13 - Haemostasis 1

Question 1

What are coagulation factors?

Answer 1

• help to form clots

- proteins denoted by roman numerals

Question 2

What are regulatory factors?

Answer 2

• stop premature firing of coagulation factors

- proteins

Question 3

What is the vWF and its features?

Answer 3

• von willebrand factor
• giant adhesive plasma protein
• several binding sites (for platelets, collagen and F8)
• monomers joined together
• bundles up in blood (binding sites hidden)

Question 4

What happens to vWF when it’s bound to collagen?

Answer 4

• low of blood pushes it along
• it stretches
• becomes long, thin molecule

Question 5

What are some features of platelets?

Answer 5

• no nucleus
• half life of ~10 days
• fragments of megakaryocytes from bone marrow
• granules full of ADP, fibrinogen and vWF
• stimulatory receptors at top (where ADP and thromboxane bind)

Question 6

What happens to activated platelets?

Answer 6

• change shape
• expose phospholipids: change in membrane composition due to autocrine and paracrine effects of ADP make platelets more sticky
• present new/activated proteins on surface (membrane changes): expression of GlpIIb/IIIa due to TXA2 allows fibrinogen binding

Question 7

What are the synthesis sites for coagulation factors and what do they produce?

Answer 7

• liver: I, V, VII and X
• endothelial cells: VIII and vWF
• megakaryocytes: V and vWF (stored inside α granules)

Question 8

What does primary haemostasis require?

Answer 8

• collagen
• platelets
• vWF

Question 9

What does secondary haemostasis require?

Answer 9

• plasma membrane
• clotting factors
• calcium

Question 10

What is the process of primary haemostasis (platelet plug)?

Answer 10

• vWF binds to collagen and gets stretched
• lots of binding sites exposed to platelets
• platelets bind to collagen via GlpIa when slowed down by vWF (binding via GlpIb)
• collagen signals into platelet and activates it (thrombin binding triggers activation)
• ADP, prostaglandin, fibrinogen and vWF released (arachidonic acid liberated)
• phospholipid taken from platelet surface and thromboxane made
• positive feedback event

Question 11

What is tissue factor (TF)?

Answer 11

• cofactor for VIIa
• physiological initiator
• regulates coagulation cascade
• released from vessel wall injury site

Question 12

What is the intrinsic clotting cascade?

Answer 12

• XII activated
• XIIa activates XI
• XIa activates IX
• IXa activates X
• damping mechanism: tissue factor pathway inhibitor binds Xa, TF and VIIa in sequested form to turn off mechanism
• coagulation activation almost immediately gets turned off

Question 13

What is the extrinsic clotting cascade?

Answer 13

• TF-VIIa complex is trigger for cascade
• IX and X are activated
• IXa also activates X
• Xa makes thrombinogen (II) which is converted to thrombin (IIa)
• IIa activates cofactors V and VIII
• VIIIa forms complex with IXa
• Va forms complex with Xa
• IIa cleaves fibrinogen to fibrin

Question 14

What is the thrombin burst?

Answer 14

• stronger, denser clot generated (resistant to fibrinolysis)
  VIII and V cross link fibrin, inhibiting fibrinolysis
• thrombin activates TAFI (fibrinolysis inhibitor)
• blood clots rapidly, minimising blood loss

Question 15

What happens to haemostasis at rest?

Answer 15

• ADPs released from platelets degraded by ADPase’s found on endothelial cells
• PGI2 and NO stop platelet activation
• endothelial cells are anti-coagulants

Question 16

What is the indirect inhibition of coagulation?

Answer 16

• antithrombin inhibits thrombin and other clotting factors (IIa, IXa, Xa, XIa) in initiation phase
• heparin accelerates action of antithrombin (used for immediate coagulation in venous thrombosis and pulmonary embolism)

Question 17

What is the direct inhibition of coagulation?

Answer 17

• inhibition of thrombin generation by protein C anticoagulant pathway
• thrombomodulin binds free thrombin and redirects it
• cleaves and activates protein c
• breaks down Va, VIIIa with cofactor protein

Question 18

What is fibrinolysis (clot breakdown)?

Answer 18

• tPA (tissue plasminogen activator) in active form activates plasminogen to plasmin
• tPA and Pgn brought together by fibrin (Ia), forms enzyme-substrate complex
• tPA and Pgn circulate in blood but don’t react until fibrin created
• plasmin breaks down fibrin (Ia) to complete wound healing
• anti-plasmin stops plasmin circulating in blood and degrading things (breaks down plasmin)

Question 19

What is thrombomodulin?

Answer 19

• extrinsic protein of endothelial cells
• creates enzyme-substrate complex to breakdown co-factors V and VIII
• paired to protein c
• binding of thrombin to thrombomodulin allows protein s in blood to bind to protein c and activate it
• activated protein c/protein s complex acts as enzyme