Coagulation And Anticoagulants Flashcards
Describe the events that take place after cutting yourself
- blood vessel damage
- disruption to the endothelium leading to exposure of the proteins under the lining - tissue factor and collagen
- primary haemostasis (recruitment of platelets)
- secondary haemostasis (activation of coagulation factors)
^ occurs simultaneously
Describe the events of primary homeostasis
- hole in endothelium causes exposure of Von Willebrand factor which attracts platelets through a receptor which allows adhesion activating them causing release of granular contents
- results in more platelet activation and eventual aggregation
- leads to exposure of phospholipids
- plug formed in hole made by clot
Describe the events that take place in secondary haemostasis
- coagulation cascade = every step requires phospholipids + calcium
- initiation
- propagation
- regulation
Describe initiation of the coagulation cascade
- exposed tissue factor activates factor VII
- this activates factor X which activates prothrombin factor (II) and factor V resulting in activation of the prothrombinase complex leading to conversion of prothrombin to thrombin
- thrombin converts fibrinogen to fibrin and activates factor XIII which cross-links the fibrin to increase the strength
Describe propagation of the coagulation cascade
- production of thrombin in initiation activates factor XI which activates factor IX
- factor VIII is also activated which stimulates the prothrombinase complex leading to production of more thrombin allowing more conversion of fibrinogen to fibrin and cross-linked fibrin
Describe regulation of the coagulation cascade
- antithrombin (naturally occurring anticoagulant) downregulates all coagulation factors in cascade
- thrombin can also downregulate itself by binding to thrombomodulin leading to activation of protein C (naturally occurring) which works with protein S (naturally occurring) to downregulate factor V and factor VIII reducing thrombin production and in turn pibrin production
- tissue factor protein inhibition (naturally occurring) is stimulated by the activation of factor X which blocks activation of factor VII when it comes into contact with tissue factor
Describe the process of fibrinolysis
- plasmin from plasminogen (conversion activated by feedback from fibrin) is able to break down fibrin to degradation products including D-dimer
- fibrin feeds back by producing tPA and uPA (plasminogen activators)
- plasmin production regulated by alpha 2 anti-plasmin and plasminogen activator inhibitors (downregulates tPA and uPA)
What are the methods of coagulation analysis?
- bleeding time (not done anymore)
- FBC, platelet function tests in haemostasis lab using light transmission aggregometry
Describe the process of light transmission aggregometry
- platelet rich plasma
- red cells are removed
- stimulation of aggregation through addition of agonists/agents
- light flow through sample is measured by detector
- as aggregation ensues, light transmission decreases
What are the tests for secondary haemostasis?
- prothrombin time (PT)
- activated partial thrombophlebitis time (APTT)
- prothrombin clotting time (TCT)
- individual coagulation factor assays
Why are citrate samples used in assessment of haemostasis?
It chelates calcium to stop the clotting process in the sample
Describe prothrombin time
- dependent on factor VII, V, II and fibrinogen (extrinsic + common)
- patient plasma + thromboplastin (tissue factor + phospholipids)
- body temperature
- Ca added
- time measured to clot (9-13s)
Describe INR
- standardised form of prothrombin time
- used for monitoring of K+ antagonists like warfarin
- dependent on factor II, VII, IX and X
Describe APTT
- patient’s plasma + contact factor (kaolin/silica) + phospholipid
- body temperature
- Ca added
- time measured to clot (26-38s)
- dependent on factors VIII, IX, XII (+ II, V and X) - intrinsic + common
Describe TCT
- measure of fibrinogen into fibrin clot
- patient plasma + bovine thrombin excess
- time to clot measured (9-16s)
What are the types of anti-thrombotic agents?
- anticoagulants: inhibit 1 or several components of coagulation cascade
- fibrinolytic agents: enhance lysis of fibrin clot
- anti-platelet agent: inhibit platelet activation/aggregation
Anticoagulants (function and examples)
- main function to inhibit formation of fibrin clot
- eg. Heparin/fondaparinux: antagonise activated factor X
- warfarin: vit K antagonist, lowers factor II, VII, IX and X
- DOACs eg. Dabigatran inhibits thrombin
What are the side effects of heparin?
- thrombocytopenia (bleeding risk)
- osteoporosis (with prolonged use)
- hyperkalaemia (rare)
Indications for heparin
- for short-acting anticoagulant effect
- acute DVT/PE
- during cardiac bypass (UFH)
- ACS (+ antiplatelet agents)
- venous thrombosis
- post-op
- obstetrics
Describe aspects of warfarin
- high inter-individual variability
- delayed onset/offset
- long half life
- narrow therapeutic window
- drug/food interactions
- requires regular INR monitoring
- rapid reversal with vitamin K
What are the contraindications of DOACs?
- pregnancy + breast feeding
- liver disease with cirrhosis
- coagulopathies
- certain drugs
What are the 2 types of fibrinolytic drugs?
- kinases (eg. Streptokinase, urokinase): more direct action on fibrin
- tissue plasminogen activators tPAs (eg. Altepase, tenecteplase): stimulate the conversion of plasminogen to plasmin
Describe the action of kinases with specific examples
- bind to plasminogen allowing release of plasmin to enhance breakdown of fibrin
- act on clot bound and free plasminogen (systemic bleeding risk)
- streptokinase: derived from bacteria so is antigenic and wont work if recent infection/previous use
- urokinase: grown from renal cells in culture and not antigenic
Describe the action of tPA derivatives with its uses
- stimulate plasminogen to cleave plasmin from it to break down fibrin
- selective for clot bound plasminogen
- used for acute MI (if unsuitable for PCI), ischaemic stroke (selectively due to bleeding risk), PE with haemodynamic instability
Describe the advantages and uses of catheter directed thrombolysis
Advantages:
- smaller doses
- administered directly into vessel requiring thrombolysis
- less systemic effect
Uses:
- acute limb ischaemia
- massive DVT
- blocked CVC
Describe the mechanisms of anti-platelet drugs
- inhibit platelet receptors
- inhibit platelet signalling pathways
Describe the action of clopidogrel/ticlodipine
- irreversible blockage of ADP receptor on platelet
- blocks signalling pathway in platelet which reduces binding of fibrinogen
Describe the mechanism of abciximab and tirofiban
- glycoprotein IIb/IIIa antagonists
- reduces platelet aggregation and binding of fibrinogen
Describe the mechanism of aspirin
- irreversibly inhibits the cyclooxygenase pathway in platelet cell
- blocks conversion of arachidonic acid to thromboxane A2
- decreases platelet activation
Describe the mechanism of dipyridamole
- acts on ADP receptors of platelet cells to increase platelet concentration of cAMP
- reduced aggregation of platelets
What are the indications of anti-platelet drugs?
- cardiovascular disease
- acute MI (aspirin indefinitely + clopidogrel
- secondary prevention of CVD
- cerebrovascular disease (without AF)
- acute stroke/TIA/secondary prevention
- peripheral vascular disease
