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What are the 3 main types of risk factors for venous thrombosis based on Virchow's Triad?
- 1. Venous stasis
- 2. Vascular Injury
- 3. Hypercoagulability
What risk factors fall into the Venous Stasis category?
- varicose veins
- atrial fibrillation (turbulent blood flow)
- increased age
What risk factors fall into the Vascular Injury category?
- indwelling catheter
- fractured bones
- surgery (hip, knee)
What risk factors fall into the Hypercoagulability category?
- antithrombin deficiency
- protein C or S deficiency
- cancer/cancer therapy
- mechanical heart valve
- previous VTE
- factor V leiden
- antiphospholipid syndrome
- prothrombin gene mutation 20210A
- lupus anticoagulant
Drugs: Estrogen-containing contraception, estrogen replacement therapy, selective estrogen receptor modulators, heparin-induced thrombocytopenia
Deep Vein Thrombosis - clot in vein, usually leg vein
clot that travels - usually from leg to lungs (pulmonary embolism) or from heart to brain (cardioembolic stroke)
MOA of UH and LMWH
- Both unfractionated heparin (UH) and low molecular weight heparin (LMWH) bind to Antithrombin-III (AT-III).
- UH inactivates Factor Xa and can also attach to and inactivate IIa
- LMWH inactivates Factor Xa
- (they are equally effective, however)
What is the onset of action of UH and LMWH?
- UH: IV onset is immediate, SQ takes 20-30 min
- LMWH: SQ onset is immediate
How long is the time to therapeutic effect with UH and LMWH?
- UH: time to aPTT - no set time - usually around 24 hours
- LMWH: 30 minutes
What are the monitoring parameters for UH and LMWH? Which patients do we need to monitor?
Monitor APTT for UH for anyone on treatment doses (not prophylactic). Check baseline, then every 6 hours until therapeutic, then q 2-3 days while in hospital.
Monitor Anti-Xa levels for LMWH in pts with obesity (150 kg+), renal dysfunction (CrCl < 30 ml/min), pregnancy on treatment doses. After 1 dose, check 4 hours post dose at steady state.
Monitor CBC with platelets for UH and LMWH at baseline then q 2-3 days while in hospital
What is the treatment dose of UH?
80 units/kg IV loading dose (bolus), then 18 units/kg/hour IV infusion
Monitor APTT q6h until therapeutic, then q24h
What is the treatment dose of Enoxaparin (LMWH)?
- 1 mg/kg SQ BID
- if CrCl < 30, 1mg/kg QD
Monitor Anti-Xa levels in pts with obesity, renal dysfxn, pregnancy
How long should a pt be treated with heparin?
- No longer than necessary.
- Continue heparin until INR has been therapeutic for 24h x 5 days
Prophylactic dose of UH
5000 units SQ q 8-12 hours (BID)
Prophylactic dose of Enoxaparin
- 30 mg SQ BID or 40 mg SQ QD
- if CrCl is < 30, give 30 mg SQ QD
Main adverse effect of heparin
Antidote for heparin
protamine sulfate (or can give blood)
Discuss the different types of thrombocytopenia that are AEs of heparin
Type I: HAT - Heparin-associated Thrombocytopenia - direct interaction betw heparin and platelets - can cause bleeding - non-immune. Tx is d/c heparin.
Type II: HIT - Heparin-induced Thrombocytopenia - serious allergic rxn - immune-mediated - heparin intx with platelets results in activation of coagulation cascade causing clots - DVT, PE, MI, stroke, etc. Tx is d/c heparin. If clots have formed, use a direct thrombin inhibitor or fondaparinux. Warfarin may be used when platelets > 150,000. UH and LMWH cross reactive in HIT.
What should you tell a pt about injection site reactions with heparin?
They are to be expected. Don't d/c the med. Rotate inj site to minimize hematoma size.
What needs to be monitored in a pt on heparin?
- s/s of bleeding/VTE
- APTT/Anti-Xa levels (in pts on tx doses)
- CBC with platelets
- duration of treatment (min 5 days, then stop)
What is the DOC to treat and prevent clots in pregnancy?
What is the MOA of lepirudin and argatroban and when are they used?
They are direct thrombin inhibitors (Factor IIa). Used to treat blood clots in patients with HIT.
What is the MOA of warfarin?
- 1. Inhibits Vitamin K epoxide reductase, keeping it from recycling the Vitamin K in the body. It thus inhibits the clotting factors II, VII, IX, and X from being activated because the recycled/reduced form of Vitamin K is what activates them. It also keeps Proteins C and S from being activated.
- 2. Doesn't dissolve preexisting thrombi
- 3. Prevents further extension of preexisting thrombi and formation of new thrombi
Warfarin is a racemic mixture. Which isomer is a more potent anticoagulant, and what significance does this have in regard to DIs?
The S-isomer is 5-8 x more potent than the R.
The S is metabolized by CYP 2C9 so there are more significant DIs with drugs that are also 2C9 substrates or are 2C9 inhibitors. (more so than 1A2 and 3A4, which metabolize the R isomer)
How long does it take for warfarin to have anticoagulant effects? How long to reach therapeutic effect?
24-48 hours to see anticoag effect because you have to wait for the existing clotting factors to leave the body since warfarin doesn't work on them.
10-14 days until it reaches therapeutic effect, aka steady state - this is also d/t the half lives of the existing clotting factors
Which clotting factor has the shortest half life? The longest?
- VII - 6 h
- Protein C, S - 8-10 h
- IX - 24 h
- X - 36-40 h
- II - 60 h
What are the warfarin indications Dr. Koski emphasized in class? (1 for treatment, 2 for prevention)
1. First VTE - reversible risk factor present (identifiable and removable)
- 1. Recurrent DVT/PE
- 2. Thrombosis in prosthetic heart valves (mechanical valve replacement)
How long is warfarin treatment for first VTE? For Recurrent DVT/PE or mechanical valve replacement?
- For 1st VTE assuming the risk factor is removed (e.g. smoking), 3 months
- For recurrent DVT/PE or valve replacement, treatment lasts the pt's lifetime
What is the Goal INR for warfarin?
It is 2-3 for pretty much all indications, except prosthetic heart valves (mechanical valve replacement) it is 2.5-3.5
- severe hepatic/renal disease
- active bleeding
- cerebral vascular attack (unless cerebral hemorrhage is ruled out)
What is normal baseline level for PTT and INR?
- PTT 10-12 seconds
- INR 0.9-1.1
What is therapeutic level PTT and INR for warfarin tx?
- PTT 1.5-2 x control
- INR 2-3 (usually)
When should CBC with platelets be measured in warfarin tx?
at baseline and anually
What is PTT?
the time it takes for a blood sample with warfarin to clot in the presence of thromboplastin
What is INR?
- International Normalized Ratio
- measure of the responsiveness of the thromboplastin
- INR = (patient's PT/control PT)xISI where ISI is international sensitivity index (acceptable ISI is < 2)
How is warfarin dosed when treating DVT/PE?
- Start at 5-10 mg PO QD (this depends on age - higher dose for younger pt)
- Overlap therapy (with heparin) for at least 5 days until INR is therapeutic for 24 hours - don't want this to happen too quickly
Dosing of warfarin for prophylaxis of DVT/PE (i.e. Afib, valve replacement)
start at 2.5-5 mg PO QD
What is monitored in order to individualize warfarin dose?
How do we adjust dose of warfarin at initiation of therapy in the hospital?
Look at the magnitude of change (and speed)
- Check INR on day 2 - if it moved, give same or lower dose on day 2 - if it didn't move give same or higher dose
- Initially check INR daily
How do we adjust chronic warfarin doses outside the hospital?
- Use a nomogram
- Adjust weekly dose by 5-20% (usually about 10%)
- For high INR hold 1-2 doses and then recheck
- For low INR give 1-2 extra doses then recheck
How often should INR be rechecked when adjusting the dose (outside the hospital)?
What are good questions to ask a pt on warfarin to determine what other factors may be affecting their INR?
- What dose of Coumadin are you taking?
- Have you missed any doses?
- Have you had any bleeding/VTE s/s?
- Have you had any changes in your diet? Other medications?
Adverse effects of warfarin
- purple toes syndrome
- teratogenicity - pregnancy category X
What anticoagulants should be used in pregnant and breastfeeding patients?
- Heparins in pregnancy
- Warfarin for breastfeeding
What is the warfarin antidote?
Is vitamin K water or fat soluble?
If a physician decides to use Vitamin K to reverse a pt's bleeding or high INR, what doses should be used for what INRs?
- INR 3-5 - no vitamin k - just hold 1-2 warfarin doses then resume at lower dose
- INR 6-9 and patient not bleeding - 2.5 mg PO vitamin K
- INR 10-20 and pt not bleeding - 5 mg PO vitamin K
- INR > 20 or seriously bleeding - 10 mg IV infusion of vitamin K
How do we avoid purple toes syndrome?
It is from using too high of a starting dose, so don't start at higher than 10 mg QD
What are the 10 A drugs that interfere with warfarin?
- 1. Antibiotics (esp FQs, macrolides, metronidazole, SMX-TMP)
- 2. Azole antifungals
- 3. Antidepressants
- 4. Antiplatelets
- 5. Anti-inflammatory agents
- 6. Amiodarone
- 7. Acetaminophen
- 8. Alternative remedies
- 9. Antiepileptics
- 10. Alcohol
What do most of the 10A drugs that interfere with warfarin do to the INR? What are the exceptions?
- Most of them increase it.
- Rifampin and the older antiepileptics decrease it.
- Alternative remedies (herbals) can increase or decrease INR.
Name 3 drugs that interact with warfarin that Dr. Koski pointed out in class because they are 2C9 inhibitors.
- 1. Fluconazole
- 2. Metronidazole
- 3. Bactrim, Septra
What is the half life of amiodarone and how does this affect warfarin therapy?
- t1/2 is 50 days
- if we need to decrease warfarin, we decrease it by 30-50% (rather than the normal 10%)
What should a pt on warfarin do if they bump their head?
go get evaluated at ER - could have subdural hematoma
6 steps for managing warfarin DIs
- 1. ALWAYS check to see if new drug intx with warfarin
- 2. Consider an alternative that does not intx
- 3. Interacting drugs are not contraindicated (but still be careful because bleeding risk could increase)
- 4. If adding warfarin to an interacting drug, consider starting with a lower warfarin dose
- 5. If adding an interacting drug to warfarin, increase frequency of INR monitoring, then adjust warfarin dose if needed
- 6. Review meds every time INR is monitored (including rx, otc, herbals, prn)
Patient monitoring for warfarin pts
- s/s of bleeding/thromboembolism
- drug intx
- duration of treatment
Why should a warfarin pt take their dose in the evening?
So that if they come into the coumadin clinic and their INR is high we can still adjust that day's dose
Which comes first in DVT treatment, heparin or warfarin?
heparin first, then once it's therapeutic start warfarin
How long should the dosing of heparin and warfarin overlap?
until the INR is therapeutic for 24 hours (5 days minimum)
Do we monitor APTT with LMWH?
no it is not necessary
Patient education topics with warfarin include:
- strict compliance needed
- anticipated duration of therapy
- MOA of the drug
- dietary instruction
- frequent need for blood draws
- signs of therapeutic failure
- MedAlert bracelet