Venous Thromboembolism

• 1. Venous stasis
• 2. Vascular Injury
• 3. Hypercoagulability

• immobility
• obesity
• CHF
• varicose veins
• pregnancy
• atrial fibrillation (turbulent blood flow)
• anesthesia
• increased age

• venipuncture
• indwelling catheter
• fractured bones
• surgery (hip, knee)
• trauma

• antithrombin deficiency
• protein C or S deficiency
• cancer/cancer therapy
• smoking
• 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

clot

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)

• 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)

• UH: IV onset is immediate, SQ takes 20-30 min
• LMWH: SQ onset is immediate

• UH: time to aPTT - no set time - usually around 24 hours
• LMWH: 30 minutes

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

80 units/kg IV loading dose (bolus), then 18 units/kg/hour IV infusion

Monitor APTT q6h until therapeutic, then q24h

• 1 mg/kg SQ BID
• if CrCl < 30, 1mg/kg QD

Monitor Anti-Xa levels in pts with obesity, renal dysfxn, pregnancy

• No longer than necessary.
• Continue heparin until INR has been therapeutic for 24h x 5 days

5000 units SQ q 8-12 hours (BID)

• 30 mg SQ BID or 40 mg SQ QD
• if CrCl is < 30, give 30 mg SQ QD

bleeding

protamine sulfate (or can give blood)

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.

They are to be expected. Don't d/c the med. Rotate inj site to minimize hematoma size.

• 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)

heparin

They are direct thrombin inhibitors (Factor IIa). Used to treat blood clots in patients with HIT.

• 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

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)

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

• VII - 6 h
• Protein C, S - 8-10 h
• IX - 24 h
• X - 36-40 h
• II - 60 h

1. First VTE - reversible risk factor present (identifiable and removable)

• 1. Recurrent DVT/PE
• 2. Thrombosis in prosthetic heart valves (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

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
• pregnancy
• active bleeding
• noncompliance
• cerebral vascular attack (unless cerebral hemorrhage is ruled out)

• PTT 10-12 seconds
• INR 0.9-1.1

• PTT 1.5-2 x control
• INR 2-3 (usually)

at baseline and anually

the time it takes for a blood sample with warfarin to clot in the presence of thromboplastin

• 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)

• Aggressively
• 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

start at 2.5-5 mg PO QD

• PT/INR
• s/s of bleeding

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

• 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

weekly

• 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?

• bleeding
• purple toes syndrome
• teratogenicity - pregnancy category X

• Heparins in pregnancy
• Warfarin for breastfeeding

Vitamin K

fat

• 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

It is from using too high of a starting dose, so don't start at higher than 10 mg QD

• 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

• Most of them increase it.
• Rifampin and the older antiepileptics decrease it.
• Alternative remedies (herbals) can increase or decrease INR.

• 1. Fluconazole
• 2. Metronidazole
• 3. Bactrim, Septra

• t_1/2 is 50 days
• if we need to decrease warfarin, we decrease it by 30-50% (rather than the normal 10%)

go get evaluated at ER - could have subdural hematoma

• 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)

• s/s of bleeding/thromboembolism
• PTT/INR
• drug intx
• compliance
• CBC
• duration of treatment

So that if they come into the coumadin clinic and their INR is high we can still adjust that day's dose

heparin first, then once it's therapeutic start warfarin

until the INR is therapeutic for 24 hours (5 days minimum)

no it is not necessary

• strict compliance needed
• anticipated duration of therapy
• MOA of the drug
• SEs
• dietary instruction
• frequent need for blood draws
• DIs
• signs of therapeutic failure
• MedAlert bracelet