Haem - Haemostasis

Question 1

What is haemostasis?

Answer 1

Blood clot

Question 2

Steps in haemostasis

Answer 2

1. Vasoconstriction
2. Primary haemostasis
3. Secondary haemostasis
4. Fibrinolysis

Question 3

What is primary haemostasis?

Answer 3

Formation of unstable platelet plug (Platelet adhesion/aggregation)

Question 4

What is secondary haemostasis?

Answer 4

Formation of stable fibrin clot

Question 5

What is fibrinolysis?

Answer 5

Dissolution of a clot

Question 6

Important balances in haemostasis

Answer 6

1. Coagulation (state change)
2. Thrombosis (Limit area)
3. Fibrinolysis (breakdown clot, healing)

Question 7

Where are platelets formed?

Answer 7

In the bone marrow, derived from myeloid stem cells, it is a fragmentation of megakaryocyte cytoplasm

Question 8

What is von Willebrand factor VWF?

Answer 8

Factor in mediating platelet adhesion, also promotes platelet-platelet aggregation

Question 9

What happens in primary haemostasis?

Answer 9

1. Platelet stick to damaged endothelium (…)
2. Adhesion activates platelets (…)
3. Platelet aggregates

Question 10

How does platelet stick to endothelium?

Answer 10

Either directly to collagen via GP1a receptor
OR
indirectly to the VWF factor with binds to GP1b receptor

Question 11

How does adhesion activate platelet?

Answer 11

1. Membrane invaginated to release content of granules
   - ADP, fibrinogen, VWF
2. Changes shape (round w/ spicules) - increase platelet-platelet interaction
3. Produces prostaglandin thromboxane A2

Question 12

What are the granules of platelet?

Answer 12

• alpha-granule

- dense granule

Question 13

What does thromboxane A2 do?

Answer 13

1. Promotes platelet aggregation

2. Vasoconstrictor (imp. in injury & inflammation)

Question 14

What signals further activation and aggregation in primary haemostasis?

Answer 14

Combo of ADP & thromboxane, giving positive feedback

Question 15

How does platelet further aggregate?

Answer 15

By binding to ADP (P2Y12) and thromboxane A2 receptors

Question 16

How does ADP + ThA2 cause further activation?

Answer 16

Conformational change in GPIIb/IIIa receptor, provide binding site - fibrinogen- to link platelet to form plug

Question 17

What chemical counter balances and stops platelet aggregation?

Answer 17

Prostacyclin (GPI 2) - powerful vasodilator & suppress platelet adhesion

Question 18

What is secondary haemostasis?

Answer 18

Clotting involving the coagulation cascade

[formation of fibrin]

Question 19

What HAPPENS in secondary haemostasis?

Answer 19

Generation of thrombin –> cleaves fibrinogen –> form fibrin clot –> stabilise plug

Question 20

What is factor II?

Answer 20

Prothrombin

Question 21

What does the synthesis of clotting factors depend on?

Answer 21

Vitamin K (for carboxylation of glutamic acid residue)
essential for clot function

Question 22

What do clotting factors work on?

Answer 22

Exposed platelet phospholipid surfaces (help localise & accelerate reactions)

Question 23

Where are clotting factors synthesised?

Answer 23

Liver (except for factor VIII & VWF - endothelial cell)

Question 24

What initiates coagulation?

Answer 24

Tissue factor - not normally exposed to blood, only injury

Question 25

How does tissue factor initiate coagulation?

Answer 25

It binds to factor VIIa - activates factor IX --> XIa - activates factor X --> Xa Activates prothrombin (Factor II)

Question 26

What are the 3 phases of secondary haemostasis?

Answer 26

1. Initiation 2. Amplification 3. Propagation

Question 27

What does activating prothrombin do?

Answer 27

Generate thrombin (factor IIa)

Question 28

What does thrombin do? (propagation)

Answer 28

Cleaves soluble fibrinogen to insoluble fibrin

Question 29

What does small amount of thrombin mediate?

Answer 29

Activation of cofactor V & VIII, zymogen (factor XI) & platelets

Question 30

What is the amplication phase?

Answer 30

Zymogen converts more FIX --> FIXa FIIIA converts more FX --> FXa Therefore, more thrombin (FIIa) converted from Prothrombin (FII)

Question 31

What ion is important in binding activated clotting factors to phospholipid surfaces?

Answer 31

Calcium ion

Question 32

What does Zymogen (FXI) turn?

Answer 32

Activate clotting co-factors FV --> FXI FVIII --> FVIIIa (by splitting of peptide bonds & expose enzyme sites)

Question 33

What happens during fibrinolysis?

Answer 33

Tissue plasminogen activator (t-Pa) activates plasmin by binding to lysine residue on fibrin Fibrin is broken down into Fibrin-degradation products (FDPs)

Question 34

What was plasmin before it was activated?

Answer 34

Inactive Plasminogen

Question 35

What do anti-platelet drugs do?

Answer 35

Prevention and treatment of cardiovascular/cerebrovascular disease

Question 36

How does anti-platelet drugs work?

Answer 36

- Inhibit thromboxane A2 production - Block ADP receptor Hence decrease platelet aggregation, and prevent formation of thrombus

Question 37

What are some examples of anti-platelet drugs?

Answer 37

Aspirin, Clopidogrel

Question 38

How long does anti-platelet drug last?

Answer 38

Until new platelets are produced (around 7 days)

Question 39

What do thrombolytic therapy/agents do?

Answer 39

eg Recombinant t-Pa intravenously injected to generate plasmin to breakdown clots

Question 40

What is the risk w/ thrombolytic therapy?

Answer 40

Bleeding

Question 41

What are thrombolytic therapies used for? What replaced them?

Answer 41

Ischaemic stroke Myocardial infarction Life-threatening pulmonary emboli (Stents, angioplasty)

Question 42

How does antifibrinolytic drug (Tranexamic acid) work?

Answer 42

Competitive inhibition - derivative of lysine 1. binds to plasminogen 2. prevent bind to lysine residue of fibrin 3. prevent activation of plasmin

Question 43

What are antifibrinolytic drugs used for?

Answer 43

Treat bleeding in: - Trauma surgical patients - Inherited bleeding disorders

Question 44

What happens when the balance leans towards fibrinolytic factors and anticoagulant proteins?

Answer 44

Bleeding - reduce platelet function - reduce coagulator factors - increase fibrinolysis

Question 45

What happens when the balance leans towards coagulation factors and platelets?

Answer 45

Thrombosis - clot in vessel - reduce anticoagulant proteins - reduce fibrinolysis - increase clotting factor/platelet

Question 46

Coagulation inhibitory mechanism:

Answer 46

1. Thrombin binds thrombomodulin - activates Protein C --> "activated protein C (APC)" 2. APC activates FVa &FVIIIa in presence of cofactor Protein S 3. Thrombin & FXa inactivated by Antithrombin

Question 47

How does heparin increase action of antithrombin?

Answer 47

Antithrombin binding to endothelial cell-associated heparin

Question 48

What use is the anticoagulant pathway?

Answer 48

To confine coagulation at site of injury

Question 49

What are the main substrates for anticoagulation?

Answer 49

Protein C Protein S Antithrombin

Question 50

What are some examples of anticoagulant drugs? (prevent thrombosis)

Answer 50

Heparin, Warfarin, Direct Oral Anticoagulants (DOACs)

Question 51

How does Heparin drug work?

Answer 51

Potentiate action of antithrombin --> inactivate FXa and thrombin

Question 52

How does Warfarin drug work and monitored?

Answer 52

Oral tablet - Interferes protein carboxylation / antagonizes Vitamin K - Reduces synthesis of vit K-dependent clotting factors (thrombin, VII, IX, X) produced by liver Monitored by regular blood tests

Question 53

How does Direct oral anticoagulants drug work and monitored?

Answer 53

Directly inhibits either thrombin/FXa No monitor

Question 54

What are the tests of coagulation?

Answer 54

- PT (Prothrombin time) | - APTT (Activated partial thromboplastin time)

Question 55

What does prothrombin time measure?

Answer 55

Time to clot following extrinsic pathway

Question 56

What does aPTT measure?

Answer 56

Time to clot following intrinsic pathway

Question 57

How to do a PT test?

Answer 57

1. Blood collected in bottle w/ sodium citrate (chelates Calcium to initially prevent clot) 2. Sample spun - produce platelet-poor plasma 3. Add Tissue factor & phospholipid + calcium Time...

Question 58

What does a 'prolonged PT' tell you?

Answer 58

Reduction in activity of FVII, X, II prothrombin, fibrinogen

Question 59

How to do an aPTT test?

Answer 59

Add contact activator, phospholipid, citrated plasma and calcium Time...

Question 60

What does a 'prolonged aPTT' tell you?

Answer 60

Reduced in one/more clotting factor

Question 61

What does a 'prolonged aPTT' and 'normal PT' tell you?

Answer 61

Haemophilia A (FVIII deficient) Haemophilia B (FIX deficient) Haemophilia C (FXI deficient) FXII deficient (does not result in bleeding, wrong in model)

Question 62

What is the combination name of Tissue factor and phospholipid?

Answer 62

Recombinant thromboplastin

Question 63

What does INR stand for?

Answer 63

International normalized ratio