; Anticoagulants
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      Please see Hemostasis for review of anticoagulation
      Warfarin has some of the highest reported adverse events of any therapeutic drug
      Trivia:
           o Warfarin = Wisconsin Alumni Research Foundation
                   Originally found in a bleeding cow after eating spoiled silage
           o Heparin
                   Found accidentally by a medical student
           o Urokinase
                   Urine found to breakdown fibrin
           o Streptokinase
                   Beta hemolytic streptococci produces t-PA



      Warfarin is part of a group called hydroxycoumarins
           o These all inhibit the Vitamin K cycle
           o Warfarin is comprised of R and S enantiomers  these are broken down in
              separate hepatic enzymes
      Vitamin K cycle:

      This cycle happens in the liver
      Vitamin K is a co-factor needed to ACTIVATE factors II, VII, IX, X, protein C and S
      Vitamin K goes through a cycle: initially it’s oxidized and then it needs to be reduced
      Once it’s reduced, it’s back in its active form  carboxylates the inactive forms of
       the clotting factors
      Warfarin inhibits the reduction of inactive Vitamin K thus limiting the
       synthesis of ACTIVATED clotting factors


      Absorption
          o 100% absorbed in the gut
          o Peak serum levels @ 3 hours
          o Binds heavily to albumin  only free form active
      Metabolism
          o ½ life = 35 hours  5-6 days before steady state effect
          o Warfarin metabolized by P450 cytochrome system:
                  R Warfarin: CYP3A4
                  S Warfarin: CYP2C9
          o Metabolites are inactive and excreted in urine and bile
      Dosing
          o Loading doses are not needed
          o Typical starting doses are 5mg/day or 0.2mg/kg in kids

Therapeutic Effect of Warfarin

Key Points

      Patients are initially hypercoagulable
           o Warfarin first acts on the extrinsic pathway (factor VIIa)
           o It simultaneously acts on Protein C/S  removed faster than factor VIIa
      INR rises b/c of Factor VIIa clearance, but this does not indicate full anticoagulation
      Full anticoagulation is not reached until all factors (intrinsic pathway) are reduced
       to 25% of their normal levels  this takes 6-7 days
           o This is the rationale to overlap with heparin for 5 days

      Genetic traits alter the overall response  makes for a very variable titration
      The Vitamin K cycle is impaired immediately, but activated factors take a while to be
           o :. Vitamin K stores are removed very quickly (that is, activated vitamin K
               stores), but the anticoagulant effect of Warfarin is dependent on a
               balance between clearance of protein C/S and activated factor ½ life
      Protein C and S are impaired through the same process and are cleared faster than
       activated factors
      Factor VIIa is removed the fastest (1/2 life = 5 hours)
      INR may begin to climb at 15 hours due to Factor VIIa clearance, but protein C/S are
           o :. Patient’s are potentially HYPERCOAGULABLE for the first 12-15 hours
               of Warfarin initiation
      The true anticoagulant effect is not present until prothrombin is cleared and the
       remaining factors have been reduced to 25% of their initial levels
           o This takes 36-72 hours
Monitoring of Warfarin

      Prothrombin time (PT), expressed as an international normalized ratio (INR; tested
       against a standardized batch of thromboplastin) is used to measure warfarin Rx
      INR tests factors II, VII, X, but NOT IX
      Intentional ingestion:
           o Check INR at presentation and q8-12h until peak
      Accidental ingestion:
           o Check INR at 48 hours
      Elevated PT in the absence of Warfarin needs to be considered in the clinical context
           o After repletion of vitamin K and liver disease is ruled out  mixing study

Adverse Effects of Warfarin (Therapeutic or Toxic)

Major bleeding:

      Requiring hospitalization, resuscitation
      Requiring transfusion
      Hgb drop > 20 g/L
      Intracranial bleed causing stroke (FNS, lasting > 24 hours)

      Bleeding:
          o The major adverse effect of Warfarin is bleeding
          o Bleeds indicative of coagulation defect (versus thrombocytopenic):
                   Intracranial bleeds
                   GI bleeds
                   Ecchymosis
                   Hemarthrosis
                   Gross hematuria
                   Menorrhagia
                   Bleeding into the neck is life-threatening as has been reported
      Warfarin Skin Necrosis:
          o Thought to be microvascular thrombosis due to a reduction in protein C 
              risk much higher in protein C/S, AT deficient patients
      Purple toe syndrome:
          o Due to throwing of atheroemboli due to lack of clot adherence to plaques
      Urticaria
      Teratogenic

Bleeding with Warfarin Therapy

      The overall clinical bleed due to an ingestion of Warfarin is due to:
          o Host bleeding risk
          o Degree of anticoagulation
          o Fluctuation in INR (degree of monitoring)
          o Duration of anticoagulation  risk of bleeding is highest during initial
          o We know that the (annual) risk of significant hemorrhage increases
             exponentially with an INR > 4.0
   A review of literature has found the AVERAGE annual major hemorrhage (ICH, GI
    bleed needing blood) rate is 1.3% (Arch Intern Med 1994;154:1449-57)
   The risk of bleeding is dependent on host factors:
        o The HAS-BLED criteria is now recommended in Canada to assess annual
           bleeding risk while on Warfarin therapy (Can J Cardiol 2011;27:27-30)
        o The overall decision to place a patient on Warfarin is when the annual risk of
           a major event from NOT being anticoagulated (stroke, PE, MI, valves) stroke
           strongly outweighs the annual risk of a major bleed (HAS-BLED)  see
           appropriate topic reviews for discussion regarding risk-benefit ratio
                For instance:
                         CHADS2 = 1  annual stroke risk of 2.8%
                         HAS-BLED = 4  annual major bleed risk 8.7%
                May NOT place on Warfarin b/c major bleed >> than stroke

                               (Chest 2010;138:1093-100)

   The OVERALL clinical effect of OAC is dependent on all these host factors +
    IMPACT of the bleed:
       o A GI bleed with a 30 Hgb drop is a patient w/o a recent MI is much different
          than the patient with a recent stent
       o :. This must all be individualized
Management of Warfarin Overdose

      ABCDE
          o ABCs as per always
          o History of ingestion
          o Bleeding?
          o Decontamination:
                  None if active GIB
                  Give within 1 hour of acute ingestion
          o Elimination
                  Single dose of AC if no contraindications
          o Reversal
      Major reversal options

   Agent                                  Contents                       Advantages               Disadvantages
   Prothrombin complex              Factors IIa, VIIa,        Immediate reversal              Cost
   concentrate (PCC;                IXa, Xa, protein C/S      Consistent dose-response, esp
   Octaplex)                                                  to factor IXa
   Fresh frozen plasma (FFP)        Factors II, V, VII, IX,   Less expensive                  Blood product
                                    X, XI                                                     Slower onset (2-3
                                                                                              Variable effect on INR
                                                                                              Slower infusion
   Vitamin K1                       Reduced Vitamin K         See Vitamin K below
   Recombinant Factor VIIa          Activated FVIIa           Fast onset                      Not validated in acute
                                                                                              bleeding due to

      Guidelines for reversal in patients on chronic OAC (Chest. 2008;133:160S)

                            INR                                                 Recommendations
   < 5.0; no significant bleeding                             Omit next dose of warfarin
   > 5.0 but < 9.0; no significant bleeding                   Evaluate bleeding risk
                                                              Omit next 1-2 doses
                                                              If reversal needed prior to next 48 hours  1-2.5mg
                                                              Vitamin K1 PO qdaily prn
   > 9.0; no significant bleeding                             Stop Warfarin
                                                              Change to heparin if ongoing anticoagulation
                                                              Vitamin K1 5mg PO once then 1-2.5mg PO qdaily prn
   Any significant bleeding (INR > 1.5 = likely               Stop Warfarin
   coagulopathic)                                             Hemorrhagic stroke: Octaplex + 10mg IV Vitamin K1
                                                              Exsanguinating bleed: Octaplex + 10mg IV Vitamin K1
                                                              All other bleeds: FFP + 10mg Vitamin K1

      Major questions to consider in the warfarin-like agent:
          o Are they bleeding?
          o Is this pharmaceutical or rodenticide
          o Intentional or accidental  intentional  risk of serious complication
          o Do they need ongoing anticoagulation
      Bleeding  see guidelines above
          o Consider FFP/PCC
      There are three ways to think about treating NON-BLEEDING patients:
           o   H + P  do they need to come in?
                   > 25mg of Warfarin likely needs to be watched for a day
           o   Naïve patients
           o   Chronic a/c patients

Vitamin K usage in the non-bleeding overdose

      See Vitamin K for details
      DO NOT give prophylactic vitamin K1
      Watch their INR and watch for elevation
      Start giving Vitamin K1 at 5-10mg TID PO when their INR bumps and titrate up until
       their INR begins to come down
      Always consider if the PO route isn’t working  may need to give IV

      Naïve patients
          o Watch their INR’s and titrate up accordingly
          o Once their INR is normal, stop vitamin K1  d/c
      Chronic A/C patients
          o What is their initial indication  decide what their therapeutic INR is
          o Give vitamin K1 as above until their INR hits their normal target and then
          o Start heparin and essentially bridge their INR like any other until back to

                                    VITAMIN K


      Fat soluble vitamin
      Vitamin K1 (phytonadione, phylloquinone)
           o Essential vitamin synthesized by plants/algae
      Vitamin K2 (menaquinones)
           o Synthesized by gut flora
      Need about 70-100ug of vitamin K / day
      Takes a few weeks of persistent vitamin K depletion before INR begins to rise
      Very safe drug in PO form
      Major concern with IV is an anaphylactoid reaction


      Absorption
          o Fat-soluble  need bile and pancreatic juice
          o Peak doses occur around 6-8 hours  incredibly variable depending on
             absorption characteristics (gut edema, gut pathology)
                  Unknown effect on clotting factors, however  likely not until 10-12
          o IV takes effect at 4-6 hours, peaks at 9 hours
        Administration
           o PO  no effects
           o IV  concern is anaphylatcoid
                   Death has occurred
                   Is mixed in a colloid solution (b/c its fat soluble) that can cause the


        Variable due to absorption properties
        Effect is measured by reduction in INR
        PO
             o 8-24 hours depending on absorption
        IV
             o Possible 6-10 hours
        Overall comparison b/w the two at 24 hours showed no major difference in
         reduction in INR at same doses


        See Warfarin management for decision making
        If the patient is bleeding:
              o 10mg IV and recheck INR in 12 hours
        If not bleeding:
              o No prophylaxis is indicated
              o Wait for the peak INR
              o Start at 5mg PO once
              o Watch the INR q8-12h and titrate Vitamin K starting at 5-10mg PO TID for
                  serious ODs or LAAR (long acting anticoagulant rodenticides)
              o May need to max out doses at 250mg/day
              o Give IV if the PO may not be working for any reason

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