Basic Haemostasis Flashcards

1
Q

What are the functions of haemostasis?

A
  • Prevention of blood loss from intact vessels

- Stop bleeding from injured vessels

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2
Q

Outline the main steps of haemostasis in reponse to injury

A
  • vessel constriction
  • formation of unstable platelet plug (platelet adhesion and aggregation)
  • stabilisation of plug with fibrin (coagulation)
  • dissolution of clot and vessel repair
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3
Q

What are the two main stages of haemostasis and describe them?

A

primary- formation of unstable plug

secondary - stabilisation

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4
Q

Define coagulation

A

process by which blood is converted from liquid to solid

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5
Q

Outline the formation of the platelet plug

A
  • endothelial damage exposes the collagen in the subendothelial layer
  • collagen is recognised by Von Willebrand factor or glycoprotein 1a receptor
  • when the glycoprotein receptors on the platelets are engaged either to the Von Willebrand Factor or directly to the collagen, the platelets become activated
  • the platelets will release ADP and prostaglandins (thromboxane)
  • thromboxane acts on the surface of the receptor
  • prostaglandins activate other platelets so the platelets aggregate - the glycoproteins IIa and IIIb receptors become available which the fibrinogen can bind to
  • protease called thrombin gets generated which can also directly activate the platelets so that they aggregate
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6
Q

What is Von willenbrand factor?

A

A plasma protein made by endothelial cells and platelets. It binds to collagen and attracts platelets. The platelets bind to glycoprotein 1b receptor on the VWF

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7
Q

Where is glycoprotein 1a receptor found?

A

platelets and directly binds to collagen

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8
Q

What determines which mechanism is used to identify collagen?

A
  • Because the circumstances within the vasculature will vary - the stressors in the blood can be different
  • In a small blood vessel there could be very high shear stress which favours the Von Willebrand mechanism
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9
Q

What is the clinical significance of thrombin?

A

specific receptors for thrombin on the platelets which are therapeutic targets

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10
Q

What happens to the platelet when it gets activated?

A
  • When platelets are activated they change shape and hence its membrane composition
  • Certain phospholipids which are usually inside the platelet come to the outside (they bind to the coagulation factors)
  • The platelet presents new or activated proteins on their surface (e.g. GlpIIb and IIIa - this becomes an active conformation so it can react with the fibrinogen)
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11
Q

Where are clotting factors, fibrinolytic factors and inhibitors made?

A
  • most made in liver
  • VWF made in the endothelium
  • factor 5 is made in the megakaryocyte
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12
Q

Describe the intrinsic pathway

A
  • factor 12 (precursor protease called zymogen) is converted to factor 12a
  • this converts factor 11 to factor 11a
  • this converts factor 9 into factor 9a
  • this converts factor 10 into 10a
  • factor 8a accelerates conversion of 10 to 10a
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13
Q

is factor 8 a zymogen?

A

no it is a cofactor

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14
Q

What is a zymogen?

A

inactive enzyme precursor

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15
Q

Describe the extrinsic pathway of blood coagulation

A
  • vessel damage means blood comes into contact with tissue factor
  • tissue factor is a smooth membrane protein not normally in blood
  • it initiates the clotting cascade
  • it binds to factor 7 and converts it into 7a
  • 7a converts 10 into 10a
  • 10a converts prothrombin into thrombin
  • 5a helps convert prothrombin to thrombin faster
  • factor 5a is generated from factor 5 by trace amounts of thrombin
  • thrombin converts finbrinogen into fibrin making an insoluble clot
  • the clot can be crosslinked by factor 13a so it is stabilised
  • tissue factor can also activate factor 9 to 9a when it binds to factor 7
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16
Q

What are the three main pathways in the coagulation cascade?

A
  • Intrinsic (involves factor 12)
  • Extrinsic (involves tissue factor and factor 7)
  • Common Pathway (where the intrinsic and extrinsic pathways converge - from factor 10a onwards)
17
Q

What is the main initiator/driver for physiological coagulation?

A

tissue factor

(Factor 12 can be activated to Factor 12a, this is mainly an in vitro reaction that is useful for some diagnostic tests

18
Q

What is the importance of the coagulation surface?

A

The surface is made of activated phospholipids which localise and accelerate the reactions

19
Q

Plasminogen and tPA

A
  • Tissue Plasminogen Activator (tPA) is a protein made by the endothelial cells
  • It converts plasminogen from an inactive zymogen to an active protease called plasmin
  • Normally, there is no interaction that takes place between these two proteins
20
Q

Describe how fibrinolysis occurs

A
  • The fibrin clot assembles the tPA and the plasminogen on its surface, bringing them close together and triggers the cleavage reaction where the tPA can convert plasminogen to plasmin
  • Plasmin is a powerful protease that can break down the fibrin clot
21
Q

What are the breakdown products of the fibrin clot?

A

Fibrin Degradation Products

22
Q

What can FDP be used for?

A

measured when giving thrombolytic therapy

23
Q

What can tPA and streptokinase be used for?

A

Therapeutic thrombolysis for myocardial infarction

24
Q

What is the clotting cascade actually?

A

An amplification system where a small amount of Factor 7a produces a large amount of thrombin

25
Q

Why doesn’t all the blood clot during clotting?

A

coagulation inhibitory mechansims

direct and indirect

26
Q

What is the direct inhibition mechanism?

A
  • Direct inhibition of the activated coagulation factors
  • This takes place by an inhibitor that circulates in the blood in quite high concentrations called antithrombin
  • It is a broad scale inhibitor of most of the coagulation proteinases
  • Antithrombin is sometimes known as antithrombin III
27
Q

What is the indirect inhibition mechanism?

A
  • Mechanism that slows down the amount of thrombin that is generated
  • This involves the activation of Protein C in the Protein C Anticoagulant Pathway
28
Q

How does antithrombin work?

A

When there is an excess of the coagulation factors, antithrombin will inhibit them by forming a complex with them and then the complexes are cleared from the circulation

Reduction in antithrombin —-> Higher risk of thrombosis

29
Q

What does herparin do?

A

it accelerates the action of antithrombin so used in immediate anticoagulation of venous and pulmonary thrombosis

30
Q

What is the importance of cofactor 5 and 8 and how are they activated?

A

activated by trace amounts of thrombin and they make coagulation faster

31
Q

Second anticoagulation mechanism

A
  • Protein C inactivates the cofactors (Factor 8/5)
  • The thrombin generated can bind to a protein on the surface of the endothelium called thrombomodulin which changes the conformation of thrombin
  • Thrombin is normally involved in forming the clot, activating the platelets and activating Factor 8 and Factor 5
  • When the thrombin binds to thrombomodulin, it changes its specification
  • It activates Protein C which is an inactive zymogen to activated protein C (along with Protein S)
  • Activated Protein C and Protein S inactivates Factor 5a and Factor 8a
  • This is the second anticoagulant mechanism
32
Q

What happens if you have a deficiency of one of the inhibitory proteins (S/C) ?

A

You can’t control the amount of coagulation via the indirect inhibitory pathway

33
Q

Factor 5 Leiden

A
  • It is a common polymorphism in the population
  • There is an amino acid change in Factor 5 called Factor 5 Leiden which cannot be inactivated as well as wild type Factor 5
  • If you have this polymorphism then the protein C anticoagulant pathway can’t inactivate Factor 5 Leiden as well and so there is higher risk of thrombosis
  • More thrombin is generated if you have this
34
Q

Which mechanism failures can lead to increased thrombosis risk?

A
  • Antithrombin Deficiency
  • Protein C Deficiency
  • Protein S Deficiency
  • Factor V Leiden
35
Q

What is the lifespan of a platelet?

A

8 days