Anticoagulants and antiplatelets Flashcards
Broadly describe the use of antiplatelet agents
- Can be used in combination with each other and/or combinations with anticoagulants
- Combinations increase the risk of side effects (particularly bleeding)
- Aspirin was the first antiplatelet (COX inhibitor) and is the most commonly used antiplatelet in practice
Describe glycoproteins IIB/IIIA inhibitors
- eg tirofiban, epitifibatide
- admin iV
- prevent binding of fibrinogen to platelet by occupying IIB/IIIA receptor thus blocking platelet aggregation
- indicated in unstabele angina, nstemi in high risk, PCI
- adverse effects include bleeding and thrombocytopenia
Describe P2Y12 antagonists
- clopidogrel, prasugrel, ticagrelor
- oral
- irreversibly bind P2y12 receptor on platelet and inhibits platelet aggregatio nfor the life of hte plateley
- (Tica binds irreversibly)
- ACS plys aspitin, clop is used as alternative to aspitin
- adverse effects: bleeding and angioedema
note while prasi and tica are more effective, they cayse more bleeding
tica is taken twice daily vs clop once
Braodly describe the use of anticoagulants
- Treatment of venous thromboembolism (VTE)
- Prevention of VTE
- Ischaemic stroke and transischaemic attack (TIA) & stroke prevention in patients with Atrial Fibrillation and a high risk (calculated using CHADSVASC score)
- Acute coronary syndromes
- Extracorporeal circuits (dialysis, cardiac bypass etc)
- Angioplasty
- Peripheral arterial occlusion
Distinguish between UFH, LMWH
- LMWH causes renal impairment and extremems of body weight
- UFN admin is subcut, used for VTE prophylaxis; IV is used for therapeutic anticoag; LMWH only adminned one way
- LMWH only partially reversed by protamine, no monioring usually needed but can use anti Xa
Describe heparin in detail
Heparin
- Binds to antithrombin (AT) causing inhibition of thrombin (IIa) and Xa
- Normally antithrombin binds to IIa and Xa and inactivates these factors, this process is accelerated by heparin
- Administered parenterally either by subcutaneous or intravenous routes
- Subcutaneously for prophylaxis (usually)
- Intravenous (infusion and loading dose) for treatment of thrombosis (usually)
- Not absorbed orally
- Short half-life
- saturable clearance (rapid internalisation of heparin on receptors on endothelial and macrophage cells) then
- non-saturable: renal clearance - increasing dose = increased apparent half-life
- Monitoring with activated partial thromboplastin time (APTT)
- Essential due to inter and intra patient variability
- Adverse effects:
- Bleeding
- hypoaldosteronism -> hyperkalaemia
- Hypersensitivities and transaminitis
- Heparin induced thrombocytopenia (HIT) see below
- Reversibility
- short half-life so can stop infusion
- Protamine binds to heparin and neutralises.- Binds to antithrombin (AT) causing inhibition of thrombin (IIa) and Xa
- Normally antithrombin binds to IIa and Xa and inactivates these factors, this process is accelerated by heparin
- Administered parenterally either by subcutaneous or intravenous routes
- Subcutaneously for prophylaxis (usually)
- Intravenous (infusion and loading dose) for treatment of thrombosis (usually)
- Not absorbed orally
- Short half-life
- saturable clearance (rapid internalisation of heparin on receptors on endothelial and macrophage cells) then
- non-saturable: renal clearance - increasing dose = increased apparent half-life
- Monitoring with activated partial thromboplastin time (APTT)
- Essential due to inter and intra patient variability
- Adverse effects:
- Bleeding
- hypoaldosteronism -> hyperkalaemia
- Hypersensitivities and transaminitis
- Heparin induced thrombocytopenia (HIT) see below
- Reversibility
- short half-life so can stop infusion
- Protamine binds to heparin and neutralises.
Describe HIT
Heparin-induced thrombocytopenia (HIT) is an uncommon but dangerous complication of heparin therapy. It is an immune-mediated condition caused by autoantibodies directed against heparin complexed with endogenous platelet factor 4. If HIT is not recognised and managed early, thrombosis can occur in up to 50% of patients, with thrombosis-related deaths ranging from 5to 10%.
The diagnosis of HIT is made by a combination of clinical features, and by laboratory demonstration of specific antibodies. It can take several days to obtain definitive laboratory antibody test results, so a clinical risk calculator (such as the 4Ts score) can make a presumptive diagnosis for the urgent management of HIT. HIT precludes the patient from ever receiving heparin or low molecular weight heparins again but the patient is at risk of thrombus and needs alternative anticoagulation.
Describe LMWH in detail
- Fragments of heparin (about 1/3 of the size of heparin molecule)
- The major effect is via inactivation of Xa (rather than thrombin inhibition) - see diagram above
- Less binding to other proteins (endothelial, platelet, plasma) therefore more predictable
- Longer plasma half-life (less endothelial cell binding)
- Renal elimination therefore prolonged half-life in renal impairment
- Monitoring
- APTT not prolonged
- Anti-Xa levels possible (not practical for all patients- used in renal impairment or extremes of body weight)
- Weight based dosing for anticoagulation leads to predictable effects in most patients
- Complications/adverse effects
- bleeding (especially in renal impairment)
- HIT - lower incidence than heparin
- LMWH not an alternative if HIT experienced with heparin
- Reversal
- long half life
- 50% reversed by protamine
Describe the DOACS
- Inhibit Xa by interacting with the active site of Xa
- Rivaroxaban and apixaban
- Works in plasma and in the prothrombinase complex within a clot (heparin can’t reach)
- Irreversible
- Short half-life and rapid onset
- Some renal excretion
Oral direct thrombin inhibitor (Dabigatran)
- Inhibits both free and fibrin-bound thrombin (prevents conversion of fibrinogen to fibrin)
- Reversing antibody idarucizumab (expensive and reserved for severe bleeding/toxicity)
- Renally excreted
Describe warfarin
- Blocks regeneration of vitamin K from its epoxide form
- Vitamin K is necessary for the addition of γ-carboxyglutamic acid residues to clotting factors, II, VII, IX and X as well as Protein C & Protein S which allows the clotting factors to undergo conformational change and participate in the coagulation cascade
- Initially decreased level of Protein C leads to hypercoaguable state
- Delayed onset of anticoagulation
- Effects of warfarin are dependent on the half-life of these clotting factors
- T1/2 can be 40 hours
- Metabolised by CYP2C9
- Lots of drug interactions with CYP2C9 inducers and inhibitors
- Unpredictable anticoagulation effects
- patient compliance
- vitamin K in diet/vitamin supplements
- concurrent illness
- antibiotics (decreased endogenous production vitamin K due to change in bacterial flora
- Genetic polymorphisms in CYP2C9 and vit K epoxide reductase
- Monitoring
- INR (international normalised ratio)
- Complications: bleeding, skin necrosis
- Reversal:
- cessation - takes 3-5 days for recovery of clotting factors
- Prothrombin complex concentrate or fresh frozen plasma (lasts 4-6 hours only)
- Vitamin K: response within 8-24 hours
Broadly discuss the thrombolytics
e.e. alteplase, tenecteplase
Convert plasminogen to plasmin, which catalyses the breakdown of fibrin.
Indications:
- Acute STEMI (where primary PCI is not possible)
- Acute massive VTE (particularly PE) in patients who are haemodynamically unstable
- Peripheral arterial thromboembolism
- (alteplase is also used for ischaemic stroke in selected patients meeting strict criteria)
Adverse effects:
- Bleeding, transient hypotension, allergic reactions, nausea and headache.
