1.

Describe the background of Anticoagulation

 Coagulation is the formation of a blood clot and involves platelet and clotting cascade activation
 Numerous factors such as blood vessel injury, blood stasis (blood flow slows or stops) and
prothrombic conditions activate the coagulation process.
 Blood clots form in the brain, heart, lungs and legs.
 An activated clotting factor activates the next clotting factor in sequence until fibrin forms and
cross links to hold clot together
 Activation pathway (Intrinsic) and Tissue factor pathway (extrinsic) lead to fibrin formation
2. Discuss the indications for anticoagulants
 Prevention of Cardioembolic stroke in Atrial fibrillation pts.
o Valvular or mitral stenosis: Warfarin is preferred.
o Non-valvular: DOACS are preferred.
 Prevention/treatment of VTE
o Acutely ill or After knee/hip replacement
o DOACS preferred, except in antiphospholid syndrome or mechanical heart valve.
o UFH, LMWH, Fondaparinux (off label for HIT)
 Immediate treatment of ACS
o Parenteral anticoagulants
 Reduction in the risk of major CVD events in CAD/PAD: Xarelto
3. Why is anticoagulation a high alert medication?
 Causes significant bleeding per ISMP
 Joint Commission require policies and protocols to initiate and mgmt therapy
 Defined process includes standardized ordering, dispensing, administration, monitoring and
pt/caregiver education to improve outcomes and decrease cost.
 Common visible bleeding or acute Hgh drop > 2g/dL signify that bleeding occurred.
o Epistaxis: nose bleeds
o Gums: from gingivitis
o Bruising
o Hematoma: bad bruise
o Hematemesis: blood in vomit from GI bleeding
o Hematuria: blood in urine
o Blood in the anus
4. What other drugs increase bleeding risk?
o Other anticoagulants, antiplatelets, and fibrinolytics
o Herbal supplements
o (5 G’s), chamomile, chondroitin, dong quai
o High doses of Vitamin E and willow bark
o NSAIDs, SSRI’s and SNRIs
5. List other drugs that can increase blood clotting risk?
o SERMS, Estrogen, and Aromatase inhibitors.
6. What supplements decrease the effectiveness of Warfarin?
o Green tea, coenzyme Q10 and St. John’s Wort and possibly ginseng
7. Compare doses of anticoagulants
o Anticoagulants prevent blood clot formation and keep existing clots from becoming larger.
o What is one purported advantage of DOACs over VKAs?
o Few drug- food interactions, shorter DOA, less comparable bleeding
o Parenteral Anticoagulants
 Heparins (Unfractionated heparin and LMWHs)
 UF VTE: 5000 units SQ Q8-12 hrs for ppx, 80 units/kg bolus, 18 units/kg/hr infusion
 UF ACS: 60 units/kg IV bolus than 12 units/kg/hr
 Enoxaparin ( Lovenox)
o VTE ppx: 30 mg SUBQ Q12 hrs or 40 mg SC daily
o VTE or NSTEMI treatment: 1 mg/kg SUBQ Q12 h or 1.5 mg/kg SC QD (inpt
VTE tx)
o STEMI treatment <75 y/o: 30 mg IV bolus plus 1mg/kg SQ
o STEMI treatment > 75 y/o: No bolus, CrCl <30: 1 mg/kg SC daily
 Dalteparin (Fragmin): Doesn’t treat STEMI
 Direct Thrombin Inhibitors
o Argatroban :Decrease dose in Hepatic impairment. Indicated for HIT and
pts at risk of HIT undergoing PCI
o Bivalirudin (Angiomax): Decease dose if crcl <30. Pts with ACS
undergoing PCI including HIT
 Factor Xa Inhibitors
o Fondaparinux (Arixtra): SC injection for VTE treatment/ppx. Caution in crcl
30-50 mL/min or crcl < 30 mL/min
o Oral Anticoagulants
 Vitamin K Antagonist (Warfarin)
o (Jantoven or Coumadin)
o Healthy outpatient: ≤ 10 mg daily for first 2 days than adjust dose
per INR
o Lower doses (≤ 5 mg) for certain conditions
 Elderly, malnourished, drugs that Inc its INR, liver disease, HF,
or high risk of bleeding
 INC INR: Metronidazole, Azoles, Amiodarone dec by 30-50%,
TMP/SMX
 Dec INR: CYP2C9 inducers and foods high in Vitamin K (greens,
broccoli, Brussel sprouts, collard greens and kale)
o Warfarin colors: pink, Lavendar, green, tan, blue, peach, teal, yellow, white
o 1 mg, 2, 2.5, 3, 4, 5, 6, 7.5, 10
 Direct Thrombin Inhibitors (Dabigatran)
o Pradaxa:
o Stroke ppx: 150 mg BID, reduce to 75 mg BID if crcl is btw 15-30.
o VTE treatment: 150 mg BID, start after 5-10 days of parenteral
anticoagulation.
 Xa Inhibitors
o Apixaban: (Eliquis)
 VTE TX: Initial 10 mg PO BID for 7 days, then 5 mg PO BID

o Rivaroxaban (Xarelto): VTE tx: Initial 15 mg PO BID x 21 days than

20 mg QD with food. Avoid if crcl < 30
o Edoxaban (Savaysa): Don't use if Crcl > 90. VTE tx: Start after
5-10 days of parenteral anticoagulation.
Stroke Prophylaxis in A. Fib

8. Compare the mechanism of action of parenteral and oral anticoagulants

 Warfarin: competitively inhibits the C1 subunit of the multi-unit vitamin K

epoxide reductase (VKORC1) enzyme complex.
o Reducing the regeneration of vitamin K epoxide and causes
depletion of active clotting factors 2,7,9 and 10 and protein C & S
 Heparins: Indirectly inhibit thrombin (factor 2a) and factor 10a by binding to
Antithrombin (AT).
 Fondaparinux: Binds to AT to increase AT activity (inactivate thrombin and
factor xa)
 DTIs: Directly block thrombin, decreasing the amt of fibrin for clot formation

9. Describe UFH uses, advantages and disadvantages.

 Uses: Continuous IV infusions for ACS tx and VTE tx/ppx bc of fast onset
and shorth half-life.
 Advantages: safer in renal impairment and has an antidote (Protamine)
 Disadvantages: Heparin Induced Thrombocytopenia (HIT), unpredictable
anticoagulation response and requires monitoring

10. List the contraindication, warning, side effects and monitoring of UFH.

 Contraindications: uc active bleed, severe thrombocytopenia or history of

HIT.
 Warning: Fatal medication errors: verify correct concentration
o Heparin lock-flushes (HepFlush) only keeps IV lines open
 o Fatal errors, esp in neonates, occur if incorrect concentration is
chosen.
o Heparin injection and flushes look and sound alike
 Side effects: bleeding (every type), thrombocytopenia, HIT, hyperkalemia.
 Monitoring: baseline plt,hgb, hct (> 50% plt dec suggest HIT), aPTT or
anti- xa levels after 6 hours and every 6 hours until therapeutic. Q24 hrs
with dose changes. aPTT therapeutic range is 1.5-2.5 x control

11. How is the mechanism of action of LMWH different from UFH?

 Accelerates AT activity and has much greater anti-factor Xa activity than

IIa.

12. How is the LMWH BBW, CI, SE and monitoring different from UFH?

 Advantage: More predictable anticoagulation response, Protamine

antidote
o Doesn't require anti-xa levels except for in pregnancy
o Obtain peak anti xa levels 4 hours after SC dose
 BBW: Risk of hematomas and subsequent paralysis for pts receiving
neuraxial anesthesia (epidural, spinal) or spinal puncture.
 CI: History of HIT or active bleed
 SE: bleeding, anemia, inj site rxns (e.g. pain, bruising, hematomas),
decreased plts (thrombocytopenia, HIT)
 Monitoring: Platelets, Hgb, Hct, SCr
o Useful in renal insufficiency, obesity, low body weight
 How is LMWH stored? Room temperature
 What causes patient to lose some drug? Expelling air bubble from springe

13. How to assess the probability of HIT? Calculate the 4Ts score

 Thrombocytopenia: unexplained >50% decrease in plts from baseline

 Timing: onset occurs 5-10 days after initiation
 Thrombosis: can be new suspected or confirmed thrombosis or skin
lesions
 Other causes: inability to identify other probable causes of HIT

14. How to treat HIT?

 Stop all forms of heparin or LMWH including heparin flushes or catheters

 If already on Warfarin and has HIT, D/C warfarin and give Vitamin K
o Restart at lower doses (5 mg max) when plt count is > 150
cells/mm^3
o Bridge with another anticoagulant for min of 5 days until INR is in
target range consecutively
 Immediate treatment: Rapid-acting non-heparin anticoagulants (e.g.
Argatroban)
 Bivalirudin is preferred anticoagulant for urgent cardiac surgery or PCI

15. Why does Warfarin have to be bridged? Delayed onset of action

16. What is HIT?

 An immune – mediated IgG drug reaction that has high risk of venous and
arterial thrombosis.
 Immune system forms antibodies that bind with heparin and platelet factor
4 (PF4) to form a complex
 The complex binds to the Fc receptors on platelets to cause platelet
activation.
 This prothrombic state and if left untreated can cause many complications
o HITT leading to amputations, post-thrombotic syndrome, and/or
death

17. List Oral Direct Factor Xa Inhibitors BBW, CI, Warning, SE, and monitoring

 BBW: Same as LMWH, Edoxaban (reduced efficacy in CrCl >90 ml/min)

 CI: Active pathological bleeding
 Warnings: not recommended w/prosthetic heart valves or antiphospholipid
syndrome
 Side effects: well tolerated, unless bleeding occurs
 Monitoring: Hgh, Hct, Scr, LFTs, no monitoring of efficacy required.

18. List Oral Direct Factor Xa Inhibitors Counseling and clinical pearls

 All can be crushed in apple sauce or in water for NG tube

 Apixaban (Eliquis): crushed into apple juice, D5W and apple juice
 Discontinue 24 hours before elective surgery or low bleeding risk for
Eliquis
 Discontinue 48 hours before elective surgery if Eliquis pt at moderate- high
risk of bleeding.
 Antidote Andexanet alfa (Andexxa) for Eliquis and Xarelto
 Take missed dose immediately on same day, don't double dose
o Rivaroxaban (Xarelto): Take once daily medication immediately
and take BID medication all at once
 Xarelto doses > 15 mg require an evening meal

19. List Fondaparinux BBW, CI, SE, Monitoring and Antidote

 Given SC
 BBW: Same as LMWH
 CI: Severe renal impairment (CrCl < 30 ml/min) and active major bleed
 SE: bleeding (all types), anemia, local injection site rxns (rash, pruritus,
bruising) and thrombocytopenia.
 Monitoring: Anti-Xa levels (3 hours post- dose), platelets, hgb, hct , SCr
 No Antidote

20. Why are there factor Xa drugs interactions?

 Other drugs increase bleeding risk

 Rivaroxaban (Xarelto): CYP3A4 and P-gp substrate
 o Avoid dual inducers or decrease dose by 50% with strong dual
inhibitors.
 Apixaban (Eliquis): CYP3A4 and P-gp substrate
o Avoid dual inducers or inhibitors

21. How to switch between oral anticoagulants and warfarin?

 From Warfarin: INR lowers (READ, <3, <2.5, <2, <2)

 To Warfarin: Oral Xa: stop it and start parenteral anticoagulant + warfarin
at next dose.
 To Warfarin: Start warfarin 1-3 days before stopping Dabigatran.

22. What is BBW, CI, Warning, SE, Monitoring and notes of Dabigatran?

 BBW: same as LMWH and Xa inhibitors

 CI: active pathological bleeding and mechanical prosthetic heart valves
 SE: dyspepsia (indigestion), gastritis- like symptoms, bleeding (including
GI bleeding)
 Monitoring: Hgb, Hct, Scr, no monitoring of efficacy required
 Antidote: Idarucizumab( Praxbind)
 Keep capsules in original container and discard in 4 months to protect from
moisture.
 Swallow capsule whole and don't administer by NG tube: took quick rapid
anticoagulation

23. What is the CI, Warning, SE and Monitoring of Injectable DTI?

 CI: active major bleeding

 Side effects; bleeding (mild- severe), anemia
 Monitoring: aPTT, activating clotting time, plts, hgb, hct, renal function
 Argatroban: increases INR, dose cautiously and avoid LD of warfarin
 Safe with active HIT or history of HIT: no cross reaction with HIT
antibodies
 NO ANTIDOTE

24. What is BBW, CI, Warning, SE and Monitoring of Warfarin?

 BBW: Major or fatal bleeding

 CI: Pregnancy (except with mechanical heart valves)
 Warnings: Tissue necrosis/gangrene, HIT (CI as initial tx in HIT), presence
of CYP2C9 *2 or *3 allele and/or polymorphism of VKORC1 increases
bleeding risk
 SE: bleeding/bruising, skin necrosis, purple toe syndrome
 Monitoring: INR after initial 2-3 doses and every 4-12 weeks if on stable
dose
o Goal: for most indications: 2-3
o Goal for mechanical mitral valve: 2.5-3.5
 Antidote: Vitamin K
  S-warfarin is more potent than R therefore drugs that interact via CYP2C9
have greater impact of Warfarin anticoagulant impact.
o Minor substrate of 2C19 and 3A4.

25. What are a few key points of Warfarin?

 Healthy pts: Initiate doses ≤ 10 mg daily for the first 2 days than adjust
based on INR
 Acute DVT/PE treatment: Start on the same day as parenteral
anticoagulant and continue for minimum of 5 days and until the INR is ≥ 2
for 24 hours
 No pharmacogenomic testing, VK supplementation or bridging with single
low INR, obtain another INR within 1-2 weeks if on stable dose and have
one out of range INR ≤ 0.5

26. Why use reversal agents?

 Reverse life-threatening bleeding or pt requires surgery.

 Protamine MOA: binds to acidic heparin to form a stable salt complex
which neutralizes anticoagulant activity of heparins

27. How does Protamine dosing differ for the heparins?

 UFH: 1mg of Protamine reverses about 100 units of heparin given in the
last 2-2.5 hours (short half life)
 Maximum dose: 50 mg
 LMWH
o Enoxaparin: 1mg per 1 mg of Lovenox given in last 8 hours
 0.5 mg Protamine per 1 mg of Lovenox given > 8 hours
o Dalteparin : 1 mg per 100 anti-xa levels of Dalteparin
 Formulation: Administer slow IV push (max rate of 50 mg over 10 minutes)

28. What are the formulations, BBW, SE and counseling points of Phytonadione?

 Vitamin K (Mephyton): comes as oral and IV

 BBW: Hypersensitivity rxns (HSR) occur rarely during or after
administration
 SE: Anaphylaxis, flushing, rash, dizziness
 Requires light protection during administration
 Why not SC or IM route? Variable absorption and risk of hematoma
o SC for slow onset

29. List other reversal agents?

 4 Factor Prothrombin Complex Concentrate (Human) (Kcentra)

o Administer with Vitamin K
o Refrigerate and sit at room temp before use
o Against Factors: 2,7,9, 10, Protein C and S
 3 Factor Prothrombin Complex Concentrate (Human) (Profilnine)
o Administer with Vitamin K (off label use)
 o Warning: Contains factor 2, 9, 10 and subtherapeutic levels of 7
 Factor 7a Recombinant ( NovoSeven, Sevenfact)
o Off-Label use
o BBW: serious thrombotic events

30. Discuss Warfarin reversal in depth.

 Elevated INRs are concerning for increased risk of bleeding

 Vitamin K + or – other medications (K centra)
 Oral Vitamin K: 2.5-5 mg preferred without significant major bleeding
 IV Vitamin K: for serious bleeding. Infuse slowly to avoid anaphylaxis
 Symptoms/INR value
o INR ≤ 4.5: Reduce or skip warfarin dose, monitor INR
o INR 4.5-10: Hold 1-2 doses of Warfarin
o INR > 10: Oral Vitamin K. Monitor INR. Resume warfarin at lower
dose
o Major Bleeding: Slow IV injection of Vitamin K (5-10 mg) & PCC

31. How to mgmt patients on Warfarin before operation?

 Stop warfarin 5 days before major surgery

o Resume 12-24 hours after surgery when hemostasis is
achieved.
 Recommend bridge therapy with LMWH or UFH for mechanical heart
valve, AF or VTE pts at high risk of thromboembolism
o Bridging means stopping warfarin and using LMWH or UFH
doses for a short period to prevent clotting.
o D/C SC LMWH 24 hours before surgery
o D/C IV UFH 4-6 hours before surgery

32. How to diagnosis patient with VTE?

 Symptoms: pain in affected limb and unilateral lower extremity swelling

 DVT diagnosed by an ultrasound
 PE diagnosed by a pulmonary CT angiogram

33. What are risk factors for the development of VTE?

 Modifiable Risk Factors

o Acute medical illness, Immobility
o Medications
 SERMS, Estrogen, ESAs
o Obesity (BMI >30 kg/m^2)
o Pregnancy/Postpartum
o Recent surgery or major trauma
 Non-modifiable Risk Factors
o Increasing age
 o Cancer or chemotherapy
o Previous VTE
o Inherited or acquired thrombophilia
 Antithrombin deficiency
 Factor V Leiden
 Antiphospholipid syndrome
 Protein C or S deficiency
o Certain disease states
 Heart failure, nephrotic syndrome, respiratory failure

34. What anticoagulants are approved for VTE ppx?

 UFH, LMWH, fondaparinux, rivaroxaban and apixaban

 If contraindicated, use nondrug alternatives
o Intermittent pneumatic compression (IPC) devices
o Graduated compression stockings (GCS)
o Long-distance travelers at risk of VTE
 Frequent ambulation, calf muscle exercises and
graduated compression stockings

35. How to determine the duration and preferred drugs in VTE tx ?

 Duration depends on if VTE was provoked or unprovoked

o Reversible risk factor: 3-month treatment
o Unprovoked risk factor: > 3-month treatment if bleeding risk is low
o 2+ Unprovoked episodes: long-term treatment considered
 Preferred drug depends on if pts had cancer
o No cancer: Dabigatran (Praxada) or Oral Xa inhibitors preferred
o Cancer: Oral Xa inhibitors are preferred

36. Why use anticoagulants in Atrial fibrillation?

  A. Fib pts can form a clot in the heart that can travel to the brain causing a
cardioembolic stroke or transient ischemic attack (TIA).
 Stroke prevention is an important goal in A fib pt.
o Some pts undergo cardioversion to regain normal sinus rhythm
o Recommended anticoagulation tx prevents atrial thrombosis and
subsequent stroke due to procedure
 AF> 48 hrs or unknown: anticoag. For 3 wks before and 4
wks after cardioversion
 AF≤48 hours: start anticoag at presentation, perform
cardioversion, and continue full anticoagulation for at least
4 wks.
 The need for chronic anticoagulation tx is based on stroke risk
o Mechanical heart valve pts has the highest risk for clotting/strokes
 Warfarin only used
o Major of pts has non-valvular AF
o CHA2DS2-VAS: estimates stroke risk
 Score of 2 (m) or 3 (w)= anticag for ppx
 HAS-BLED assesses bleeding risk for pts on anticoag. For stroke ppx
o Higher score= greater bleeding risk

37. What is recommended for stroke ppx in A. Fib pts?

 DOACS recommended warfarin.

38. Which agent is the best choice for prevention or treatment for a pregnant
woman with DVT?

 Pneumatic compression devices + or – LMWH preferred.

 Warfarin is teratogenic, switch back to warfarin in pts with mechanical
heart valve or inherited thrombophilia than converted back to LMWH
closer to delivery.
 Monitoring the anti-Xa levels are recommended with LMWH use.
39. Where can a patient inject Enoxaparin?

 On the left or right side of tummy

 2 inches from belly button
 Don't rub inj site