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Y2 Haem (MCD) > Haemostasis > Flashcards

Haemostasis Flashcards

1
Q

State the 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 and 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 and thrombin

Tissue factor is also expressed on the surface of the cell that underlie blood vessels

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3
Q

State some important factors produced by endothelial cells.

A

Prostacyclin

Thrombomodulin

Von Willebrand Factor

Tissue Plasminogen Activator

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4
Q

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

A

Granulation

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5
Q

How many platelets are produced by one megakaryocyte?

A

4000

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6
Q

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

A

ADP

ATP

Serotonin

Ca2+

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7
Q

What do alpha granules in the platelets contain?

A

VWF

Factor V

Growth factors

Fibrinogen

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8
Q

State the two ways in which platelets can bind to collagen. Name the receptors involved and the conditions they occur in.

A
  • It can bind via vWF to collagen (via the GpIb receptor) in high sheer stress vessels.
  • It can bind directly to the collagen (via the GPVI and α2β1 proteins) in low sheer stress
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9
Q

What happens following the passive adhesion of platelets andengagement of receptors?

A

The receptors signal inside the cell to release ADP from the storage granules and to synthesise then release thromboxane

These bind to receptors on the surface of passing platelets and activate them

Once activated, integrin αIIbβ3 (GpIIb/IIIa) becomes available.

One fibrinogen can then bind to several platelet’s αIIbβ3, crosslinking and aggregating the platelets

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10
Q

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

A

αIIbβ3 (GpIIb/IIIa) - an integrin These bind to fibrinogen

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11
Q

Which enzyme converts phospholipids to arachidonic acid?

A

Phospholipase

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12
Q

What does COX convert arachidonic acid to?

A

Endoperoxides

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13
Q

Describe what happens to endoperoxides in platelets and in the endothelial cells.

A

Platelets – thromboxane synthetase converts endoperoxides to thromboxane (potent inducer of platelet aggregation) Endothelial Cells – prostacyclin synthetase converts endoperoxides to prostacyclin (important regulator of haemostasis)

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14
Q

What effect does aspirin have on this entire pathway? What effect does aspirin have on this entire pathway?

A

Aspirin is a COX1 inhibitor

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15
Q

State some important drug targets in platelet aggregation.

A

COX

Integrin αIIbβ3

ADP Receptor

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16
Q

State two ADP receptor antagonists.

A

Clopidogrel “clo-pid-o-grel”

Prasugrel “praz-u-grel” ggggrel not dgrell

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17
Q

State three Integrin αIIbβ3 (GlpIIb/IIIa) antagonists.

A

Abciximab

Tirofiban

Eptifibatide

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18
Q

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

A

Platelet count

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19
Q

What is a common cause of spontaneous bleeding?

What are the signs?

A

Autoimmune thrombocytopenia (autoimmune antibodies clear platelets from the circulation)

This results in:

purpura (red/purple spots under skin) “purps-ur-ah”

multiple bruises

ecchymoses (large purpura, similar to bruises but not necessarily caused by trauma) “ekky-mo-sez”

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20
Q

What is the normal range for platelet count?

A

150-400 x 109/L

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21
Q

Why do you get thrombocytopenia in leukaemia?

A

Leukaemic cells populate the bone marrow so it crowds out the megakaryocytes so the platelets aren’t produced in sufficient numbers

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22
Q

What is the bleeding time test used to observe?

A

This checks the platelet-vessel wall interaction This isn’t used any more

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23
Q

Describe the platelet aggregation test.

A

The platelets are stimulated with ADP/thromboxane/collagen to study their function This is used to diagnose platelet disease e.g. von Willebrand disease

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24
Q

Where is von Willebrand factor produced?

A

Endothelial cells and a little bit by megakaryocytes

25
Q

What factors do megakaryocytes produce?

A

Factor V

Von Willebrand Factor

26
Q

What role does TF-FVIIa complex have?

A

proteolyses coagulation factor zymogens IX and X to remove activation peptide

9 to 9a – slower but produces more thrombin

10 to 10a – faster, generates only small amount of thrombin

27
Q

State two accelerating factors. What are they activated by?

A

Factor VIII Factor V They are activated by trace amounts of thrombin

28
Q

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

A

X to Xa

II to IIa (prothrombin to thrombin)

For IXa to activate X it needs to come in close proximity with X.

They both bind to the surface of the platelet mediated by calcium ions, and factor VIIIa brings the two close together so that IXa can proteolytically cleave X to Xa

Factor Va does the same with Xa and II (thrombin)

29
Q

Which factors are affected by warfarin?

A

VII

IX

X

pro-thrombin (II)

30
Q

What is common to all of the factors affected by warfarin and what is the significance of this common feature?

A

They have a Gla domain containing glutamic acid residues The glutamic acid is recognised by an enzyme in the liver and undergoes post-translational modification in the presence of vitamin K to Gamma-carboxyglutamic acid Once this extra carboxyl group is added, calcium binds to the Gla domain, causing a structural transition to a phospholipid binding state

31
Q

How does warfarin actually inhibit the post-translational modification of these factors?

A

Warfarin inhibits vitamin K epoxide reductase which reduces vitamin K after it has been oxidised in the carboxylation of glutamic acid residues in blood coagulation enzymes.

Eventually the stores of reduced vit k run out - inhibiting the gamma-carboxylation of factors II, VII, IX and X.

This means the Gla domain cannot bind calcium and so is unable to bind to phospholipid membranes.

32
Q

Which factors are inhibited by anti-thrombin?

A

IIa (thrombin)

IXa

Xa

XIa

Theses are all serine proteases, but are not all the serine proteases.

33
Q

How does heparin have its effect?

A

Heparin potentiates the action of anti-thrombin

34
Q

In what situation is heparin used?

A

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

35
Q

Describe how anti-thrombin inhibits the clotting factors.

A

Anti-thrombin has a reactive loop that irreversibly inhibits the active site on the serine protease clotting factors So anti-thrombin acts as a scavenger in stopping inappropriate action of serine protease clotting factors

36
Q

By what mechanism does heparin have its effect and why is the chain length important?

A

Heparin is a linear negatively charged polysaccharide

Once bound to anti-thrombin it changes the position of the reactive loop and makes the inhibition occur faster

When inhibiting factor Xa, a relatively SHORT chain of heparin is sufficient (low molecular weight heparin)

When inhibiting thrombin, you require a LARGE chain (standard/unfractionated heparin)

NOTE: standard/unfractionated heparin inhibits either Factor Xa or thrombin

37
Q

State three laboratory tests for blood coagulation.

A

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

38
Q

What do each of these laboratory tests represent?

A
  • APTT – detects abnormalities in the INTRINSIC and COMMON pathways (coagulation is triggered by activation of factor 12)
  • PT – detects abnormalities in the EXTRINSIC and COMMON pathways (tissue factor is added to trigger the extrinsic pathway)
  • TCT – shows abnormality in the fibrinogen -> fibrin conversion (not important any more)
39
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

40
Q

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

A

Plasminogen Tissue Plasminogen Activator (tPA) Plasminogen is a plasma protein tPA is produced by endothelial cells

41
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) This is elevated in DIC

42
Q

What factors are used in therapeutic thrombolysis of myocardial infarction?

A

tPA and bacterial activator streptokinase

43
Q

Describe the function of the Protein C anticoagulant pathway.

A

Thrombin also has a role in anticoagulation

It binds to thrombomodulin on the surface of endothelial cells at the border of the vessel injury

This thrombin-thrombomodulin complexe activates protein C to activated protein C (APC)

APC along with its co-factor protein S, inactivates FVa -> FVai and FVIIIa -> FVIIIai

44
Q

What is a platelets average lifespan in the circulation?

A

10 days

45
Q

What is a platelets average size?

A

Small (2-4µm)

46
Q

What levels of platlets start to result in spontaneous bleeding?

A

<40x10^9

47
Q

How is extrinsic pathway of coagulation initiated?

A

Vessel damage exposes tissue factor on the surface of sub-endothelail cells.

FVII binds to the phospholipid membrane of the exposed cells via Gla domain and all of its domains interact with tissue factor to activate FVII to FVIIa

48
Q

List examples of locations where tissue factor levels are high and give a reason for this.

A

lungs, brain, heart, testis, uterus, and placenta bleeding into these sites can have disastrous consequences, so they need further haemostatic protection

49
Q

What is the next step in the coagulation cascade after activaion of factor IX and X?

A

Factor Xa cleaves a small amount of pro-thrombin to thrombin

50
Q

What is haemophilia A and B caused by?

A

A = deficiency in FVIII B = deficiency in FIX

51
Q

What is the final step in the coagulation cascade?

A

Thrombin cleaves fibrinogen to fibrin

FXIIIa crosslinks fibrin

52
Q

Draw the coagulation cascade with inhibitory mechanisms

A
53
Q

What is the thrombin activation loop?

A
  • Thrombin cleaves FVIII to FVIIIa
  • FVIIIa is a co factor for FIXa
  • FVIIIA-FIXa complex cleaves FX -> FXa very efficiently
  • Thrombin also activates FV to FVa which complexes with FXa to cleave pro-thrombin up to 300,000x more efficiently
54
Q

How does TFPI work?

A

After TF-VIIa complex actiavtes FX -> FXa, TFPI binds to FXa via its K2 domain and then ‘re-docks’ onto TF-VIIa complex. This effectively prevents them from participating in coagulation.

55
Q

How does thrombolysis work?

A

tissue plasminogen activator (TPA) binds to fibrin which activates TPA activated TPA activates plasmin to plasminogen plasminogen then degrades the fibrin clot

56
Q

List proteins containing a Gla domain

A

Prothrombin

FVII

FIX

FX

Protein C

Protein S

57
Q

What does FXIII do?

A

FXIII is activated by thrombin to FXIIIa

FXIIIa helps to convert fibrin to crosslinked fibrin

58
Q

What extra steps does the intrinsic pathway add to coagulaiton?

A

FXII -> FXIIa

FXIIa cleaves FXI -> FXIa

FXIa cleaves FIX -> FIXa similarily to the TF-FVIIa complex

59
Q

What causes VWF to unravvel?

A

The sheer stress in the vessel

Y2 Haem (MCD) (11 decks)

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