Haemostasis 1 Flashcards
What is haemostasis and thrombosis?
The control of the clotting and coagulation pathways in blood in normal and disease states, respectively
What does haemostasis involve?
(4)
Constriction of blood vessels
Adhesion and aggregation of platelets
Formation of a fibrin mesh by coagulation cascade
Followed, ultimately, by dissolution of the clot in a process called thrombolysis or fibrinolysis
Define thrombosis
A pathological state within the vascular system which results in inappropriate activation of the normal haemostatic process
What is a thrombus?
A blood clot
What does thrombus formation cause?
The blockage of blood flow to vital areas
Why do we need haemostasis
(3)
To ensure the maintenance of blood flow under normal physiological conditions
To maintain the integrity of the vasculature
Haemostasis has tight control over the initiation and termination of coagulation, localised to the are of vessel injury
What is haemostasis coordinated with?
Inflammatory and immune responses
How are clots removed?
The clot is removed as part of vascular remodeling
What does the haemostatic response do?
(3)
Prevents the loss of blood into the tissues and maintains vascular integrity
It localises the damage to the site of injury
Repairs and re-establishes blood flow through the repaired blood vessels
The haemostatic response is said to be in dynamic balance, what does this mean?
There is balance between activation and inhibition of the pathways involved e.g. clot formation and clot dissolution
What happens when there is a congenital or acquired deficiency in the haemostatic response?
The patient presents with haemorrhage
What happens when there is uncontrolled activation of the pro-coagulants?
(2)
This may result in excessive clotting or persistence of clot
Patients may present with thrombosis or blockages
What does the haemostatic balance favour?
Naturally favours anti-coagulant e.g. no clots unless needed
What would happen without haemostatic balance
Excessive bleeding or vaso-occlusion
What is vaso-occlusion
(2)
Uncontrolled formation of thrombin in vascular system
These occlude vessels and deprive organs of blood and therefore oxygen
Define thrombus formation
Inappropriate formation of a blood clot in an intact blood vessel
Define an embolus
A floating clot that has dislodged from the position where it was formed
Comment on the dynamics of haemostasis balance
The formation and dissolution of thrombi is maintained in a delicate balance (naturally anti-coagulant)
Briefly describe how haemostasis responds to vessel injury
(5)
Severed vessel - Vasoconstriction
Platelets adhere/agglutinate and become sticky, forming a plug
Fibrin appears
Fibrin clot forms
Clot retraction occurs
How is thrombin formed (briefly)?
(2)
Prothrombin is converted to thrombin
Thrombin converts fibrinogen to fibrin
What happens when there is vessel injury?
(3)
Vasoconstriction
Release of tissue factor
Collagen becomes exposed
What does vasoconstriction do to repair blood vessels?
This reduced blood flow and therefore reduces blood loss
Why is collagen exposure important?
This allows for platelet adhesion at the site of injury
What exactly is meant by platelet activation?
Platelets change shape, secrete their granules and activate GPIIb/IIIa
What does platelet activation bring about?
Release of serotonin
Thromboxane A2, ADP
Platelet Phospholipid
What does serotonin do?
brings about vasoconstriction
What does thromboxane A2, ADP do?
Brings about vasoconstriction
Brings about platelet aggregation
What does platelet phospholipid do?
Part of the blood coagulation cascade
What activates the blood coagulation cascade?
Tissue factor
What does platelet aggregation do?
Forms the primary haemostatic plug
What is needed to form a stable haemostatic plug
(2)
Primary haemostatic plug of aggregated platelets
With the addition of fibrin from the coagulation cascade
List the four components of haemostasis
Vascular endothelium
Platelets
Coagulation pathways (pro-coagulants and anti-coagulants)
Fibrinolysis
How many stages are there to the haemostatic response?
Three stages
What is the primary haemostatic response?
(2)
Rapid response to seal the injured vessel
Components include the endothelium, sub-endothelium, VWF and platelets
What is the secondary haemostatic response?
Formation and stabilisation of the platelet plug
What is the tertiary haemostatic response?
Fibrinolysis, degradation of fibrin clot
What is primary haemostasis
The initial response after vessel injury is mediated by interactions between the vessel wall and circulating platelets to begin the formation of the clot
Main players: blood vessels, VWF, platelets
How does the blood vessel wall respond to trauma?
(4)
Platelets adhere to subendothelium and form platelet plug
Vasoconstriction occurs in response to localised release of vasoactive amines from activated platelets
Tissue factor is released from the endothelium which activates coagulation
vWF is also released which acts as a glue to stick platelets to the wall
What brings about vasoconstriction and what produces them?
Vasoactive amines released from activated platelets
What activates coagulation and where is it released?
Tissue factor, released from the endothelium
What acts as the glue to hold the platelets together
Von Willebrand Factor
Describe the role of blood vessels in haemostasis
(6)
Higher blood flow rate is seen in the centre of the lumen, lower flow near endothelium surface
As a result, larger RBCs are more concentrated in the centre of the blood vessel and smaller platelets are found nearer the vessel wall
Under normal conditions the endothelial layer of intima is antithrombotic (prostaglandin I2)
Upon vessel injury the endothelial cells become prothrombotic
Post injury, endothelin-1 (strong vasoconstrictor) is released to minimise blood lost
The adventitia expresses tissue factor which is crucial for initiation of the secondary response
What gives endothelial intima it’s antithrombotic effect
Prostaglandin I2
What is the strong vasoconstrictor released post injury in endothelial cells
Endothelin-1
Where is tissue factor expressed from?
Adventitia
What inhibits fibrin formation?
Heparan sulphate
What act as vasodilators in blood vessels?
Prostacyclin and Nitric oxide
List the anti-coagulant properties of endothelium (healthy)
(4)
Thrombomodulin/Tissue Factor Pathway Inhibitor: controls coagulation
Heparan Sulphate: inhibits fibrin formation
Prostacyclin and nitric oxide: vasodilators
Enzymes inhibit platelet function
How does the subendothelium respond to vascular injury
(5)
The basement membrane and extracellular matrix becomes exposed
Collagen, VWF and fibronectin promote platelet adhesion
The endothelium vasoconstricts and becomes pro-thrombotic
Tissue factor is expressed which initiates coagulation cascade
Plasminogen activator inhibitor (PAI-1) inhibits the activation of fibrinolytic system
What is PAI-1 and what does it do?
Plasminogen activator inhibitor
It prevents fibrinolysis -> breakdown of fibrin i.e. fibrin accumulates
What is von Willebrand Factor
A large adhesive glycoprotein produced in endothelial cells and in the megakaryocytes
What does vWF bind to?
(4)
Subendothelium collagen
GPIb on surface of non-activated platelets
GPIIbIIa on surface of activated platelets
FVIII protecting it from proteolytic degradation
Describe in your own words how the platelet plug is formed
(5)
Collagen is exposed
Platelets express collagen receptors
VWF tethers the platelets to the endothelial cells by binding to GPIba
Platelets roll along endothelium which activates aIIbB3 on platelets
Platelets then bind to collagen using collagen receptors
(Need to research this more)
What are the four steps of vasoconstriction
Collagen becomes exposed, platelets bind to this collagen
This brings about the release of platelet factors
This attracts more platelets
Platelets aggregate into a platelet plug
What are platelets?
(5)
Anucleate cells
Discoid shape
Life span of 10 days
Critical role in haemostasis and thrombosis
Rapidly activated when vessel wall is damaged
What facilitates platelet activation
Signalling proteins and surface receptors
What facilitates platelet activation
Signalling proteins and surface receptors
What does defective platelets lead to?
Serious bleeding
What does activation of platelets in diseases blood vessels lead to?
Arterial thrombosis i.e. stroke or myocardial infarction
What is found in the granules (a-granules) of platelets?
Adhesive proteins and coagulation factors
What is attached to the surface of platelets?
(2)
GPIb (+ VWF + Collagen fibres)
GPIIbIIa (+ fibrinogen)
What are the seven functions of platelets?
Interact with VWF to seal damaged blood vessels
Platelet-platelet interactions (primary response to form primary plug)
Negative charged surface to support coagulation complex formation (secondary response)
Deliver haemostatically active molecules locally
Localise clot fomration
Promote vasoconstriction
Promote vessel repar
What are the three main platelet functions in haemostasis?
Adhesion (first three seconds)
Aggregation (10 seconds)
Coagulation (5 minutes)
What happens in the adhesion step, first 3 seconds of clot formation?
(3)
Platelet-endothelial cell interactions
Platelet shape change
Release reactions
What happens in the aggregation step of clot formation?
(3)
Platelet-platelet interactions
Formation of primary platelet plug
Secretion of alpha granules and dense bodies from platelets
What happens in the coagulation step of clot formation
Fibrin formation
How do platelets tether to collagen?
(3)
VWF anchors exposed to collagen
Blood flow facilitates the unravelling of VWF to exposue the GPib-binding site
Platelets circulating at the edge of the vessel are then captured and tethered by VWF via binding to the constitutively expressed GPIb
Explain what is meant by platelet rolling
(2)
Once platelets are tethered to endothelium via VWF-GPIb interactions, the blood flow forces the platelet to roll over from the tethering point
This promotes further VWF-GPIb interactions i.e. more tethering can take place
How does the stable adhesion of platelets take place
(3)
Binding to glycoproteins additional to GPIb occurs
GPIa and GPVI binds directly to collagen and GPIIbIIa binds to VWF
This brings about the stabilisation of platelet adhesion
Define secondary haemostasis
Reinforcement of the platelet plug through the generation of a meshwork of insoluble fibrin
Tightly regulated pathways of caogulation factors, cofactors and inhibitos (pro-coagulation proteins and anti-coagulant proteins)
What is the coagulation cascade?
A series of reactions, in which an inactive enzyme precursor is activated to cleave the next component in the cascade, ultimately resulting in the formation of cross-linked fibrin
What are the components of the coagulation cascade?
Enzymes
Specifically proteases
What is required for the coagulation cascade?
Calcium ions and phospholipid
What are the two pathways of the coagulation cascde
Intrinsic system
Extrinsic system
What indicates an activated coagulation factor
Lowercase a
e.g. Factor Xa
What are the vitamin K dependent factors?
(6)
II
VII
IX
X
Protein C
Protein S
What are the non vitamin K dependent factors
XII and XI
What factors make up the intrinsic pathway?
(4)
XII -> XIIa
XIIa converts XI to XIa
XIa converts IX to IXa (needs Ca2+)
IXa + VIIIa converts X to Xa (needs Ca2+)
What factors are involved in the extrinsic pathway?
Tissue factor converts VII to VIIa
VIIa converts X to Xa (needs Ca2+)
What is the common pathway?
(3)
Xa with V converts prothrombin to thrombin (needs Ca2+)
Thrombin converts fibrinogen to fibrin and XIII to XIIIa
XIIa converts fibrin to a stable fibrin clot
What is TFPRI
Tissue factor pathway inhibitor
What does TFPI do?
It limits the action of tissue factor
What is protein C
A major physiological anticoagulant
What does thrombomodulin do?
Activates protein C
What does activated protein C do?
Activated protein C along with protein S and phospholipid cofactors, degrades FVa and FVIIIa
What does anti-thrombin II do?
Its a plasma protease inhibitor
It inhibits other proteases such as thrombin, IXa, Xa, XIa and XIIa
Deficiencies of what factors cause thrombosis
(5)
Antithrombin
Protein C
Protein S
TFPI
Fibrinolysis
What are the functions of fibrinolysis/tertiary haemostasis?
(4)
Defends against vascular occlusion preventing excess fibrin formation
Removes fibrin clot as part of vascular remodelling
Active enzyme is plasmin produced from plasminogen
Occurs once coagulation is initiated
