Haemostasis, thrombosis & embolism Flashcards
What is haemostasis?
The process by which bleeding from an injured vessel is arrested or reduced
What sequence of events does haemostasis involve?
- vascular spasm
- platelet aggregation, activation and release of chemical mediators - platelet plug formation
- blood coagulation cascade - blood clotting
- Clot repair
- removal of the clot - allowing repair → fibrinolysis
What is thrombosis?
Haemostasis in the wrong place
- e.g. blood clotting within veins or platelet activation within arteries
- a thrombus can travel in he circulation as an embolus and block the arterial and venous circulation - pulmonary embolism
Describe vasospasm
- injury to vessel endothelium leads to contractile response
- this lowers downstream BP
- in addition, the upstream arterioles and small arteries construct, limiting blood flow to damaged areas
- designed to limit bleeding
- reduced blood flow also facilitates contact activation of platelets and coagulation factors
What is the initial trigger for vasospasm and what takes over?
- initially it is trauma
2. then, local factors (e.g. serotonin, bradykinin and thromboxane A2) from platelets mediate the constriction
What features of the vessel endothelium prevent clotting?
Surface heparan sulphate acts as a co-factor for anti-thrombin III and thus prevents platelet aggregation and coag cascade initiation
What pro-thrombogenic molecules may be released from the vessel endothelium in response to damage?
- tissue factor → activates extrinsic clotting pathway
- Von Willebrand factor → enables binding of platelets to damaged vesicles
- Plasminogen activator inhibitor 1 → secreted in response to angiotensin - inhibits removal of clots that are forming
- collagen → leads to platelet aggregation through binding of receptors on the surface
How may the vascular endothelium limit coagulation to allow healing?
- PGI2 and NOs → ADP to adenosine which inhibits platelet function
- Tissue plasminogen activator → accelerates plasmin formation and clot removal
- Thrombomodulin → activates anti-coagulant, protein C
Describe platelets
- no nucleus, mitochondria, little ER
- lots of granules and vacuoles
- alpha granules contain fibrinogen
- delta granules contain ADP
Describe platelet adhesion
Following changes in the vascular endothelial lining, platelets adhere to the damaged endothelial cells and sub-endothelial tissues. This adhesion is mediated byglycoproteinson the platelet surface
- Glycoprotein Ia– Binds directly to the exposedcollagen, leading to adhesion - Glycoprotein Ib– Binds tovon Willebrand factor, which then binds tosubendothelial macromolecules, allowing platelet adhesion - Glycoprotein VI– Binds collagen and snake venom. Snake venom can coagulate all of the blood in the entire body very quickly, as it bypasses the need to bind collagen and therefore the need for actual tissue damage
What happens to the platelets following adhesion?
They can change shape
Change from smooth discs to spiny spheres with protruding pseudopodia
What leads to platelet activation and what does activation mean?
- adhesion to collage and thrombin exposure = activation of platelets
- release of their granule contents
- collagen and thombin activate platelet prostaglandin G2 and H2 synthesis from arachidonic acid
- prostaglandin then initiate synthesis of thromboxane A2 which lowers cAMP
- decreases in cAMP increase the conc of Ca2+ which induces the release of granules
Describe the two types of platelet storage granule
a-granules
○ Pro-coagulant molecules– E.g.platelet factor 3.These interact with the clotting cascade to accelerate the formation of a fibrin clot, which can stabilize the initial platelet plug
○ Fibrinogen– Important in the formation of the fibrin clot and platelet aggregation
○ PDGF(platelet derived growth factor) – Initiates simultaneousvascular repair
○ Thrombospondin, fibronectin and von Willebrand factor
Dense bodies(dgranules)
○ Serotonin– Induce vasoconstriction
○ ADP– Induces a conformational change in theGPIIb/IIIareceptor,allowing it to bind tofibrinogenand thus localize platelet aggregation and blood clot formation to the site of injury. ADP can alsofeed backto cause further activation of platelets
○ ATP, GDP, GTP and calcium
What does platelet aggregation form?
An unstable primary haemostatic plug
This is subsequently stabilized by fibrinogen
Describe the mechanism behind aggregation
Various agonists, includingcollagen, thrombin, ADP and thromboxane A2(ADP and TXA2are the key mediators)act on receptors at the platelet surface. These induce the expression ofGPIIb/IIIa receptors (integrin family receptors)on the surface of the platelets. These receptors bindfibrinogen, which is present in the plasma, and thus enable the formation of links between adjacent platelets. This draws platelets together and thus leads to aggregation. Binding of fibrinogen to these receptors inducesfurther degranulation, which in turn induces more GPIIb/IIIa receptor expression, and thus the process is self-perpetuating.
TheGPIIb/IIIareceptor can be targeted by monoclonal antibodies foruse in arterial stenting procedures.
Describe clot stabilisation by fibrin
Exposure ofacidic phospholipidson the outer surface of platelets activates the formation ofthrombin, which in turn is able tocleave fibrinogen to fibrin. Fibrin polypeptides form a meshwork with the primary platelet clot, and thereforestabilise the plug. In addition, thisactivates further plateletsthroughthrombin receptorson the platelet surface
How does contraction of the clot occur?
Following the formation of the clot, it is thoughtCa2+releasewithin platelets, stimulated bythrombin, activatescontractile proteins. This results inretractionof the clot. In addition, as the clot evolves platelets become fused together (stimulated by ADP, thrombin and factors from the release action), which further stabilises the clot
