Haemostasis Flashcards
What is haemostasis?
The process in which excessive blood loss in prevented at the site of a damaged vessel through activation of the clotting factors and platelets
What does a platelet contain?
GPIb receptor GPIIb/IIIa receptor Glycogen for energy Alpha granules Actin and myosin fibrils that enable the platelet to change shape
What is in an alpha granule?
Clotting factors V, VIII, fibrinogen (I), vWF, and PDGF
What are the sequences of events that occur within a damaged vessel?
Localised vasoconstriction by humoral factors —> Platelet adhesion to subendothelium —> Platelet activation and aggregation —> Activation of platelet cascade —> Fibrin formation —> Thrombus formation —> Fibrinolytic degradation of clot and vessel repair
How does a damaged vessel cause platelet adhesion?
Collagen in the endothelium becomes exposed. Platelets adhere to the collagen through vWF and GPIb for tethering and rolling of the platelets. GPIIb/IIIa receptors then interact with vWF for a stronger bond.
How does platelet aggregation occur?
Receptors interact with neighbouring platelets.
What does the damaged endothelium produce?
ADP is released from the injured cell to activate metabolites in the platelets.
What do platelets release in order to recruit more platelets?
Thromboxane A2.
What do the platelets release for coagulation activation?
Dense and alpha granules released to activate the cascade for fibrin formation
What does fibrin do?
Fibrin deposits over the platelets and traps RBCs to form a clot.
What is the coagulation cascade?
Sequence of protein interactions that cause fibrin deposits.
What is the function of the extrinsic pathway?
Initiates coagulation
What is the function of the intrinsic pathway?
Amplifies the cascade
What must be present in order for coagulation factors to be present?
Clotting factors must be bound to the -vely charged phospholipid surface of the disrupted membrane to form a binding site.
Where are coagulation factors synthesised?
In the liver and travel in the circulation as inactive precursors.
Which coagulation factors require fat soluble vitamin K?
Prothrombin, FVII, IX, X - activate to proteases
What is FV a cofactor for?
FX
What is FVIII a cofactor for?
FIX
What is vWF?
Helps platelet aggregation and acts as a carrier protein for FVIII.
Where is vWF synthesised?
Vessel endothelium and in megakaryocytes
What happens in the extrinsic pathway?
FVIIa joins TF released from the damaged tissues, to initiate the sequence of events leading to Fibrin formation in the common pathway.
What happens in the intrinsic pathway?
1) FXII converts to FXIIa on contact with the -vely charged surface of the membrane
2) XIIa activates XI
3) XI activates IX
4) IX combines with VIII, brought by vWF, to activate X
5) X activates to trigger the common pathway for fibrin formation
What is the common pathway that leads to fibrin formation?
1) Xa combines with Va to convert Prothrombin into thrombin
2) Thrombin converts fibrinogen into fibrin
What effect does thrombin have on its own production?
It has a +ve feedback to accelerate the production of acitvated XI, VIII and V and it causes the release of VIII from vWF
What is the process of fibrinolysis once the bleeding resolves?
1) Thrombin induces release of tPA (tissue plasminogen activator) from the surrounding intact endothelium
2) Plasminogen binds into the clot
3) tPA converts plasminogen to plasmin
4) Plasmin protelyses fibrin into its products
How are the fibrin products removed?
By the reticulo-endothelial system
How does vessel repair occur?
PDGF causes smooth muscle and endothelial cells close to the injury to divide as the clot degrades.
What is EPI?
An extrinisic pathway inhibitor - Inhibits direct activation of X by VIIa upon the formation of thrombin from the extrinsic pathway, to allow the intrinsic pathway to take over
Why is control over the coagulation pathway needed?
To prevent coagulation at intact endothelium and to prevent thrombus formation.
What are the anticoagulant proteins involved in the control of the pathway?
They neutralise activated coagulation factors:
- Antithrombin III
- Heparin
- tPA and streptokinase
- Protein C
What are the anticoagulant functions of Antithrombin III?
Inactivates thrombin, IX, X, XI
What are the anticoagulant functions of Heparin?
Enhances antithrombin acitivity and synthesis of prostacyclin, platelet inhibiting PG.
What are the anticoagulant functions of tPA and steptokinase?
Activate conversion of plasminogen to plasmin.
What are the anticoagulant functions of Protein C?
Thrombin binds to thrombomodulin on the intact cell membrane to allow protein C to bind. Once activated it forms a complex with Protein S and V to degrade Va and VIIIa to restrict the clot.
Why is fat soluble Vit K needed for prothrombin, VII, IX and X?
Glutamic acid, O2 and CO2 form the alpha-carboxyglutamic acid component of these factors which requires reduced Vit K. Reduced Vit K is produced from Vit K by Vit K reductase
What will inhibit Vit K reductase?
Warfarin is a reductase inhibitor that will prevent the cascade as there is no production of the coagulation factors.
What is the complication of liver failure in regards to coagulation?
Reduced synthesis of the coagulation factors
What is Bernard-Soulier syndrome?
A hereditary deficiency in GPIb.
What is Glanzmann’s thrombosthenia?
A hereditary deficiency in GPIIb/IIIa.
What is thrombocytopenia?
A low platelet count due to AI or BM failure
What do deficiencies of VIII and IX lead to?
Haemophilia A and B - hereditary clotting disorders
Why may an acquired deficiency result?
Due to liver disease or Vit K deficiency
What is thrombophilia?
An increased tendency to form clots.
Hereditary:
FV leiden mutation = resistance to protein C
Protein C, S and antithrombin deficiences
Hyperhomocysteinamiea (Increased AA)
Acquired:
Long haul flights, immobility, smoking, pregnancy, surgery, malignancy, myeloproliferative disorder, lupus
What does prothrombin time detect?
Prolonged = VII deficiency (EXTRINSIC)
What does activated partial thromboplastin time detect?
If APTT presents as prolonged the Pt’s plasma is mixed with normal plasma.
Normal time = clotting factor deficiency in INTRINSIC pathway
Prolonged = inhibitor present e.g. VIII Ig, lupus anticoagulation
What if both PT and APTT is prolonged?
Single deficiency in the COMMON pathway or multiple factors due to liver disease, vit K deficiency, warfarin treatment or DIC.
What is DIC?
Disseminated intravascular coagulopathy causing uncontrolled response. Causes bleeding and thrombosis in microvascular structures resulting in death.
