Thrombosis and hemostasis 5-9-2019
Primary hemostasis: platelet adhesion and aggregation
Secondary hemostasis: blood coagulation and fibrinolysis
Thrombosis: arterial and venous → pathologic
PRIMARY HEMOSTASIS
What is a platelet?
→ Under normal conditions, it is round, has a little bit of a granular surface and they are
considered cell fragments: originate from megakaryocytes, and they get snared off by
the bloodstream and fragment further into platelets. They don’t have a nucleus and are
2-3 µm.
→ If they are activated, they can very quickly change shape. They get these spikes which
help them to get entangled. They can adhere to surfaces and form sort of a “pancake”
surface.
→ Platelets look like sponges, with open structures (canals). If you cut them, you can see
this. The canals are called the OCS → open canalicular system. If they secrete vesicles,
they can go very quickly into the canal system, they don’t need a long way to the cell
surface.
,→ In the dense granules of the platelets you find smaller substances like
polyphosphates, calcium, serotonin and ADP.
→ In the α-granules you find von Willebrand factor, fibrinogen (more proteins)
→ The platelets from aggregates that can
stop the bleeding. The platelets adhere onto
each other and are reinforced by fibrin.
Platelet signalling
The image that is shown could be from any
cell, not for a platelet per se. For a platelet,
we have some ion channels, a receptor
complex, GPCR’s etc. There is a stimulus of
the receptor (the yellow thingy), then we
have the activation step and we get to the
transduction step (some
changes in the receptor
occur which will cause the
receptor to pass along the
signal that it got. Then we
have second messengers,
which is mostly a precursor
that is converted into a
second messenger, which
may e.g. open a calcium
store. The calcium flows in
and leads to for example the
opening of an ion channel
that leads to more influx of
ions. This is the amplification
of the signal. You can also
have further amplification or also inhibition, which depends on the nature of the signal.
There could be secretion of factors that support or inhibit the reaction.
,Important receptors: ADP, thrombin (you should know these ones)
ADP activates P2Y12 and P2Y1. Thrombin can activate the PAR1 or PAR4 receptors (in
human). There are also some inhibitory receptors, like PGI2 (prostacyclin), it is a factor
that is released by endothelial cells of the vessel wall to inhibit platelet function.
There are also some adhesion receptors. Like GP1b-V-IX complex, integrins, signal
receptors. A very important integrin is αIIbβ3. The GP1b-V-IX complex is interesting
because it can bind to von Willebrand factor. The α2β1 and GPVI that can adhere to
collagen → induces platelet activation. We also have αIIbβ3 which can bind to von
Willebrand factor and to fibrin and fibrinogen (very important for platelet aggregation =
binding to each other)
GPVI can be activated by
collagen. We need to know that
the receptors on the right are
almost all used as drug targets.
The thromboxane A2 production
is targeted by aspirin → TA2.
This is just a small selection of
the different receptors.
If platelets get activated, they
secrete ADP and/or
thromboxane to amplify the
reaction.
, Platelet adhesion
Here you see the inside of a vessel. You have a lamina flow. In the middle there is the
least shear rate, at the edges there is the highest shear rate → by definition, at the very
surface of the endothelial cell the shear rate is 0. In the middle there is not really a
difference. At the surface of the vessel wall, the shear forces are the strongest. This
means that the forces that act on any cell attaching to the vessel wall (like a platelet) are
very high.
The forces cause the platelets to roll. This
gives a rolling effect of cells like platelets. It is
also the same principle with the rolling of
leukocytes. The receptors cluster, so they
form a very strong layer of different receptors
that can stick to the vessel wall pretty tightly
→ important because we want to have a very
stable platelet plug.
The lower picture are the adhesion receptors.
Most of the time, you have different
molecules in the vessel wall that platelets can
adhere to. They work together
to give a stable platelet
adhesion. You also have
calcium mobilization, because
the adhesion also leads to
signalling (outside-in
signalling), this gives rise
together with a soluble agonist
to a certain reaction of the
platelet.
Primary hemostasis: platelet adhesion and aggregation
Secondary hemostasis: blood coagulation and fibrinolysis
Thrombosis: arterial and venous → pathologic
PRIMARY HEMOSTASIS
What is a platelet?
→ Under normal conditions, it is round, has a little bit of a granular surface and they are
considered cell fragments: originate from megakaryocytes, and they get snared off by
the bloodstream and fragment further into platelets. They don’t have a nucleus and are
2-3 µm.
→ If they are activated, they can very quickly change shape. They get these spikes which
help them to get entangled. They can adhere to surfaces and form sort of a “pancake”
surface.
→ Platelets look like sponges, with open structures (canals). If you cut them, you can see
this. The canals are called the OCS → open canalicular system. If they secrete vesicles,
they can go very quickly into the canal system, they don’t need a long way to the cell
surface.
,→ In the dense granules of the platelets you find smaller substances like
polyphosphates, calcium, serotonin and ADP.
→ In the α-granules you find von Willebrand factor, fibrinogen (more proteins)
→ The platelets from aggregates that can
stop the bleeding. The platelets adhere onto
each other and are reinforced by fibrin.
Platelet signalling
The image that is shown could be from any
cell, not for a platelet per se. For a platelet,
we have some ion channels, a receptor
complex, GPCR’s etc. There is a stimulus of
the receptor (the yellow thingy), then we
have the activation step and we get to the
transduction step (some
changes in the receptor
occur which will cause the
receptor to pass along the
signal that it got. Then we
have second messengers,
which is mostly a precursor
that is converted into a
second messenger, which
may e.g. open a calcium
store. The calcium flows in
and leads to for example the
opening of an ion channel
that leads to more influx of
ions. This is the amplification
of the signal. You can also
have further amplification or also inhibition, which depends on the nature of the signal.
There could be secretion of factors that support or inhibit the reaction.
,Important receptors: ADP, thrombin (you should know these ones)
ADP activates P2Y12 and P2Y1. Thrombin can activate the PAR1 or PAR4 receptors (in
human). There are also some inhibitory receptors, like PGI2 (prostacyclin), it is a factor
that is released by endothelial cells of the vessel wall to inhibit platelet function.
There are also some adhesion receptors. Like GP1b-V-IX complex, integrins, signal
receptors. A very important integrin is αIIbβ3. The GP1b-V-IX complex is interesting
because it can bind to von Willebrand factor. The α2β1 and GPVI that can adhere to
collagen → induces platelet activation. We also have αIIbβ3 which can bind to von
Willebrand factor and to fibrin and fibrinogen (very important for platelet aggregation =
binding to each other)
GPVI can be activated by
collagen. We need to know that
the receptors on the right are
almost all used as drug targets.
The thromboxane A2 production
is targeted by aspirin → TA2.
This is just a small selection of
the different receptors.
If platelets get activated, they
secrete ADP and/or
thromboxane to amplify the
reaction.
, Platelet adhesion
Here you see the inside of a vessel. You have a lamina flow. In the middle there is the
least shear rate, at the edges there is the highest shear rate → by definition, at the very
surface of the endothelial cell the shear rate is 0. In the middle there is not really a
difference. At the surface of the vessel wall, the shear forces are the strongest. This
means that the forces that act on any cell attaching to the vessel wall (like a platelet) are
very high.
The forces cause the platelets to roll. This
gives a rolling effect of cells like platelets. It is
also the same principle with the rolling of
leukocytes. The receptors cluster, so they
form a very strong layer of different receptors
that can stick to the vessel wall pretty tightly
→ important because we want to have a very
stable platelet plug.
The lower picture are the adhesion receptors.
Most of the time, you have different
molecules in the vessel wall that platelets can
adhere to. They work together
to give a stable platelet
adhesion. You also have
calcium mobilization, because
the adhesion also leads to
signalling (outside-in
signalling), this gives rise
together with a soluble agonist
to a certain reaction of the
platelet.
