Antithrombolytic Therapy Flashcards
(29 cards)
general classes of anticoagulant drugs
Heparin and related drugs
- Require antithrombin as cofactor
Warfarin
- Vitamin K antagonist
“Direct” oral anticoagulants (DOACs)
- Inhibit specific clotting proteases, do not require antithrombin
Unfractionated Heparin (UFH)
- 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)
antidote for unfractionated heparin (UFH)
protamine sulfate
Low Molecular Weight Heparin (LMWH)
- 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
LMWH advantages vs UFH
- 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
Heparin & LMWH: Indications
- 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
Fondaparinux (super small heparin): about med and indications
- 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)
UFH, LMWH, and Fondaparinux: size to half life; anti-Xa to anti-IIA ratio
the smaller the longer the half life and the greater specificity for Xa as opposed to IIa
Heparin-induced Thrombocytopenia (HIT)
- 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
Mechanism of Heparin-Induced Thrombocytopenia
- 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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types of anticoagulant vs. HIT
- 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
Treatment of HIT
- 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
Warfarin
- 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)
Mechanism for Warfarin
- 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
why there’s variability in effects of Warfarin
- 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
Indications for Warfarin
Prevention of recurrent VTE
- Typically given for 3-6 mo, target INR 2-3
- Longer/indefinite duration in selected cases
Prevention of stroke in atrial fibrillation
- Target INR 2-3 (indefinite)
Prevention of stroke/embolism in patients with artificial heart valves
- Target INR 2.5-3.5
Do not use to treat HIT
Warfarin-Associated Skin Necrosis
Warfarin lowers levels of protein C faster than vitamin k –> leads to initial period of hypercoagulability that can result in warfarin-associated skin necrosis
- can also be from protein s deficiency or Factor V Leidin
- microvascular skin necrosis on breast, buttocks, thighs, and/or abdomen
Treatment of warfarin overdose
- Vitamin K (oral or IV) – takes 12-24 hours (depending on situation might not be fast enough)
- Fresh frozen plasma (excess volume problematic)
- Prothrombin complex concentrate- contains FVII, IX, X, II, less volume needed than fresh frozen plasma
- Mixture of all the vitamin k dependent factors; concentrated so we need less volume
- In treating actute condition could give this and additionally give vitamin k for a prolonged reversal effect
Direct Oral Anticoagulants (DOACs)
- Small molecules that inhibit specific clotting factors
- Given orally
- Work right away; not a delay like in Warfarin
- Thrombin inhibitor:
- Dabigatran (Pradaxa) – BID dosing; reversal agent now available
- Factor Xa inhibitors:
- Rivaroxaban
- Apixaban
- Edoxaban
- No reversal agents for Xa inhibitors
FDA-approved for:
- Stroke prevention in non-valvular atrial fibrillation
- Treatment and secondary prophylaxis of VTE
- VTE prophylaxis in orthopedic surgery (except Dabigatran)
Direct vs. Indirect Anticoagulants
Indirect inhibitors – require antithrombin; examples: heparin, LMWH, fonduparinox
Direct inhibitors – no cofactor required
DOACs vs “standard” therapy
Advantages • Oral adminstration • Once or twice daily dosing • Do not require monitoring(reliable dose response effect) • Rapid onset of action – can be used as single agent for VTE treatment • Many patients won’t require hospitalization • Safer option for many patients
Disadvantages • Cost (about 10x warfarin) • No widely available method to determine drug level (hard to measure level in the blood)• No reversal agent yet for Xa inhibitors • Potential for accumulation in kidney or liver disease • Not suitable for all warfarin indications (particularly true with prosthetic valve
Antiplatelet drugs
- Aspirin
- ADP receptor antagonists
- Clopidogrel (others include prasugrel, ticagrelor, cangrelor)
- IIb-IIIa antagonists
- Abciximab, eptifibatide, tirofiban
- Often used by cardiologists during interventional procedures
- Aspirin and ADP receptor antagonists used widely to prevent arterial thrombosis; aspirin more preventative and ADP receptor antagonists in pts that have already had an event
IIb-IIIa receptor antagonists
- Abciximab: Fab portion of monoclonal antibody to IIb IIIa
- Eptifibatide, tirofiban – small molecule inhibitors (mimic RGD binding sequence in fibrinogen and other adhesive proteins)
- All given IV
- Block platelet aggregation regardless of mechanism of platelet activation
- Used to prevent coronary occlusion during percutaneous coronary intervention
Fibrinolytic Drugs
- Activate plasminogen to plasmin (plasmin chews up clots)
- Clot-bound plasminogen activated most efficiently
- May cause bleeding due to uncontrolled clot lysis
- Used to treat people who have had a recent clotting event (heart attack, stroke)
- Recombinant t-PA most widely used (t-PA = tissue plasminogen antigen)
- Alteplase, reteplase
Clinical Use
• Myocardial infarction • Peripheral vascular thrombosis • Ischemic stroke • Massive PE w/ hemodynamic compromise
Effective in reducing damage from arterial clot when given early (within a few hours of onset), especially in stroke; someone has stroke and if you can response quickly to give t-PA you can try to lyse clot to prevent neurological damage • Not indicated in routine treatment of VTE (no improvement in long-term outcomes) • Significant risk of hemorrhage – 0.5-1% risk of cerebral hemorrhage in most trials • Often given in conjunction with anticoagulants to prevent vessel re-occlusion
