IC3 Anticoagulants

Question 1

What are the 4 stages of hemostasis and thrombosis?

Answer 1

1. Vasoconstriction
2. Primary hemostasis - platelet aggregation
3. Secondary hemostasis - thrombin activation
4. Clot stabilizzation

Question 2

Which stage do anticoagulants act on?

Answer 2

Secondary hemostasis - thrombin activation

By blocking different clotting factors in the intrinsic, extrinsic, or common pathway of the coagulation cascade

Question 3

What do each of these drugs block:

• Warfarin
• Dabigatran
• Rivaroxaban
• Heparin
• LMWH (Enoxaparin)

Answer 3

• Warfarin: VII, IX, II, X
• Dabigatran: II
• Rivaroxaban: X
• Heparin: intrinsic, II, IX, X, XI, XII
• LMWH (Enoxaparin): X, II (lesser extent)

Question 4

MOA of Warfarin

Answer 4

Normal physiology:

• active Vit K hydroquinone is oxidized to inactive Vit K epoxide in a step coupled to carboxylation of glutamic acid residues on coagulation factors II, VII, IX, X
• this carboxylation step activates the coagulation factors IIa, VIIa, IXa, Xa

=> Vit K activates clotting

Warfarin:

• inhibits the VKORC1 (Vit K reductase) enzyme that is responsible for reactivating oxidized inactive Vit K epoxide into reduced active Vit K hydroquinone
• hence, inhibiting activation of the coagulation factors

Question 5

Reversal agent for Warfarin

Answer 5

Vitamin K

Question 6

Onset of action of Warfarin: 24-72h

Why is there a delayed onset?

Answer 6

1. Delayed onset due to endogenous stores/reserves of active Vit K
2. Warfarin confers an initial hypercoagulable state due to depletion of protein C & S (endogenous anticoagulants)

• Protein C depletion occurs quickly, and disrupts normal inhibition of factors V and VIII

*Therefore bridging therapy with LMWH needed in VTE treatment

Question 7

Metabolism of Warfarin is primarily via ____

Answer 7

CYP2C9

• S-Warfarin is the active enantiomer that is metablized by CYP2C9

Question 8

Genetic polymorphisms in which 2 genes may cause variability in response to Warfarin

Answer 8

CYP2C9
VKORC1

Question 9

Adverse effects of Warfarin

Answer 9

• bleeding
• GI SEs: dyspepsia, diarrhea, N/V
• Hirsutism, Alopecia
• cutaneous necrosis - due to reduced blood supply to adipsoe tissue, typically occurs 3-5 das after initiating tx
• hepatitis (rare) - greatest risk for >60yo, male, on warfarin for <1m, alcohol, obesity
• calciphylaxis (rare, in ESRD)
• cholesterol microemboli

Question 10

Contraindications with Warfarin

Answer 10

• hypersensitivity
• active bleeding/risk of pathological bleeding
• recent major surgery
• severe/malignant HTN
• severe hepatic impairment (child-pugh C)
• severe renal impairment (stage 5 CKD)
• pt w bacterial endocarditis, pericarditis, pericardial effusion
• blood dyscrasias (esp bleeding/thrombocytopenia)
• pregnancy (except in women with mechanical heart valve at high risk for thromboembolism)

*For pregnancy - most teratogenic 1st trimester, 2-4 weeks before delivery

Question 11

Caution with Warfarin

Answer 11

• Bariatric surgery - gastric bypass, gastrectomy
• Heparin-induced thrombocytopenia (inhibition of protein c synthesis may accelerate thrombotic process)
• Hepatic impairment - impair synthesis of clotting factors, reduces warfarin metabolism (incr INR)
• renal impairment
• acute infection (disruption to gut flora, febrile state => incr INR)
• thyroid disease (hyperthyroidism => incr INR)

Others:
- diverticulitis, colitis
- mild-mod HTN
- PUD within last 3m
- chronic alcohol use (dcr INR)
- drainage tubes in any orifice

Question 12

MOA of dabigatran

Answer 12

Dabigatran and its acyl glucuronide metabolites are competitive reversible non-peptide antagonists of thrombin (factor IIa)
*Directly binds to thrombin

Dabigatran etexilate (prodrug) => Dabigatran

Question 13

Dabigatran formulation and why?

Answer 13

Enteric coated due to low oral bioavailability

Question 14

Dabigatran formulation and why?

Answer 14

Enteric coated due to low oral bioavailability

Question 15

Reversal agent for Dabigatran

Answer 15

Idarucizumab
- humanized mAb that binds to dabigatran and its acyl glucuronide metabolites with higher affinity than the binding affinity of Dabigatran + Thrombin

*Dabigatran has half-life 12-17h, hence effects can be reversed in 3-5days of discontinuation

Question 16

Adverse effects of Dabigatran

Answer 16

• bleeding
• GI symtpoms (dyspepsia, abdominal discomfort)

Question 17

DDIs with Dabigatran

Answer 17

Dabigatran is largely excreted unchanged, renally
NOT metabolized by CYP3A4 (unlike other DOACs)

• incr risk of bleeding with antiplatelets, anticoagulants, NSAIDs
• Rifampicin might reduce Dabigatran levels

Question 18

Rivaroxaban MOA

Answer 18

Competitive reversible antagonist of activated factor Xa

Question 19

Adverse effects of Rivaroxaban

Answer 19

• Bleeding
• Gastroenteritis (stomach discomfort)
• N/V

Question 20

Severe adverse effects of Rivaroxaban

Answer 20

Hemorrhage, spinal/epidural blood hematomas

Question 21

Absolute contraindications to the use of Rivaroxaban

Answer 21

• Severe hypersensitivity
• Active pathological bleeding (e.g., PUD)
• Hepatic disease (child-pugh B and C), a/w coagulopathy and bleeding risk
• Incr risk of significant bleeding
• valvular disease - mechanical prosthetic mitral heart valve implant (DOC: Warfarin)

Relative
- APS (DOC: Warfarin)

Question 22

Metabolism and Clearance of Rivaroxaban

Answer 22

33% cleared renally unchanged

66% metabolised by liver:

• 33% of liver metabolite cleared renally
• 33% of liver metabolite cleared in feces

Question 23

Can Rivaroxaban be used in pregnancy and lactation?

Answer 23

Not recommended, switch to LMWH

Question 24

Reversal agent for Rivaroxaban

Answer 24

Andexanet alfa (NA in SG)
- recombinant modified human factor Xa decoy protein for reversal of -xabans (and off-label LMWHs)
- Xaban binds to decoy factor Xa instead of endogenous Xa

Question 25

Rivaroxaban is a substrate of:

Answer 25

CYP3A4 PGP BCRP OATP

Question 26

Rivaroxaban administration with regards to food

Answer 26

- 2.5mg and 10mg may be administered without regards to food - 15mg and 20mg should be administered with/after food Why? - bioavailability is lower for high doses due to dissolution-limited absorption

Question 27

Heparin and LMWHs dosage form

Answer 27

Parenteral (IV/SC) only

Question 28

MOA of Heparin

Answer 28

Potentiates the action of antithrombin III (AT III), thereby inactivating thrombin Heparin binds to AT III and causes a conformational change, which exposes AT III's active site for more rapid interaction with proteases Heparin-AT III complex inactivates coagulation factors: II, IX, X, XI, XII

Question 29

What structure common in UFH and LMWH binds to antithrombin and causes a conformation change that accelerates interaction with factor Xa

Answer 29

Pentasaccharide sequence Therefore, both UFH and LMWH able to catalyze the inactivation of factor Xa by antithrombin

Question 30

Which structure is missing in LMWH, such that it has less able to inactivate factor IIa (thrombin)?

Answer 30

18 units long saccharide => form ternary heparin-antithrombin-thrombin complex

Question 31

Heparin can cause ______ What about LMWHs?

Answer 31

Drug-induced thrombocytopenia LMWH shows cross-reactivity with Heparin

Question 32

LMWH have longer _______ and higher ________ compared to Heparin

Answer 32

Longer half life Higher bioavailability Thus, LMWH preferred Unless desire easy reversibility, then might choose UFH (e.g., in high risk PE UFH + Alteplase)

Question 33

Between UFH and LMWH, which is more easily reversible?

Answer 33

UFH - half-life of 1h LMWH - half-life of 4h Therefore, UFH recommended in high-risk PE

Question 34

Reversal agent for Heparin *Partial reversal for LMWH

Answer 34

Protamine sulfate IV infusion - 5kDa highly basic cationic polypeptide derived from salmon sperm, binds to negatively charged heparin and neutralizes its anticoagulant properties

Question 35

Adverse effects of Heparin

Answer 35

- Bleeding - Increased risk of epidural or spinal hematoma and paralysis in pt receiving epidural or spinal anesthesia or spinal puncture - Heparin-induced thrombocytopenia (HIT)

Question 36

Explain the mechanism behind HIT

Answer 36

Heparin binds to platelet factor 4 (PF4) on activated platelet surface and triggers the formation of IgG antibodies against heparin-PF4 complex

Question 37

Can heparin and LMWH be used in pregnancy

Answer 37

Yes DOAC not recommended in pregnancy, Warfarin CI => switch to LMWH or Heparin

Question 38

Contraindications with Heparin

Answer 38

- hypersensitivity to heparin + pork pdt (cross-reactivity) - active major bleeding - thrombocytopenia, or antiplatelet antibodies

Question 39

Caution with Heparin

Answer 39

- elderly pt - risk of bleeding or hematoma

Question 40

LMWH is mainly ______ excreted

Answer 40

renally If CrCl <30ml/min, use UFH rather than LMWH