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YR2: MCD Haematology > Haemostasis > Flashcards

Haemostasis Flashcards

1
Q

State the 4 steps involved in haemostatic plug formation from the time of injury.

A

Vessel constriction
Formation of an unstable platelet plug (platelet adhesion + platelet aggregation)
Stabilisation of plug with fibrin (blood coagulation)
Dissolution of clot + vessel repair (fibrinolysis)

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2
Q

What component found underneath the endothelium is involved in triggering the coagulation cascade?

A

Procoagulant subendothelial structures e.g. collagen
Tissue factor expressed on surface of cells underlying blood vessels but it is NOT normally expressed within the circulation

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3
Q

What process during maturation of megakaryocytes is important for formation of platelets?

A

Granulation

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4
Q

How many platelets are produced by 1 megakaryocyte?

A

4000

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5
Q

What do the dense granules in platelets contain that is important for platelet function?

A

ADP

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6
Q

What do alpha granules in the platelets contain?

A

vWF
Factor V
Growth factors
Fibrinogen

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7
Q

State the 2 ways in which platelets can bind to collagen. Name the receptors involved.

A

Via vWF to collagen (via GpIb receptor)

Bind directly to the collagen (via GpIa receptor)

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8
Q

What happens following the passive adhesion of platelets and engagement of receptors?

A

Receptors signal inside the cell to release ADP from storage granules + to synthesise thromboxane
These bind to receptors on the surface of platelets + activate them
Once activated, GpIIb/IIIa receptors become available, which can bind to fibrinogen + allows platelets to aggregate

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9
Q

Which receptors on the platelets become available following activation of the platelets and what do they bind to?

A

GlpIIb/IIIa

Bind to fibrinogen

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10
Q

What else can activate platelets?

A

Thrombin

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11
Q

What is the most important test for monitoring platelets and their function?

A

Platelet count

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12
Q

What is a common cause of spontaneous bleeding?

A 
AI thrombocytopenia (AI antibodies clear platelets from the circulation) 
Results in purpura, multiple bruises + ecchymoses
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13
Q

What is the normal range for platelet count?

A

150-400 x 10^9/L

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14
Q

Why do you get thrombocytopenia in leukaemia?

A

Leukaemic cells populate the BM which crowds out megakaryocytes so platelets aren’t produced in sufficient numbers

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15
Q

What is the bleeding time test used to observe?

A

Checks the platelet-vessel wall interaction

Isn’t used any more

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16
Q

Describe the platelet aggregation test.

A

Platelets stimulated with ADP/thromboxane/collagen to study their function
Ued to diagnose platelet disease e.g. von Willebrand disease

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17
Q

Where is von Willebrand factor produced?

A

Endothelial cells + a little by megakaryocytes

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18
Q

What factors do megakaryocytes produce?

A

Factor V

Von Willebrand Factor

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19
Q

Tissue factor activates the clotting cascade by converting 9 to 9a and by converting 10 to 10a. What difference does this make?

A

9 to 9a: slower but produces more thrombin

10 to 10a: faster

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20
Q

State 2 accelerating factors. What are they activated by?

A

Factor VIII
Factor V
Activated by trace amounts of thrombin

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21
Q

Which factors are activated on the surface of the platelet? Describe how this works.

A

10 to 10a
2 to 2a (prothrombin to thrombin)
For 9a to activate 10 it needs to come in close proximity with 10. They both bind to the surface of the platelet mediated by calcium ions, + factor VIIIa bring the two close together so that 9a can proteolytically cleave 10 to 10a
Factor Va does the same with 10a and 2 (prothrombin)

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22
Q

Which factors are affected by warfarin?

A

2, 7, 9, 10

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23
Q

What is common to factors 2, 7, 9 + 10 and what is the significance of this common feature?

A

Have a cluster of glutamic acid
-recognised by liver enzyme + undergoes post-translational modification in the presence of vitamin K to Gamma-carboxyglutamic acid (Gla)
Once this extra carboxyl group is added, calcium can facilitate the binding of Gla to the activated platelet membrane phospholipid

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24
Q

How does warfarin actually inhibit the post-translational modification of factorsn 2, 7, 9 + 10?

A

Warfarin inhibits vitamin K epoxide reductase thus inhibiting the gamma carboxylation of factors 2, 7, 9 + 10

25
Q

What is antithrombin? Which factors are inhibited by anti-thrombin?

A

Serine Protease Inhibitor (SERPIN)

2, 9, 10, 11

26
Q

What effect does heparin have on anti-thrombin?

A

Heparin potentiates the action of AT

27
Q

In what situation is heparin used?

A

Heparin is used for immediate anticoagulation in venous thrombosis + pulmonary embolism

28
Q

Describe how anti-thrombin inhibits the clotting factors.

A

AT has a reactive loop that irreversibly inhibits the active site on the clotting factors
So AT acts as a scavenger in stopping inappropriate action of clotting factors

29
Q

State three laboratory tests for blood coagulation.

A

Activated Partial Thromboplastin Time (APTT)
Prothrombin Time (PT)
Thrombin Clotting Time (TCT)

30
Q

What do each of these laboratory tests represent?

A

APTT – abnormalities in INTRINSIC + COMMON pathways (coagulation is triggered by activation of factor 12)
PT – abnormalities in the EXTRINSIC + COMMON pathways (tissue factor is added to trigger the extrinsic pathway)
TCT – abnormality in the fibrinogen -> fibrin conversion (not important any more)

31
Q

What are the main uses of these laboratory tests?

A

APTT and PT are used together for screening causes of bleeding disorders
APTT is used to monitor heparin therapy for thrombosis
PT is used to monitor warfarin treatment

32
Q

What two proteins assemble on the surface of a clot to allow fibrinolysis to take place? Where are these proteins made?

A

Plasminogen (a plasma protein)

Tissue Plasminogen Activator (tPA) (produced by endothelial cells)

33
Q

What is produced from the break down of the fibrin clot and how does this level change in DIC?

A

Fibrin degradation products (FDP)

Elevated in DIC

34
Q

What factor is used in therapeutic thrombolysis of myocardial infarction?

A

tPA “clot buster”

35
Q

What is haemostasis? What is the purpose of haemostasis)

A

Cellular + biochemical process that enables both specific + regulated cessation of bleeding in response to vascular insult
Prevents blood loss from intact + injured vessels, enables tissue repair

36
Q

What 2 things must be balanced for normal haemostasis?

A

Bleeding

Thrombosis

37
Q

What can tip the balance towards bleeding?

A

Reduced platelet function + coagulant factors

Increased anticoagulant proteins + fibrinolytic factors

38
Q

What can tip the balance towards Thrombosis?

A

Increased platelets + coagulant factors

Reduced anticoagulant proteins + fibrinolytic factors

39
Q

Why does each step of haemstatic plug formation occur?

A

Vessel constriction: limits blood flow
Unstable platelet plug formation: limits blood loss + provides surface for coagulation
Fibrin stabilisation: Stops blood loss
Dissolution of clot: Restores vessel integrity

40
Q

List 3 characteristics of platelets

A

Small (2-4um)
Anuclear
10 day lifespan

41
Q

How does the phospholipid membrane of platelets change once activated?

A

Negatively charged phospholipids get exposed onto surface

Makes surface highly attractive to clotting factors

42
Q

Why is the platelet cytoskeleton important for its function?

A

Allows rapid conversion from passive cell to interactive cell
Allows shape change from disc like to activated egg like structure

43
Q

List 5 processes that platelets are involved in

A 
Haemostasis + Thrombosis
Cancer
Atherosclerosis
Immune response to infection
Inflammatory response
44
Q

How do clotting factors circulate?

A

As inactive precursors
Either serine protease zymogens or cofactors
Activated by specific proteolysis

45
Q

Describe the mechanism of action for serine protease domain-containing proteins

A

Once activated, catalyse proteolysis of target substrate

Cleave substrates after specific Arg (+Lys) residues

46
Q

What is the primary initiator of coagulation? Where is it located?

A

Tissue factor
Extravascular sites
Higher expression in certain areas e.g. brain provides further haemostat protection

47
Q

What 5 features do factor VII, IX, X + PC share?

A

A homologous modular structure
Gla domain (ability to bind to phospholipid surface)
EGF domain involved in protein-protein interactions
All circulate in plasma in zymogen form
Activated by proteolysis

48
Q

What produces FXa much more efficiently than the TF-FVIIa complex?

A

FVIIIa + FIX

49
Q

What complex converts prothrombin to thrombin?

A

FVa + FXa

50
Q

What does increased levels of thrombin allow?

A

Cleavage of fibrinogen to form fibrin fibres

51
Q

Name the diseases resulting from deficiency of FVIII + FIX. Who is primary effected by these diseases?

A

FVIII: Haemophilia A
FIX: Haemophilia B
X-linked so primarily effects males

52
Q

What are the 3 mediators of coagulation?

A

TFPI: Regulates initiation phase of coagulation
Protein C: Regulates FVa + FVIIIa
Antithrombin: Inhibits thrombin + FXa

53
Q

How does TFPI regulate coagulation?

A

2nd Kunitz domain of TFPI inactivates FXa

Dampens pro-coagulant response to small injuries

54
Q

How does Protein C regulate coagulation ?

A

Cleaves FVa + FVIIIa at various locations causing these cofactors to fall apart

55
Q

What is FV Leiden disease?

A

Mutation of arginine 506 residue, which would have been a site of cleavage for Protein C
Thus FVa can’t be inactivated as efficiently

56
Q

Describe activation of protein C

A

Thrombin binds to Thrombomodulin on healthy endothelial cells
TM converts thrombin into an anticoagulant enzyme which can activate Protein C (Removes activation peptide) to APC
APC + cofactor protein S ring fence CC

57
Q

What are D-Dimer tests?

A

D dimer is a fibrin degradation product
Following coagulation, increased D-dimer in circulation
Indicates amount of clotting in recent past

58
Q

What are commonly used to treat arterial and venous thrombosis?

A

Arterial: Anti-platelet agents
Venous: Anticoagulant drugs

YR2: MCD Haematology (11 decks)

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