CVS 10 - Haemostasis & Thrombosis

Question 1

What are the two main mechanisms involved in haemostasis?

Answer 1

Platelets and Clotting Cascade

Question 2

What happens in primary and secondary haemostasis?

Answer 2

Primary - platelet activation and aggregation - formation of an unstable platelet plug
Secondary - stabilisation of the plug with fibrin

Question 3

Define coagulation.

Answer 3

The process by which blood is converted from a liquid to a solid.

Question 4

What cells secrete Von Willebrand Factor?

Answer 4

Endothelial cells and platelets

Question 5

What is exposed when the endothelial layer is damaged?

Answer 5

Subendothelial layer - collagen

Question 6

How can the subendothelial layer be recognised?

Answer 6

The Von Willebrand factors bind to the collagen and the GlpIb receptors on the platelet binds to VWF (high sheer conditions)

OR

GlpIa receptors on the platelets can bind directly to the collagen (less sheer stress)

Question 7

When the platelets bind to collagen/VWF what do they release?

Answer 7

ADP and prostaglandins (thromboxane) which will cause the second process - platelet aggregation - release activates other platelet

Question 8

What receptors become available on the platelets to allow fibrinogen to bind?

Answer 8

GlpIIa and GlpIIIb - receptors change conformation as a response to ADP and thromboxane

Question 9

Describe the effect of thrombin on the formation of the primary platelet plug.

Answer 9

Thrombin stimulates the activation of platelets so that they aggregate.

Question 10

Describe the changes in the morphology of the platelets that take place when they are activated.

Answer 10

The platelets become more spiculated and their membrane changes composition. Phospholipids that were on the inside of the membrane move to the outside, which is important because they bind to coagulation factors. The platelets express GlpIIa and GlpIIIb receptors that can bind to fibrinogen.

Question 11

Where are clotting factors, fibrinolytic factors and inhibitors synthesised?

Answer 11

Mainly in the LIVER
Von Willebrand Factor is produced in high concentration by the endothelial cells
Factor V is produced by megakaryocytes (platelets)

Question 12

Which factors are cofactors?

Answer 12

Factor 8 and Factor 5

Question 13

Describe the extrinsic pathway.

Answer 13

The extrinsic pathway is activation of factor 10 to 10a by Tissue factor bound to Factor 7 and calcium. This is the normal physiological activation of the clotting cascade.

Activation of FXII to FXIIa is mainly an in vitro reaction (intrinsic pathway).

Question 14

What are factor 1 and factor 2 more commonly called?

Answer 14

Factor 1 = Fibrinogen —> Fibrin

Factor 2 = Prothrombin —> Thrombin

Question 15

What protein breaks down fibrin clots and what is its precursor? How is it activated?

Answer 15

Plasmin - the precursor is plasminogen.
Plasminogen is converted to plasmin by the action of Tissue Plasminogen Activator (tPA).
tPA (in tissue) doesn’t usually come into contact with plasminogen (in plasma) but when a fibrin clot forms, it assembles tPA and plasminogen on its surface so they come into contact and plasminogen is converted to plasmin.
Plasmin breaks down fibrin clot to give FDP.

Question 16

What products can be given in therapeutic thrombolysis of myocardial infarction?

Answer 16

tPA (tissue plasminogen activator) and bacterial activator (streptokinase)
(Clot busters)

Question 17

What are the two main coagulation inhibitory mechanisms?

Answer 17

DIRECT inhibition - eg. antithrombin

INDIRECT inhibition - Protein C inhibition pathway (target co factors 5 and 8)

Question 18

What factors are inhibited by antithrombin?

Answer 18

Factor 2a (=thrombin), 9a, 10a and 11a 
It is a broad scale clotting factor inhibitor

Question 19

Describe the effect of heparin.

Answer 19

Heparin accelerates the action of antithrombin

Question 20

What are factor 8 and factor 5 activated by?

Answer 20

Trace amounts of thrombin

Question 21

Describe the protein C inhibitory pathway.

Answer 21

Thrombin, once produced is usually involved in clot formation, activating platelets and activating factor 8 and factor 5.
Thrombin can binds to thrombomodulin when more thrombin has been activated (a protein on the surface of the endothelium) which changes its specification.
It then activates Protein C and Protein S, which then inactivate Factor 8 and Factor 5. This is the second anticoagulant mechanism.
SO thrombin has 2 opposing roles.

Question 22

What are the consequences of Factor V Leiden?

Answer 22

Factor V Leiden is a common polymorphism in the population (4%). Factor V Leiden can’t be inactivated as well as wild type Factor V. If protein C can’t inactivate the factor V leiden as well, there is increased risk of thrombosis.

Question 23

State four failures of coagulation inhibitory mechanisms that cause increased risk of thrombosis.

Answer 23

Antithrombin deficiency
Protein C deficiency
Protein S deficiency
Factor V Leiden

Question 24

What constitutes the unstable platelet plug?

Answer 24

Exposed collagen - von Willebrand factor - platelets

Question 25

A disease of primary haemostasis could be due to the affectation of what components of the unstable platelet plug?

Answer 25

Collagen/vessel wall -> ageing and steroids can damage the endothelium Von Willebrand factor -> VWF disease means that you have no VWF Platelets -> warfarin and other drugs affect platelets. Thrombocytopenia.

Question 26

Describe the pattern of bleeding of a defect in primary haemostasis.

Answer 26

IMMEDIATE - prolonged nose bleeds, easy bruising, menorrhagia, prolonged gum bleeding

Question 27

What is a characteristic feature of thrombocytopenia?

Answer 27

Petechiae

Question 28

What is the main role of secondary haemostasis?

Answer 28

To produce fibrin from fibrinogen and stabilise the platelet plug by forming an insoluble mesh around it.

Question 29

Why is there a lag between the administration of a tissue factor trigger and the thrombin burst?

Answer 29

This is when cofactors and clotting factors are synthesised.

Question 30

State some other causes of problems with secondary haemostasis.

Answer 30

Liver disease (failure to produce clotting factors), drugs, consumption of clotting factors

Question 31

What is DIC?

Answer 31

Disseminated intravascular coagulation - widespread activation of the coagulation cascade. Associated with sepsis, major tissue damage, inflammation. Leads to consumption of the clotting factors and platelets - that's why it's also called consumptive coagulopathy. Activation of fibrinolysis depletes fibrinogen. Consequences: organ failure due to deposition of fibrin in vessels; widesprad bleeding.

Question 32

What is haemophilia defined as?

Answer 32

Failure to generate enough fibrin to stabilise the platelet plug because of factor VIII or FIX deficiency. Primary haemostasis remains ok, secondary no.

Question 33

Describe the pattern of bleeding of defects in secondary haemostasis.

Answer 33

DELAYED - people with defects in secondary haemostasis are generally fine with small cuts. They bleed deeper into joints and muscles. Do NOT tend to bleed excessively from small cuts (because the primary haemostasis is fine)

Question 34

What is the hallmark of haemophilia?

Answer 34

Haemarthrosis - bleeding into joints

Question 35

State some defects of clot stability.

Answer 35

``` Excess fibrinolytic (tPA) Deficient antifibrinolytic (eg. antiplasmin deficiency) ```

Question 36

What are the consequences of thromboembolism?

Answer 36

Thrombophlebitic syndrome | Pulmonary hypertension

Question 37

How does risk of thrombosis change with age? What is thromboembolism's prevalence?

Answer 37

Increases | Overall 1 in 1000 - 10 000 per annum

Question 38

What are the three components of Virchow's triad?

Answer 38

Hypercoagulability Vessel wall injury Stasis

Question 39

Why is pregnancy associated with an increase in the risk of thrombosis?

Answer 39

Pregnancy involved reduced mobility and reduced flow and a decrease in protein S meaning that blood becomes procoagulant

Question 40

What is the only circumstance in which thrombolytic therapy is given? Why is it not given more often?

Answer 40

STROKE | Because giving thrombolytic therapy increases the risk of bleeding.

Question 41

What happens in haemophilia?

Answer 41

Deficiency of factor 8 or factor 9. Massively slows down the production of thrombin and so there is no real thrombin burst. Not much fibrin mesh is formed and so the clot is not stabilised.

Question 42

What are the two functions of haemostasis?

Answer 42

1. Prevention of blood loss from intact vessels | 2. Arrest of bleeding from injured vessels

Question 43

Describe the overview of a haemostatic plug formation

Answer 43

Response to injury: Vessel constriction Then primary haemostasis: Formation of an unstable platelet plug (platelet adhesion, platelet aggregation) Then secondary haemostasis: Stabilisation of the plug with fibrin (blood coagulation) Then dissolution of clot and vessel repair (fibrinolysis)

Question 44

Describe the intrinsic pathway of blood coagulation

Answer 44

Ends up with factor Xa. Process takes place on activated platelets. Starts with factor XII which activates XI which will activate X with the help of co factor 8 and PI (platelet membrane phospholipid)

Question 45

Describe the common pathway of blood coagulation

Answer 45

Factor X activates (with the help of co factor V and PI) prothrombin to give thrombin. Then thrombin activates Fibrinogen to Fibrin. Thrombin crosslinks fibrin by activating XII.

Question 46

What are the 2 things that need to be in equilibrium for normal haemostasis?

Answer 46

Fibrinolytic factors, anticoagulant proteins and coagulation factors, platelets