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MCD - Haematology > Haemostasis > Flashcards

Haemostasis Flashcards

1
Q

What are the steps involved in normal haemostasis?

A

Injury

  1. Vessel constriction
  2. Formation of unstable platelet plug
    a) Platelet adhesion
    b) Platelet aggregation
  3. Stabilisation of plug with fibrin
    a) Blood coagulation
  4. Dissolution of clot and vessel repair
    a) Fibrinolysis
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2
Q

Why does the unstable platelet plug need to be stabilised?

A

Alone, unstable platelet plug quickly breaks down

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3
Q

What are the functions of endothelial cells in haemostasis?

A

Maintain barrier between blood and procoagulant subendothelial structures

Synthesise prostacyclin, thrombomodulin, vWF, plasminogen activators

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4
Q

How does a platelet plug form?

A
  1. Endothelial monolayer is damaged
  2. Subendothelial structures exposed
  3. Platelets bind to collagen in 2 ways:
    a) vWF binds to collagen at site of damage and unfolds so that it can capture platelet via GPIbRs
    b) Platelets bind directly to collagen via GPIaRs
  4. Receptors signal inside cell to release ADP from storage granules and to synthesise and release thromboxane
  5. ADP and thromboxane bind to Rs on platelet surface + activate platelets
  6. Platelets release storage granules
  7. Once platelet is activated, GPIIb/IIIaRs become available
  8. Rs can bind fibrinogen - helps platelets clump together = aggregation
  9. Platelets aggregate and form haemostatic plug
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5
Q

How are platelets activated?

A

By ADP and thromboxane released from platelet
OR
by thrombin (generated in coagulation)

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6
Q

What does platelet activation lead to?

A

Prostacyclin metabolism

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7
Q

Explain prostacyclin metabolism

A

Platelet activation
Occurs in endothelial cells and platelets
1. Phospholipase mobilises the membrane phospholipid and converts it to arachidonic acid
2. Arachidonic acid –> endoperoxides (PGG2, PGH2) by COX
3. Endoperoxides to:
a) prostacyclin (PGI2) by prostacyclin synthetase in endothelial cells
b) thromboxane A2 by thromboxane synthetase in platelets

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8
Q

How does prostacyclin affect platelet function?

A

Potent inhibitor of platelet function

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9
Q

How do endoperoxides and thromboxane affect haemostasis?

A

Potent inducers of platelet aggregation

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10
Q

What lab tests are used to investigate coagulation?

A

Activated partial thromboplastin time (APTT)
Prothrombin time (PT)
Thrombin clotting time (TCT)

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11
Q

How can coagulation test results contribute to a clinical diagnosis?

A

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

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12
Q

How does warfarin work?

A

Normal coagulation:
Nascent clotting factors in liver have glutamic acid cluster
Recognised by enzyme and converted in post-translational modification in presence of vitamin K to gamma-carboxyglutamic acid
Once extra carboxyl group added, calcium facilitates binding of gamma-carboxyglutamic acid to activated platelet membrane phospolipid

Warfarin inhibits vitamin K epoxide reductase - enzyme for gamma carboxylation
Inhibits localisation of CFs on platelet surface
Tf reduces thrombin production

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13
Q

How does heparin work?

A

Heparin potentiates action of plasma inhibitor antithrombin

Makes antithrombin work more efficiently at directly inhibiting FXa and thrombin

Heparin binds to antithrombin
Changes position of reactive loop

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14
Q

What are the indications for warfarin?

A

Long term anticoagulation following venous thrombosis

Treatment of AF

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15
Q

What are the indications for heparin?

A

Immediate anticoagulation in venous thrombosis and pulmonary embolism

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16
Q

How do you measure the effects of warfarin and heparin in the lab?

A

APTT used to monitor heparin therapy in thrombosis

PT used to monitor warfarin treatment in thrombosis

17
Q

What are the different types of antiplatelet agents?

A
  1. ADP receptor antagonists - inhibit platelet activation
  2. COX-1 antagonist - inhibit PGI2 metabolism
  3. (GPIIb/IIIa antagonists)
18
Q

What are the indications for antiplatelet therapy?

A

CVD

During interventions, e.g. angioplasty, stents

19
Q

Why is heparin used over warfarin for immediate anticoagulation?

A

Warfarin takes more time to build up in the circulation and become effective

20
Q

How does antithrombin work?

A

Circulates in high conc in blood
Directly inhibits FXa and thrombin
Reactive loop irreversibly blocks active site of coagulation factors
Antithrombin acts as a scavenger that stops inappropriate CF action

21
Q

How does the action of heparin differ when it’s inhibiting FXa vs. thrombin?

A

Heparin binds to thrombin
Changes position of reactive loop
Accelerates inhibition

FXa: SHORT section of heparin chain is sufficient to make antithrombin block FXa more quickly

Thrombin: LARGE heparin chain needed

22
Q

How do the 2 forms of heparin differ?

A

Low molecular weight heparin = favours FXa inhibition

Standard/unfractionated heparin = inhibits FXa or thrombin

23
Q

What is APTT used for?

A

Activated partial thromboplastin time
Detects abnormalities in intrinsic and common pathways
Initiates coagulation through FXII activation
Measures clotting time

Used to monitor heparin therapy for thrombosis
Used with PT for screening for causes of bleeding disorders

24
Q

What is PT used for?

A

TF added to trigger extrinsic pathway
Detects abnormalities in extrinsic and common pathways

Used to monitor warfarin treatment in thrombosis
Used with APTT for screening for causes of bleeding disorders

25
Q

What is TCT used for?

A

Shows abnormalities in fibrinogen –> fibrin conversion

Not used clinically anymore

26
Q

Explain fibrinolysis

A

Plasma protein = plasminogen
Endothelial cells produce tissue plasminogen activator
Normally no interaction between the 2
1. Fibrin clot forms
2. 2 proteins assemble on clot surface
3. Plasminogen converted to PLASMIN by tPA
4. Plasmin breaks down clot
5. Leaves fibrin degradation products, FDP

27
Q

What does elevated fibrin degradation products suggest?

A

DIC

28
Q

What are tPA and streptokinase used for?

A

Therapeutical thrombolysis for MI

Clot busters

29
Q

Why doesn’t the blood clot completely when the cascade is activated?

A

Antithrombin - plasma protein directly inhibits CFs

Protein C anticoagulant pathway:
Thrombin binds to thrombomodulin on endothelial cell surface
Thrombin activates Protein C
Protein C with Protein S inactivates FVa and FVIIIa
Reduces production of thrombin on platelet surface

30
Q

Where are most coagulation proteins synthesised?

A

Liver

31
Q

Where is vWF synthesised?

A

Endothelial cells

Platelets

32
Q

What are the 2 main routes of coagulation?

A

Extrinsic

Intrinsic

33
Q

How do platelets accelerate blood coagulation?

A

For IXa to activate X–>Xa, must get in close proximity to FX
Both bind to platelet surface mediated by Ca2+
FVIIIa brings FIXa and FX close together so that FIXa can proteolytically activate FX
FXa activates prothrombin (FII) to thrombin (FIIa) on platelet surface (catalysed by FVa)
FVa helps FXa recognise FII and bind to it

All these reactions on platelet surface are possible bc platelet has been activated and its surface has changed allowing CFs to bind

MCD - Haematology (11 decks)

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