Primary Haemostasis Flashcards
What is Haemostasis?
Maintains the fluidity of the blood.
Process of arresting bleeding, to maintain the integrity of the circulatory system
Haemostasis is a two stage process
- Primary
And
-secondary
What are the main components of Haemostasis?
- vascular endothelium
- platelets
- coagulation cascade
Leading sequence to clot formation
- initial injury causes brief vasoconstriction
- endothelial damage exposes subendothelium causing platelets to become activated and adhere
- tissue factor is released and activates the coagulation cascade forming fibrin
- platelet activation furthers coagulation
- fibrin and platelets form a haemostatic plug (clot), thereby closing the damaged vessel
What does brief vasoconstriction do?
Reduces blood flow to the damaged vessel
Prothrombotic
Release of von Willebrand factor and tissue factor release which is induced by endotoxin and some cytokines
Anti-thrombotic
Acts as a barrier to sub-endothelial exposure, produces prostacyclin (PGI2) and NO which inhibits platelet aggregation.
Produces tissue plasminogen activator which is a key component of fibrinolysis
What are platelets?
- small, anucleate cytoplasmic fragments, released from megakaryocytes in the bone marrow
What is megakaryocyte proliferation stimulated by?
Thrombopoietin (TPO) from a common myeloid progenitor
Normal platelet count
150-400 x 10^9/L
How long do platelets survive in circulation?
7-10 days
Platelets
2/3 of platelets circulate in the peripheral blood and remaining 1/3 are sequestered in the spleen and extravascular pool
Where is thrombopoietin (TPO) produced ?
Liver, kidney, spleen, bone marrow
2 type of platelet structure :
- resting platelet
- activated interacting platelets
What are platelets initially activated by?
- collagen
-von Willebrand factor
-tissue factor - thrombin
What are platelets subsequently activated by?
- ADP
- Thromboxane A2 (TXA2)
Diagrammatic representation of platelet activation :
- Collagen exposed after endothelium damage stimulates platelet activation and adhesion to vascular wall
- Activation results in a change in platelet shape
- The content of intraplatelet granules is released, including serotonin (5-HT) from dense granules and thromboxane A2 produced from arachidonic acid (AA)
- All these phenomena are calcium (Ca2+) dependent and subsequently amplify platelet activation
Platelet activation part 2
- Glycoprotein IIb/IIIa receptors are then expressed in platelet membrane to bind to fibrinogen, the common pathway for platelet aggregation
- Serotonin acts on 5-HT 2A receptors located in the vascular wall and platelets, and it is then recaptured by a specific serotonin reuptake transporter (5-HTT) in the cell membrane
- Selective serotonin reuptake inhibitors (SSRIs) block 5-htt, leading to a deletion of the serotonin content of platelets over time, partially impairing their functionality.
Platelet adhesion
- initial adhesion of platelets to subendothelial collagen via GPVI and GPIb is not a firm adherence and insufficient to maintain a haemostatic plug
- Von Willebrand Factor links the sub-endothelium to the GPIb-IX-V receptor complex on the platelets which strengthens this adhesion
Von Willebrand Factor
- vWF is a large multimeric glycoprotein found in plasma synthesised by endothelial cells and megakaryocytes
Von Willebrand Factor- 4 physiologically important binding activities, it binds to:
- collagen- the subendothelial matrix
- platelet glycoprotein Ib (GP1b)
- Platelet receptors GPIIb/IIIa
- factor VIII to protect it from proteolytic degradation and delivering FVIII directly to the site of injury
Platelet adhesion
-vWF is immobilised to the exposed collagen, promoting the binding of platelet receptor GPIb-IX-V complex to vWF
- platelets become activated, which upregulates the GPIIb/IIIa receptor and causes the release of platelet granules
-fibrinogen in blood is attracted to this receptor and consequently forms a complex which then attracts other platelets to eventually form a stable platelet plug
Platelet aggregation
- platelet aggregation is the formation of platelet to platelet linkages through the binding of fibrinogen to activated GPIIb/IIIa on adjacent cells, allowing the thrombus to grow beyond the initial monolayer
- activated platelets can also attach to areas of undamaged blood vessels
Steps of primary Haemostasis
- Platelet adhesion
- Shape change
- Granule release (ASO, TXA2)
- Recruitment
- Aggregation (haemostatic plug)
Platelet activation and secretions
- calcium: essential co-factor for the coagulation cascade
- ADP: mediates platelet aggregation which drives further platelet aggregation at the injury site
- platelet factor 4 (PL4) binds to and inactivates heparin
- serotonin induces vasoconstriction
- thromboxane A2 (TXA2) stimulates further platelet aggregation
-cytokines released by platelets contribute to a localised inflammatory response and influence wound surveillance, wound repair and vascular remodelling (e.g., interleukin IL-1B and IL-18, transforming growth factor-B, platelet derived growth factor, vascular endothelial growth factor)
What do cytokine release contribute to?
A localised inflammatory reaction by influencing wound surveillance with the recruitment of neutrophils and monocytes, wound repair and vascular remodelling (angiogenesis) with the release of growth factors
Extrinsic factors of haemostatic plug
- local availability and concentration of platelet agonists
- type of adhesive surface
- local rheology
- platelet interactions with other platelets and cells
Intrinsic factors of haemostatic plug
- platelet size and volume
- levels of membrane receptors
- levels of cytoplasmic, granular, and cytoskeletal proteins
- platelet age
