Antithrombolytic Therapy Flashcards
1
Q
general classes of anticoagulant drugs
A
Heparin and related drugs
- Require antithrombin as cofactor
Warfarin
- Vitamin K antagonist
“Direct” oral anticoagulants (DOACs)
- Inhibit specific clotting proteases, do not require antithrombin
2
Q
Unfractionated Heparin (UFH)
A
- Inhibits IIa, Xa, IXa, XIa in presence of antithrombin (needs antithrombin to do anything)
- Relative anti-Xa:anti-IIa activity 1:1
- Eliminated by the liver and kidney
- Administered IV or (when used as prophylaxis) SQ (sub-Q)
- Variable dose-response, must be monitoredaPTT or anti-Xa activity
- PTT prolonged in presence of heparin
- risk of bleeding, HIT, osteoporosis
- reversable with antidote (protamine sulfate)
3
Q
antidote for unfractionated heparin (UFH)
A
protamine sulfate
4
Q
Low Molecular Weight Heparin (LMWH)
A
- Made by partial depolymerization of UFH
- Relative anti-Xa:anti-IIa activity 2:1 to 4:1
- Eliminated mainly by kidney (use with care in renal failure)
- 4-6 hour half life
- Monitor with anti-Xa levels if needed (aPTT not sensitive) (Doesn’t need to be monitored as closely as UFH)
- Only partially neutralized by protamine sulfate; not a readily available reversal option
5
Q
LMWH advantages vs UFH
A
- Longer half-life → once or twice daily subcutaneous admin
- Can give to outpatients
- Less “sticky” due to smaller size, so more predictable dose-response
- Routine monitoring not required
- Lower HIT risk (but don’t use to treat HIT)
- Preferred anticoagulant during pregnancy – does not cross placenta, not teratogenic
- As effective as UFH for VTE treatment/prevention, while being significantly safer
6
Q
Heparin & LMWH: Indications
A
- Treatment of acute VTE
- VTE prophylaxis in hospitalized patients
- lower dose, not monitored
- Acute coronary syndromes (ACS)
- Peripheral artery occlusive disease (UFH)
- High dose unfractionated heparin (UFH)
- Cardiopulmonary bypass (CPB)
- Extracorporeal membrane oxygenation (ECMO)
- Dialysis circuits
7
Q
Fondaparinux (super small heparin): about med and indications
A
- Only Inhibits Xa, does not inhibit IIa
- Eliminated by kidney (avoid in renal failure)
- Long 17-21 hour half life (once daily SQ admin)
- No routine monitoring - anti-Xa levels if needed
- No HIT risk (can treat HIT), outpatient Rx (one per day shot in outpatient)
- No antidote (not neutralized by protamine sulfate) – potential disadvantage
Indications
- VTE prophylaxis (2.5 mg/day) - FDA approved for high risk orthopedic surgery patients
- VTE treatment (7.5 mg/day) - Mainly used for this purpose in patients with HIT (heparin/LMWH contraindicated)
8
Q
UFH, LMWH, and Fondaparinux: size to half life; anti-Xa to anti-IIA ratio
A
the smaller the longer the half life and the greater specificity for Xa as opposed to IIa
9
Q
Heparin-induced Thrombocytopenia (HIT)
A
- Caused by giving anticoagulant; we’d think this leads to bleeding but patients get blood clots
- Drop in platelet count (typically > 50%) in patient receiving heparin
- Usually begins 5-7 days after starting heparin
- Not a dose dependent phenomenon; it’s the type of heparin, not the dose, that matters
- Intensely prothrombotic
- Use of LMWH is associated with a lower risk of HIT and HITT compared with use of UFH
10
Q
Mechanism of Heparin-Induced Thrombocytopenia
A
- Platelets contain protein PF4 (platelet factor 4)
- PF4 is a potent heparin neutralizing protein; binds to heparin tightly
- This is why we can’t predict the dose response of heparin; don’t know how much PF4 there is
- PF4 complexes with heparin to make a neoantigen
- IgG can bind to this to make a greater complex (IgG + heparin + PF4)
- This complex can bind to Fc receptors (found on platelets and monocytes)
- Binding can lead to activation of platelets and monocytes
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11
Q
types of anticoagulant vs. HIT
A
- Smaller heparin molecules → less platelet activation by HIT antibodies
- The size of the heparin molecule is going to help determine the size of the possible immune complex that is formed
- Larger complex can occupy multiple Fc receptors
- Fondaparinux barely binds to PF4 let alone antibody and Fc receptor
12
Q
Treatment of HIT
A
- Do not give heparin or LMWH
- Warfarin may increase risk of thrombotic complications (due to low protein C?) → don’t use
- Screen thoroughly for arterial or venous thrombosis
- Want to give an anticoagulant that is not heparin or warfarin
- If thrombosis present give non-heparin rapid acting anticoagulant:
- Parenteral thrombin inhibitors - argatroban, bivalirudin
- Fondaparinux
- DOAC
- If no thrombosis apparent, consider anticoagulating anyway due to high risk of subsequent thrombosis
13
Q
Warfarin
A
- Inhibits vitamin K-dependent carboxylation of the Gla domains (factors VII, IX, X, and prothrombin)
- Monitored by the INR (doses for patients can vary dramatically)
- Takes several days to achieve therapeutic anticoagulant effect; doesn’t work right away
- Usual range INR= 2.0-3.0 (little higher in people with prosthetic valves)
- Use complicated by inherited differences in drug sensitivity and by extensive drug and diet interactions (vit k in diet)
- Contraindicated in pregnancy! (Teratogenic)
14
Q
Mechanism for Warfarin
A
- In normal process, vitamin k is oxidized when it carboxylates clotting factors
- In order to be used again, vitamin k has to be reduced; vit k reduced by vit k epoxide reductase
- Warfarin targets vitamin k epoxide reductase –> results in lots of non-functiobal oxidized vit k
15
Q
why there’s variability in effects of Warfarin
A
- Genetic polymorphisms in its target enzymes (vitamin K reductases) and in the enzymes that metabolize warfarin
- Variation in dietary vitamin K
- Drugs that increase warfarin metabolism
- Barbiturates, chronic alcohol use, many others
- Drugs that decrease warfarin metabolism
- Phenytoin, acute alcohol intoxication, some antibiotics
- Drugs that decrease vitamin K synthesis by gut bacteria
- Antibiotics
- Drugs that displace warfarin from albumin
- Aspirin
- Concomitant hemostatic defects
