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3154 Haematology > IC3 Anticoagulants > Flashcards

IC3 Anticoagulants Flashcards

1
Q

What are the 4 stages of hemostasis and thrombosis?

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

Which stage do anticoagulants act on?

A

Secondary hemostasis - thrombin activation

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

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3
Q

What do each of these drugs block:

  • Warfarin
  • Dabigatran
  • Rivaroxaban
  • Heparin
  • LMWH (Enoxaparin)
A
  • Warfarin: VII, IX, II, X
  • Dabigatran: II
  • Rivaroxaban: X
  • Heparin: intrinsic, II, IX, X, XI, XII
  • LMWH (Enoxaparin): X, II (lesser extent)
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4
Q

MOA of Warfarin

A

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
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5
Q

Reversal agent for Warfarin

A

Vitamin K

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6
Q

Onset of action of Warfarin: 24-72h

Why is there a delayed onset?

A
  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

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7
Q

Metabolism of Warfarin is primarily via ____

A

CYP2C9

  • S-Warfarin is the active enantiomer that is metablized by CYP2C9
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8
Q

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

A

CYP2C9
VKORC1

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9
Q

Adverse effects of Warfarin

A
  • 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
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10
Q

Contraindications with Warfarin

A
  • 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

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11
Q

Caution with Warfarin

A
  • 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

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12
Q

MOA of dabigatran

A

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

Dabigatran etexilate (prodrug) => Dabigatran

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13
Q

Dabigatran formulation and why?

A

Enteric coated due to low oral bioavailability

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14
Q

Dabigatran formulation and why?

A

Enteric coated due to low oral bioavailability

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15
Q

Reversal agent for Dabigatran

A

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

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16
Q

Adverse effects of Dabigatran

A
  • bleeding
  • GI symtpoms (dyspepsia, abdominal discomfort)
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17
Q

DDIs with Dabigatran

A

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
18
Q

Rivaroxaban MOA

A

Competitive reversible antagonist of activated factor Xa

19
Q

Adverse effects of Rivaroxaban

A
  • Bleeding
  • Gastroenteritis (stomach discomfort)
  • N/V
20
Q

Severe adverse effects of Rivaroxaban

A

Hemorrhage, spinal/epidural blood hematomas

21
Q

Absolute contraindications to the use of Rivaroxaban

A
  • 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)

22
Q

Metabolism and Clearance of Rivaroxaban

A

33% cleared renally unchanged

66% metabolised by liver:

  • 33% of liver metabolite cleared renally
  • 33% of liver metabolite cleared in feces
23
Q

Can Rivaroxaban be used in pregnancy and lactation?

A

Not recommended, switch to LMWH

24
Q

Reversal agent for Rivaroxaban

A

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

25
Q

Rivaroxaban is a substrate of:

A

CYP3A4
PGP
BCRP
OATP

26
Q

Rivaroxaban administration with regards to food

A
  • 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

27
Q

Heparin and LMWHs dosage form

A

Parenteral (IV/SC) only

28
Q

MOA of Heparin

A

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

29
Q

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

A

Pentasaccharide sequence

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

30
Q

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

A

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

31
Q

Heparin can cause ______

What about LMWHs?

A

Drug-induced thrombocytopenia

LMWH shows cross-reactivity with Heparin

32
Q

LMWH have longer _______ and higher ________ compared to Heparin

A

Longer half life
Higher bioavailability

Thus, LMWH preferred

Unless desire easy reversibility, then might choose UFH (e.g., in high risk PE UFH + Alteplase)

33
Q

Between UFH and LMWH, which is more easily reversible?

A

UFH - half-life of 1h
LMWH - half-life of 4h

Therefore, UFH recommended in high-risk PE

34
Q

Reversal agent for Heparin
*Partial reversal for LMWH

A

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

35
Q

Adverse effects of Heparin

A
  • Bleeding
  • Increased risk of epidural or spinal hematoma and paralysis in pt receiving epidural or spinal anesthesia or spinal puncture
  • Heparin-induced thrombocytopenia (HIT)
36
Q

Explain the mechanism behind HIT

A

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

37
Q

Can heparin and LMWH be used in pregnancy

A

Yes

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

38
Q

Contraindications with Heparin

A
  • hypersensitivity to heparin + pork pdt (cross-reactivity)
  • active major bleeding
  • thrombocytopenia, or antiplatelet antibodies
39
Q

Caution with Heparin

A
  • elderly pt
  • risk of bleeding or hematoma
40
Q

LMWH is mainly ______ excreted

A

renally

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

3154 Haematology (14 decks)

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