haemostasis Flashcards
What 3 processes take part in haemostasis
vasoconstriction, primary haemostasis, secondary haemostasis (coagulation)
describe primary haemostasis
Formation of a platelet plug:
platelet adhesion, platelet release reaction, platelet aggregation
what are platelets
non-nucleated, granule-containing cells formed from the fragmentation of megakaryocyte cytoplasm
mechanism of adhesion
injury to vessel walls –> platelets stick to damaged endothelium- on collagen, the GPIb receptor or indirectly through VWF which then binds to GPIb receptor
adhesion changes platelet shape from a disc to rounded with spicules
What happens to platelets after platelet adhesion?
they get activated
contents of alpha and dense granules released
through invaginated membrane
components of alpha and dense granules in platelets?
ADP, fibrinogen, von Willebrand factor
What is thromboxane A2?
vasoconstrictor
involved in platelet aggregation
prostaglandin
derived from arachidonic acid in cell membrane
what happens after granular release in primary haemostasis?
platelet activation causes conformational change in GPIIb/IIIa receptor on endothelial cells to allow for fibrinogen binding
fibrinogen has a key role in linking platelets to form the platelet plug
how are the effects of primary haemostasis counterbalanced?
active flow of blood and the release of prostacyclin PGI2 from endothelial cells
prostacyclin is a powerful vasodilator and suppresses platelet activation
name anti platelet drugs
aspirin, clopidgrel
how does aspirin work?
irreversibly binds to platelets, inhibiting them (single dose aspirin effects persist for around 7 days)
aspirin binds specifically to cycle-oxygenase COX
how does clopidogrel work
irreversible blocking of ADP receptor on platelet cell membranes (effects also last for 7 days)
what is the VWF?
glycoprotein synthesised by endothelial cells and megakaryoctes
mediates adhesion of platelets to sites of injury, promotes platelet-platelet aggregation
also specific carrier for factor 8
What’s secondary haemostasis?
coagulation - formation of a stable fibrin clot
where are most clotting factors synthesised?
the liver
factor VIII and VWF are made by endothelial cells
Which factors are dependent on vitamin K for function, and therefore effected by warfarin?
factors II, VII, IX and X
2 5 7 10
vit K needed for carboxylation of glutamic acid residues on them
What does calcium do in coagulation?
plays an important role in the binding of activated clotting factors to the phospholipid surfaces of platelets
What is the trigger to initiate coagulation?
Tissue factor (TF)
found only in tissue so does not come into contact with blood until vascular injury occurs
What is the initiation phase in coagulation?
TF binds to VIIa, triggering factor X and IX to be activated- this leads to the activation of factor II (prothrombin) being activate to form small amounts of thrombin (factor IIa)
What is the amplification phase in coagulation?
small amount of thrombin mediates activation of factors V and VIII (co-factors) and the zymogen factor X11 (11) and platelets.
Factor XI activates factor IX to IXa, which, with factor VIIIa, amplifies the conversion of factor X to Xa
What is the propagation phase in coagulation?
a rapid burst in thrombin generation
cleaves circulating fibrinogen to form insoluble fibrin (the clot)
inhibitory mechanism ensuring coagulation is confined to site of injury? (anticoagulation pathway)
antithrombin inhibits thrombin and factor Xa
protein C activated by binding of thrombin thrombodulin on endothelial cell surfaces to form APC
APC inactivates factors Va and VIIIa in the presence of co-factor protein S
anticoagulant drugs
heparin, warfarin, direct oral anticoagulants
heparin
mixture of glycosaminylglycan chains extracted from porcine mucosa
works indirectly- potentiates action of antithrombi, leading to inactivation of factors Xa and IIa (thrombin)
administered intravenously/subcutaneous injection
warfarin
vit K antagonist- reduces synthesis of factors II, VII, IX and X by liver
oral tablet, effect must be regularly monitored
takes several days for effect
Direct oral anticoagulants (DOACs)
Orally available drugs that directly inhibit either thrombin or factor Xa (i.e. without the involvement of antithrombin)
These do not usually require monitoring
what’s fibrinolysis?
breakdown of fibrin to generate fibrin-degradation produces (FDPs)
what is the principal fibrinolytic enzyme?
plasmin (zymogen form plasminogen) activation of plasmin is mediated by tissue plasminogen activator, t-PA
how do thrombolytic agents work?
e.g. recombinant t-PA
generate plasmin to lyse clots- administered intravenously to patients w ischaemic stroke
high risk of bleeding
what does tranexamic acid do?
binds to plasminogen (it is similar to lysine) competitively
prevents activation of plasminogen to plasmin
less fibrinolysis
when is tranexamic acid used mainly
to treat bleeding in trauma and surgical patients, and patients with inherited blood disorders
what’s the intrinsic pathway
where all the factors are found inside the blood-
XII-> XI -> VIII and IX
then common
common is V X –> II –> fibrinogen to fibrin
what’s the extrinsic pathway
kicked off by TF, then common
what’s prothrombin time(PT)?
measures integrity of extrinsic pathway
mechanism of the PT test?
blood collected in bottle with sodium citrate
stops blood from clotting by chelating calcium in sample
sample spun to produce platelet poor plasma
TF and phospholipid added to the citrated plasma with calcium to start the reaction
time taken for clotting is measured
when is PT prolonged?
when there is a reduction in factors VII, X, V, II
or fibrinogen
how are results expressed when PT is used to monitor via K antagonist anticoagulant therapy (eg warfarin)?
INR - international normalised ratio
involves correction for diff thromboplastin reagents sued by diff labs around the world- so all labs have the same INR result for a given sample
what does Activated partial thromboplastin time (APTT) measure?
integrity of intrinsic pathway
mechanism of APTT?
performed by contact activation of factor XIIa by a surface like glass, or using a contact activator like silica or kaolin
contact activator and phospholipid added to citrated plasma followed by calcium
time for clotting measured
when is APTT prolonged?
where there is a reduction in a single or multiple clotting factors- in the latter there could be a prolonged PT as well
isolated prolonged APTT is seen in patients w haemophilia A, B and factor XI deficiency (sometimes also by factorXII deficiency which doesn’t result in bleeding)
what can bleeding be caused by?
reduction in platelet number or function
reduction in coagulation factors
increased fibrinolysis
what is haemophilia a
deficiency of factor VIII (x linked)
what is haemophilia B
factor IX deficiency, x linked
acquired causes of reduced coagulation factors?
liver disease
anticoagulant drugs
disseminated intravascular coagulation
what Is thrombosis
term used to describe formation of a blood clot where it is not needed
3 contributory factors to thrombosis?
blood, vessel wall, blood flow
which factors increase the risk of venous thrombosis?
- reduced levels of anticoagulant proteins
- -reduced fibrinolytic activity - increased levels of clotting factors/ platelets
- hyperviscosity (e.g. due to polycythaemia)
