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
o
o
Other anticoagulants, antiplatelets, and fibrinolytics
Herbal supplements
o (5 G’s), chamomile, chondroitin, dong quai
o High doses of Vitamin E and willow bark
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
o
Anticoagulants prevent blood clot formation and keep existing clots from becoming larger.
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
Oral Anticoagulants
o
What is one purported advantage of DOACs over VKAs?
o Few drug- food interactions, shorter DOA, less comparable bleeding



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.



10.
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
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?

12.
Accelerates AT activity and has much greater anti-factor Xa activity than
IIa.
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