Haemostasis

Question 1

What are some substances secreted by endothelium to prevent adhesion of blood cells to the vascular wall?

Answer 1

Heparans 
TFPI
Thrombomodulin
Nitric Oxide
Prostacyclin

Question 2

What initiates the activation of platelets at the sight of a clot?

Answer 2

• Abnormal surface: platelets have collagen receptors that sense the presence of collagen in the lumen
• Tissue factor release by the injured epithelium

Question 3

Which receptors are on the surface of platelets that help them realize that a clot has occurred?

Answer 3

• ADP receptor
• Epinephrine receptor
• Thrombin receptor

Question 4

Other than receptors, what is on the surface of platelets?

Answer 4

Glycoproteins

Act as binding sites for different ligands

• Von Willebrand Factor
• Thrombin
• Collagen

Question 5

How do platelets anchor themselves to the exposed collagen at wound sites?

Answer 5

• Collagen glycoproteins bind to the collagen

- Von Willebrand factor glycoproteins binds to VWF, thre VWF is anchored to collagens via its own glycoproteins

Question 6

Once the platelets are anchored to the collagen what is the next step in clotting?

Answer 6

A conformational change occurs where the platelets bind fibrinogen

Fibrinogen is then cleaved to fibrin to form the fibrin clot

Question 7

What are the broad roles of platelets in haemostasis?

Answer 7

• Adhere to vessel surface
• Activation
• Aggregation at clot area
• Provide phospholipid surface for coagulation reactions (flip their phospholipid surface)

Question 8

What are two of the important platelet activation pathways? Examples of drugs that inhibit them?

Answer 8

• ADP (P2Y12) pathway: functions to make the platelet sticky and facilitate clotting. Inhibited by clopidogrel
• Cyclooxygenase (COX) pathway: converts arachadonic acid to thromboxane A2 to facilitate aggregation. Inhibited by aspirin

Question 9

What is the function of the enzyme scramblase in platelets?

Answer 9

To flip the phospholipids from the inner surface of the platelet to the outer surface

Important as they provide a site for coagulation reactions to take place on

Question 10

Steps in clotting?

Answer 10

• Platelets bind collagen, VWF
• ## Platelets are activated, change conformation and bind fibrinogen

Question 11

How is the fibrinogen that is bound to activated platelets transformed into fibrin to form the fibrin clot?

Answer 11

• Prothrombin is cleaved to thrombin, thrombin then cleaves fibrinogen to fibrin
• The prothrombin to thrombin pathway is mediated by two different factor cascades, when combined they result in enough thrombin to facilitate haemostasis
• The absence of any of the factors preceding the prothrombin to thrombin cascade may result in an inability to effectively form clots

Question 12

What is the function of TFPI? (tissue factor pathway inhibitor)

Answer 12

Inactivates factor VII & X which are involved in the conversion of prothrombin into thrombin

This results in insufficient thrombin levels to initiate haemostasis and so inhibits the clotting pathway

Question 13

What is the function of activated protein C?

Answer 13

Switches off factor V and VIII which results in reduced thrombin production and therefore inhibits the clotting pathway

Question 14

What is the function of antithrombin?

Answer 14

Serum protease - natural anticoagulant

Binds to and inactivates multiple factors in the thrombin cascade, most importantly factor X and thrombin itself

Most potent natural anticoagulant

Question 15

What is the effect of antithrombin and protein C deficiency?

Answer 15

Predisposes patients to development of blood clots

DVT / pulmonary emboli most predominant

Question 16

Which hormones are secreted by the endothelium and are responsible for the cleavage of plasminogen?

Answer 16

T-PA - tissue plasminogen activator

U-PA - Urokinase

Question 17

What Is plasminogen cleaved into? What is the action of this molecule?

Answer 17

Plasmin

Serum protease - functions to facilitate the degradation of fibrin clots into fibrin degradation products (FDP)

Question 18

Why might a person struggle to degrade their blood clots?

Answer 18

• High levels of plasminogen inhibitors: PAI-1/2

- High levels of plasmin inhibitors: antiplasmin / macroglobulin

Question 19

What are some antithrombotic drugs that inhibit the ADP platelet activation pathway?

Answer 19

Clopidogrel

Prasugrel

Ticagrelor

Question 20

What are some antithrombotic drugs that inhibit the COX platelet activation pathway?

Answer 20

Aspirin

Question 21

What are some examples of drugs that inhibit the fibrinogen binding of platelets? How do they accomplish this?

Answer 21

Abciximab
Tirofiban
Eptifibatide

Prevent the binding of fibrinogen to glycoprotein IIb / IIIa

Question 22

How does warfarin inhibit the clotting process?

Answer 22

It inhibits vitamin K which is key in the post translational modification of factors VII, IX and X

This inhibits the cleavage of prothrombin which inhibits clotting

Can be reversed by the administration of vitamin K or by the administration of a prothrombin concentrate containing factors VII, IX and X

Question 23

How do heparins inhibit clotting?

Answer 23

Heparins bind antithrombin and allows the antithrombin to cleave the thrombin and activated factor X

Question 24

How do rivaroxaban, edoxaban and apixaban work as anticoagulants?

Answer 24

They bind the active site of factor X which inhibits the cleavage of prothrombin into thrombin

Question 25

How do dabigatran, bivalirudin and argatroban work as anticoagulants?

Answer 25

They bind thrombin and inhibit it from cleaving fibrinogen to fibrin

Question 26

How is the spread of clots stopped from expanding beyond their localized area?

Answer 26

Natural anticoagulants such as antithrombin, TFPI and protein C limit the spread of clots beyond where they are needed