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Lily PoM Haematology > Haemostasis > Flashcards

Haemostasis Flashcards

1
Q

What two factors must always be balanced in blood?

A

Fibrinolytic factors
Anticoagulant proteins

Coagulation factors
Platelets

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2
Q

Why is the haemostatic balance important?

A

Coagulation after an injury

Limit the extent of the bleeding so as not to cause a thrombosis

Start the process that leads to the breakdown of the clot

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3
Q

What are the three processes involved in haemostasis? (Halting of blood)

A

Vasoconstriction

Primary haemostasis (platelet plug)

Secondary haemostasis (fibrin clot)

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4
Q

What are some features of platelets?

A

Discoid
Non nucleated
Granule containing
Derived from myeloid stem cells

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5
Q

What is the lifespan of a platelet?

A

10 days

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6
Q

Where are platelets formed?

A

In the bone marrow by the fragmentation of megakaryote cytoplasm

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7
Q

What are the two ways platelets stick to damaged endothelium?

A

Directly to collagen via the platelet GPIa receptor (glycoprotein Ia)

Via Von willebrand factor (WFE) which binds to the platelet GPIb receptor

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8
Q

What happens when a platelet binds to damaged endothelium?

A

Activates them and changes their shape from a disc to rounded shape with spicules to encourage platelet-platelet interaction
The release of the contents of their storage granules

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9
Q

What are the two main types of granules in platelets?

A

a-granules

Dense granules

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10
Q

Through what are the platelet granules released?

A

Surface-connected cannalicular system

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11
Q

What are some of the important contents of the granules?

A

ADP
Von willebrand factor
Fibrinogen

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12
Q

Platelets are stimulated to produce the prostaglandin thromboxane A2, where from?

A

Arachidonic acid that is derived from the cell membrane

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13
Q

What is the role of thromboxane A2?

A

Involved in platelet aggregation

Vasoconstrictor

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14
Q

What does the release of ADP and generation of thromboxane A2 create a positive feedback loop of? And how?

A

Platelet recruitment activation and aggregation

Binding respectively to P2Y12 and thromboxane A2 receptor

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15
Q

Why does platelet activation cause a conformational change in the GPIIb/IIIa receptor?

A

To provide binding sites for fibrinogen

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16
Q

Fibrinogen has a key role in linking platelets together to form the platelet plug. What counterbalances this effect?

A

The active flow of blood

The release of prostacyclin from endothelial cells.

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17
Q

Prostacyclin is released form endothelial cells, what does it do?

A

It is a powerful vasodilator
Surpresses platelet activation

This prevents inappropriate platelet aggregation

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18
Q

Aspirin is an anti platelet drug, how does it work?

A

Inhibits the production of thromboxane A2 by irreversibly blocking the action of COX resulting in a reduction in platelet aggregation.

A single done of aspirin lasts around 7 days as this is the time taken for most of the platelets to have been replaced

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19
Q

Clopidegrel is an anti platelet drunk. How does it work?

A

Irreversibly blocks the ADP receptor (P2Y12) on the platelet cell membrane

Lasts 7 days as new platelets must be produced

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20
Q

Where is Von willebrand factor synthesised?

A

Endothelial cells and megakaryocytes

Circulates in plasma as multimedia of different sizers

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21
Q

What does VWF do?

A

Von willebrand factor mediates the adhesion of platelets to sites of injury and promotes platelet-platelet aggregation

It is a specific carrier for factor VIII (FVIII)

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22
Q

What is the role of thrombin in secondary haemostasis?

A

Cleaves fibrinogen to generate a fibrin clot that stabilises the platelet plug

Useful in injuries to larger vessels

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23
Q

Where are most clotting factors synthesised?

A

The liver

24
Q

Two clotting factors are not made in the liver. What are these and where are they made?

A

Factor VIII
VWF

Endothelial cells

25
Q

What are factors II (prothrombin), VII, IX and X dependant on to work?

A

Vitamin k

For decarboxylation if their glutamic acid residues

26
Q

How is each step of blood coagulation activated sequentially?

A

The conversion of an inactive zymogen (proenzyme) into an active clotting factor

Done by the splitting of one or more peptide binds to expose the active site.

27
Q

Which two factors are co factors?

A

V and VIII

28
Q

Where do clotting factors work?

A

Phospholipid surface of platelets

Accelerated reactions

29
Q

What role do calcium ions play in coagulation?

A

In the binding of activated clotting factors to the phospholipid surfaces of platelets

30
Q

What is the trigger to initiate coagulation?

A

Exposure of the tissue factor (TF) on the surface of endothelial cells and on leukocytes and on most extravascular cells in an area of tissue damage

Sites that are not usually exposed to blood

31
Q

What does the binding of TF of VIIa lead to?

A

Activation of factor IX to IXa

Activation of factor X to Xa

32
Q

What does the activation of IX to IXa, and X to Xa lead to?

A

The activation of prothrombin (factor II) to generate a small initial amount of thrombin (IIa)

33
Q

What is the initiation phase of coagulation?

A

When TF + VIIa —> IX + X to IXa and Xa —> prothrombin to a small initial amount of thrombin

34
Q

The small amount of thrombin leads to what? (Amplification phase)

A

The activation of the co factors V and VIII, the zymogen factor XI and platelets

35
Q

What happens in the propagation phase?

A

Factor XI converts more factor IX to IXa, which in concert with factor VIIIa, amplifies the conversion of factor X to Xa

Causes a rapid burst in thrombin generation

This cleaves the circulation fibrinogen (soluble) to form an insoluble fibrin clot

36
Q

What is the action of anticoagulant pathways important?

A

So coagulation is confined to the size of Injury and doesn’t occur spontaneously

37
Q

What are the most important anticoagulant pathways?

A

Protein C
Protein S
Antithrombin

38
Q

What does the binding of thrombin to thrombomodulin do?

A

Activates protein C to APC

APC inactivates Factors Va and VIIIa in the presence of co factor protein S

39
Q

What does antithrombin do?

A

Inactivates factor Xa and Thrombin (IIa)

The action of antithrombin is potentiated by heparin: this occurs physiologically by the binding of antithrombin to endothelial cells associated heparins

40
Q

What are the three main anticoagulant drugs?

A

Heparin
Warfarin
Direct oral anticoagulants (DOACs)

41
Q

What is heparin?

A

An mixture of glycosaminylglycan chains extracted from porcine mucosa

It works indirectly by potentiating the action of antithrombin leading to the inactivation of factors IIa (thrombin) and Xa

Inactivation of thrombincrequires linger chains of heparin that wrap around both thrombin and antithrombin

It is administered intravenously or by subcutaneous injection

42
Q

What is warfarin?

A

Derived from coumarin, a vitamin K antagonist that works by interfering with protein carboxylation. Reducing the synthesis of fictional factors II, VII, IX and X by the liver.

Oral tablet, effects need to be monitored

Takes several days to take effect

43
Q

How do DOACs work?

A

Orally avaliable

Directly inhibit either thrombin or factor Xa (w/o antithrombin)

Don’t usually require monitoring

44
Q

What does the fibrinolytic system do?

A

Break down clots

45
Q

What is the principal fibrinolytic enzyme?

A

Plasmin

Which circulates in its inactive zymogen form plasminogen

46
Q

How is the activation of plasmin mediated?

A

Tissue plasminogen activator (t-PA)

However this only happens when they are brought together by lysine residues on fibrin

47
Q

What does the breakdown of fibrin lead to the generation of?

A

Fibrin degradation products (FDPs)

48
Q

Is plasmin specific to fibrin?

A

No
It can also break down other protein components in plasma ( fibrinogen, Va, VIIIa)

Plasmin is inhibited by antiplasmin

49
Q

What is thrombolytic therapy?

A

Theombolytic agents (e.g. recombinant t-PA) generate plasmin to lose clots

Administered intravenously to patients with ischaemic stroke

Must be given ASAP
Also patients with pulmonary emboli

50
Q

How does the antifibrinolytic drum transexamic acid work?

A

It is a synthetic derivative of lysine that binds to plasminogen (acts as a competitive inhibitor as opposed to lysine)

Plasminogen can’t be turned into plasmin

So no fibrinolysis

51
Q

PT time is a coagulation test. How does it work?

A

Measures the integrity of the extrinsic pathway (see slide)

Blood is collected In a bottle containing sodium citrate (chelates calcium so clotting won’t occur)

Sample is spun to produce platelet poor plasma

A source of TF and phospholipid is added along with calcium to start clotting. The time taken is recorded

PT time is prolonged due to reduced activity of factors VII, X, V, II or fibrinogen

52
Q

How does the coagulation test APTT work? (Activated partial thromboplastin time)

A

Measured the integrity of the intrinsic pathway (see slide)

Performed by the contact activation of factor XII by glass/silica

This is added along with phospholipid to citrates plasma, followed by calcium, time taken to clot is recorded

53
Q

A loss of balance between the two results In bleeding. What causes this?

A

Reduction in platelet number

Reduction in coagulation factors

Increased fibrinolysis

54
Q

What is thrombosis?

A

Formation of a blood clot within an intact vessel

Can result in obstruction of blood flow

55
Q

What is virchows triad (contributing factors to thrombosis)

A

Blood
Dominant in venous thrombosis

Vessel wall
Dominant in arterial thrombosis

Blood flow
Both

56
Q

What changes in blood can lead to venous thrombosis?

A

Reduced anticoagulant proteins
Usually genetic

Reduced fibrinolysis
Eg during pregnancy

Increased clotting factors/ platelets
Also can occur during pregnancy

Lily PoM Haematology (6 decks)

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