Platelets and coagulation

Question 1

Define haemostasis:

Answer 1

process of stopping bleeding following blood vessel injury - normal haemostatic response involving complex interactions between plasma clotting factors and platelets

Question 2

What is the concentration of the platelets in the blood and how long do they circulate for?

Answer 2

Produced in bone marrow by megakarocytes
Normal conc= 150-450x10(power of 9)/L
8-12 days is normal lifespan

Question 3

What does the plaletet membrane consist of and what granules does it contain ?

Answer 3

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

Question 4

What is contained within the platelet granules?

Answer 4

Dense granules: serotonin, ADP, catecholamines and Ca2+
Alpha granules: Factor V, VII, fibrinogen, vWF, platelet factor 4 and PDGF
Glycogen granules: energy source

Question 5

What is the initial response of blood vessels?

Answer 5

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

Question 6

What happens when vWF binds GPIb?

Answer 6

it causes an upgrading process to GPIIb/IIIa which interact more strongly with vWF = platelet aggregation

Question 7

What activates platelet metabolic pathway?

Answer 7

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

Question 8

Where are coagulations factors synthesised?

Answer 8

Liver - released into circulation in inactive precursor form

Question 9

What factors require a specific vitamin for synthesis?

Answer 9

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

Question 10

Other than platelet adhesion what is the function of vWF?

Answer 10

natural carrier protein for factor VII

Question 11

What are examples of hereditary disorders of platelet ?

Answer 11

Bernaud Soulier syndrome:- deficiency of platelet membrane GPIb
Glanzmann’s thrombasthenia:-deficiency of GPIIb/IIIa
Both are characterised by severe bleeding tendency

Question 12

What are the most common causes of acquired thrombocytopenia?

Answer 12

Autoimmune destruction and bone marrow failure

Question 13

What are the most important hereditary clotting factor disorders?

Answer 13

Haemophilia A (factor VIII deficiency) 
Haemophilia B (Factor IX deficiency) 
Also hereditary deficiencies in vWF

Question 14

How can you acquire clotting factor deficiencies?

Answer 14

Liver disease or vitamin K deficiency

Question 15

What is fibrinolysis?

Answer 15

process of degrading the fibrin clot - involves the enzyme plasmin

Question 16

What does thrombin do in the vicinity of the clot?

Answer 16

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

Question 17

What is occurring alongside fibrinolysis?

Answer 17

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

Question 18

What are the naturally anticoagulant control mechanisms in place to prevent unnecessary platelet coagulation?

Answer 18

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

Question 19

What are hereditary thrombophilia states?

Answer 19

• 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

Question 20

What are acquired thrombophilia states?

Answer 20

Conditions predisposing to thrombosis
- myeloproliferative disorders, malignancy and lupus anticoagluant, surgery, long haul flights and prolonged periods of immobility, pregnancy and smoking

Question 21

What is lupus anticoagulant?

Answer 21

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

Question 22

What are some laboratory tests to investigate clotting cascade?

Answer 22

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

Question 23

What does prolongation of PT indicate?

Answer 23

Factor VII deficiency - caused by hereditary deficiency, liver disease or vit K deficiency