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Flashcards in Haemostasis Deck (20):

Definition of haemostasis

Maintaining the balance of clotting vs blood fluidity, process is controlled by balance of pro- and anti-thrombotic mediators



Process leading to clot formation



Process that breaks down clots


Inhibition of haemostasis

Normally haemostasis is inhibited, achieved via numerous mechanisms, important cell layer = endothelium


Inhibitors of haemostasis

Endothelial synthesis of prostacyclin and nitric oxide
Endothelial production of plasminogen activator
Endothelial expression of thrombomodulin
Endothelial barrier to underlying tissue matrix
Endothelial expression of antithrombin III and heparin sulphate proteoglycans
Endothelial production of tissue factor pathway inhibitor


Key components of haemostasis

The primary players in haemostasis include blood vessels, platelets and plasma proteins
Process relies upon cascade- positive feedback


Stages of haemostasis

Primary- initial response to vascular injury, ends with formation of a platelet plug
Secondary- continuation of process from primary haemostasis if required, ends with formation of fibrous clot


Primary haemostasis

Initiation: damage to endothelial cells
Processes: vasoconstriction, platelet adhesion, platelet aggregation
NB there is no specific order to this response as all elements can and do occur at the same time
Secondary haemostasis or platelet plug disaggregation


Platelet function in haemostasis

Provide negatively charged surface for factor X and prothrombin activation
Release substances that mediate vasoconstriction, platelet aggregation, coagulation and vascular repair
provide surface membrane proteins to attach to other platelets, bind collagen and sub-endothelium
Form primary platelet plug (fragile and easily dislodged)


Platelet activation

Removal of inhibition due to damage to endothelium activates platelets inducing a change in shape
Once activated, platelets will release other factors that will activate more platelets


Vasoconstriction mediators

Myogenic (spontaneous contraction in response to damage)
Neuronal (sensory nerves)
Platelet release of thromboxane A2


Vasoconstriction effects

Narrows the lumen of the vessel to minimise the loss of blood
Reduces flow thereby increasing local concentration of prothrombotic components
Increases proximity of the haemostatic components of the blood (platelets and plasma proteins) to the vessel wall


Platelet adhesion

Platelets come into contact with damaged vessel (endothelium disrupted)
Glycoprotein complex Ia/IIa binds to collagen, glycoprotein complex Ib/V/IX binds to von Willebrand's factor
ADP stimulates purinergic receptors, thrombin stimulates protease activated receptors, thromboxane activates TP receptors
Both of these processes elevate intracellular calcium levels, activating glycoprotein IIb-IIIa complex allowing binding of fibrinogen and platelet aggregation


Platelet aggregation

Begins 10-20 seconds after vascular injury and platelet adhesion
Requires stimulation via agonist binding (ADP, thrombin, TxA2 etc)
Requires fibrinogen and fibrinogen receptors GPIIb and IIIa


Platelet aggregation mechanism

ADP released from platelet cytoplasm upon adherence induces exposure of fibrinogen receptors
Fibrinogen binds to the exposed receptors
Extracellular Ca dependent fibrinogen bridges link adjacent platelets



Deep large wounds depend on coagulation or blood clotting in addition to vascular spasms and platelet plugs to heal
Coagulation is regulated by:
Clotting factors- molecules that stimulate its formation
Anticoagulants- molecules that inhibit their formation or disrupt clots


Coagulation pathway: formation of thrombin

Enzyme complexes are formed from blood-borne factors and tissue factor released from damaged tissue on the surface of activated platelets
The enzyme complexes generate the formation of the prothrombin activator complex that converts prothrombin into thrombin
The formation of the prothrombin activator complex and conversion of prothrombin into thrombin are all Ca dependent processes- rationale for inclusion of EDTA to prevent blood samples from clotting


Coagulation pathway: effect of thrombin

Thrombin converts soluble blood-borne fibrinogen into fibrin monomers
Polymerisation of fibrin monomers results in fibrin threads
Mesh of fibrin threads traps erythrocytes and other blood cells forming the strong clot
Thrombin is involved in a positive feedback promoting its own synthetic pathway as well as inhibiting the breakdown of fibrin fibres
Clot expansion continues until the production of anti-coagulant agents from healthy tissue attains sufficient concentration to inhibit coagulation process


Fibrinolysis- clot retraction and dissolution

Once a damaged blood vessel has been repaired, it is necessary to remove the clot
The clot is removed by dissolving the fibrin that holds the clot in place
The endothelial cells release plasminogen activator as the damaged tissue is being repaired then it is changed into plasmin
Plasmin, as an enzyme, dissolves the clot by removing fibrin


Factors limiting clot growth or formation

Two homeostatic mechanisms prevent clots from becoming too large:
Swift removal of clotting factors
Inhibition of activated clotting factors by secretions from healthy tissue