HEME - Anticoagulants

Question 1

What is the mechanism of action of heparin? How does it differ from Warfarin/Coumadin?

Answer 1

Heparin activates anti-thrombin, which normally inhibits the coagulation factors 2a and 10a.

Warfarin is an vitamin K antagonists, thus it inhibits the synthesis of Vitamin K dependent factors (2, 7, 9, 10, C, S, Z)

Question 2

How is heparin metabolized and cleared? How does it differ from Warfarin/Coumadin? (How does their mechanism of metabolism/clearance affect their half-lives?)

Answer 2

Heparin: initial rapid binding to endothelial cells, macrophages, and plasma proteins, and second phase where there is slow excretion by the kidneys. The half-life is morecomplex: lower dose saturates the first initial phase, resulting in a shorter half-life, but a higher dose results in a slow excretion by the kidneys, thereby increasing the half-life.

Warfarin/Coumadin: binds to plasma proteins, metabolized by CYP450 and renally cleared. Half-life is 33 hours.

Question 3

How is heparin affect PTT and PT? How does it differ from Warfarin/Coumadin?

Answer 3

Heparin: prolong PTT, no effect on PT.

Warfarin/Coumadin: prolong PT and PTT

Question 4

How are the effects of heparin reversed? How does it differ from Warfarin/Coumadin?

Answer 4

Heparin: short half-life, so discontinue before invasive procedures; for immediate reversal, use protamine sulfate.

Warfarin: saturate system with Vitamin K or prothrombin concentrates (bypasses the missing clotting factors in the coagulation cascade)

Question 5

How is heparin dosed? How does it differ from Warfarin/Coumadin? (How is warfarin dosed for patients with heart valves?

How is dosing monitored for both?

Answer 5

Heparin: mini-dose used for thromboprophylaxis; monitored via PTT

Warfarin/Coumadin: every dose is individualized based on the PT/INR; for patients with heart-valves require a higher dose; monitored via PT

Question 6

What is Heparin-Induced Thrombocytopenia? What is the mechanism behind this?

Answer 6

Heparin binds to a protein on the platelets surface and an IgG binds it and activates the platelet, resulting in an paradoxical hypercoagulable state, where there is massive thrombin activation (leading to increased thrombosis) and thrombocytopenia (due to increased consumption)

Question 7

Which one is more appropriate to give a pregnant patient? Heparin or Warfarin?

Answer 7

Heparin, because it does not cross the placenta.

Question 8

What must one consider when dosing Warfarin?

Answer 8

Warfain has a slow onset of action, and requires that patients be started on a fast-acting anticoagulant (ie LMW heparin) for patients with acute thrombosis for at least two days.

Question 9

What are some of the side effects of warfarin?

Answer 9

It causes skin necrosis because it may be related to the transient hypercoaguable state at the beginning of therapy (since warfarin affects factor 7 quickly, but fators 2a, 10a have longer half-lives than factor 7) which causes thrombosis in venules and capillaries of subcutaneous fat. Patients with Protein C/S deficiencies are pre-disposed to skin necrosis, but it can also occur in patients without risk factors.

Question 10

Why is there such large variation in heparin bioavailability?

Answer 10

heparin binds plasma proteins, which levels vary depending on the health-status of the patient. Sicker patients tend to have more + charged proteins, which sequester the heparin, and this can lead to an ineffective dose or heparin resistance.

Question 11

What is the difference between unfractionated heparin and LMW heparin and fondaparinux in terms of:

how it's produced?
its mechanism of action?
plasma binding protein/bioavailability?
excretion?
monitoring?
HIT risk?
antidotes?

Answer 11

production:
unfractionated heparin: directly from pigs gut
LMW heparin: fractionation
Fondaparinux: synthetic

mechanism of action:
unfractionated heparin: binds to AT + thrombin
LMW heparin: binds to AT
Fondaparinux: binds to 10

plasma binding protein/bioavailability
unfractionated heparin: extensive/30-35%
LMW heparin/Fondaparinux: low/95-100%

excretion
unfractionated heparin: fast (cells/plasma) slow (renal)
LMW heparin/Fondaparinux: Renal

monitoring:
unfractionated heparin : Yes
LMW heparin/Fondaparinux: No

HIT risk:
unfractionated heparin: High 1-5%
LMW heparin: Low

Question 12

What is the mechanism of action for:

Argatroban (Bivalirudin)
Dabigatran
Rivaroxaban
Apixaban

Answer 12

Argatroban (Bivalirudin)
Dabigatran (Pradaxa)
–> blocks Thrombin (2a)

Rivaroxaban (Xarelto)
Apixaban
–> blocks Factor Xa

Question 13

What are the general uses of these oral anticoagulants

Argatroban (Bivalirudin)
Dabigatran
Rivaroxaban
Apixaban

Answer 13

stroke prevention in atrial fibrillation patients

Question 14

RIvaroxaban is contraindicated with use of these class of drugs:

Answer 14

Drugs that are inhibitors of CYP3A4 (ritonavir, clarithromycin, erythromycin, ketoconazole)

or

inducers of CYP3A4

both of these will increase/decrease rivaroxaban levels

Question 15

What are the pros and cons of using these new oral anticoagulants?

Argatroban (Bivalirudin)
Dabigatran
Rivaroxaban
Apixaban

Answer 15

pros: no lab monitoring necessary
cons: no antidote - can lead to severe bleeding

Question 16

Match these drugs with their proper anti-coagulation indications:

Argatroban
Bivalirudin
Dabigatran
Rivaroxaban

Atrial fibrillation
HIT patients
PCI patient
DVT, Atrial fibrillation

Answer 16

Argatroban - HIT patients
Bivalirudin - PCI patient
Dabigatran - Atrial fibrillation
Rivaroxaban - DVT, Atrial fibrillation

Question 17

5 drugs:

aspirin
clopidogrel
prasurgel
ticagrelor
Abciximab

with 2 main inhibitory effects on:
platelet aggregation
platelet plug formation

What does what?

Answer 17

blocks platelet aggregation
aspirin
ticagrelor
Abciximab

platelet plug formation
clopidogrel
prasurgel

Question 18

What are these drugs generally used for? In what situations would you use or not use a particular drug? (only ones with asterisks)

aspirin*
clopidogrel*
prasurgel*
ticagrelor
Abciximab

Answer 18

all of these drugs can be used for acute coronary syndromes, but…

USE aspirin in patients with prosthetic heart valves

DO NOT USE

• clopidogrel in patients on statins
• prasurgel - in patients with a hx of TIA/strokes (since it increases the risk of stroke)

Question 19

How does resistance for these drugs compare?

aspirin
clopidogrel
prasurgel
ticagrelor

Answer 19

aspirin - no resistance because platelets are constantly being regenerated

clopidogrel - resistance is high due to metabolism by a single enzyme

prasurgel - resistance is less due to metabolism by multiple enzymes

ticagrelor: resistance is less because parent+metabolized drug are both active

Question 20

Which ones are reversible? Irreversible?

aspirin
clopidogrel
prasurgel
ticagrelor
Abciximab

Answer 20

On this list, only Ticagrelor is REVERSIBLE.

Question 21

Why is the individual response to Clopidogrel so much greater than Prasurgel (even though they both inhibit the P2Y12 receptor)?

Answer 21

Both Clopidogrel and Prasurgel are metabolized to the active form by cytochrome P450, but Clopidogrel is more dependent on CYP2C19 than Prasurgel.

2-14% of patients have genetic polymorphisms in the CYP2C19 gene, which decreases the metabolism of clopidogrel to its active metabolite.

Prasurgel is less dependent on CYP2C19 and therefore has much less genetic variability in platelet inhibition than clopidogrel.

Question 22

What do these drugs target specifically? Are these effects reversible or irreversible?

aspirin
clopidogrel
prasurgel
ticagrelor
Abciximab

Answer 22

aspirin - COX1/2, irreversible
clopidogrel - P2Y12, irreversible
prasurgel - P2Y12, irreversible
ticagrelor - GPIIb/IIIa, REVERSIBLE
Abciximab - GPIIb/IIIa, irreversible