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Haematology > 7. Haemostasis > Flashcards

7. Haemostasis Flashcards

1
Q

Describe the formation of a haemostatic plug?

A

• Vessel constriction - first-response to vessel injury
• Formation of the unstable platelet plug
- platelet adhesion
- platelet aggregation
• Stabilisation of the plug with fibrin
- blood coagulation system
• If not completely stabilised, some platelet mass embolises
• Dissolution of the clot and vessel repair - fibrinolysis

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2
Q

Which 2 important molecules involved in blood vessel damage repair, are blocked by endothelial cells?

A
  • Collagen - important in the platelet response

* Tissue factor - triggers coagulation

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3
Q

What are the functions of the endothelium with reference to haemostasis?

A
  • Maintain barrier between blood and procoagulant subendothelial structures
  • Synthesis of PGI2, thrombomodulin, vWF, plasminogen activators
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4
Q

How does an unstable platelet plug form?

A
  • Collagen exposed in injury
  • vWF binds to collagen
  • Glycoprotein-1-b receptors on platelets bind to vWF - vWF forms a bridge between platelets and collagen
  • Glycoprotein-1-a receptors on platelets bind directly to exposed collagen
  • Binding of platelets partially activates the platelet => release of ADP and thromboxane
  • Further activation of platelets (positive feedback)
  • Glycoprotein IIb/IIIa on platelets are activated - bind to fibrinogen to form a platelet aggregate
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5
Q

How is an unstable clot stabilised?

A
  • Fibrinogen is converted to fibrin

* Thrombin is generated and also activates platelets and the IIb/IIIa complex

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6
Q

How is thromboxane generated within the platelet?

A

1) Phospholipases activated during platelet activation
2) Act on membrane phospholipids to generate arachidonic acid
3) Cyclo-oxygenase converts arachidonic acid to endoperoxides
4) Thromboxane A2 generated (potent activator of platelets)

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7
Q

How does aspirin work?

A

Targets COX 1 irreversibly - prevents arachidonic acid => endoperoxides

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8
Q

What are ADP receptor antagonists?

A
  • Drug class of antiplatelet agents
  • Prevent platelet activation
  • Dampen down platelet response in acute coronary syndrome or those at risk of a clot
  • e.g. clopidogrel, prasugrel
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9
Q

What are Gp IIb/IIIa inhibitors?

A
  • Drug class of antiplatelet agents
  • Prevent platelet aggregation and thrombus formation
  • Used during interventions - angioplasty
  • e.g. abciximab, tirofiban, eptifibatide
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10
Q

What is the normal range of platelets in circulation?

A

150-400 x 10^(9)/l

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11
Q

How is bleeding affected when the platelet count drops below 100 x 10^(9)/l

A
  • No spontaneous bleeding

* Bleeding occurs with trauma

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12
Q

What do we see in the limbs in autoimmune thrombocytopenia and why?

A
  • Extensive bruising of the limbs

* Autoantibodies against the GpIIb/IIIa complex

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13
Q

What are the 2 ways of testing the haemostatic function of platelets?

A

• Bleeding time
- done when platelet count is normal but bleeding taking place
- tests platelet vessel wall interaction
- can be used in renal disease
• Platelet aggregation
- measures the clumping of the platelets
- used in inherited platelet abnormalities and vW disease

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14
Q

Where are most coagulation proteins made?

A

Liver

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15
Q

Where is von Willebrand factor made?

A

Endothelial cells

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16
Q

What is the potent initiator of the clotting cascade?

A

Tissue factor

17
Q

Outline the extrinsic pathway of the clotting cascade to the formation of factor 10a

A
  • TF binds to factor 7
  • Factor 7 => 7a
  • Factor 7a converts factor 10 => 10a
18
Q

Outline the clotting cascade from factor 10a

A
  • Factor 10a converts prothrombin (II) => thrombin
  • Factor 5a can help this process
  • Thrombin converts fibrinogen (soluble) => fibrin (2 cleavages) forming a fibrin clot (insoluble)
  • Thrombin also converts factor 13 => 13a
  • Fibrin clot can be covalently cross-linked by factor 13a to stabilise it - can’t be broken down by shear forces
19
Q

Outline the intrinsic pathway of the clotting cascade to the formation of factor 10a

A

Damaged endothelium
• Factor 12 => 12a
• Factor 11 => 11a

(• TF binds to factor 7, => 7a)
• Factor 11a and 7a convert factor 9 => 9a
• Factor 9a converts factor 10 => 10a (using 8a and Pl)

20
Q

What activates factor 8 and 5?

A

Traces of thrombin

21
Q

How does factor 8a work?

A
  • Binds to both factor 9a and 10 on the surface of the platelet
  • Pulls them together
  • Activation is a proteolytic process
22
Q

How does factor 5a affect the speed of thrombin generation?

A

10,000 fold acceleration

23
Q

How is vitamin K significant in coagulation?

A

In the liver…
• Glutamic acid (residues in clotting factor molecules) => γ-carboxyglutamic acid
• This binds to the platelet membrane
• Vitamin K mediates this conversion
• Coagulation factors can assemble on the platelet surface

24
Q

How does warfarin work and what is it used for?

A
  • Anticoagulant
  • Inhibits vitamin-K epoxide reductase
  • Prevents platelet binding of the clotting factors to the phospholipid membrane
  • Complexes not formed - thrombin production inhibited

• Therapeutic agent for long-term anticoagulation

  • following venous thrombosis (6 months)
  • treatment of AF (lifelong)
25
Q

How does heparin work and what is it used for?

A
  • Anticoagulant
  • Accelerates the action of a natural plasma inhibitor - antithrombin
  • Antithrombin inhibits the coagulation proteases: thrombin, 10a, 9a, 11a
  • Forms irreversible complexes

• Immediate anticoagulation in venous thrombosis and pulmonary embolism

26
Q

What are the 3 lab tests for blood coagulation and what do they detect?

A

• Activated partial thromboplastin time (APTT)
- initiates coagulation through factor 12
- detects abnormalities in intrinsic and common pathways
• Prothrombin time (PT)
- initiates coagulation through TF
- detects abnormalities in extrinsic and common pathways
• Thrombin clotting time (TCT)
- add thrombin
- detects abnormalities in the fibrinogen => fibrin conversion

27
Q

What are the 3 lab tests for blood coagulation used for?

A
  • Activated partial thromboplastin time (APTT) and prothrombin time (PT) - used together for screening for causes of bleeding disorders
  • APTT - monitoring heparin therapy in thrombosis
  • PT - monitoring warfarin treatment in thrombosis
28
Q

What does fibrinolysis involve the activation of?

A

• Activation of plasminogen by tissue plasminogen activator (tPA)
• Both plasma proteins:
- plasminogen = zymogen
- tPA = proteinase
• When a clot forms, they both assemble on the surface to form => plasmin

29
Q

When is tissue plasminogen activator used therapeutically?

A
  • Post-myocardial treatment

* Break down clots

30
Q

How can you detect the fibrin fragments from fibrinolysis?

A

Assay

31
Q

What is disseminated intravascular coagulation (DIC) and how does it affect fibrin degradation products?

A
  • Small blood clots develop throughout the blood stream
  • Depletes platelets and clotting factors
  • Causes excessive bleeding
  • Elevation of fibrin degradation products
32
Q

What is plasmin?

A
  • Powerful proteolytic enzyme

* Breaks down the fibrin clot

33
Q

What are the 2 mechanisms that prevent the clotting cascade from clotting all of the blood in the body?

A
  • Direct inhibition

* Indirect inhibition

34
Q

How does direct inhibition work as a coagulation inhibitory mechanism?

A
  • Direct inhibition of the activated coagulation factors
  • Inhibitor - antithrombin - circulates in high concentrations
  • Broad scale inhibitor of most of the coagulation proteinases e.g. 9a, 10a, thrombin
35
Q

How does indirect inhibition work as a coagulation inhibitory mechanism?

A
  • Slows down the amount of thrombin (specifically) generated
  • Involves the activation of protein C in the protein C anticoagulant pathway
  • Activation: thrombin => thrombomodulin => protein C => protein S
  • Protein S inhibits 8a and 5a
36
Q

How are the coagulation inhibitory mechanisms significant as risk factors for thrombosis?

A

Deficiencies of antithrombin, protein C and protein S are important risk factors

Haematology (11 decks)

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