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Pom > Haemostasis > Flashcards

Haemostasis Flashcards

1
Q

Normal haemostasis

A

Blood flows within the vascular system transporting oxygen nutrients and hormonal information around body. Dependant on balancing factors constituting coagulation factors and platelets

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2
Q

Why is balance of blood constituents important

A

1)coagulation-allow stimulation of blood clotting processes following injury when blood changes from liquid state
2)thrombosis-limit extent of response to the area of injury to prevent excessive or generalized blood clotting
3)fibrinolysis-start process that breaks down the clot as part of the healing process

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3
Q

What is an overall view of the Haemolysis

A

Halting of blood trauma to blood vessels has 3 processes
1)vasoconstriction of blood vessels
2)primary haemostasis formation of an unstable platelet plug at the site of vessel wall damage
3)secondary haemostasis stabilization of the plug with fibrin
Then fibrinolysis happens

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4
Q

Why is it important to understand homeostatic mechanisms medically

A

Diagnose and treat bleeding disorders
Monitor drugs used to treat bleeding
Indetify thrombosis risks
Control bleeding in individuals who don’t have an underlying dirosder or blood

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5
Q

Vasoconstriction of primary haemostasis

A

Nitric oxide and prostacylin (vasodilators) concentrations are less than endothelin (vasoconstriction) concentration reducing the amount of blood being lost

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6
Q

What are platelets

A

Discoid,non nucleated,granule containing cells derived from myeloid stem cells
Formed in bone marrow by fragmentation of megakaryocyte cytoplasm and circulate for 10 days
Plasma membrane contains glycoproteins

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7
Q

How do platelets react following injury to vessel wall

A

Stick damaged endothelium either directly to collagen via the platelet GPIa receptor or indirectly by the von willer brand factor which binds to platelet GPIb receptor
Causes activation and change shape from disc to rounded form with spicules to encourage platelet to platelet interaction

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8
Q

What do platelets do after being activated

A

They release the content of their storage granules
Alpha granules or dense granules
Contents include ADP,fibronegen,VWF

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9
Q

What other chemicals do platelets produce

A

Prostaglandin thromboxane A2 from arachidonic acid which is derived from the cell membrane
Useful in platelet aggregation but is a vasoconstrictor
Activated platelets also produce calcium

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10
Q

What does the release of ADO and generation of thromboxane A2 do

A

ADP binds to p2y12 receptor and thromboxane binds to thromboxane A2 receptor which has a positive feedback effect

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11
Q

How does fibrinogen bind to platelets

A

Platelet activation causes a conformational change in the GPIIb/IIIa receptor (inside out), which provide binding sites for fibrinogen

This binding causes outside-in signalling which further activates the platelets

Fibrinogen has a key role in linking platelets together to form the platelet plug

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12
Q

How is inappropriate platelet aggregation avoided

A

Active flow of blood and release of prostacylin (PG12)
Is a powerful vasodilator
Released by endothelial cells

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13
Q

What does aspirin do an an antiplatelet drug

A

Inhibits the production of thromboxane A2 by irreversibly blocking the action of cyclo-oxygenase (COX), resulting in a reduction in platelet aggregation
Effect last for 7 days

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14
Q

Why is prostacylin production less inhibited by COX action

A

endothelial cells are nucleated so can synthesise more COX whereas the non-nuclear platelet can’t

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15
Q

How does clopidogrel work as an antiplatelet drug?

A

It irreversibly blocks the ADP receptor (P2Y12) on the platelet cell membrane

The effect of clopidogrel also lasts 7 days until new platelets have been produced

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16
Q

What is von Willebrand factor (VWF) and what is it synthesised by

A

A glycoprotein synthesised by endothelial cells and megakaryocytes and circulates in plasma as multimers (proteins with >1 monomer) of different sizes

VWF mediates the adhesion of platelets to sites of injury and promotes platelet-platelet aggregation

-
Is a specific carrier for factor vIII

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17
Q

Why and when is fibrin formation needed

A

The primary platelet plug is enough for small vessel injury but would fall apart in larger vessels, so fibrin formation is needed to stabilise the platelet plug

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18
Q

Coagulation

A

Thrombin is generated which cleaves fibrinogen to generate a fibrin clot that stabilises the platelet plug

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19
Q

Where are clotting factors made

A

Most are made in the liver
Factor VIII and VWF are made by endothelial cells
VWF is also made in megakaryocytes

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20
Q

Which vitamins do some factors rely on

A

Vitamin K for carboxylation of their glutamic acid residues which is essential for their function

II (prothrombin), VII, IX and X are the factors

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21
Q
  • What is each step of coagulation characterised by?
A

The conversion of an inactive zymogen (proenzyme) into an active clotting factor by splitting 1/more peptide bonds and exposure of the enzyme active site

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22
Q

What are 2 factors in coagulation

A

V and VIII

23
Q

Where do clotting factors work

A

On exposed phospholipid surfaces of platelets which help localize and accelerate these reactions

24
Q

Calcium ions role in secondary homeostasis

A

Important in binding of clotting factors to phospholipid surfaces of platelets

25
Q

What happens in the initiation phase

A

Tissue factor (TF) is exposed on the surface of endothelial cells, leukocytes and most extravascular cells in an area of tissue damage- TF is normally located at sites not usually exposed to blood normally, so when blood encounters TF at the injury site, this initiates coagulation

TF makes factor VII into VIIa which leads to activation of factors IX to IXa and X to Xa

This leads to activation of factor II (prothrombin) which generates a **small initial amount of factor IIa (thrombin)

26
Q

Amplification phase

A

The small thrombin amount (IIa) mediates the activation of cofactors V into Va and VIII into VIIIa, factor XI into XIa and platelets

27
Q

What happens in the propagation phase

A

Factor XI converts more factor IX to IXa,

IXa and factor VIIIa, amplifies the conversion of factor X to Xa leading to a rapid burst in IIa and therefore thrombin generation

This cleaves the circulating soluble fibrinogen to form the insoluble fibrin clot

28
Q

Why are coagulation inhibitory mechanisms important

A

As they prevent blood from completely clotting which ensures coagulation is confined to site of injury

29
Q

How is antithrombin involved in coagulation inhibition

A

It inactivates thrombin (IIa) and factor Xa

The action of antithrombin is potentiated by heparin- this occurs by the binding of antithrombin to endothelial cell-associated heparins

30
Q

What does heparin do

A

It’s a mixture of glycosaminoglycan chains extracted from porcine mucosa and works indirectly by binding to and potentiating the action of antithrombin which inactivates thrombin and factor Xa

Heparin **is administered intravenously or by subcutaneous injection

Inactivation of thrombin requires larger chains of heparin to wrap around both antithrombin and thrombin

31
Q

What does warfarin do

A

It’s a vitamin K antagonist and works by interfering with protein carboxylation- this reduces synthesis of functional factors II, VII, IX and X by the liver
Oral tablet and regular blood testing is needed
Takes several days as it reduces synthesis of coagulation factors rather than inhibiting existing factors
Derived from coumarin

32
Q

Direct oral anticoagulants

A

Orally available drugs that directly inhibit either thrombin or factor Xa without the involvement of antithrombin

They usually don’t require monitoring

33
Q

Fibrinolytic system

A

Plasmin, which circulates in its inactive zymogen form plasminogen

It’s activated by tissue plasminogen activator (t-PA) when both t-PA and plasminogen together bind to lysine residues on fibrin

The breakdown of fibrin produces fibrin-degradation products (FDPs)

Plasmin isn’t specific to fibrin and also breaks down fibrinogen and clotting factors Va and VIIIa for example

Plasmin is inhibited by antiplasmin which circulates in the blood, also inhibited by alpha-2-macroglobulin

34
Q

What does thrombolytic therapy entail

A

Thrombolytic agents like recombinant t-PA are given to ischaemic stroke patients intravenously to make plasmin and lyse clots- this is time dependent however so t-PA needs to be given to eligible patients ASAP, preferably within the first hour of onset of symptoms

There’s a high risk of bleeding associated with use

35
Q

Who can be given thrombolytic therapy

A

Patients with life threatening pulmonary emboli

36
Q

What does antifibrinolytic drug tranexamic do

A

It’s a synthetic derivative of the amino acid lysine and binds to plasminogen which prevents plasminogen from binding to lysine residues on fibrin- this is competitive inhibition

This prevents activation of plasminogen to plasmin which would lead to fibrinolysis

Tranexamic acid is used to treat bleeding in trauma and surgical patients and patients with inherited bleeding disorders

  • Has a similar structure to the amino acid lysine, (synthetic derivative of the amino acid lysine)
  • Binds to lysine binding sites on plasminogen, which prevents plasminogen from binding to lysine residues on fibrin, thus acts as a competitive inhibitor
  • Which prevents activation of plasminogen to plasmin which would lead to fibrinolysis
37
Q

Intrinsic vs extrinsic model

A

Intrinsic-components in plasma

factors IX, X, XI, XII and cofactors VIII and V
Extrinsic-TF and factors VII, X and cofactor V

38
Q

Prothrombin time tests for

A

Integrity if the extrinsic pathways
Blood collected to which sodium citrate is added which chelates calcium to prevent blood clotting
Sample spun and recombinant thromboplastin added to citrates plasma with calcium to start clotting reaction

39
Q

When is PT prolonged

A

If there’s a reduction in activity of factors VII, X, V, prothrombin or fibrinogen
We see bleeding in factor VII deficiency

40
Q

Internalized normalized ratio

A

A correction for the different thromboplastin sources used by different labs when PT is used to monitor Vit K antagonist anticoagulant therapy like warfarin- this is so everyone can obtain the same INR result for a given sample irrespective of the source of thromboplastin.

41
Q

Activated partial thromboplastin tests for

A

Measures the integrity if the intrinsic pathways

Performed by the contact activation of factor XII by a surface like glass/using a contact activator like silica or kaolin- this activator is added along with phospholipid to citrated plasma and then calcium- the time taken to clot is measured

42
Q

When is APTT prolonged

A

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

43
Q

In which 3 deficiencies do we see bleeding with an isolated prolonged APTT

A

Factor VIII deficiency (haemophilia A)
Factor IX deficiency (haemophilia B)
Factor XI deficiency

44
Q

In which deficiency is there non bleeding patients with an isolated prolonged APTT

A

factor XII

45
Q

What can lead it bleeding

A

Reduction in platelet number
Reduction in function of platelets
Reduction in coagulation factors due to congenital diseas or drugs,liver disease,DIC
Increased fibrinolysis may be due to administration of thrombolytic therapy

46
Q

What so thrombosis

A

Formation of a blood clot within an intact vessel that occurs due to obstruction of blood flow

47
Q

What is Virchow’s triad of contributory factors to thrombosis?

A

1) Blood- dominant in venous thrombosis

2) Vessel wall- dominant in arterial thrombosis

3) Blood flow- complex, contributes to both arterial and venous thrombosis

-

48
Q

Which 3 changes in blood increase the risk of venous thrombosis

A

Reduced levels of anticoagulant proteins
Reduced fibrinolytic activity eg inhibition of plasminogen activation through PAI2 by the placenta
Increased levels of clotting factors or platelet

49
Q

Which factor increases during pregnancy

A

VIII

50
Q

Direct vs indirect inhibition

A

Direct-antithrombin,an inhibitor of thrombin
Indirect-inhibition of thrombin generation by protein c and s anticoagulant pathways

51
Q

Primary haemostasis

A

1) endothelial injury where secretion of nitric oxide and prostaglandin stop and secretion of endothelin starts
2) damage to endothelial cells exposes collagen which release vin willebrand factor
3)platelet changes shape releases more von willerbrand factor,calcium,ADP,thromboxane A2.
ADP binds to p2y12 and thromboxane binds to thromboxane A2 receptor in a positive feedback loop

52
Q

How does vitamin k deficiency affect PT and APTT

A

APTT is increased as vitamin k is needed to make factor 9 10 and 2
pT is increased as there is deufcuney of factor 7 and ten

53
Q

Severe haemophilia

A

Severe’ haemophilia refers to undetectable plasma levels of factor IX (haemophilia B) or factor VIII (haemophilia A) . Henry receives infusions of recombinant factor IX concentrate . These are known as prophylaxis, and reduce the risk of spontaneous bleeding, which he would be prone to given the severity of his disease

54
Q

Beta thalassemia

A

Autosomal recessive
Affects beta chains of haemoglobin
Causes microcytic anaemia as haemoglobin not produced efficiently
Blood transfusion given

Pom (44 decks)

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