Warfarin/UFH

Question 1

Warfarin MOA

Answer 1

• Antagonizes Vitamin K epOxide Reductase Complex 1 (VKORC1)
• Inhibits carboxylation of factors II, VII, IX, X (procoags)
• Inhibits protein C and S (anticoags)

Question 2

Warfarin polymorphism

Answer 2

• Accounts for 30-40% of interpatient variability in daily warfarin dose**
• CYP2C9*2/3 & VKORC1 A/A require lower doses of warfarin

Question 3

Warfarin Indications

Answer 3

• Prevention and tx VTE
• Prevention/tx thromboembolism d/t valvular/nonvalvular AF or prosthetic valve (Preferred anticoag for AF with CAD, valvular AF, prosthetic valves**)
• May be used for recurrent TIA

Question 4

Warfarin dosing

Answer 4

• Start 2-4 mg/d or 5-10 mg/d for younger/healthier –> adjust dose based on INR
• Half life is 40 hrs** –> takes 2 days to see effect
• Large loading dose (>10 mg) create transient hypercoagulable state dt ec [Protein C]***

Question 5

Traditional Warfarin Dosing

Answer 5

• Lower doses may be required for: hepatic impairment, poor nutrition, HF, elderly**, pts on CYP2C9 inhibitors/polymorphisms of CYP2C9
• Higher doses may be required for: pts on CYP2C9 inducer, polymorphism of VKOR1

Question 6

Newer Warfarin dosing

Answer 6

Managed by “anticoagulation specialists”

Question 7

Warfarin Monitoring

Answer 7

• Anemia/bleeding–> H&H
• PT/INR (assess extrinsic, coagulation factors in common pathway)
• Prolongation of PT 1st few days d/t depression of factor VII

Question 8

Warfarin and LMWH/UFH

Answer 8

• Intrinsic pathway not initially altered by warfarin

- Must overlap w UFH or LMWH for at least 5d if rapid anticoag needed (VTE)**

Question 9

What should INR be of a patient on Warfarin? How often should you monitor?

Answer 9

• 2-3 (AF target is 2.5)
• Daily until stable, then q4wks
• Monitor more frequently if unpredictable response (ex concomitant meds that interact w warfarin)***

Question 10

Warfarin Reversal: non-life threatening

Answer 10

I.e. epistaxis: Vit K1 (phytonadione)–> PO takes 24-hr to restore factors II, VII, IX, X

Question 11

Warfarin Reversal: life threatening

Answer 11

• I.e. intracranial: Iv vit K PLUS PCC&raquo_space; FFP
• PCC lowers INR faster than FFP–> standard of care**
• FFP: not concentrated form of coag proteins & [clotting factor] vary**

Question 12

**KNOW THIS: INR >10 in Warfarin pt–> whatcha gonna do?

Answer 12

• Hold warfarin and give vit K 2.5-5 mg PO, even if not bleeding
• Monitor INR. Resume warfarin at lower doses with INR therapeutic
• Can give IV formulation of vit K orally. Mix w OJ to improve taste

Question 13

**KNOW THIS: INR 4.5-10 in Warfarin pt–> whatcha gonna do?

Answer 13

• Hold 1-2 doses of warfarin. Monitor INR. Resume warfarin at lower dose with INR therapeutic
• Vit K not routinely recommended if no evidence of bleeding
• Vit K can be used if urgent surgery needed (<5mg, w additional 1-2 mg in 24 hrs if needed) or bleeding risk high (1-2.5 mg)

Question 14

**KNOW THIS: INR above therapeutic range but <4.5 in Warfarin pt–> whatcha gonna do?

Answer 14

• Reduce or skip warfarin dose. Monitor INR. Resume warfarin when INR therapeutic
• Dose reduction may not be needed if only slightly above therapeutic range

Question 15

Warfarin drug interactions

Answer 15

• Pk: drugs that decrease absoprtion and CYP2C9 inhibitors and inducers (antimicrobials are worst–> TMP-SMX, metro, rifampin)
• Pd: other antiplatelet/anticoag–> bleeding
• Assume everything interacts with warfarin

Question 16

Warfarin ADRs

Answer 16

• Bleeding: don’t assume pts on chronic stable warfarin who develop heraturia is always 2ndary to anticoag**
• Skin necrosis/gangrene–> pt may have underlying protein C def**
• Purple toe syndrome
• Teratogen**

Question 17

UFH MOA

Answer 17

• Indirect thrombin inhibitor

- Converts circulating cofactor from slow to rapid inactivator of thrombin > factor Xa > others

Question 18

UFH indications

Answer 18

• DVT prophy
• Systemic anticoag (VTE tx)
• Anticoag for ECMO/HD
• ACS with PCI (unlabeled indication)

Question 19

UFH advantages

Answer 19

• Cheap, familiarity of use
• Rapid/complete reversal by protamine
• Not renally eliminated and may be safer in renal impairment
• Shorter 1/2 life (1.5 hr)–> might be better with high risk of bleeding pts

Question 20

UFH limitations

Answer 20

• Low therapeutic window
• Anticoag response varies widely
• Reduced ability to inactivate thrombin bound fibrin as well as Xa to activated platelets within a thrombus–> thrombus may grow***
• Possibility of HIT

Question 21

UFH dosing

Answer 21

• Situation dependent
• Usually want pt 1-5-2.5x baseline aPTT
• Optimal to get anticoagulated within 24 hrs**

Question 22

UFH monitoring

Answer 22

-aPTT–> intrinsic pathway (XII, XI, IX< VIII) and final common pathways (II, V, X)

Question 23

How often should you monitor platelets for patients on UFH?**

Answer 23

-q2-3d from day 4-14 or until heparin stopped

Question 24

Heparin reversal

Answer 24

• Nonurgent: turn down/stop heparin

- Urgent: Protamine by slow IV infusion

Question 25

UFH drug interactions

Answer 25

other antiplatelets, anticoags, NSAIDS–> bleeding

Question 26

UFH hemorrhage risk

Answer 26

• Congenital bleeding disorder
• Active ulcerative GI dz
• Severe uncontrolled HTN
• Use after recent brain/eye/spinal surgery***
• Pts on other anti-coag
• Severe liver dz
• Osteoporosis another risk

Question 27

Who is at risk for Heparin Induced Thrombocytopenia?

Answer 27

Pts after MAJOR surgery or trauma&raquo_space; minor surgery or medical therapy

Question 28

What is HIT?

Answer 28

• Immune mediated prothrombotic rxn that occurs when heparin binds to platelet factor 4
• Platelets get consumed and endothelial damage–> thrombi develop at site of damage
• Decline in plts >50%
• Thromboembolic events occur in ~50% of HIT cases (venous > arterial)

Question 29

Dx/Tx HIT

Answer 29

1) d/c all UFH/LMWH
2) administer direct thrombin inhibitor (argatroban) –> reduces thrombosis risk
3) Avoid prophy plt transfusion
4) Test for HIT abs (EIA)
5) d/c warfarin if on, give vit K
6) add “heparin allergy” to list, med bracelet
7) dx study for thrombosis (ex VTE)