8/24- Anti-thrombotic Therapy Flashcards
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
Name 3 oral anti-platelets and 1 intravenous
?
Name the anticoagulant protein to which heparin binds
?
Name 2 direct thrombin inhibitors and an approved indication for each
?
List four key differences between unfractionated heparin and LMW heparin
?
Name 3 diseased states for which thrombolytic therapy is used
?
Describe 3 key difference between warfarin and direct anticoagulants such as dabigatran, rivaroxaban, apixaban, and edoxaban
?
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)
Compare heparin-heparin analogues: derivation/source?
- UFH: isolated from animals
- LMWH: enzymatic/chemical cleavage of UFH
- Fondaparinux: synthetic
Compare heparin-heparin analogues: mechanism/inhibition?
- UFH: inhibits Xa and IIa equally
- LMWH: more specific Xa effect (4:1)
- Fondaparinux: inhibits Xa only
Compare heparin-heparin analogues: delivery method
- UFH: IV or subcutaneous
- LMWH: subcutaneous (almost always)
- Fondaparinux: subcutaneous
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)
Compare heparin-heparin analogues: other binding/specificity?
- UFH: non-specific binding to plasma proteins, cells
- LMWH: non-specific binding
- Fondaparinux: Lacks non-specific binding
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
Compare heparin-heparin analogues: neutralization
- UFH: neutralized by protamine
- LMWH: 50% neutralization by protamine
- Fondaparinux: no neutralization
Overview: Comparison of heparin-heparin analogues
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)
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!!
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!
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
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)
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
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)
Compare direct oral anticoagulants: target?
Dabigatran (Pradax): Thrombin
Rivaroxaban (Xarelto): Factor Xa
Apixaban (Eliquis): Factor Xa
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
Compare direct oral anticoagulants: routine lab monitoring?
No routine lab monitoring for any of them!
Which direct oral anticoagulant has the most renal clearance?
Dabigatran
Caveats for novel anticoagulants?
- Ximelagatran: liver toxicity
- Dabigatran: bleeding, possible CV risk
- They lack reversal agents
Comparison of oral anticoagulants
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”
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)
Fact: Warfarin is NOT APPROVED for starting in pt presenting with new DVT (some DOACs are)
IMPORTANT
Mechanisms of action for:
- Aspirin
- Clopidogre
l - Dipyridamole
Mechanisms of action for:
- Aspirin: COX2 inhibitor
- Clopidogrel: ADP receptor blocker
- Dipyridamole: thrombin receptor blocker
???
Mechanism of fibrinolysis/thrombolysis?
- Plasminogen converted into plasmin (tPA)
- Plasmin converts fibrin into its degradation products
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)
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)
Estimated drug costs? (FYI)
UFH >> Warfarin > Aspirin
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(?))
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
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
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
When would you put in a net/aortic mesh?
Only really when you have contraindications to anti-thrombolytics??
Key concepts
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