Platelets and coagulation Flashcards
Define haemostasis:
process of stopping bleeding following blood vessel injury - normal haemostatic response involving complex interactions between plasma clotting factors and platelets
What is the concentration of the platelets in the blood and how long do they circulate for?
Produced in bone marrow by megakarocytes
Normal conc= 150-450x10(power of 9)/L
8-12 days is normal lifespan
What does the plaletet membrane consist of and what granules does it contain ?
Phospholipid bilayer incorporates a number of glycoprotein receptors = key ones include GPIb and GPIIb/IIIa
Cytoplasm contains myosin and actin - enable shape changes
Dense granules
Alpha granules
Glycogen granules
What is contained within the platelet granules?
Dense granules: serotonin, ADP, catecholamines and Ca2+
Alpha granules: Factor V, VII, fibrinogen, vWF, platelet factor 4 and PDGF
Glycogen granules: energy source
What is the initial response of blood vessels?
transient localised vasoconstriction - reduce blood loss = mechanical plug
- platelets adhere to the exposed sub-endothelial collagen - main mediator of this is vWF which binds GPIb
What happens when vWF binds GPIb?
it causes an upgrading process to GPIIb/IIIa which interact more strongly with vWF = platelet aggregation
What activates platelet metabolic pathway?
ADP released from damaged endothelial cells + exposed collagen and thrombin
= activates platelets causing the contents of alpha and dense to be released - consolidating platelet and coagulation response
Where are coagulations factors synthesised?
Liver - released into circulation in inactive precursor form
What factors require a specific vitamin for synthesis?
Prothrombin (factor II), factors VII, IX and X require fat soluble vitamin K - therefore if you have a deficiency in vitamin K then you have a bleeding tendency
Other than platelet adhesion what is the function of vWF?
natural carrier protein for factor VII
What are examples of hereditary disorders of platelet ?
Bernaud Soulier syndrome:- deficiency of platelet membrane GPIb
Glanzmann’s thrombasthenia:-deficiency of GPIIb/IIIa
Both are characterised by severe bleeding tendency
What are the most common causes of acquired thrombocytopenia?
Autoimmune destruction and bone marrow failure
What are the most important hereditary clotting factor disorders?
Haemophilia A (factor VIII deficiency) Haemophilia B (Factor IX deficiency) Also hereditary deficiencies in vWF
How can you acquire clotting factor deficiencies?
Liver disease or vitamin K deficiency
What is fibrinolysis?
process of degrading the fibrin clot - involves the enzyme plasmin
What does thrombin do in the vicinity of the clot?
induces the release of tissue plasminogen activator (tPA) from intact endothelial cells, which is then incorporated into the clot to enable binding of plasminogen
tPA converts plasminogen to active form plasmin which starts the proteolytic dissolution of the clot releasing fibrin degradation products
What is occurring alongside fibrinolysis?
blood vessel repair - blood vessel smooth muscle and endothelial cells undergo cell division and continue until the vessel is closed
PDGF plays a key role in this process
What are the naturally anticoagulant control mechanisms in place to prevent unnecessary platelet coagulation?
1) Anti-thrombin inactivates not only thrombin but also factors IX, X and XI
2) Protein C system (most important) - works in venous circulation. In vicinity of clot formation, free thrombin binds to membrane protein, thrombomodulin. This complex then binds protein C (adjacent to it)- thrombin cleaves protein C making it active, so it binds protein s and inactive FV and enzymatically degrades factor V and VIII- resulting in suppression of coagulation activation
3) natural heparins on the endothelial surface bind and enhance activity of anti-thrombin. Prostacylin is also released which is a platelet inhibitory factor
What are hereditary thrombophilia states?
- most prevalent is factor V leiden mutation = factor V molecule with impaired protein C cofactor activity and in its activated form it is resistant to neutralisation by protein c
- other inherited states include, protein S, protein C and AT deficiencies and mutations in prothrombin gene
What are acquired thrombophilia states?
Conditions predisposing to thrombosis
- myeloproliferative disorders, malignancy and lupus anticoagluant, surgery, long haul flights and prolonged periods of immobility, pregnancy and smoking
What is lupus anticoagulant?
autoantibody which causes prolongation of phospholipd based in vitro coagulation tests and is associated with both arterial and venous thrombosis - presents recurrent thrombosis and recurrent miscarriage
What are some laboratory tests to investigate clotting cascade?
Platelet count Prothrombin time - MOST IMPORTANT Activated partial thromboplastin time - MOST IMPORTANT Fibrinogen level vWF levels
Used to investigate bruising or bleeding or monitoring warfarin or heparin
What does prolongation of PT indicate?
Factor VII deficiency - caused by hereditary deficiency, liver disease or vit K deficiency
