Haemostasis

Question 1

What are the main anti-coagulation substances/factors that are found in the blood?

Answer 1

Heparans

TFPI*

Thrombomudulin

Nitric oxide (NO)

Prostacyclin

*Tissue factor pathway inhibitor

Question 2

When you cut yourself - your blood should solidify at the site of trauma and stop the bleeding

What substances/systems are responsible for:

a) making the clot
b) confining the clot to the site of injury
c) removing the clot after healing

Answer 2

a) Making the clot:

• platelets
• vWF (von Willebrand factor)
• coagulation factors

b) confining the clot to the site of injury:

• natural anticoagulants

c) removal of the clot

• fibrinolytic system

Question 3

What stops all the various coagulation factors and platelets etc from clumping together normally?

Answer 3

They exist in the blood in an unactivated form

They are only activated under certain conditions that arise through trauma - by signals

Question 4

What signals cause the activation of platelets and coagulation factors?

Answer 4

There are 2 main signals that do this…

1) Damage to the endothelium exposes collagen which activates platelets
2) Damage causes local release of physiological factors which activate the coagulation factors

Question 5

What receptors and glycoproteins are present on the surface of platelets?

Give an overview of what these moelcules are responsible for?

Answer 5

Platelet surface has cell surface receptors and platelet glycoproteins

Cell surface receptors:

• respond to chemicals released at site of injury
• ADP, Epinephrine, thrombin

Platelet glycoproteins:

• allow platelets to adhere by binding to ligands
• binding sites for:
  
  • fibrinogen
  • vWF
  • collagen

Question 6

On this diagram of a platelet - identify the different bits

Answer 6

Question 7

What is the function of the open cannalicular system that is found in platelets

Answer 7

Allows the contents of the alpha and dense granules and the lysosomes to be released onto the surface of the platelets

Question 8

In platelets, what is released by:

a) aplha granules
b) dense granules

Answer 8

a) alpha granules:

• vWF
• thrombin

b) dense granules:

• ADP/ATP
• calcium
• serotonin

Question 9

Platelets have a number of glycoproteins on their surface that allow them to attach to certain ligands

How does the platelet attach to the exposed collagen?

Answer 9

Attaches directly to the exposed collagen using two different glycoproteins

But also attaches indirectly to collagen by attaching to vWF which itself attaches to collagen

Question 10

FOllowing the adherance of platelets to the exposed collagen following an injury - how is the definitive fibrin clot formed?

Answer 10

Once platelet is activated and has adhered to the injury sit - one of the glycoproteins undergoes a confirmational change and allows binding to fibrinogen

This allows the A&B peptides on fibrinogen to be cleaved which paves the way towards the final fibrin clot

Question 11

What drugs target the ADP (P2Y12) pathway to stop platelets from working properly?

(antiplatelets)

Answer 11

Prasugrel

Clopidogrel

Ticagrelor

Question 12

What drug works by inhibiting the COX (cyclooxygenase) pathway, thus reduces platelet activity?

Answer 12

Aspirin

Question 13

What is dual antiplatelet therapy?

Answer 13

Combination of:

1) ADP pathway inhibitors (clopidogrel, ticagrelor etc)
2) COX pathway inhibitors (aspirin)

Question 14

What is the function of the scramblase enzyme in platelets?

Answer 14

Scramblase causes some phospholipid molecules which are normally contained on the internal surface of platelets to be expressed on the external surface

This is important as this external expression of phospholipids is key in activating coagulation factors

Question 15

vWF basically exists to help stuff stick together in clots. What are the different molecules that vWF binds to?

Answer 15

Factor VIII

GP 1b (platelet glycoprotein)

Collagen

GP 2b/3a

Question 16

As we know, the primary haemostatic plug (platelet plug) is the first and rapidly forming plug that plugs over a cut, plug

It is made up of adhered platelets, vWF and fibrinogen

What is the next step in the haemostatic process?

Answer 16

Fibrinogen is cleaved by thrombin to form fibrin

once this plug is formed - bleeding stops

fibrin is produced through the coagulation cascade

Question 17

Go and look at the coagulation cascade if you fancy

Answer 17

All you really need to know is that every factor (factor VIII etc) is needed for it to work effectively

Question 18

Natural anticoagulants act to confine a clot to the area of injury.

What are the 3 most important natural anticoagulant systems?

Answer 18

TFPI - tissue factor pathway inhibitor

Protein C and S

AT - antithrombin

Question 19

How does TFPI act?

Answer 19

TFPI binds to and inhibits:

• Factor VIIa
• Factor Xa

the ‘a’ after the factor means its activated form so TFPI binds to and inhibits the activated form

this prevents the conversion of prothrombin to thrombin and thus the conversion of fibrinogen to fibrin

Question 20

How do protein C and protein S prevent coagulation once activated?

Answer 20

Inhibit Factor VIIIa and Va

Question 21

How does the AT system prevent coagulation?

Answer 21

Most powerful of the natural anticoagulants

Binds to and inactivates:

• a fair dinkum of factors (esp Factor Xa)
• thrombin

Question 22

The fibrinolytic system is what breaks down clots after stuffs healed

How does it work?

Answer 22

The clot induces local endothelial cells to release chemicals called plasminogen activators:

t-PA (tissue plasminogen activator)

u-PA (urokinas plasminogen activator)

These molecules convert plasminogen (a zymogen) into plasmin

Plasmin is what breaks down fibrin into fibrin degredation products

Question 23

What is the most clinically significant FDP (fibrin deg product) that we can measure?

Answer 23

D-dimer

d-dimer blood tests are used to detect thromboses

Question 24

Like with all of these pathways, the fibrinolytic system has a number of inhibitors

What are the main ones?

Answer 24

Inhibitors of plasminogen:

PA1-1

PA1-2

Inhibitors of plasmin:

a2 anti-plasmin

a2 macroglobulin

Question 25

What drugs prevent the binding of platelets to fibrinogen?

What glycoprotein do they specifically block?

What is the indication for their use?

Answer 25

Abciximab

Tirofiban

Eptifibatide

GP IIb/IIIa

Used in PCI patients who continue to thrombose despite dual antiplatelet therapy and heparin etc

Question 26

Warfarin used to be the most commonly used oral anticoagulant

What is its effect?

Answer 26

Vitamin K antagonist

It blocks several stages of the coagulation cascade - such as factor activation and the conversion of prothrombin to thrombin

Question 27

How can the effects of warfarin be reversed?

Answer 27

Vitamin K

Either oral or IM

Prothrombin complex concentrate

infusion of coagulation factors basically

Question 28

What is the most commonly used parenteral anti-coagulant?

How does it work?

Answer 28

Heparins

Heparins bind to anti-thrombin (AT) and allow it to cleave Factor Xa and Thrombin

Various types incl. LMWH (eg dalteparin)

Question 29

What oral anticoagulants prevent the conversion of prothrombin to thrombin by factor Xa?

Answer 29

Rivaroxaban

Edoxaban

Apixaban

Question 30

What anticoagulants are direct thrombin inhibitors?

Which of these is oral and which are parenteral?

Answer 30

Dabigatran (oral)

Bivalirudin / argatroban (parenteral)