Haemostasis and the coagulation cascade Flashcards
Define haemostasis.
A precisely orchestrated series of regulatory processes that culminate in the formation of a blood clot that limits bleeding from an injured vessel
What 3 key things does haemostasis allow for?
Blood to be in a fluid state in normal vessels
Formation of a localised haemostatic clot at sites of vascular injury
Prevents haemorrhage
Define coagulation.
Formation of a haemostatic plug (clot)
Define fibrinolysis.
Breakdown of fibrin within a haemostatic plug (clot)
Define haemorrhage.
Extravasation of blood into the extravascular space
Define thrombosis.
Formation of a solid mass of blood products in a vessel lumen
What are the 3 main components of haemostasis?
Vascular wall (endothelium and subendothelial structures)
Platelets
Coagulation cascade
Describe normal endothelium in terms of platelets, coagulation, and fibrinolysis.
Antiplatelet
Anticoagulant
Fibrinolytic
What 2 substances do endothelial cells release which prevents platelet aggregation?
Prostacyclin
Nitric oxide
What 2 substances do endothelial cells release which prevents coagulation?
Heparan sulfate
Thrombomodulin
Which substance do endothelial cells produce which helps dissolve clots? How does it work?
Tissue plasminogen activator (tPA)
It converts plasminogen to plasmin. Plasmin breaks down fibrin in clots
What are the 2 main roles of platelets in coagulation?
Form the primary haemostatic plug
Provide a surface for the recruitment and concentration of coagulation factors and acts as a catalytic membrane
What are the 4 steps of haemostasis?
Vasoconstriction
Primary haemostasis
Secondary haemostasis
Clot stabilisation and resorption
In the vasoconstriction step of haemostasis, the release of what substance causes vasoconstriction?
Endothelin
What are the 2 aims of the initial step of vasoconstriction in haemostasis?
Minimise blood loss
Maximises interactions between platelets, clotting factors, and vessel wall
What are the 3 stages of primary haemostasis (formation of the primary platelet plug)?
Platelet adhesion
Platelet activation
Platelet aggregation
Describe how platelets adhere to the exposed subendothelial collagen at a site of injury.
They first bind via von Willebrand factor (vWF) and then bind directly to the collagen
Describe how platelets change during platelet activation and which 3 substances they release.
Platelets change shape to become more spiky. They release substances such as ADP, serotonin, thromboxane A2
In platelet aggregation, how do platelets link together?
Fibrinogen acts as a bridge between GPIIb/IIIa receptors on adjacent platelets, linking them together
Secondary haemostasis is otherwise known as what?
Coagulation cascade
Describe how fibrin is generated in secondary haemostasis.
Tissue factor (TF) is expressed on subendothelial cells and is exposed when a blood vessel is damaged. Tissue factor binds to and activates Factor VII. Thrombin is generated and cleaves fibrinogen into fibrin
Factor II is otherwise known as what?
Prothrombin
What are the 6 coagulation factors?
Factors II, VII, IX, X, XI, XII
What are the 2 coagulation cofactors?
Factors V and VIII
What are the 5 coagulation cascade requirements?
Coagulation factors (pro-enzymes) and activated coagulation factors (enzymes)
Cofactors (reaction accelerators)
Negatively charged phospholipid surface (activated platelets)
Calcium ions
Vitamin K
The extrinsic coagulation pathway is measured clinically as what?
Prothrombin time
What is the extrinsic coagulation pathway initiated by?
Tissue factor
The intrinsic coagulation pathway is measured clinically as what?
Activated partial thromboplastin time (aPTT)
What is the intrinsic coagulation pathway initiated by?
When FXII comes into contact with a negatively charged surface, activating it to become FXIIa
Which 2 complexes can Factor X in the common pathway be activated by in each pathway?
TF-FVIIa-Ca2+ complex (extrinsic pathway)
Tenase complex (intrinsic pathway)
What comprises the tenase complex?
FIXa-FVIIIa-Ca2+
What comprises the prothrombinase complex?
FXa-FVa-Ca2+
What is the action of FXIII?
Covalently cross-linking fibrin polymers, stabilising the secondary haemostatic plug
Which substance is a circulating inhibitor of coagulation?
Antithrombin III
Describe the 3 anticoagulant effects of the adjacent intact endothelium.
Tissue factor pathway inhibitor – inhibits TF-FVIIa-Ca2+ complexes
Thrombomodulin and endothelial protein C receptor – activates protein C – protein C/ protein S complex inhibits factors Va and VIIIa
Heparin-like molecules – binds and activates antithrombin III
What causes the fibrinolytic effect of the adjacent intact endothelium?
Tissue plasminogen activator (t-PA)
How does heparin reduce coagulation?
It binds reversibly to antithrombin II and enhances its inactivation of thrombin and FXa. It induces a conformational change that “opens up” antithrombin III
What is the key effect of low dose heparin?
Inhibits thrombosis
What is the key effect of high dose heparin?
Prevents progression of existing clots
What are the 2 types of heparin?
Unfractionated heparin
Low molecular weight heparin (LMWH)
What does unfractionated heparin inactivate?
FXa and thrombin
What does low molecular weight heparin inactivate?
4FXa
Which type of heparin is preferred for use as treatment and what is the exception to this?
Low molecular weight heparin is preferred, except in patients with severe renal failure
What is the molecular structure of fondaparinux?
Synthetic pentasaccharide
What is the MOA of fondaparinux?
Binds irreversibly to antithrombin III. Enhances antithrombin III’s ability to inhibit factor Xa, but does not inactivate thrombin
List 2 uses of fondaparinux.
VTE prophylaxis for surgical patients
Treatment of unstable angina and NSTEMI
What are the 2 ways plasminogen is converted to plasmin?
FXII-dependent pathway
Tissue plasminogen activator (t-PA)
What is the degradation product of fibrin?
D-Dimer
Name an inherited defective haemostasis disorder.
Haemophilia A (factor VIII deficiency)
Name an acquired defective haemostasis disorder.
Disseminated intravascular coagulation (DIC)
