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Haem (not Zara) > Haemostasis > Flashcards

Haemostasis Flashcards

1
Q

What does the balance of haemostasis depend on?

A

The balance between coagulation factors which cause a clot and fibrinolytic factors which break the clot down

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2
Q

Why is the balance of haemostasis important?

A
  • Coagulation
  • Thrombosis
  • Fibrinolysis
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3
Q

What are the three processes that make up haemostasis

A

1) Vasoconstriction
2) Primary Haemostasis
3) Secondary Haemostasis

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4
Q

Why must we understand haemostatic mechanisms?

A
  • Diagnose bleeding disorders
  • Identify risk factors for thrombosis
  • Treat THROMBOTIC DISORDERS
  • Monitor drugs used to treat bleeding and thrombotic disorders
  • Control bleeding
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5
Q

Describe platelets (shape, derivation, formation, lifespan)

A

Shape - Discoid, non nucleated, granule containing cells
Derived from myeloid stem cells
Formed in the bone marrow by the fragmentation of megakaryocyte cytoplasm
Lifespan- 10 days

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6
Q

Describe platelets (shape, derivation, formation, lifespan)

A

Shape - Discoid, non nucleated, granule containing cells
Derived from myeloid stem cells
Formed in the bone marrow by the fragmentation of megakaryocyte cytoplasm
Lifespan- 10 days

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7
Q

Describe platelet adhesion

A

Platelets bind to collagen on damage endothelium either directly or indirectly:
DIRECTLY - Platelet binds to GPIa receptor
INDIRECTLY - Platelet binds to VWF which binds to GPIb receptor

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8
Q

What effect does adhesion have on platelets?

A
  • Activates them
  • Changes their shape from a disc to a more rounded form with spicules.
  • Releases contents of storage granules
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9
Q

What are the identifiable platelet storage granules?

A

Alpha granules and dense granules

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10
Q

Describe the platelet release reaction

A

Platelet membrane invaginated to form a surface-connected cannalicular system through which the contents of platelet granules are released

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11
Q

What is released from platelets in the platelet release reaction?

A

ADP, fibrinogen and VWF

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12
Q

What is thromboaxane A2?

A

Prostoglandin and vasoconstrictor made from arachidonic acid derived from the CSM.

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13
Q

Describe the action of arachidonic acid

A
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14
Q

How does ADP and thromboaxane A2 cause platelet activation and aggregation

A
  • ADP binds to P2Y12
  • Thromboaxane A2 binds to Thromboaxane A2 receptor
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15
Q

How is the unstable platelet plug formed?

A

1) Platelet activation causes a conformational change in the GPIIb/IIIa receptor to provide binding sites for fibrinogen.
2) Fibrinogen binding to GPIIb/IIIa signals further activation of the platelets.
3) Fibrinogen has a key role in linking platelets together to form the platelet plug.

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16
Q

What is Prostacyclin (PGI2)

A
  • Released from endothelial cells
  • Vasodilator
  • Suppresses platelet activation and thus prevents inappropriate platelet aggregation
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17
Q

How does aspirin work as an anti platelet drug?

A

Inhibits the production of Thromboaxane A2 by irreversibly blocking the action of cyclo-oxygenase (COX), resulting in a reduction in platelet aggregation
- Lasts for 7 days as prostacyclin cannot be produced by platelets as they have no nucleus

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18
Q

How does clopidogrel work as an anti platelet drug?

A

Clopidogrel works by irreversibly blocking the ADP receptor (P2Y12) on the platelet cell membrane.Therefore the effect of clopidogrel ingestion also lasts for 7 days until new platelets have been produced.

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19
Q

What is Von Willebrand factor

A
  • VWF is a glycoprotein that is synthesised by endothelial cells and megakaryocytes and circulates in plasma as multimers of different sizes.
  • VWF is a specific carrier for factor VIII (FVIII).
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20
Q

Where are most clotting factors synthesised?

A

Liver

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21
Q

Where is Factor VIII and VWF synthesised

A

Endothelial cells

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22
Q

How do Factors 2, 7, 9 and 10 function?

A

Vitamin K carboxylates their glutamic acid residues

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23
Q

What is Factor 2

A

prothrombin

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24
Q

Describe the initiation phase of coagulation

A

1) Tissue factor binds to Factor 7a
2) Factor 9 to 9a and 10 to 10a activated
3) Factor 2 activated to generate a small initial amount of thrombin (2a)

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25
Q

Describe the amplification phase of coagulation

A

Thrombin mediates the activation of cofactors 5 and 8, zymogen factor 11 and platelets

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26
Q

Describe the propagation phase of coagulation

A

1) Factor 11 converts more factor 9 to 9a which, with factor 8a, amplifies the conversion of factor 10 to 10a.
2) This results in a rapid burst in thrombin generation
3) Thrombin cleaves fibrinogen to form fibrin clot

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27
Q

Describe the natural anti coagulant pathway

A

1) Thrombin binds to thrombomodulin on the endothelial cell surface leading to activation of protein C to activated protein C (APC).
2) APC inactivates factors 5a and 8a in the presence of a co-factor protein S.
3) Thrombin and factor 10a are inactivated by the circulating inhibitor antithrombin.
4) The action of antithrombin is made more powerful by heparin: this occurs physiologically by the binding of antithrombin to endothelial cell-associated heparins.

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28
Q

What are the main anticoagulant drugs

A

Heparin, warfarin and direct oral anticoagulants (DOACs)

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29
Q

What is heparin

A

Heparin is a mixture of glycosaminylglycan chains

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30
Q

How does heparin work?

A
  • Heparin works indirectly by potentiating the action of antithrombin leading to the inactivation of factors 10a and 2a (thrombin).
  • Long chains of heparin are used so they are able to wrap around both the antithrombin and thrombin
31
Q

How is heparin administered?

A

Heparin is administered intravenously or by subcutaneous injection

32
Q

What is warfarin

A

vitamin K antagonist

33
Q

How does warfarin work?

A

vitamin K antagonist that works by interfering with protein carboxylation. It therefore reduces synthesis of functional factors 2, 7, 9 and 10 by the liver.

34
Q

How is warfarin administered

A

Oral tablet monitored with regular blood testing that takes several days to take effect

35
Q

Why does warfarin take several days to take effect?

A

Because it reduces synthesis of coagulation factors rather than inhibiting existing factor molecules

36
Q

How do DOACs work?

A

directly inhibit either thrombin or factor 10a (i.e. without the involvement of antithrombin)

37
Q

How are DOACs administered

A

Orally

38
Q

Describe the process of fibrinolysis

A

1) t-PA and plasminogen bind to lysine residues on fibrin
2) This causes plasminogen to be activated and converted to plasmin
3)3) Plasmin breaks the fibrin clot down into fibrin degradation products(FDP

39
Q

How is plasmin inhibited?

A
  • Antiplasmin which circulates in blood
  • Aplha 2 macroglobulin in plasma
40
Q

Which conditions does thrombolytic therapy help?

A
  • Ischaemic strome
  • Life threatening pulmonary emboli
41
Q

Name a antifibrinolytic drug

A

Tranexamic acid

42
Q

What is tranexamic acid

A

A synthetic derivative of the amino acid lysine

43
Q

How does tranexamic acid work?

A

Acts as a competitive inhibitor by binding to the lysine binding site on plasminogen preventing from binding to the lysine residues on fibrin and activating plasmin so fibrinolysis stops.

44
Q

What does intrinsic mean?

A

A system in which all components are in the plasma (factors 12, 11, 9, 10 cofactors 8 and 5)

45
Q

What does extrinsic mean?

A

A system that comprises of TF and factors 7,10, cofactor 5

46
Q

What does prothrombin time measure?

A

Measures the integrity of the extrinsic pathway

47
Q

How is PT measured?

A

​1) Blood is collected into a bottle containing sodium citrate preventing the blood from clotting in the bottle
2) The sample is spun to produce platelet-poor plasma
3) A source of TF and phospholipid is added to the citrated plasma sample, together with calcium to start the reaction; 4) the length of time taken for the mixture to clot is recorded.

48
Q

Why would the PT be prolonged?

A

Reduction in the activity of factors 7, 10, 5 , 2 or fibrinogen

49
Q

What is the INR

A

The international normalised ratio (INR). It is a correction for the different thromboplastin reagents used by different laboratories and means that all laboratories would be expected to obtain the same INR result for a given sample irrespective of the source of thromboplastin.

50
Q

What does activated partial thromboplastin time measure?

A

Measures the integrity of the intrinsic pathway

51
Q

How is APTT measured?

A
  • Performed by the contact activation of factor XII by a surface such as glass, silica or kaolin.
  • Contact activator, together with phospholipid, is added to the citrated plasmasample followed by calcium;
  • the time taken for this mixture to clot is measured
52
Q

When is APTT prolonged?

A

When there is a reduction in a single or multiple clotting factors

53
Q

When is an isolated APTT seen?

A

In patients with haemophilia A (factor VIII deficiency), haemophilia B (factor IX deficiency), factor XI deficiency. and factor XII deficiency

54
Q

What is bleeding caused by?

A

Loss of haemostatic balance caused by:
- Reduction in platelet number or function
- Reduction in coagulation factor(s)
- Increased fibrinolysis

55
Q

What is reduction in platelet number (THROMBOCYTOPENIA) caused by?

A
  • Failure of platelet production caused by drugs, viruses, bone marrow infiltration, megaloblastic anaemia resulting from B12 or folate deficiency or hereditary thrombocytopenia
  • Shortened platelet survival caused by immune thrombocytopenia, disseminated intravascular coagulation (DIC, see below)
  • Increased splenic pooling
56
Q

What is reduction in platelet function caused by?

A
  • Antiplatelet drugs such as aspirin
  • Inherited causes
57
Q

What are the congenital causes of reduced coagulation factors?

A
  • Von Willebrand disease (VWD)
  • Haemophilia A
  • Haemophilia B
    -Deficiencies of one of the other clotting factors
58
Q

What is VWD?

A
  • Caused by reductions in VWF level or function
  • Most common inherited bleeding disorder
  • Autosomally inherited
59
Q

What is Haemophilia A?

A
  • Factor VIII deficiency
  • X linked
60
Q

What is Haemophilia B?

A
  • Factor IX deficiency
  • X linked
61
Q

Describe the conditions where patients have deficiencies of other clotting factors

A
  • Autosomal recessive
  • More common in areas with lots of consanguinity (incest)
62
Q

How are congenital bleeding disorders treated?

A

Replacement of the missing clotting factor using recombinant factor concentrates

63
Q

What are the acquired causes of reduced coagulation factors?

A
  • Liver disease
  • Anticoagulant drugs
  • Disseminated intravascular coagulation (DIC)
64
Q

What is DIC?

A

Process in which there is generalised and uncontrolled activation of coagulation followed by marked activation of the fibrinolytic system.

65
Q

What happens when the fibrinolytic system is activated in DIC?

A

This activation results from the expression of TF within the circulation. It causes:
- Generationand dissemination of large amounts of thrombin
- The activation and consumption of platelets (leading to thrombocytopenia)
- The widespread formation of thrombi in the small blood vessels (microcirculation)
- The clotting factors and fibrinogen in the plasma become depleted
- There are high levels of fibrin degradation products (FDPs)

66
Q

How can DIC be identified on a blood film?

A

Presence of red blood cell fragments (schistocytes)
This is caused by thrombi in the blood vessels causing shearing of the circulating RBCs

67
Q

What are the causes of DIC?

A
  • Bacterial sepsis
  • Advanced cancer
  • Obstetric emergencies
68
Q

How is DIC treated?

A
  • Missing clotting factors and platelets are replaced to control bleeding
  • However underlying cause of DIC must be addressed to cure.
69
Q

What is thrombosis?

A

Formation of a blood clot within an intact vessel

70
Q

What is Virchow’s Triad?

A

The three contributory factors for thrombosis:
1) Blood (venous)
2) Vessel wall (arterial)
3) Blood flow (both)

71
Q

What increases the risk of venous thrombosis?

A
  • Reduced levels of anticoagulant proteins (usually genetic eg. inherited antithrombin deficiency)
  • Reduced fibrinolytic activity (eg. inhibition of plasminogen activation)
  • Increased levels of clotting factors or platelets
  • Hyperviscosity (eg. due to polycythaemia)
72
Q

What are some examples of levels of clotting factors or platelets being increased?

A
  • Levels of Levels of factor VIII increase during pregnancy
  • Factor V Leiden which makes factor V more resistant to inactivation by protein C.
  • Platelets are increased in number in some myeloproliferative disorders where the bone marrow output is increased e.g. essential thrombocytosis.
73
Q

What is the role of calcium ions

A

Helps activated clotting factors bind to phospholipid surfaces of platelets

Haem (not Zara) (4 decks)

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