Haemostasis and Inherited bleeding disorders Flashcards
what are the key components of haemostasis
- Platelets
- Von Willebrand factor
- Clotting proteins
what makes up primary haemostasis
- platelets and VWF dependent
what makes up secondary haemostasis
- fibrin
where are platelets derived from
- Non nucleated cytoplasmic fragments derived from bone marrow megakaryocytes
What is the structure of platelets
- 1-4um
- Cellular membrane is made out of lipid bilayer, cell membrane, and glcyorpotein receptors
- Lipid bilayer with underlying microtubular system – series of granules
- Multiple components in each granule – dense granule important agonists, alpha granules fibrinogen, FV, P selectin
- Platelet membrane – complex of at least 9 glycoproteins.
what is the average amount of platelets in the blood
- Reference range for platelets in blood 140 to 400-450x109/
what is the lifespan of a platelet
- 8 to 14 days
what system removes platelets from the blood
- Removed from the circulation by the reticuloendothelial system
describe what the cell membrane of a platelet it like
- glycoproteins molecules have receptors for agonist, adhesive, coagulation factors and other platelets
- the receptors that are most abundant are GPIIb/IIIa and Gp1b
- the cell membrane also contains phospholipids
- it is associated with prostaglandin synthesis, calcium mobilisation, localisation of coagulant activity to the platelet surface
what are the organelles in a platelet
- there are platelet specific granules such as
- dense osmophilic granules (dense bodies, d-granules)
- a granules are the glue that hold the platelets together
what are the substances that can be in a-granules
- VWF
- platelet factor 4
- b-thromboglobulin,
- thrombospondin,
factor V,
fibrinogen,
fibronectin,
platelet derived growth factor
high molecular weight
kininogen,
tissue plasminogen activator inhibitor-1
where is VWF found
- VWF from plasma or from granules
How does VWF react when it attaches to collagen
- Collagen exposed and the nature of the collagen allows the VWF to bind to it
- VWF binds to GPIb – intitial monolayer of platelets – subsequent activation, via a G-protein mechanism(facilitated by agonist relese ) – Shape change – disc to sphere – pseudopods – complex of Gpib IX, IIbIIIa, VWF, fibrinogen.
what are the agonist for VWF
– collagen, ADP, thrombin, adrenaline, serotnonin AA metabolites – TXA2
what acid does VWF release when it binds to IIb
arachidonic acid
describes what happens to the arachidonic acid released when VWF binds to IIb
- Arachidonic acid is released converted to by lipo-oxygenase enzymes to leucotrienes – chemoattractants to white cells, remaining Arachidonic Acid converted by cyclooxygenase and then TXA synthetase into Thrombocxane.
- Thromboxane causes further granule release and local vasoconstriction and further local aggregation – exerts this by intracellular calcium shifts.
what is another pathway by which VWF carries out its role
- 2nd pathway of activation by agonists interaction on membrane surface receptors and G protein activation of phopholipase C. – further calcium release – stimulate contractile system – liberation of Arachidonic Acid and further generation of TXA2
- Flip fop of membrane charge – negative charged moieties onto outer surface – procoagulant
name some serious inherited platelet disorders
- Lack GpIb – Bernard Soulier syndrome – have thrombocytopenia as well
- Lack GpIIb/IIIa – Glanzmann’s – all the clotting tests look normal except the fact that the platlets don’t work
- Likely to need platelets or Novoseven medication that is a turbo boost to the clotting system that try’s to get some thrombin activity
what is the disorder called when you lack Gp1b
– Bernard Soulier syndrome
What is the disorder called when you lack GpIIb/IIIa
Glanzmann’s – all the clotting tests look normal except the fact that the platlets don’t work
what are the less serious platelet conditions
- Storage pool disorders
* Weak agonist response defects
what is the most common inherited blood clotting disorder
von willebrand disease
what is the genetics of VW disease
• Autosomal inheritance – girls & boys
what are the types of VW disease
- Type 1 – mild to moderate deficiency
- Type 2 – protein present but defective
- Type 3 – total absent protein
how do you treat von willebrand disease
- treat with DDAVP
- tranexamic acid
- VWF containing concentrate
How is tissue factor III activated
- it is present on sub endothelial tissue
- expressed by cells which are normally not exposed to flowing blood
- physical injury exposes tissue factor to flowing blood
- necessary for the initiation of coagulation via factor VII
what pathways do APPT test
intrinsic and common
what pathways do PT test
extrinsic and common
what factors does thrombin activate
V to Va
VIII to VIIIa
XI to XIa
what inactivates the tissue factor
Tissue factor pathway inhibitor is an antagonist to the tissue factor at the start and starts to slow the whole process, then it ultimately turns it off
describe the factors of haemophilia A
- Deficiency of IXa
- Cannot amplify
- They clot a little bit and then it breaks away
describe the factors of haemophilia b
- deficiency of VIII
what are the symptoms of haemophilia
Bleeds Soft tissue Joints (knees, ankles, elbows) Psoas Intracranial bleeds Operative sites
how do you prevent the onset of haemophilia symptoms
Learn to self administer factor concentrate
Moderate fVIII levels
what does prophylaxis mean
how to prevent something
what is used to treat mild haemophilia a
DDAVP
what does antithrombin inhibit
major inhibitor of thrombin and Xa
• also inhibits VII, IX, XI
what protein family is antithrombin a part of
• Member of the SERine Protease INhibitor family
what increases the action of antithrombin
- Inhibitory activity increased 5 -10,000 fold in the presence of heparin
- Physiologically binds to heparan sulphate on the surface of the vascular endothelium
what are the vitamin K dependent glycoproteins synthesised in the liver
Protein C and Protein S
how is protein C activated
- it is activate by thrombin
- the activation is increased 20,000 fold with thrombomodulin
what does activated protein C do
- serine protease
- inactivates Va and VIIIa
- Protein S
- cofactor for Activated Protein C (APC)
what do protein C and S do
proteins C and S help adjust the rate of blood clot formation.
