT is insensitive
  • Assay unnecessary in uncomplicated treatment situation
  • Assay needed for infants, children, obese or underweight patients, or those with renal disease, long-term treatment, pregnancy, or unexpected bleeding or thrombosis
  • Collect blood specimen 4 h after subcutaneous dose
  • Target for prophylaxis: 0.2 to 0.4 anti-Xa U/mL
  • Therapeutic target for twice-daily SQ administration: 0.5-1.0 anti-Xa U/mL
  • Therapeutic target for once-daily SQ administration: 1.0-2.0 anti-Xa U/mL[top]

     

     

    Fondaparinux (Arixtra®, pentasaccharide)


    Dosage

     

    • Prophylaxis: 2.5 mg SQ once a day
    • Therapeutic: Not established
    Laboratory monitoring of Fondaparinux

    • Use chromogenic anti-Xa heparin assay; PTT is insensitive
    • Assay not necessary in uncomplicated treatment situation
    • Assay needed for infants, children, obese or underweight patients, or those with renal disease, long-term treatment, pregnancy, or unexpected bleeding or thrombosis
    • Collect blood specimen 4 h after a subcutaneous dose
    • Pentasaccharide target: 0.14 to 0.19 mg/L
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    Direct Thrombin Inhibitors (DTIs): Argatroban and Lepirudin 


    DTI indications

    • Substitute for heparin when HIT is suspected or confirmed. Even when HIT's only manifestation is thrombocytopenia and heparin is stopped, risk of thrombosis in subsequent 30 days approaches 50% unless alternative anticoagulant is used.
    DTI dosages

    • Lepirudin: 0.4 mg/kg slowly IV, then 0.15 mg/kg continuous infusion for 2-10 days depending on indication
    • Argatroban: 2 µg/kg/min IV
    DTI half-lives

    • Lepirudin: 20 minutes
    • Argatroban: 39-51 minutes
    Laboratory monitoring of DTIs

    • PTT is used to prevent bleeding or thrombosis
    • Lepirudin: collect blood four (4) hours after initial dosage, adjust dosage to PTT 1.5-3.0 x mean of reference interval
    • Argatroban: collect blood two (2) hours after initial dosage, adjust dosage to PTT 1.5-3.0 x mean of reference interval
    • Lepirudin accumulates in kidney failure
    • Argatroban accumulates in liver failure
    • Do not start in patients with PTT longer than 2.5 x mean of reference interval
    • In HIT, warfarin may be introduced when platelet count starts to increase but DTIs should be continued until platelet count normalizes. After 4-5 days of warfarin, if platelet count is normal and PT is therapeutic, stop DTI for a few hours and recheck INR. If between 2-3, it is safe to discontinue DTI.
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