Haematology 3 Coagulation

Question 1

What function does thrombin have?

Answer 1

It’s formed by the activation of the coagulation cascade.

• enhances platelet activation and recruitment
• cleaves fibrinogen to fibrin
• fibrin network stabilises platelet clot (secondary haemostasis)

Question 2

Coagulation factors

Answer 2

• mostly sarin proteases
• need to be activated (proenzymes)
• produced in liver
• stored in platelets and endothelial cells

Question 3

Intrinsic and extrinsic systems of coagulation cascade

Answer 3

Intrinsic pathway:

• relevance unknown
• activated by surface contact (kvllikrein, HMWK
• Factors XII, XI, Prekallikrein, high weight molecular kininogen

Extrinsic pathway:

• triggers blood coagulation
• actives by tissue factor → activates F VII → activates F X

Question 4

Coagulation cascade: intrinsic Tenase complex

Answer 4

F IXa and F VIIIa activate F X → binds to FVa → accelerates clotting

Question 5

Coagulation cascade: Extrinsic Xase

Answer 5

Factor VIIa and Tissue Factor activate F X → accelerates clotting

Question 6

Coagulation cascade: Josso-loop

Answer 6

Connection between intrinsic and extrinsic pathways: F VIIa can activate F IX and F X

Question 7

Coagulation cascade: feedback activation by thrombin

Answer 7

Thrombin can activate F XI, F VIII, F V

Question 8

Cell-based model of coagulation: Initiation

Answer 8

Tissue factor-expressing cells get into contact with plasma → FVII binds to TF and activates FX and F IX → F V attaches to FX and F IX → small amount of thrombin is released though prothrombin cleavage by F X (“ Thrombin spark”)

Question 9

Cell-based model of coagulation: Amplification

Answer 9

Thrombin activates platelets → activates FV, FVII and FIX → perfect conditions for thrombin generation

Question 10

Cell-based model of coagulation: Propagation

Answer 10

Tenase and Prothrombinase are formed → thrombin generation (“ Thrombin burst”) → coagulation occurs on platelet surface (localised)

Question 11

What does F XIIIa do?

Answer 11

Induced crosslink of fibrin through transglutaminase reaction and guarantees fibrin stability

Activated (cleaved) by Thrombin, Fibrin and Ca2+

Question 12

Haemophilia A

Answer 12

F8 gene defect → lacks factor VIII

Question 13

Haemophilia B

Answer 13

F9 gene defect → lacks factor IX

Question 14

Thrombin positive feedback loop

Answer 14

Thrombin activates F V, XI and VIII → increases Thrombin release

Thrombin binds to Thrombomodulin which activates TAFI (= Thrombin activated fibrinolysis inhibitor) → clot won’t resolve until coagulation is finished

Question 15

Thrombin negative feedback loop

Answer 15

Protein C binds to Thrombin → inactivates F V and VIII

Question 16

Inhibitors of coagulation

Answer 16

1. Antithrombin II
2. Tissue Factor Pathway Inhibitor (TFPI)
3. Protein C/S System

Question 17

What are Glycosaminoglycans? And how to they work?

Answer 17

Cofactors for Antithrombin III example: Heparin, Heparan sulfate → accelerate inhibition 1000x

Binding of Heparin → conformational change → higher affinity of antithrombin III to F Xa + detaches FVa from cell surface

“Template effect”: both Thrombin and Antithrombin use Heparin to get in contact with each other

Question 18

Where can you find Heparin in humans?

What is Heparin made of?

Answer 18

In basophil granulocytes in blood and mast cells in tissue.

Polymer of glucuronic acid and glucosamine → has different lengths and molecular weight

Question 19

What does Antithrombin III inhibit?

Answer 19

Thrombin (F IIa), F Xa, F IXa, XIa, XIIa, Kallikrein

Question 20

What does TFPI (Tissue Factors Pathway Inhibitor) inhibit?

Answer 20

Binds to FXa → leads to an inhibitory complex that inhibits extrinsic Tase complex (VIIa + PL + Ca2+)

Question 21

How does Protein C inhibit Thrombin?

Answer 21

Thrombomodulin binds to thrombin → activates Protein C (+ Cofactor Protein S) → inhibits FV and FIII

Question 22

Fibrin structure

Answer 22

Dimer with two of each alpha, beta and gamma chains.
Fibrinopeptide A is on alpha chain
Fibrinopeptide B is on beta chain
Chains connected though disulfate bridges

Question 23

How does Fibrinolysis work?

Answer 23

Plasminogen is cleaved by t-PA (tissue plasminogen activator, endothelial cells) or u-PA (urokinase plasminogen activator, kidney) to Plasmin → Plasmin dissolves fibrin clot

t-PA and u-Pa are activated once fibrin binds to them!

Question 24

Inhibitors of fibrinolysis

Answer 24

1. Alpha2-antiplasmin → Plasmin
2. PAI 2 (Plasminogen activator inhibitor) → u-PA and t-PA
3. TAFI (Thrombin actionable fibrinolysis inhibitor) → Plasminogen + proteolysis of fibrin

Question 25

Bernard Soulier Syndrom

Answer 25

Lack of GPIa: mutation within glycoprotein Ib which is part of the vWF receptor (GPIb + V + IX) → binding of platelets to vWF is impaired
(inherited Thrombocytopathy)

Question 26

Glanzmann Syndrome/Thrombasthenia

Answer 26

Lack of GPIIb/IIIa: mutation in GPIIb/IIIa → weak platelet-platelet-interaction → less aggregation
(inherited Thrombocytopathy)

Question 27

von Willebrand Disease

Answer 27

Mutation in vWF gene → disturbed or non functional vWF → disturbed coagulation
(inherited Coagulopathy, autosomal, dominant)