Week 2- Haemostasis

Question 1

What is haemostasis the balance between?

Answer 1

Coagulating factors and platelets vs anticoagulating proteins and fibrinolytic factors

Question 2

What are the aims of haemostasis?

Answer 2

1. To allow stimulation of blood clotting (coagulation)
2. To prevent excessive blood clotting (thrombosis)
3. To allow the fibrin clot to break down (fibrinolysis)

Question 3

What are the 3 stages of haemostasis?

Answer 3

1. Construction of blood vessels
2. Primary haemostasis: Formation of a temporary platelet plug (platelet aggregation and adhesion)
3. Secondary haemostasis: Formation of a fibrin clot (coagulation)

Question 4

Which cells do platelets come from?

Answer 4

Myeloid stem cells

Question 5

What is the lifespan of an average platelet?

Answer 5

10 days

Question 6

How are platelets made?

Answer 6

Via megakaryocyte fragmentation

Question 7

Describe the structure of platelets

Answer 7

They are discoid, non nucleated, have glycoproteins on their cell surface, contain granules

Question 8

How do platelets attach to endothelium cells?

Answer 8

Directly: to collagen via GP1a receptor

Indirectly: via Von Willebrand factor (VWF) and GP1b receptor

Question 9

What granules do platelets contain and describe how granular contents are released from platelets

Answer 9

They contain alpha and dense granules, contents are released via cannicular system that is formed from invaginated surface

Question 10

What do granules in platelets contain?

Answer 10

ADP, fibrinogen and VWF

Question 11

How is thromboxane A2 synthesized?

Answer 11

From arachadonic acid that comes from the cell membrane

Question 12

What is the function of thromboxane A2?

Answer 12

To help with platelet aggregation and vasoconstriction

Question 13

Describe the process of platelet aggregation

Answer 13

1. Granular release of ADP and thromboxane A2
2. Conformational change in GPIIb/IIIa receptor
3. Fibrinogen binds to receptor
4. Fibrin clot can form

Question 14

What is prostacyclin and where is it used?

Answer 14

It is a chemical vasodilator that is released during platelet aggregation to prevent excessive aggregation

Question 15

Name the anti-platelet drugs and their mechanism of action

Answer 15

Aspirin- blocks thromboxane A2 synthesis

Clopidrogel- blocks ADP receptors on cell membrane

Question 16

When may anti-platelet drugs be prescribed?

Answer 16

In cardiovascular/cerebrovascular disease to prevent strokes/heart attacks

Question 17

What is VonWillebrand factor?

Answer 17

It mediates adhesion of platelets to the sight of injury and promotes platelet to platelet aggregation. It is also a carrier of factor VIII

Question 18

What chemical do coagulating pathways rely on and what is its function?

Answer 18

Thrombin- it cleaves fibrinogen to allow fibrin clots to form

Question 19

Where are the main clotting factors produced? What are the exceptions?

Answer 19

Nearly all are produced in the liver apart from factor V which is produced in megakaryocytes and VWF which is produced in endothelial cells or megakaryocytes

Question 20

Which clotting factors need Vit K and why?

Answer 20

Factors II, VII, IX & X need vit K to cleave their glutamic acid residues

Question 21

What characterizes the steps in the blood coagulation pathway?

Answer 21

The conversion of an inactive zymogen (proenzyme) into an active clotting factor by breaking peptide bonds to expose the active site

NOTE: often occurs on phospholipid surface of platelets to accelerate activity and Ca2+ plays a role in allowing binding of active clotting factors to phospholipid surfaces of platelets

Question 22

Describe the coagulation pathway

Answer 22

INITIATION PHASE:
Blood encounters tissue factor (TF) at sites of vascular injury only
TF binds to factor VIIa causing conversion of factors IX to IXa and X to Xa
Leads to activation of prothrombin to generate a small amount of thrombin

AMPLIFICATION PHASE:
Small amount of thrombin mediates activation of factors V and VIII, zymogen factor XI and platelets

PROPAGATION PHASE:
Factor XI converts more IX to IXa and along with VIIa this amplifies conversion of X to Xa. This causes a burst of thrombin to be produced which cleaves fibrinogen to form an insoluble fibrin clot

Question 23

What are the anticoagulant drugs and their mechanisms of action?

Answer 23

Heparin- administered orally or by subcut injection, prevents the conversion of IX to IXa or X to Xa

Warfarin- administered orally, requires regular blood tests, prevents vit K cleaving glutamic acid residues so no factors II, VII, IX, X made

DOACs- administered orally, no need for observation, inhibits thrombin (factor X)

Question 24

What proteins are involved in natural anticoagulant pathways

Answer 24

Protein C,S and antithrombin

Question 25

Describe the anticoagulant pathway

Answer 25

Thrombin binds to thrombomodulin Protein C (APC) is activated It inactivates factor Va and VIIIa in the presence of co factor protein S Antithrombin binds to thrombin and factor Xa inactivating them (it’s actions are amplified by heparin)

Question 26

What is the enzyme involved with fibrinolysis

Answer 26

Plasmin (present as plasminogen- an inactive zymogen)

Question 27

Describe the fibrinolytic pathway

Answer 27

In presence of t-pa (tissue plasminogen activator) plasminogen is activated to plasmid when they come together on lysine on the fibrin clot. This allows the breakdown of fibrin to occur, releasing fibrin degradation produces

Question 28

How is thrombolytic therapy administered and how does it work?

Answer 28

Recombinant t-pa is given intravenously and it breaks down clots in the event of stroke etc. Has to be administered very quickly for it to be effective

Question 29

What is the main antifibrinolytic drug and how does it work?

Answer 29

Tranexamic acid competitively binds to lysine on fibrin clots, preventing plasminogen activation as it and t-pa can’t come together

Question 30

What are the 2 main tests for coagulation?

Answer 30

Prothrombin time and activated partial thromboplastin time

Question 31

How is the prothrombin test for coagulation carried out?

Answer 31

Blood is mixed with sodium citrate It is spun and phospholipid, tissue factor and calcium are added A longer time for coagulation can indicate a lack of prothrombin ie factors II, V, VII or X

Question 32

How is the activated partial thromboplastin time test for coagulation carried out?

Answer 32

A contact activation test for factor XII is done by spreading blood onto a silica plate Prolonged time can indicate hemophilia A/B or factor XI deficiency

Question 33

What is Von Willebrand’s disease?

Answer 33

When there is a lack of WVF, autosomally inherited, treated by replacing clotting factors w recombinant ones, both males and females affected with males having mainly haemophilia A and sometimes B

Question 34

What are acquired causes of decreased coagulation factors?

Answer 34

Liver disease, anticoagulant drugs and dessimated intravascular coagulation (DIC)

Question 35

What is dessimated intravascular coagulation?

Answer 35

Widespread excessive thrombosis due to over expression of tissue factor, leads to small thrombi in blood vessels (known as micro circulation)

Question 36

What are the contributory factors to thrombosis?

Answer 36

Virchow’s triad: Blood (more for venous thrombosis) Vessel wall (more for arterial thrombosis) Blood flow (for both)

Question 37

What changes in blood contribute to increased risk of venous thrombosis?

Answer 37

Reduction in anticoagulation proteins, pregnancy (increased factor VIII) and factor V Leiden (when factor V fails to be inactivated by vit C)