7: Haemostasis

Question 1

What is haemostasis

Answer 1

Cellular and biochemical processes that enables the SPECIFIC and REGULATED cessation of bleeding in response to vascular insult

Question 2

What can cause bleeding?

Answer 2

Fibrinolytic factors

Anticoagulant proteins

Question 3

What can cause thrombosis?

Answer 3

Coagulant factors

Platelets

Question 4

Summarise plug formation in response to endothelial damage

Answer 4

Vessel constriction (limits blood flow)
Unstable platelet plug (platelet adhesion + aggregation)
Stabilisation of plug with fibrin (stops blood loss)
Vessel repair + Dissolution of clot

Question 5

Describe the structure of a normal arterial vessel wall

Answer 5

Layer of endothelial cells - ‘anti-coagulant’

Subendothelium - contains tissue factor, ‘pro-coagulant’

Question 6

Which cells are platelets derived from?

Answer 6

Haematopoietic stem cells -> pro-megakaryocytes -> Megakaryocytes -> platelet

Question 7

What are present inside platelets?

Answer 7

Granules containing factors for coagulation as well as ATP/Ca to augment function of other platelets

Question 8

What happens when a platelet is activated?

Answer 8

Converts from a passive to an INTERACTIVE cell

Question 9

Describe platelet adhesion

Answer 9

1. Vascular injury exposes sub-endothelial collagen
2. Globular VWF binds
3. Tethered VWF unravels by sheer force of blood flow and exposes platelet binding sites (Gp1b)
4. Platlets bind - this binding recruits more platelets

Platelets can also bind directly to collagen via GPVI + a2b1 (only at LOW sheer force) and become activated, recruiting more platelets

Question 10

Describe platelet activation

Answer 10

Collagen and thrombin activate platelets
Platelets bound to collagen/VWF release ADP + thromboxane which activates platelets
Activated platelets recruit additional platelets via aIIBb3
aIIBb3 also binds fibrinogen
Platelet plug develops (slows bleeding, provides surface for coagulation)

Question 11

How does platelet change shape?

Answer 11

Flowing disc shape
Rolling ball shape
Hemisphere (Firm but reversible adhesion)
Spreading platelet (IRREVERSIBLE adhesion)

Question 12

What does thrombin do?

Answer 12

Converts fibrinogen to fibrin

Question 13

Where are plasma clotting factors produced?

Answer 13

Mostly the liver
Some in endothelial cells
Megakaryocytes

Question 14

How do clotting factors circulate in the blood?

Answer 14

As inactive precursors

Activated by specific proteolysis

Question 15

How is coagulation initiated?

Answer 15

Tissue damage exposes Tissue Factor to F7/7a

Activates Tissue factor

Question 16

Where is tissue factor found?

Answer 16

Normally located at extravascular sites (not exposed to blood)

Question 17

Describe the structure of Factor 7

Answer 17

Serine protease zymogen
Expressed/secreted by liver
Only around 1% of f7 circulates as f7a (active form)
Activated by proteolysis
Gla domain allows binding to phospholipid surfaces

Question 18

Describe the Gla domain

Answer 18

Vitamin-K dependent - adds a COOH group, giving it extra charge, allowing it to bind to Ca2+
6/7 Ca2+ ions bound to it causes structural change
Folds up into phospholipid-binding conformation

Question 19

How does warfarin work?

Answer 19

Vitamin K antagonist

Results in clotting factors with non-functional Gla domains meaning they can’t bind to phospholipid surfaces

Question 20

What does TF/F7a do?

Answer 20

Activates F10, forming F10a

Question 21

What does F10a do?

Answer 21

Activates pro-thrombin to generate THROMBIN

Very inefficient step, small amount of thrombin produced

Question 22

What factors can activate f10 more efficiently?

Answer 22

f8a/9a activates f10 more efficiently than TF/f7a

Question 23

What factors can activate pro-thrombin more efficiently?

Answer 23

f5a/10a

Question 24

What are the 3 natural inhibitory systems involved in regulating coagulation?

Answer 24

1. TFPI (Tissue factor pathway inhibitor)
2. Protein C Pathway (APC)
3. Antithrombin

Question 25

What does TFPI do? How does it work?

Answer 25

Targets initiation phase of coagulation

TFPI/f10a complex INHIBITS TF/f7a

Question 26

How does the protein C pathway work?

Answer 26

Thrombin escapes clot and binds to thrombomodulin on endothelial cells at the EDGE of the clot
Protein C activated by this complex
Activated protein C (APC) inactivates f5a/8a therefore DOWN-REGULATING (not inhibiting) thrombin generation

Question 27

How does antithrombin work?

Answer 27

Anti-thrombin is a SERPIN (Serine protease inhibitor)

It ‘mops up’ and inhibits any thrombin/f10a that ESCAPES the clot to prevent initiation of coagulation elsewhere

Question 28

How are clots broken down?

Answer 28

Fibrinolysis
tPA (tissue plasminogen activator) converts plasminogen to PLASMIN
Plasmin breaks down the fibrin clot