PBL 8 - haemostasis Flashcards
what are the 5 key components of haemostasis?
- blood vessels — vascular spasm
- platelets — platelet plug formation
- coagulation factors (coagulation phase)
- coagulation inhibitors (coagulation phase)
- fibrinolysis — breakdown of clot
what do endothelial cells in intact blood vessels secrete and what do they do?
- nitric oxide — vasodilator and inhibits platelet aggregation
- endothelin — vasoconstrictor
- prostacyclin (PGI2) — inhibits platelet activation
what do endothelial cells in intact blood vessels express?
- heparin sulfate — activates antithrombin (inhibitor of coagulation)
- thrombomodulin — changes thrombin’s (a very potent a activator of platelets) affinity from pro-clotting to anticoagulant factors
what is the first and most immediate protection against blood loss (first response to vessel damage)?
injury to smooth muscle —> VASOCONSTRICTION
= reflex response to protect against blood loss
- effects only last a few seconds to a minute
- other mechanisms then take over
what are chemical vasoconstrictors released by? name one
activated platelets release them eg. serotonin
describe platelets
- produced in bone marrow
- involved in platelet plug formation
- produced from myeloid stem cell
- fragmentation of megakaryocyte (MK) cytoplasm
- 1 MK produces 4000 platelets
- production stimulated by thrombopoietin (TPO) — produced in liver
- TPO helps control platelet numbers
- 2-4um diameter
- normal platelet count: 150-400 x 10^9/L
- lifespan roughly 8-9 days, production roughly 7 days
- can donate platelets 24 x per year
describe thrombopoiesis
- myeloid stem cell
- megakaryoblast
- pro megakaryocyte
- megakaryocyte
- platelets
what process is used to make megakaryoblast?
endomitosis
where is thrombopoietin made?
mainly liver, some in kidney
describe the structure of a platelet
what is the role of the surface-connecting tubule in platelets?
granule contents of platelets released through the surface-connecting tubule when the platelets are activated — take place in platelet plug formation and coagulation
what is the ration of RBC : platelet : WBC ?
700 : 40 : 1
what happens to the platelet as it adheres to the damaged endothelium?
changes shape — allows them to come into contact with surface more easily and with each other — allows them to aggregate together to form the platelet plug
what is the first trigger of platelet activation?
contact with exposed collagen in vessel wall
what is the main way in which platelets are activated in order to take part in the haemostatic process?
exposed endothelium —> COLLAGEN
what do activated platelets release and what is the effect of this?
release substances including ADP from dense bodies — activates other resting platelets
ADP release allows platelets to swell — promotes adhesion (as it can come into contact more easily with other platelets)
how to platelets come into contact with collagen?
via glycoproteins or von Willebrand factor (vWF)
as a platelet is activated, it begins to get bigger and develop what? effect?
pseudopodia and lamellipodia — allow the platelet to move much more easily and to move along on the damaged blood vessel wall
what does degranulation release?
substances such as ADP, calcium and thromboxane
what is expressed on the surface of the platelet and what do they do?
expression of phospholipids and phosphatidylserine — the phospholipid surface is the surface on which the stable fibrin clot can form.
(expression of the phospholipids is preparing the surface of the platelet for the production of platelet plug but also for the fibrin clot to form on top of it)
expression of what allows the platelets to adhere to the surface of the damaged endothelium?
eg. P-selection, GpIIb/IIIa
what does prostaglandin synthesis by activated platelets promote?
production of TXA2
what is TXA2?
a potent platelet activator and vasoconstrictor
what positive feedback does coagulation provide?
more ADP and TXA2
describe GP1b vs GP1a adherence
GP1b uses vWF to adhere, GP1a adheres directly with the damaged endothelial surface
how do GPIIb and GPIIIa adhere?
via vWF
release of what induces platelet to platelet aggregation and formation of the platelet plug?
ADP and TXA2
what is haemophilia A a deficiency in?
FVIII
what is haemophilia B a deficiency in?
FIX
where are coagulation factors mostly made?
liver, some in platelets in granules
what form a complex on damaged collagen in the intrinsic (contact) pathway and what are they activated to?
- high molecular weight kininogen (HMWK) —> kininogen
- prekallikrein —> kallikrein
- FXII —> XIIa
what is coagulation initiated by?
tissue factor (III)
where is TF?
exposed by tissue damage on exposed endothelium
what is in the extrinsic tenase complex?
TF, VIIa, [Ca++]
what does extrinsic tenase complex convert?
X —> Xa
also activates small amounts of FIXa
what does Xa allow?
a trace amount of thrombin (IIa) production
what is the intrinsic tenase complex?
FIXa, FVIIIa, FX
what does the intrinsic tenase complex do?
activates FX to FXa
which tenase complex produces more FXa?
intrinsic (90% more)
what enters amplification from initiation?
small amount of thrombin
what is the prothrombinase complex?
FXa, FVa, [Ca++]
what is the product of the prothrombinase complex?
thrombin
what does thrombin do?
converts fibrinogen to fibrin (1–>1a)
what is a cofactor for FX?
FVa
what is a cofactors for FIX?
FVIIIa
what stabilises the fibrin clot?
FXIIIa
what is the most potent platelet activator?
thrombin (IIa)
what is vitamin K needed for?
the production of many clotting factors
what is calcium needed for?
needed at almost every step of coagulation process (some releaed from platelets)
importance of phospholipids?
phospholipids are where the fibrin clot is produced and grow on primary platelet plug
what does tissue factor pathway inhibitor (TFPI) do?
inhibits VIIa and Xa
what does antithrombin III do?
inhibits Xa and thrombin
what do protein C and S do?
PC inactivates Va and VIIIa, action of activated PC enhanced by PS
what is the 1st inhibitor to act?
TFPI
where is TFPI found?
plasma and platelets
where is antithrombin produced?
liver and endothelium
where are PC and PS made?
liver
how does protein C enhance fibrinolysis?
by inactivating the tissue plasminogen activator (tPA) inhibitor
what is fibrinolysis?
the enzymatic breakdown of fibrin in a blood clot
what is fibrinolysis initiation dependent on?
tPA (tissue plasminogen activator) — activates plasminogen to plasmin
what does plasmin do?
plasmin degrades fibrin (1a)
what does fibrinolysis generate?
soluble fragments called fibrin degradation products (FDPs)
what are D-dimers?
positive test when we have more fibrin degradation products that normal (allows us to assume there is an overproduction of clots)
