8/24- Anti-thrombotic Therapy Flashcards Preview

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Flashcards in 8/24- Anti-thrombotic Therapy Deck (43):
1

Overview of anti-thrombotic therapy

Anticoagulants

- Heparin/others

- Vitamin K antagonists

- Direct thrombin/Xa inhibitors (direct oral anticoagulants- DOACs)

Antiplatelet agents

- Aspirin

- ADP and thrombin receptor antagonists

- Glycoprotein IIb/IIIa inhibitors

Thrombolytic agents

Non-pharmacologic approaches

2

Name 3 oral anti-platelets and 1 intravenous

?

3

Name the anticoagulant protein to which heparin binds

?

4

Name 2 direct thrombin inhibitors and an approved indication for each

?

5

List four key differences between unfractionated heparin and LMW heparin

?

6

Name 3 diseased states for which thrombolytic therapy is used

?

7

Describe 3 key difference between warfarin and direct anticoagulants such as dabigatran, rivaroxaban, apixaban, and edoxaban

?

8

What is the mechanism of action of heparin?

- Heparin binds antithrombin, inducing a conformational change

- Degree of thrombin (IIa) inactivation is dependent on molecular length

Unfractionated heparin: anti-Xa and anti-thrombin effects

LMW heparin: anti-Xa (but not thrombin) 

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9

Compare heparin-heparin analogues: derivation/source?

- UFH: isolated from animals

- LMWH: enzymatic/chemical cleavage of UFH

- Fondaparinux: synthetic

10

Compare heparin-heparin analogues: mechanism/inhibition?

- UFH: inhibits Xa and IIa equally

- LMWH: more specific Xa effect (4:1)

- Fondaparinux: inhibits Xa only

11

Compare heparin-heparin analogues: delivery method

- UFH: IV or subcutaneous

- LMWH: subcutaneous (almost always)

- Fondaparinux: subcutaneous

12

Compare heparin-heparin analogues: half life?

- UFH: 0.5 - 4 hrs (preferred short term in hospital when you don't know if a procedure might be coming up)

- LMWH: half life 4 hrs

- Fondaparinux: 17 hrs (daily dosing)

13

Compare heparin-heparin analogues: other binding/specificity?

- UFH: non-specific binding to plasma proteins, cells

- LMWH: non-specific binding

- Fondaparinux: Lacks non-specific binding

14

Compare heparin-heparin analogues: monitoring?

- UFH: aPTT/anti-Xa monitoring

- LMWH: usually no monitoring (when needed, done through anti-Xa activity); may do for kids or morbidly obese

- Fondaparinux: no monitoring

15

Compare heparin-heparin analogues: neutralization

- UFH: neutralized by protamine

- LMWH: 50% neutralization by protamine

- Fondaparinux: no neutralization

16

Overview: Comparison of heparin-heparin analogues

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17

What are some side effects of heparin?

Bleeding (major: 1-5%), risk factors:

- Advanced age, low performance status

- Recent trauma, surgery or stroke

- HTN (DBP > 120 mmHg)

- Peptic ulcer disease

Osteopenia/bone loss

Heparin-induced thrombocytopenia (HIT)

18

What is the mechanism of heparin-induced thrombocytopenia (HIT)?

- Platelet factor-4

----Cationic tetramer secreted from -granules of activated platelets

----Negatively-charged heparin binds PF-4 tetramers near platelet surfaces

- IgG is produced against PF-4/heparin neo-antigens

- Fc portion of IgG binds to platelet surface Fc-gamma receptors and activates platelets

- Progressive decline in platelets as they aggregate and occlude arteries and/or veins (may result in limb gangrene)

HIT is distinct among the many causes of drug-induced TCP as being associated with platelet activation, and thus thrombosis as opposed to bleeding!!

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19

Important "HIT" points:

- Affect of heparin molecule size

- Kids vs. adults

- Diagnosis

- Treatment

- Larger heparin molecule -> more effective neoantigen formation and more HIT (UFH 5% > LMWH 0.5% > fondaparinux 0%)

- Less common in pediatrics

- Clinically diagnosis with lab confirmation: suspect with fall in platelet count 5-14 days after heparin exposure (may be earlier if previous)

Treatment:

- Stop ALL heparin (including flushes and heparin-coated catheters)

- Treat with alternative anticoagulant (e.g. direct thrombin inhibitor)

- Avoid prophylactic platelet transfusions!

20

What is the mechanism of action of Warfarin (Coumadin)?

Vitamin K antagonist

affects F II, VII, IX, X, proteins S and C)

- The above factors require gamma-carboxylation at gamma residue to become activated

- This process requires Vitamin K as a cofactor (reduced form)

- Vitamin K is oxidized during this process and must be regenerated/reduced for the process to continue

- Vitamin K antagonists block the regeneration of reduced Vitamin K

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21

Characteristics of Warfarin:

- Method of delivery

- Half life

- Monitoring required?

- Interactions

- Antidotes

- Unique side effects

- Orally administered (tablet only)

- 40 hr half life; dose changes -> "tail chasing" (get overlapping effect; not immediate changes)

- Pharmacogenetic variability

- Frequent monitoring via prothrombin time (PT) and International Normalized Ratio (INR)

- Many food/drug interactions -> INR variability

Antidotes:

- Vitamin K

- K centra (prothrombin complex concentrate)

- Fresh frozen plasma

Unique side effects:

- Embryopathy (6-12 wks GA) (hypoplastic nose, flat face, low nasal bridge, altered calcification: stippling, CNS effects)

- Warfarin-induced skin necrosis: initially transient hypercoagulative state (anti-Prot C) (pic 5)

22

What are some Warfarin food/drug interactions?

High Vitamin K content foods:

- Green tea, avocado, turnip greens, brussel sprouts, chickpeas, broccoli, cauliflower, lettuce)

- Beef liver

Drugs that increase effect:

- Amiodarone

- Aspirin

- Erythromycin!!

- Azoles

- Thyroid hormones

Drugs that increase effect:

- Barbiturates

- Griseofulvin

- Phenytoin

- Rifampin

23

Direct thrombin/Xa inhibitors

- Don't require what?

- Delivery method

- Uses

- Clearance

IV agents: don't require presence of antithrombin IV agents (primarily indicated for HIT)

- Bivalirudin (renal clearance)

- Argatroban (hepatic clearance)

Oral agents (no monitoring, no antidotes)

- Dabigatran (renal clearance)

- Direct anti-Xa inhibitors (rivaroxaban, apixaban, edoxaban) (some renal clearance)

24

Compare direct oral anticoagulants: target?

Dabigatran (Pradax): Thrombin

Rivaroxaban (Xarelto): Factor Xa

Apixaban (Eliquis): Factor Xa

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25

Compare direct oral anticoagulants: drug interactions?

Dabigatran (Pradax): P-Gp inhibitors

Rivaroxaban (Xarelto): P-Gp and CYP3A4 inhibitors

Apixaban (Eliquis): P-gp and CYP3A4 inhibitors

Just need to know that they have a few drug interactions (e.g. Rifampin and azole medicines) but way fewer than with Warfarin

26

Compare direct oral anticoagulants: routine lab monitoring?

No routine lab monitoring for any of them!

27

Which direct oral anticoagulant has the most renal clearance?

Dabigatran

28

Caveats for novel anticoagulants?

- Ximelagatran: liver toxicity

- Dabigatran: bleeding, possible CV risk

- They lack reversal agents

29

Comparison of oral anticoagulants

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30

What is aspirin?

- Mechanism?

- Adverse effects?

- Monitoring?

- Most commonly used antiplatelet agent; reduces odds of events by 25%

 - Irreversibly acetylates ser529 of COX-1 -> impaired TxA2 production (from arachidonate) for the life of the platelet

Adverse effects:

- Bleeding

- GI toxicity

Monitoring and "aspirin resistance"

31

Non-aspirin antiplatelet agents?

ORAL

- Clopidogrel: prodrug that irreversibly blocks platelet ADP (P2Y12) receptor [rash, GI toxicity]

- Prasugrel: also a prodrug; less variability

- Ticagrelor: direct, reversible P2Y12 inhibitor; cyclopentyl-triazolo-pyrimidine

- Dipyridamole: several potential mechanisms of action [headache, dizziness, GI toxicity]

- Vorapaxar: blocks thrombin (PAR-1) receptor

PARENTERAL

- GpIIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban): block fibrinogen binding and platelet aggregation [thromboctyopenia via Ab binding in 1-2%]

- Cangrelor: direct, reversible P2Y12 inhibitor (recent) 

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32

Fact: Warfarin is NOT APPROVED for starting in pt presenting with new DVT (some DOACs are)

IMPORTANT

33

Mechanisms of action for:

- Aspirin

- Clopidogre

l - Dipyridamole

Mechanisms of action for:

- Aspirin: COX2 inhibitor

- Clopidogrel: ADP receptor blocker

- Dipyridamole: thrombin receptor blocker

???

34

Mechanism of fibrinolysis/thrombolysis?

- Plasminogen converted into plasmin (tPA)

- Plasmin converts fibrin into its degradation products 

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35

Risks of thrombolytic therapy?

- Increases risk of major bleeding events by 1.5-3x

- Non-major bleeding occurs in many (most frequently at venipuncture sites, sites of invasive procedures)

36

Indications for thrombolytic therapy?

- Acute ischemic stroke within 4.5 hrs of Sx onset

- PE with hemodynamic compromise

- Acute MI

- Extensive acute DVT (systemic vs. catheter-directed administration)

37

Estimated drug costs? (FYI)

UFH >> Warfarin > Aspirin 

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38

What are some non-pharmacologic approaches for thombosis prevention/treatment?

Prevention:

- Importance of hospital thromboprophylaxis policy

- Mobilization

- Mechanical prophylaxis

Treatment:

- Catheter-directed interventions (mechanical, U/S)

- Surgical thrombectomy

- Inferior vena cava filter

- Post-thrombotic syndrome (compression stockings(?))

39

Case)

- Obese 17 yo female on oral contraceptives for Tx of polycystic ovary syndrome

- 2 day Hx of increasing leg pain and swelling after trip to West coast

- No respiratory symptoms and normal pulse oximetry

- PE and Doppler US are consistent with L femoral vein thrombus

- No other medical problems except for acne for which she was prescribed erythromycin

- Admission labs (including platelet count, PT/aPTT, fibrinogen, and creatinine are normal and D-dimer is markedly elevated)

How would you initiate treatment for her DVT?

A. IVC vilter placement to prevent PE

B. Warfarin

C. Rivaroxaban or apixaban

D. Enoxaparin (LMWH)

E. Systemic thrombolysis with tPA

How would you initiate treatment for her DVT? 

A. IVC vilter placement to prevent PE 

B. Warfarin 

C. Rivaroxaban or apixaban 

D. Enoxaparin (LMWH) 

E. Systemic thrombolysis with tPA

- Rivaroxaban and apixaban are approved for acute treatment in adults, but not approved in pediatrics

- Enoxaparin is what is used most often in pediatrics

- Don't want to start warfarin urgently

- Not sick enough for systemic thrombolysis

40

Case continued)

Which of the following should be incorporated into her plan of care?

A. Discontinuation of erythromycin

B. Consideration of continuing OCPs

C. Transition to long-term aspirin therapy

D. Use of a compression stocking given strong evidence this prevents PTS

E. Both A and B

Which of the following should be incorporated into her plan of care?

A. Discontinuation of erythromycin 

B. Consideration of continuing OCPs 

C. Transition to long-term aspirin therapy

D. Use of a compression stocking given strong evidence this prevents PTS 

E. Both A and B

- Erythromycin interacts with warfarin

- Oral contraceptives is risk factor for thombus formation

41

Case continued)

The patient’s status improves. Erythromycin and OCPs have been stopped. Each of the following is an appropriate step in management EXCEPT:

A. stopping enoxaparin immediately and beginning warfarin

B. following INRs carefully and titrating warfarin to reach and maintain INR target range

C. dietary counseling regarding warfarin-food interactions

D. precautions against trauma and unnecessary NSAID use

E. close clinical follow-up to assess adherence and response to therapy

The patient’s status improves. Erythromycin and OCPs have been stopped. Each of the following is an appropriate step in management EXCEPT: 

A. stopping enoxaparin immediately and beginning warfarin 

B. following INRs carefully and titrating warfarin to reach and maintain INR target range 

C. dietary counseling regarding warfarin-food interactions 

D. precautions against trauma and unnecessary NSAID use 

E. close clinical follow-up to assess adherence and response to therapy

- You don't want to rely on warfarin alone in the acute end of treatment phase

42

When would you put in a net/aortic mesh?

Only really when you have contraindications to anti-thrombolytics??

43

Key concepts 

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