Haemostasis Flashcards
Give a simple rundown of coagulation.
- blood is our key transport system
- blood must remain in the fluid phase
- coagulation plugs an holes in this system
What is Haemostasis?
This involves the interaction of:
- platelets - coagulation factors - coagulation inhibitors - fibrinolytic processes - blood vessels/endothelium/cellular membranes (mononuclear cells)
Explain the difference between primary haemostasis, secondary haemostasis and fibrinolysis.
Primary:
- vasoconstriction
- platelet adhesion
- platelet aggregation
- timing: immediately (seconds/minutes)
Secondary:
- Activation of coagulation factors
- Formation of fibrin
- timing: minutes
Fibrinolysis:
- activation of fibrinolysis
- lysis of the clot
- timing: minutes/hours
What is Virchow’s Trias?
Virchow’s Triad is made up of three elements necessary for thrombus formation.
- blood composition
- vessel wall damage
- blood flow
Explain the significance of the vessel wall in clotting.
- endothelial cell surface
- dynamic and active
- interacts with blood and subcutaneous tissue
- can be antithrombotic or prothrombotic depending on expression of surface molecules and secretion of proteins
- arteries and veins differ with the arterial smooth muscle layer being important
- endothelium changes with age and is different in different vascular beds
- no mechanism to test functional integrity
What elements of blood are involved in clotting?
Platelets: stop bleeding
Plasma: coagulation/clotting system
What are the basic principles of coagulation?
- tissue factor is the starter motor
- complex system of positive and negative feedback loops
- redundancy
- thrombin is the key enzyme that must be controlled
- linked to inflammatory, angiogenic, wound repair and other regulatory systems
- intrinsic and extrinsic defintitions are not physiological
- finrinolytic system is less well understood.
What are the three phases of coagulation?
- Initiation Phase
- Amplification Phase
- Propagation Phase
Explain the initiation phase of coagulation?
Injury of vessel walls leads to contact between blood and subendothelial cells.
Tissue factor (TF) is exposed and binds to FVIIa or FVII which is subsequently converted to FVIIa.
The complex between TF and FVIIa activates FIX and FX
FXa binds to FVa on the cell surface.
Explain the amplification phase of coagulation.
The FXa/FVa complex converts small amounts of prothrombin into Thrombin.
The small amount of thrombin generated activated FVIII, FV, FXI and platelets locally. FXIa converts FIX to FIXa.
Activated platelets bind FVa, FVIIIa and FIXa.
Explain the propagation phase of coagulation
The FVIIIa/FIXa complex activates FX on the surfaces of activated platelets.
FXa in association with FVa converts large amounts of prothrombin into thrombin creating a ‘thrombin burst’.
The ‘thrombin burst’ leads to the formation of a stable fibrin clot.
Explain thrombin.
Thrombin is essential to convert Fibrinogen to fibrin, critical for clot formation, reinforcement of platelet plug.
If insufficient thrombin is generated it leads to bleeding, whereas excessive thrombin leads to thrombosis.
Thrombin is the on/off switch for haemostasis.
What are the actions of thrombin?
- Fibrinofen (Fi) Fibrin (insoluble fibrin clot)
- XIII activation (terminal cross-linkage of fibrin)
- XI (Fi) XIa
- V → Va
- VIII → VIIIa
- IX (Fi) IXa
- Binds to thrombomodulin (APC inhibition of VIIIa and Va)
- Activation of TAFI (clot stabilization)
- Platelet activation
Explain thrombin inactivation.
- Binding to thrombomodulin (APC down-regulates ability to cleave fibrinogen
- Irreversible inhibition by antithrombin (accelerated by Heparin 1000 fold)
- Binding to heparin co-factor II, dermatan suplhate
- Binding to alpha-2 macroglobulin
What are some actions of thrombin outside of the coagulation pathway?
Thrombin may potentially cause:
- Activation of Protease-activated receptors (PARs): group of cellular receptors that regulate platelet actvation, tumour growth/spread, blood vessel formation, inflammation, atheroschlerosis, monocyte/neutrophil migration and neuron survival/growth.
They may also be important in embryonic growth, tumour spread and vascular disease.
