Review of haemostatic and fibrinolytic systems.
Heparin (unfractionated).
- Bind to antithrombin –> conformational change –> expose active site –> enhance its inactivation of IXa, Xa and thrombin 1000 fold
- Needs APTT monitoring of levels in therapeutic levels.
- Surgeons prefer due to reversibility
- Toxicity – bleeding, allergy, alopecia, osteoporosis
- Heparin induced thrombocytopenia
- Systemic hypercoagulable state
- 1-4% of people treated for a minimum of 7d. Esp surgical patients.
- Usually venous thrombosis, sometimes arterial occlusions.
- Platelet count should be performed regularly when giving heparin
- Rx – stop heparin give direct thrombin inhibitor (hirudin, agatroban)
LMW Heparin.
- Bind to antithrombin and enhance its inactivation of Xa and also to a lesser extent inactivation of thrombin
- Equal efficacy to heparin, better bioavail from S/C injection, less freq dosing required, less risk of HIT
- Measured with anti Xa levels
Protamine
- Reverses heparin (heparin antagonist)
- 100mg per 10000units heparin
Oral direct thrombin inhibitors
- Dabigatran
- Rivaroxiban (Xa inhibitor)
- Used for prev of venous thromboembolism and non vavlular AF
- No monitoring
- No reversal agent
Warfarin.
- PD – Vitamin K inhibitor, inhibit Protein C and S first then partially inhibit synthesis of factor II, VII, IX, X(with normal degradation so coag levels fall).
- PK – 100% bioavailability, 99% albumin bound, Small Vd, T1/2 36hrs
- Toxicity – can cross placenta and cause fetal haemorrhage, birth defects. Initial procoagulant then anticoagulant –> bleeding
- Lot of diet and drug interactions. Narrow therapeutic window therefore needs lots of INR monitoring.
- Reversed with Vit K
| Increase INR | Decrease INR |
|---|---|
| Phenylbutazone
Amiodarone Disulfram Metronidazole Fluconazole Trimethoprim-sulfamethoxazole Asprin Heparin Cephalosporins Hepatic disease Hyperthyroidism |
Barbiturates& rifampicin(induce enzymes in liver to increase bd of warfarin),
Cholestyramine(reduce absorption), Diuretics(increase cloting factor concentration), Vit K, hypothyroidism Carbamazepine |
No significant effect – etOH, benzos, phenothiazides, acetaminophen, opioids, indomethacin
Streptokinase.
- Increase formation of plasmin from plasminogen
- Made by streptocci
t-PA.
- Endogenous plasminogen activator
- These preferentially activate plasminogen bound to fibrin so is a bit more selective to the thrombus formed
- Recombinant DNA tech has allowed us to make manufactured t-PA (alteplase/tenecteplase(longer half life))
- Indications – PE with haemodynamic compromise, STEMI, severe DVT, stroke within 4hrs of onset.
Aspirin (antithrombotic effects)
- Irreversibly inhibit cyclo-oxygenase in platelets (inhibit thromboxane production–> inhibit platelet activation and aggregation).
Clopidogrel
- Irreversibly block ADP receptor on platelets
- Duration of effect 7-10d.
G2b/3a inhibitors
- Used in ACS
- GP2b and 3a Receptor on platelets bind to fibrinogen and vWF. Activation of these receptors is the final common pathway for platelet aggregation.
- ABCiximab, tirofiban/ eptifibatide
Vitamin K.
- Reverses warfarin
Blood products:
- FFP.
- Coag factors + plasma proteins + fibrinolytics + complement
- Indications: Replacement of factors that aren’t available individually, warfarin reversal, massive transfusion protocol, antithrombin 3 deficiency, TTP
- Cryoprecipitate.
- Precipitate of FFP when thawed and centrifuged
- Fibrinogen + Factor 8, Factor 13, vWF
- Indications – haemphilia, vWF disease, low fibrinogen levels, qualitative problems with fibrin, bleeding from excessive anticoagulation, DIC
- Factor VIII.
- Haemophilia A
- Factor IX.
- Haemophilia B
- Desmopressin can release more vWF.
Viva questions:
- Tell me about Heparin.
- What are the differences between unfractionated Heparin and LMW Heparin ?
- How can you reverse the actions of Heparin ?
Protamine sulfate 1mg IV per 100units heparin
- Tell me about warfarin
- Tell me about the PK/PD/interactions of Warfarin.
- How can you reverse the action of Warfarin ?
- Tell me about the antithrombotic efects of Asprin
- Tell me about STK / t-PA.
- What pharmacological agents could be used to treat a patient with a major haemorrhagic complication following administration of STK ?
Aprotinin – inhibits fibrinolysis by plasmin and inhibits plasmin-streptokinase complex.
- Tell me about clopidogrel
Tell me about Abciximab/Tirofiban/Eptifibatide