Haemostasis #2 Flashcards
Why is treating thrombosis a balancing act?
- between clot formation + risk of haemorrhage as 1 will dom other
Which drugs are used in treating thrombosis?
- anti-platelet drugs
- anti-coagulant drugs
- fibrinolytic drugs
What is function of anti-platelet drugs?
- limit growth/dec risk of arterial thrombosis
- inhib platelet aggregation
List anti-platelet drugs + their action
- aspirin: inhib COX enz which prod thromboxane in platelets
- P2Y12 receptor antag: P2Y12 activation amp activates platelet activation by platelet agonists so antag inhib platelet activation by ADP + potentclass
- GPIIb-IIIa (glycoprotein) + alpha IIb beta III (integrin) antag
What is thromboxane A2 (TXA2)?
- potent platelet agonist
- vasoconstrictor
- mitogen of sm cells
- major product of cyclo-oxegenase-1
When is low dose aspirin given + what it does?
- 2ndary prevention of cardio-vas events
- irrev inhib of COX-1 (all other NSAID’s rev) + so TXA2 prod
Why doesn’t low-dose aspirin affect PGI2 syn + effect?
- endo can continually syn COX-2 which can prod PGI2 which inhib platelet activation
- prod more PGI2 which dec TXA2:PGI2 ratio so PGI2 dom
What does P2Y12 activation cause?
- full platelet aggregation
- amplifies aggreg initiated by P2Y1 + complete aggreg induced by all other platelet agonists (ADP, collagen, thrombin, TXA2, adrenaline, 5-HT)
- irrev clot formation
What are 2 drug classes of GPIIa-IIb antag?
- Fab fragments (small antibody) e.g. abciximab
- small mol inhib e.g. eptifibatide
- all used IV
What is action of GPIIb-IIIa antag?
- compete with fibrinogen-vWF for binding to GPIIbIIIa receptors
- v. potent + fast-acting
- inhib aggreg irrespective of agonist
What are clinical benefits of GPIIb-IIIa antag?
- improve ischaemic outcomes in patients with acute coronary syndrome undergoing percutaneous coronary intervention
- block immediate re-stenosis following coronary angioplasty
Why are GPIIb-IIIa antag not intended for long-term use?
- cause of major thrombocytopaenia - high rates of bleeding complications
- not for long term use but alt. treatments with improved safety
Is there any benefit of anti-platelet drugs for primary prevention of CV events?
- diff to determine at risk patients + so don’t want to cause haemorrhage
What is adv + disadv of anti-platelet drugs?
- block restenosis following angioplasty e.g. IV P2Y12 antag
- multiple pathways to platelet activation limit effect of specific pathway inhib which leads to incomplete efficacy even though pharmacological inhib is complete
What is dual anti-platelet therapy?
- more effective + synergistic
- used in unstable angina, non-ST segment elevation, MI MI with S-T elevation
- e.g. aspirin + clopidogrel
What is clopidogrel + disadv of using it?
- PYP12 inhib - safer than old antag
- can lead to adverse thrombolytic events due to non-uniform platelet inhib effects aka inter-indiv variability = indiv with high reactivity despite clopidogrel therapy at inc risk of other thrombolytic occurances
What led to dev of anti-thrombotic agents + new PYP12 antag?
- other platelet signalling pathways continue to be activated + can contribute to fungus formation so new drugs have improved safety profiles
What is anticoagulant + fibrinolytic therapy for?
- inhib coag cascade
- prophylaxis + treatment of venous thrombi
- prevent propagation of blood clot but don’t dissolve clot
What are the established anticoagulants?
- heparin
- warfarin
What are novel anticoag drugs + issues?
- factor X
- thrombin inhib
- studies required to determine replacement for short + long term anticoag therapy of heparin + warfarin
What are thrombolytics used for?
- rapid removal of thrombus in coronary + cerebral artery thrombosis
What is purpose of fibrinolytic system?
- acts as dynamic equ to stop over-activation of coag cascade + so is target for fibrinolytic drugs
What is function of heparin?
- prevention + rapid treatment of venous thrombi
- inhib serine-protease factors: XIIa, XIa, Xa, IXa + thrombin directly or potentiation plasma-serine inhib anti-thrombin III
What forms of heparin are there?
- unfractionated heparin = lengths of sugar chains uncontrolled
- low mol weight heparin e.g. enoxaparin
What are pros of unfractionated heparin?
- pros:
- effective
- cheap
- short half life
- rev with protamine (antidote)
What are cons of unfractionated heparin?
- continuous infusion
- variable bioavaliability due to diff in pharmacokinetics of diff fractions
- monitoring required for patients
- unpredictable pharmacokinetics
- HIT
- haemorrhage
What are pros of LMWH?
- inc bioavailability
- inc half-life
- dec risk of HIT
What are cons of LMWH?
- expensive
- partial reversible with protoamine
- haemorrhage
What is heparin induced thrombocytopaenia?
side effect in 1% of patients
What causes HIT?
- heparin highly -ve charged mol + binds to platelet factor 4 - causes antibody prod on 1st exposure
- PF4-heparin complex causes immune-mediated platelet activation of HIT
What is function of vit K antag?
- e.g. warfarin inhib vit K dependent epoxide reductase activity in liver
- mod FVII, FIX, FX + FII (prothrimbin) during syn in liver
What are features of vit K antag therapy?
- long term anticoagulant therapy
- orally active
- takes 1-3 days for full effect as it inhib de-novo syn of CF
- activity affected by diet + gen variation of liver
What is disadv of vit K antag?
- requires frequent monitoring for safety + efficacy
- 1-3% of warfarin patients have major bleeding events
What are drug interactions of vit K antag?
- displacement from plasma albumin
- alteration in metabolism in liver
What is antidote to vit K antag?
- vit K
- replace CF by plasma transfusion if haemorrhage severe
What are 2 ways of giving FXa inhib?
- injection e.g. fondaparinux
- orally e.g. rivaroxiban
What are FXa inhib?
- pentasacc
- active moiety of heparin based on antithrombin binding sequence
- act indirectly via antithrombin
What are pros of injectable FXa inhib?
- IV/SC - 100% bioavalability
- more predictable PK than heparin
- HIT rarely observed (doesn’t bind to PF-4)
- sup. to LMWH pre + post operatively: 70% dec in thrombus risk, no inc bleeding risk
How do oral FXa inhib work?
- directly inhib FXa
What are adv of oral FXa inhib?
- favourable safety
- don’t require frequent blood monitoring
- becoming more widely used
What are thrombin inhib?
- aka FIIa inhib, direct thrombin inhib
- block active site of thrombin
- inhib both clot bound + free thrombin
What is IV infused thrombin inhib used for?
- e.g. hirudin (from leeches), lepirudin + desirudin
- short acting
- as effective as LMWH
- used for anticoagulant therapy + treatment of patients with HIT
What are pros of orally active thrombin inhib?
- pros: as effective as warfarin
- cons: less chance of haemorrhage
Which endogenous mol prevent inappropriate clot formation?
- endo cell NO + prostacyclin
- tissue factor pathway inhib
- active protein C
- antithrombin (III)
What is function endo cell NO + prostacyclin?
- inhib platelet activation + aggreg
What is tissue factor pathway inhibitor?
- from endo + other cells
- inactivates + forms complex with FXa which inactivates mem-bound TF-VIIa complex + limit process in extravas space
What is active protein C?
- activated by thrombin-thrombomodulin
- with cofactor protein S - inactivates FVa, VIIIa
What is antithrombin?
- activated by heparans on endo cells + heparin
- inactivates thrombin IXa-XIIa when not in clot/combined in prothrombinase
Describe process of APC system
- thrombomodulin released by endo + comb with thrombin
- cause inactivated protein C to become activated (APC)
- APC comb with protein S to cause inactivation of FVa + FVIIIa
Describe process of fibrinolysis using plasmin system
- damaged endo stim by bradykinin, thrombin + kallikrein to release tissue plasminogen activator
- TPA binds to plasminogen + cause release of plasmin which degrades fibrin into degradation products (FDPs + D-dimers)
What is plasminogen activator inhib inhib by + sig?
- inhib by APC
- acts as -ve feedback to inhib inhibition of PAI
What is alpha-2 antiplasmin?
- inhin role of plasmin
What is function of fibrinolytics?
- activate plasminogen-fibrin pathway to breakdown fibrin clot
- remove arterial thrombi (MI - up to 12hrs, stroke - up to 3hrs)
How are fibrinolytics given + disadv?
- IV
- high risk of haemorrhage
What is antidote to fibrinolytics?
- severe haemorrhage treated with transexamic acid (inhib activation of plasminogen)
List 2 e.g.s of fibrinolytics
- streptokinase
2. alteplase
What is streptokinase?
- non-enz protein from streptococci
- binds + activates plasminogen
- allergenic
What is alteplase?
- non-allergenic
- clot selective - only activates plasminogen bound to fibrin in thrombus
