2. Learning Objectives
• List different intravenous and oral anticoagulant options
• Describe the mechanisms of action, administration route,
monitoring parameters, pharmacodynamics, and pharmacokinetics
for each anticoagulant covered
• Summarize the indications and reversal agent(s) for each
anticoagulant
• Describe the pros and cons for the different classes of
anticoagulants
7. Indirect thrombin inhibitors
Wikimedia Commons, Creative Commons License. 2011. User Jü.
Unfractionated heparin Low molecular weight
heparin
Fondaparinux
Onset of action IV: immediate
SQ: ~ 20 – 30min
3 – 5 hours 2 -3 hours
Half-life elimination 1 – 2 hours 4.5 – 7 hours 17 – 21 hours
Bioavailability 20 – 30%
Significant inter & intra-
individual variation
70 – 100% 100%
Metabolism Hepatic and spleen Hepatic Not established
Excretion Mostly non-renal Urine ~40% unchanged
drug, decreased by 30%
in patients with CrCl <
30 ml/min
Urine (70% unchanged
drug)
Continuous infusion
Frequent monitor
and adjustment
No renal
adjustmen
Intermittent SC
More predictable
Caution in renal failure
8. Indirect Thrombin Inhibitors: Pros and Cons
Unfractionated heparin Enoxaparin Fondaparinux
Administration Treatment: Continuous IV
infusion
Prophylaxis: SC
SC (once or twice daily) SC (once daily)
Lab monitor aPTT or anti Xa or ACT
Frequent monitor and
adjustment
Anti Xa
Not required routinely
(except: extreme weight,
pregnancy, renal failure)
Anti Xa
Not required
Reversible agent Protamine Partly reversible with protamine Not available
Renal failure Safe Use with caution Contraindicated
ADR High risk of heparin
induced
thrombocytopenia (HIT)
Higher risk of bleeding
Lower risk of HIT
Bleeding
Very low risk of HIT
Bleeding
10. Question 1
• A 65-year-old woman is evaluated in the emergency department for a 1-
day history of pain and swelling in her left leg. Medical history is significant
for coronary artery bypass graft surgery 8 days ago with vein harvesting
from the right leg. She also has hypertension and hyperlipidemia.
Medications are atorvastatin, atenolol, clopidogrel, and aspirin.
• On physical examination, temperature is 37.0 °C, BP 115/68 mm Hg,
pulse rate 65/min, and respiration rate 18/min. Oxygen saturation is 96%.
Her sternotomy incision is healing well. The cardiopulmonary examination
is normal. The left leg is swollen to the mid-thigh.
• Laboratory studies reveal a hematocrit of 33%, leukocyte count of
12,000/µL (12 × 109/L), and platelet count of 55,000/µL (55 × 109/L).
• Duplex ultrasonography of the left leg shows acute thrombus in the
common femoral vein.
• What is the most appropriate next step?
11. Heparin induced thrombocytopenia
Mechanism
• Platelet factor 4 (PF4)
• Located in platelet α-granules
• PF4 on platelet surface combined with
glycosaminoglycans (GAG)
• Heparin forms complex with PF4
• PF4/heparin complexes may be immunogenic
• Form antibodies to PF4/heparin and PF4/GAG
complexes
• Antibodies to PF4/heparin/GAG complexes bind
on surface of platelets
• Fc tails of the IgG bind to platelet FcγIIa
receptors
• Results in platelet activation and formation of
platelet microparticles (and resulting
thrombocytopenia)
• Microparticles accelerate thrombin formation
Uptodate.com
12. Heparin Induced Thrombocytopenia (HIT)
• Heparin-induced Thrombocytopenia (HIT) is a clinical diagnosis
• Occurs in ~1-3% of postoperative patients
• Occurs after first-time heparin exposure within past 5 to 10 days OR repeat
exposure within 1 day if first dose within past 100 days
• Causes platelet count <150,000 OR drop of 30-50% from baseline
• Check 4Ts score: pretest clinical scoring system for HIT
• Thrombocytopenia
• Timing of thrombocytopenia relative to heparin exposure
• Thrombosis or other sequelae of HIT
• Likelihood of other causes of thrombocytopenia
13. HIT diagnosis
IMMUNOASSAYS
- ELISA to detect PF4-heparin antibody
- Fast and easy to interpret
- Very high sensitivity (91 – 97%)
- Higher incidence of false positive
FUNCTIONAL ASSAYS
- Serotonin release assay
- High specificity and sensitivity (> 90%)
- ~ 5% false negative
- Prolonged turnaround time
14. HIT diagnosis & management
• Reverse warfarin with vitamin K if patient on warfarin
(due to transient hypercoagulable state during
initiation)
• Anticoagulate with fondaparinux, argatroban,
bivalirudin, or DOAC and follow platelet count
recovery >150,000 before restarting warfarin
• Avoid prophylactic platelet transfusions
• Anticoagulat with DOAC/warfarin (INR 2-3) for 3
months
Clinical suspection
of HIT
HIT confirmed
HIT is unlikely.
Resume or
continue heparin
if indicated
Immuno-
assay
Functional
assay
16. Mechanism of action
• Mechanism: inhibits vitamin K epoxide-reductase and vitamin K-
reductase; interferes with synthesis of vitamin K dependent clotting
factors, including factors II, VII, IX, X and protein C and S
Transient hypercoagulable state during initiation.
Delayed anticoagulating effect
17. Warfarin – clinical pearls
• Slow onset and offset – bridging might be necessary in certain
circumstances.
• Dose varies significantly, depending on many factors.
• Long t1/2 weekly dose can be used for dose adjustment
• Target INR is 2.0 – 3.0 in most but not all cases
• Very sensitive to drug-drug and drug-food interaction please
check!!!
18. Warfarin: Drug Interaction Examples
• Serious INR Elevations:
• Broad spectrum antibiotics impair vitamin K
production/absorption by affecting gut bacteria
(in addition to enzymatic pathway interaction:
2C9/3A4)
• Majority of antifungals (-azoles) increase INR
by inhibition of warfarin metabolism
• High dose steroids (dexamethasone) increase
INR by an unknown mechanism
• Serious INR Reductions:
• Drug interaction between Nafcillin/Warfarin and
Rifampin/Warfarin can be significant
• Onset of induction may take 5-7 days and
the effects last two-four weeks after
discontinuation
• May require 50% to 300% increase in
previous warfarin dose to achieve
therapeutic INR levels
19. Wafarin: Drug interaction examples
INHIBITOR
• Competitive inhibition
• Fast onset
19
INDUCER
• Increase enzyme production
• Slow onset
20. Question 2
• A 73-year-old woman is evaluated in the emergency department following
a fall in her home. She tripped and fell over a rug. She did not lose
consciousness but is experiencing left hip pain. Medical history is
remarkable for atrial fibrillation. Her only medication is warfarin.
• On physical examination, the patient is afebrile, BP 137/88 mm Hg, pulse
rate 105/min and irregular, and respiration rate 14/min. The lungs are
clear to auscultation, and the cardiac examination is significant only for an
irregular rate. She has mild tenderness to palpation over the left hip. No
hematoma or other bleeding is evident. The remainder of the examination
is unremarkable.
• Laboratory studies show a normal hemoglobin level and an INR of 10.2.
• Radiographs of the left hip are negative for fracture.
• Question: what is the appropriate management of this patient’s
anticoagulant?
24. Question 3
• A 38-year-old man is evaluated in the emergency department for swelling of the left lower
extremity of 24 hours' duration. Medical history is noncontributory, and he takes no
medications.
• On physical examination, temperature is 36.1 °C, BP 120/75 mm Hg, pulse rate 80/min, and
respiration rate 14/min. Pulses are intact. He has a swollen left calf that is slightly tender to
palpation.
• Laboratory studies show an activated partial thromboplastin time of 32 seconds, platelet count
of 256,000/µL (256 × 109/L), and INR of 1.0.
• Doppler ultrasonography of the left leg shows an acute clot in the left popliteal vein extending
to the iliac vein.
• The patient expresses significant concern about anticoagulant therapy. An uncle died of a
cerebral hemorrhage while being treated for acute coronary syndrome.
• What’s the best treatment plan for him?
26. Comparision VKA and DOAC
• DOAC is at least as effective or even more effective than VKA
• DOAC reduce risk of major and fatal bleeding, intracranial bleeding at risk of
increased GI bleeding (except apixaban and edoxaban)
Makam, et al. PLOS ONE 2018. https://doi.org/10.1371/journal.pone.0197583
27. 1. Long-term safety profile less
established
2. Difficult to monitor
3. Drug cost
4. Short half-life
Pros Cons
1. Efficacy (non-
inferior/superior to
warfarin)
2. Safety (less bleeding than
warfarin)
3. No need for monitoring
4. Few interactions with
medications and diet
5. Easier to “turn” on and off
DOACs vs Warfarin: Pros and Cons
28. Consideration when initiate DOAC
• Preferred over VKA in VTE/AF
• VKA preferred in mechanical valve, antiphospholipid
syndrome
Indication
• Fewer interactions
• Difficult to manage if major interaction occurs
Drug interaction
• Poor adherence: VKA preferred
• Long term affordability is problematic
Adherence/Affordability
• VKA is historically preferred due to ability to monitor
• Growing evidence supports DOAC
Extreme conditions
(weight, renal, hepatic failure…)
29. Reversal of DOAC
• Idarucizumab: specific antidote for
dabigatran
• Can pull dabigatran out of circulation and off
of thrombin and render it inactive.
• Andexanet alfa:
• Decoy factor Xa protein with a high affinity
for Xa inhibitor (also LMWH and
fondapariux)
• Only reverse antiXa activity during and
shortly after infusion, then returns to placebo
only provide a time window to locate and
treat the bleed
• Officially approve for rivaroxaban and
apixaban.
N Engl J Med 2015; 373:2413-2424
30. Pros & Cons of different DOACs
Pros Cons
Dabigatran • First DOAC available Data available in
certain rare indications
• The only DOAC that significantly reduce
ischemic stroke.
• Antidote is readily available
• Twice daily dosing
• Higher risk of GI bleeding, dyspepsia 10%
• Significantly depend on renal function, drug
interaction not idea for elderly
• Break the capsule increase 70% bioavailability
Rivaroxaban • Once daily dosing
• Most popular DOAC in Vietnam
• Higher risk of bleeding
• Avoid in liver failure
Apixaban • Lower risk of bleeding (both ICH and GI)
• Suitable for elderly
• Can be used in ESRD and Hemodialysis.
• Twice daily dosing
Edoxaban • Once daily dosing
• Lower risk of bleeding (both ICH and GI)
• Very low dose may be used in patients
deemed unsuitable for anticoagulation
• Least sensitive to drug interaction
• Significantly depend on renal function and
weight
• Andexanet alfa may be used as antidote but off
label
31. Current data of DOAC in special population
Support Against
Overweight Rivaroxaban, Apixaban Dabigatran, edoxaban
Underweight Edoxaban
Renal failure Apixaban Dabigatran
Hepatic failure Apixaban, edoxaban, dabigatran (CTP
class A, B)
Rivaroxaban
Elderly Apixaban Dabigatran
Breastfeeding Dabigatran Apixaban
Check with your
pharmacist
33. PATIENT CASE
• H.T is a 51 year old Japanese man with no significant medical history. He presents to the ED
with symptoms of chest pain which intensify when he moves his hand and lessen as he stays
still.
• On presentation, he is alert and oriented, BP 130/80, HR 64, RR 19. Lab test is insignificant
except for D-dimer > 1400 ng/mL,
• CT scan shows: presence of thrombus in the pulmonary artery branches in the both sides
(segmental and sub-segmental arteries), prominence on the left side.
• Lower extremity arterial Doppler shows no presence of thrombosis or insufficiency veins of the
bilateral lower limbs.
• Normal echo.
• Question
• Estimate the risk of this patient and design an appropriate treatment plan.
34. Risk stratification
• Distal DVT
• May not be treated in low risk patients
• Factors favor treatment: severe symptoms,
ongoing risk factors.
• Duration: no more than 3 months
• Proximal DVT
• More likely to cause PE
• Anticoagulant is a must regardless of symptoms.
• Phlegmasia cerulea dolens
• Marked swelling and obstruction in veins lead to
arterial ischemia and gangrene
• High risk of amputation and mortality
• UFH is preferred
• Surgery/endovascular thrombectomy or
thrombolysis may be employed
35. Risk stratification
• Isolated subsegmental PE
• Without anticoagulant: 8%
recurrence VTE with no fatal PE.
• May/maynot use anticoagulant
base on individual risk/benefit.
36. Risk stratification
Non massive PE Sub-massive PE Massive PE
RV dysfunction or
myocardial injury or
high PESI risk score
No Yes Yes
Hypotension No No Yes
Anticoagulation DOAC preferred LMWH/UFH maybe preferred
DOAC acceptable in lower risk
UFH preferred
LMWH may be acceptable
tPA No Maybe consider in very high risk Yes
38. Treatment of vte
Duration is different
between DOACs and can
not be logically explained
Trials were not powered to
detect differences between
lower and higher DOAC
doses
Dose adjustment criteria
and contraindication are
different than those of
AF
40. Patient case
• He is prescribed rivaroxaban 15mg twice daily and tolerates the
treatment
• Day 3, his lab test results come back as follow
• Lupus anticoagulant screen: positive
• Lupus anticoagulant confirm: positive
• Anti beta2 glycoprotein IgM: negative
• Anti beta 2 glycoprotein IgG: negative
• Anticardiolipin IgM: negative
• Anticardiolipin IgG: negative
• Question:
• What does it mean and how does it affect your plan?
41. Antiphospholipid syndrome
• Systemic autoimmune thrombophilia
• Characterized by
• arterial, venous, or small vessel
thrombosis
• Recurrent early pregnancy loss or
pregnancy morbidity.
43. Clinical Laboratory assessment
• Positive antibodies must be confirmed 12 weeks
apart.
• Testing during the acute phase carries significant
risk of false-positive.
• LA, aCLs or anti-B2GPI may individually be
present or absent.
• Conflict data regarding which antibody carrying
higher thrombosis risk than other.
• Triple positive is considered as the highest risk.
44. Anticoagulant for APS
• Warfarin remain gold standard.
• Optimal INR target is less clear. Guidelines suggest:
• APS venous events: INR 2.0 – 3.0
• APS arterial events: INR 2.0 – 4.0 +/- aspirin
• In highest risk APS patients (triple positive or arterial events),
DOACs increase risk of thrombotic events with no change in
bleeding risk.
• In lower risk APS patients, role of DOAC is unclear.
45.
46. Question?
• Positive antibodies must be confirmed 12 weeks
apart.
• Testing during the acute phase carries significant
risk of false-positive.
Which OAC to use while
waiting for
confirmation tests?
