What is the life span of a platelet? Describe platelets?
Small annucleated
Normal platelet count 150-350
10 days
Describe how the megakaryocyte looks on the blood film
Large - 10 regular cells
has nuclear lobes
and heavily granulated cytoplasm
what are the platelet functions?
They form the primary platelet plug
They act as a surface for coagulation factors
They are important in promoting endothelial repair
Produce finbrinogen, FV vwf
How do platelets slow down to clot?
They bind weakly with the A1 domain of vwf via Glp1b at damaged endothelium - this is rapid on/off binding which slows down the platelet
After slowing of the platelet, where does it bind?
It binds to collagen via GPVI and Glp1a2a at the damaged surface this activates them
What happens to activated platelets?
They recruit more platelets and degranulate releasing ADP and thromboxane A2
What happens to ADP?
It binds the P2Y12 receptor
What happens to thromboxane?
It recruits more platelets as it causes activated platelets to express Glp2b3a receptors
Where does the platelet bind via Glp2b3a?
It binds to the c4 domain of vwf causing platelet adhesion.
What is primary haemostasis?
Formation of an unstable platelet plug, platelets adhesion and aggregation
Where are platelets stored?
They are stored in the spleen
How are the platelets released?
2 thoughts: shear forces forces the platelets from bone marrow out
or into the lungs and microvasculature which leads to release of platelets from the megakaryocytes
What are the 2 types of granules?
ADP and dense granules
What is found on the surface of the platelts
Important receptors
A2b3 - Platelet platlet binding
P2y12 - adp
Par - thromboxane
Describe platelet cytoskeleton
from rest -> more round -> more spread platelet is activeated
Microtubules maintain discoid shape
and actin myosin filaments lead to movement
How do platelets bind to vwf what is the bidning site?
gp1ba
How does the platelet bind to the collagen directly?
glp6
glp1a2a
What is released when there is activation of platelet? What happens?
Increase release of adp and thromboxan
activating glpa2b3 which then binds fibrinogen leading to growth of haemostatic plug
WHat is the importance of the platelet activation?
Exposures phosphatidylserine to act as a site for coagulation to occur
At what level is spontaneous bleeding a possibility?
<40
What receptor is affected in glanzmann thrombasthenia?
glpa2b3
Platelets are unable to aggregate normally
bleeding patterns are variable
but it is a rare disease
What is the problem with bernard soulier syndrome?
GP1Ba GP1bB and GPIX THrombocytopenia these platelets are not able to adhere properly from the start Giant platlets result
WHat is the platelet form VWD?
Increased in binding of vwf and platelets this is a gain of function due to mutation in Glp1ba
What is grey platelet syndrome?
mutation in NBEAL2 - mild .moderate bleeding syndrome, problem with trafficking
How do platelets bind to collagen?
Platelets bind via gpiba complex with vwf in rapid on rapid off binding, slowing it down so it can bind via its other receptors a2b1 and GPVI complex to collagen
What happens after binding?
Trigger intrcellular signalling via plc gamma which leads to calcium entry leading to exposure of a2b3 binding site which then bridges another platelets with fibrinogen
What happens once fibrinogen is bound?
THis further stimulates the cells to influx calcium to have more activation of the cells and exposure of a2b3. There is also production of thromboxane and ADP release which binds to each of their own receptors on the platelet.
How are platelts able to act as the surface for coagulation?
Scramblase from the platelets switched the symmetry of the membrane and lead to exposure of PS on the outside which allows for coagulation factors to bind and generate thrombin
What is the role of the endothelium in activation/inhibition of platelets?
THe endothelium produces nitric oxide and prostacyclin which act to increase cAMP and this inhibits platelet function, there is also adp-atp production which also leads to cAMP release
What are the intrinsic regulators that platelets have?
They have receptors like PECAM, CEACAM, JAM-A and ESAM which act as intrinsic regulators and inhibitors of platelet activity
Where is thromboxane and prostacyclin made?
Thromboxane - platelet
Prostacyclin - endothelial cells
both made from arachidonic acid
PGI2 is a potent inhibitor of platelet function, thromboxane is a potent inducer of platelet aggregation
Mechanism of Clopidogrel?
inhibits ADP binding to the p2y12 receptor so prevents activation of platelets