ACEM Primary
Drugs affecting coagulation
Antiplatelet medications
| Aspirin -ACS, CVA, GCA, chronic CAD, PVD -C/I Reye Syndrome (fever+ liver failure + encephalopathy) | Irreversibly binds and inhibits COX -> decreased TXA2 Reduced stimulation phospholipase C -> Reduced IP3/ DAG activity and thus reduced Ca2+ release from ER Reduced degranulation and PLT aggregation for PLT lifespan ~10 days |
| P2Y12 R inhibitors: Pasugrel -ACS Ticagrelor -ACS Clopidogrel -ACS -reduced risk TTP -poor metabolisers (CYP2C19) Ticlopidine – stroke px in TIA -risk TTP | Inhibit P2Y12 R (ADP R) Decreased Gi protein activity Reduced inhibition adenylyl cyclase -> reduced ATP to cAMP to protein kinase A Maintains VASP in phosphorylated form (inactive) Reduced stimulation of GpIIa/IIIb complex Reduced PLT interactionDecreased Gq protein Reduced degranulation via PLC/ IP3/DAG pathway No effect on PG metabolism |
| GpIIb/IIIa inhibitors: Abcixiban Tirofiban Eptafibide | Directly inhibit PLT interactionPotent |
| PDE-3 inhibitors: Dipyridamole -CVA Cilostazol -PVD | Inhibit PDE-3 enzyme Reduced conversion of cAMP to AMP and cGMP to GMP On PLT will stabilise VASP-P thus reducing GpIIb/IIIa activity On vascular smooth muscle will inhibit myosin light chain kinase (MLCK) phosphorylation, reducing vasoconstriction |
| Adverse effects: Bleeding = epistaxis, gingiva, GIB, petechial rash/ purpura, PV bleeding TTP = thrombotic thrombocytopenic purpura vWF monomers-> multimers, usually broken back down by ADAMS T13 enzyme Reduction of this enzyme (anti-PLT, chemotherapy, SLE) leads to increased vWF multimers Attract PLT-> thrombi + consumption of PLT Sx: “FAT-RN” fever, haemolytic anaemia ( LDH BR ¯ haptoglobin), thrombocytopaenia, renal insufficiency, neurologic sequelae Tx: plasmapheresis, steroids |
Anticoagulants
Heparins and Fondaparinux
| UFH: Heparin | Pentasaccharide + long glycosaminoglycan (GAG) chain Bind anti-thrombin III and enhance inhibition of factor X and thrombin (II) and IXa Used IV for bolus (80-100U/ kg) + infusion (15-22U/kg/hr) and SC (5000U BD) Short t ½ Safe in renal impairment Higher bleeding risk Higher incidence HIT Antidote is protamine sulfate: for every 100U heparin in patient, give 1mg IV Measured via aPTT pathway:Intrinsic + common pathway “Activator” added to form XIIa-> time measured to clot (Normal range 30-40 seconds) With heparin, should become longer Recommended 1.5-2.5 x normal range (45-100 seconds) |
| LMWH: Enoxaparin -prophylactic dose 30mg SC BD -therapeutic dose 1mg/kg SC BD Dalteparin | Pentasaccharide + short GAG Bind anti-thrombin III and enhance factor X inhibition Used SC Not used in renal impairment (need CrCl >30 mL/min) Longer t ½ Levels not measured in except in renal insufficiency, obesity and pregnancy |
| Fondaparinux | Pentasaccharide alone Bind anti-thrombin III and enhance factor X inhibition Longer t ½ 15 hours |
| Indications = acute PE/DVT or prophylaxis, STEMI/ NSTEMI, cardiac thrombus AE = bleeding, HIT C/I = bleeding, recent CVA, uncontrolled HTN Will not be as effective in disease states with reduced anti-thrombin III (liver cirrhosis, nephrotic syndrome) Heparin induced thrombocytopaenia: 1-4% patients treated with heparin Heparin binds to platelet factor IV on PLT-> incites immunogenic reaction -> Plasma cells form IgG which bind to heparin-PLT complex: – Can either tag PLT for splenic destruction = low PLT or – Activate PLT to form clots to form DVT/PE/MI/CVA/CVT/acute limb ischaemia First exposure, takes 1-2 weeks to present On second exposure, take 0-1 days Diagnosis via serotonin release assay – combine patient serum + heparin + donor platelets-> if PLT activated, will release serotonin Treatment is to cease heparin and give alternative direct thrombin inhibitor |
Warfarin
MOA
- Inhibits vitamin K epoxide reductase enzyme in hepatocytes
- Disrupts vitamin K metabolism
- Reduced ability for carboxylase enzyme to carboxylate clotting proteins
- Reduced functionality of factors II, VII, IX and X + protein C and S
- Reduced clotting
- Initial stages: reduced protein C and S (anticoagulants) due to shorter t ½ = levels Va and VIIIa = hypercoagulable state, resolves in few days. Can lead to warfarin induced skin necrosis (limbs/ breasts and penis) which can be prevented by bridging therapy with heparin.
Interactions: Metabolised by CYP450 oxidase enzyme
- “ODEVICES” inhibit P450 thus warfarin levels ( INR)
- Omeprazole, Disulfiram, Ethanol (acute), Valproate, Isoniazid, Ciprofloxacin/ Cimetidine, Erythromycin, Sulfa drugs
- Amiodarone, Metronidazole, Fluconazole
- Aspirin (increased turnover of clotting factors and platelets)
- Third generation cephalosporins (eliminate bacteria that produce Vitamin K)
- Hyperthyroidism
- “CPBARS” induce P450 thus ¯ warfarin levels (¯ INR)
- Carbamazepine, Phenytoin, Barbiturates, Alcohol (chronic), Rifampin, St John’s Wort
- Cholestyramine
- Vitamin K, diuretics ( synthesis clotting factors)
- Hypothyroidism (¯ turnover rate of clotting factors)
Dose:
- 100% bioavailability
- 5-10mg PO
- 8-12 hour delay in action, then 5-7 days to balance anti/ procoagulant action
- Inhibition of II, VII, IX and X (t ½ 60, 6, 24 and 40 hours respectively)
- Inhibition of protein C (t ½ 6 hours)
- t ½ ~ 36 hours
Indications:
- Prophylaxis PE/DVT
- Anticoagulation for AF
- Post MI (LV thrombus prevention)
- CCF
- Mechanical heart valves
Monitoring: PT/ INR = extrinsic pathway
- Patient serum + add TF-> time to clot is prothrombin time
- Standard ratio required, ratio to control PT-> INR
AE: Bleeding, warfarin induced skin necrosis
Contraindications:
- High bleeding risk
- Pregnancy (teratogenic)
- Liver disease
- Low vitamin K states (pancreatitis, coeliac, prolonged Abx use)
Antidote:
- Vitamin K IV infusion or PO
- Prothrombin complex concentrate (II, VII, IX, X + protein C/S) – quicker however $$
- FFP (all clotting factors)
Direct Factor Xa inhibitors
MOA:
- Inhibit Xa in common pathway
- Dosage fixed and nil need for monitoring
- Rapid onset of action and shorter half life than warfarin
Drugs:
- Rivaroxaban
- High oral bioavailability if taken with good
- Peak plasma level 2-4 hours
- Substrate cytochrome P450 system and P glycoprotein transporter
- Drugs inhibiting CYP3A4 and P glycoprotein = rivaroxaban effect
- Ketoconazole
- Given in AF for anticoagulation, DVT prophylaxis and treatment
- Apixaban
- Oral bioavailability 50%
- T ½ 12 hours
- Similar metabolism to rivaroxaban
Contraindications:
- Excreted by kidneys and liver, take care in failure
- No antidotes exist
Direct thrombin inhibitors:
Parenteral = Hirudin, Bivalirudin, Argatroban
Oral = Dabigatran
- Dose 150mg BD
- Oral bioavailability 3-7%
- Substrate for P glycoprotein-> levels by ketoconazole, amiodarone, quinidine and clopidogrel
- Avoid in severe renal impairment
- Used for prevention of stroke and embolism in non-valvular AF
- Nil monitoring required
- Antidote exists (Indarucizumab)
Thrombolytics
Steptokinase (protein synthesised by streptococci)
Anistreplase (anisoylated plasminogen streptokinase activator complex = APSAC)
Urokinase (synthesised by kidney)
Tissue plasminogen activators (t-PAs) = Alteplase, Tenecteplase (longer t ½) preferentially activates plasminogen bound to fibrin – known as fibrin-specific thrombolytic
MOA:
- Lyse thrombi by catalysing formation of plasmin from plasminogen
Indications:
- IV for PE with haemodynamic instability, severe DVT (SVC syndrome) and phlegmasia cerulea dolens
- AMI
- Acute ischaemic stroke within 3 hours of symptom onset
Dose:
- Streptokinase = loading dose 250 000U, 100 000U/hour for 24-72 hours
- Anti-streptococcal Ab may develop
- Alteplase = 15mg bolus, 0.75mg/kg over 30 min then 0.5mg/kg over 60 min
- Tenecteplase = single bolus 30-50mg
Contraindications:
- GI bleed in last 2-4 weeks
- TIMI trial showed that haemorrhagic stroke is most common side effect
Tranexamic acid:
- Analog of aminocaproic acid = inhibitor of fibrinolysis
- Inhibits plasminogen activation
- PO 15mg/kg loading dose then 30mg/kg every 6hrs
- IV 1000mg infusion over 5 min then 1g over 8 hours as infusion in haemodynamically unstable trauma patients (within first 3 hours of injury)
Last Updated on August 12, 2021 by Andrew Crofton
Andrew Crofton
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