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Physiology for Anaesthetists > Haem - Haemostasis > Flashcards

Haem - Haemostasis Flashcards

1
Q

Define haemostasis

A

Collective term for mechanisms that stop blood loss

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2
Q

Define Coagulation

A

The action or process of a liquid, especially blood, changing into a solid or semi-solid state

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3
Q

Define thrombosis

A

The process of blood clot formation

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4
Q

What are the three components involved in haemostasis

A
  1. Platelets
  2. Endothelium
  3. Coagulation proteins

All three must be functional for haemostasis to be effective

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5
Q

How does the ENDOTHELIUM inhibit platelet adhesion in health

A

INHIBITION OF PLATELET ADHESION

  1. NO
  2. PGI2 - prostacyclin
  3. Adenosine diphosphatase (degrades ADP)

ANTICOAGULANT EFFECTS

  1. Heparan sulphate (similar to heparin)
  2. Thrombomodulin

FIBRINOLYTIC EFFECTS
1. Tissue plasminogen activator (t-PA)

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6
Q

Describe the mechanism by which the endothelium prevent platelet adhesion in health

A
  1. Secrete NO and PGI2 (prostacyclin)
    - -> Prevent platelet adhesion to endothelium
  2. Adenosine Diphosphatase
    - -> Breaks down ADP (essential for platelet activation)
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7
Q

Describe the mechanism by which the endothelium has anticoagulant effects preventing coagulation in health

A
  1. Secretes heparan sulphate
    –> Similar structure to heparin
    –> Activates plasma protein ANTITHROMBIN III
    (antithrombin III inactivates IIa and Xa)
  2. Secretes thrombomodulin
    - ->Binds thrombin (removing from circulation)
    - -> The thrombin-thrombomodulin complex activates Protein C (and cofactor protein S) –> Inactivate Va and VIIIa
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8
Q

Describe the mechanism by which endothelial cells have fibrinolytic effects

A

Secrete tissue plasminogen activator (t-PA)

–> t-PA cleaves plasminogen into plasmin –> degrades fibrin clots from the surface of the endothelial cell.

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9
Q

How is haemostasis initiated

A

Damage –> plasma exposure to a number of substances:

  1. VON WILLEBRAND FACTOR (vVF)
    - -> normally small amounts –> binds and protects factor VIII from degradation

–> damaged vessel –> large amounts vWF –> bind platelets to subendothelial collagen fibres

  1. COLLAGEN FIBRES
    - -> damage exposes subendothelial collagen fibres –> platelets bind collagen (through vWF) –> activated platelets attract more platelets
  2. TISSUE FACTOR
    - -> Expressed by subendothelial cells (not normally by endothelial cells) –> TF activates coagulation proteins (extrinsic pathway)
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10
Q

Where is vWF synthesized

A

Endothelial cells

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11
Q

What are platelets, what is their life span circulation and what does platelet ‘activation’ mean?

A

Platelets are small disc shaped anuclear cell fragments with a short half life in circulation of 7 days.

Damaged endothelium:

vWF + Collagen + thrombin (result of TF activation of coagulation cascade) –> activate platelets which means

  1. Shape change from disc to stellate
  2. Release of stored granules
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12
Q

What 9 substances are stored in platelet granules and released when platelets are activated

A
  1. 5-HT Serotonin
  2. TXA2 Thromboxane
  3. ADP Adenosine Diphosphate
  4. Ca2+ Calcium
  5. PAF Platelet Activating Factor
  6. PDGF Platelet Derived Growth Factor
  7. IIa Thrombin
  8. XIII Fibrinogen
  9. vWF von Willebrand Factor
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13
Q

Describe the steps involved in platelet activation and aggregation

A
  1. Damage + exposure vWF, collagen, TF
  2. Passing platelets bind
  3. Disc–> Stellate and release granules (activate)
  4. VC (5-HT and TXA) reduced blood flow
  5. Layer 1 platelets on exposed collagen
    (No collagen available for further binding)
  6. ADP from these platelets further platelet activation
  7. Activated platelets have glycoprotein IIB/IIIa receptor on surface: Fibrinogen + vWF glue platelets together using this receptor –> soft platelet plug.
  8. Coagulation cascade turns fibrinogen into fibrin (strong insoluble protein) –> forming strong clot.
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14
Q

Explain the effect of aspirin on haemostasis

A

Nucleated endothelial cell membranes are catabolised by COX 1 and 2 to produce PGI2 to prevent platelet adhesion (and activation to endothelium).

Anucleated platelets cell membranes are catabolised by COX 1 and 2 to produce TXA2 which activates platelets and causes localised vasoconstriction.

Aspirin irreversibly COX 1 and 2 thereby preventing PGI2 and TXA2 from being produced. There is initially a combined procoagulant + anticoagulant effect. However, as platelets are anucleated they cannot continue to produce TXA2 for the duration of their life span (7days) whereas, endothelial cells may produce new cox within hours (nucleus). Therefore the net effect is anticoagulant with increased PGI2 : TXA2 ratio.

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15
Q

Describe the mechanism of action of ADP receptor antagonists and give an example

A

Clopidogrel

Blocks ADP receptors which PREVENTS expression of glycoprotein IIb/IIIa on platelet surface preventing platelet aggregation.

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16
Q

Describe the mechanism of action of Glycoprotein IIb/IIIa inhibitors and give an example

A

Abciximab

Blocks Glycoprotein IIb/IIIa inhibiting platelet aggregation

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17
Q

Give an example of a phosphodiesterase inhibitor and explain the proposed mechanism for its effect on haemostasis

A

Dipyrimadole

Inhibition of platelet phosphodiesterase enzyme –> reduced breakdown of cAMP –> accumulation cAMP inhibits ADP release –> impaired platelet aggregation and reduced TXA2 synthesis.

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18
Q

If the new CELL-BASED COAGULATION MODEL better reflects the mechanism of in vivo coagulation, then why is it still important to understand the classical (intrinsic and extrinsic) pathways of coagulation.

A

The classical pathways explain the mechanism of coagulation in vitro and reflect the laboratory clotting screen.

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19
Q

Explain the basis for the names: intrinsic and extrinsic pathways

A

The extrinsic pathway is activated by tissue factor - NOT NORMALLY FOUND within the lumen of intact blood vessels

Intrinsic pathway is so called as it was recognised that initiation of coagulation did not always require TF, especially in vitro –> plasma can clot without the addition of any extrinsic material.
- subsequent discovery that the intrinsic pathway is activated by NEGATIVELY CHARGED substances: e.g. subendothelial collagen in vivo and glass in vitro.

20
Q

Which pathway Extrinsic or Intrinsic plays a more minor role in coagulation

A

Intrinsic

21
Q

Describe the final common pathway

A

Either 7a + 3 (extrinsic ) AND/OR 9a + 8a + Ca + PF3 (intrinsic)

Convert factor 10 to 10a

10a + 5a + Ca + PF3 convert 2 to 2a

2a converts:
1 to 1a
13 - 13a

1a + 13a –> Cross linked (13a) Fibrin (1a) Clot

22
Q

Describe the Intrinsic pathway

A

Surface contact (negatively charged collagen) converts 12 to 12a

12a converts 11 to 11a

11a converts 9 to 9a

(8 to 8a by 2a)

9a + 8a + Ca + PF3 convert 10 to 10a

10a enters final common pathway

23
Q

Describe the extrinsic pathway

A

Damage to tissue releases tissue factor

Tissue factor = thromboplastin = Factor III converts 7 to 7a

7a + 3 convert 10 to 10a

10a enters the final common pathway

24
Q

What are protein C and protein S. Describe their function

A

Vitamin K dependent natural anticoagulants

Thrombomodulin is an endothelial protein

Thrombin binds to thrombomodulin forming a thrombin-thrombomodulin complex. This complex activates protein C and with protein S as a co-factor –> Factors 5 and 8 are inhibitant –> anticoagulant effect.

25
Q

Which vitamin K dependent clotting factors have the shortest half life and why is this clinically relevant

A

Factor 7

  • -> As the other clotting factors will remain active for longer than 7 and that factor 7 is measured by promthrombin time (PT), the initial increase of PT without change of PTT indicates:
    1. Early DIC
    2. Early Vit K antagonism (onset of warfarin action)
    3. Factor 7 deficiency

Protein C
During the initiation of warfarin, due to the short half life of protein C, there is an initial paradoxical hypercoagulable phase which is countered by the overlapping administration of heparin during this period.

26
Q

What is the normal PTT, PT and TT?

A

PTT 25 - 29 s (depends on lab)

PT 12 s (depends on lab)

TT 14 - 19 s (depends on lab)

27
Q

When will PTT be elevated without change of PT

A 
Deficiency of
12
11
9
8
28
Q

When will PT be elevated without change PTT

A
  1. Deficiency of factor 7
  2. Early DIC (short t1/2 of 7)
  3. Early action of warfarin (short t1/2 of 7)
29
Q

When will PT and PTT be elevated

A
  1. Vit K deficiency (Nutritional/Warfarin)
  2. DIC
  3. Liver Dx
  4. Heparin / DOACs
30
Q

What test is done to test the final common pathway

A

Thrombin Time (TT) normal 14 - 19 s

31
Q

What is Haemophilia A

A

X-linked recessive disease, which results in a deficiency in factor 8.

Soft platelet plug forms with ineffective fibrin formation –> prolonged bleeding

32
Q

What is van Willebrand disease

A

Most common hereditary coagulation disorder.

Deficient or defective vWF.

vWF function

  1. Bridge platelets to subendothelial collagen
  2. Bind clotting factor 8 –> protecting it from degradation
33
Q

What is the treatment for Haemophilia and and van Willebrand Disease

A

Mild disease

  1. Prophylactic (prevent trauma)
  2. DDAVP (ADH) Desmopressin

Moderate –> Severe disease
1. Recombinant factor VIII (rich in vWF)

34
Q

What is the mechanism of action of desmopressin (DDAVP) = synthetic ADH = Vasopressin

A
  1. ADH analogue binds to V2 receptors collecting ducts (nephron) –> Increased cAMP –> insertion aquaporins into luminal walls –> increased water reabsorption.
  2. Stimulates release of vWF and Factor VIII from platelets and endothelial cells
35
Q

What is the cell-based model of anticoagulation?

A
  1. Better explains in vivo mechanism of coagulation.
  2. Factor 12 (from intrinsic pathway) makes little in vivo contribution to coagulation.
  3. THREE phases

INITIATION PHASE
- Damage –> endothelial cell bearing TF/vWF exposed –> 5 and 7 nearby activated –> activation other nearby clotting factors –> small amount of thrombin formed. Passing platelets activated by: vWF, TF and thrombin.

AMPLIFICATION PHASE
- Thrombin activates more platelets, and factors 5,8,10 to make more THROMBIN

PROPAGATION PHASE
- Platelets activated with coagulation factors on surface–> make more thrombin –> fibrin + activates XIII to cross link FIBRIN

Thrombin at the centre of this model

  • -> Thrombin involved in its own generation
  • -> And own regulation through feedback loops
  • -> And formation of cross linked fibrin polymer
36
Q

How is PT done, what does it measure and what is INR

A

PT is the prothrombin time used to measure the extrinsic pathway. Tissue factor (Thromboplastin) is added to sample of plasma and the time to clot formation measured.

International normalized ratio (INR) is the patient’s PT divided by the PT of the control sample all raised to the power of the international sensitivity index (reduce inter-laboratory different normal range confusion).

37
Q

When is PT prolonged. And when will PT be prolonged with a normal PTT

A

Measures extrinsic pathway so

  1. Factor 7 deficiency
  2. Warfarin therapy
  3. DIC
  4. Liver disease
  5. Fat malabsorption (Vit K deficiency)

PT prolonged with normal PTT
–> Factor 7 has the shortest half life of all clotting factors
which means PT will be elevated with normal PTT in:
1. Early DIC
2. Early Warfarin therapy or Early Vit K deficiency
3. Factor 7 deficiency

38
Q

How is aPTT performed

A

Activated partial thromboplastin time

Add phospholipid + activator (silica) to the plasma sample and measure the time taken to clot.

39
Q

Which clotting factors does aPTT assess?

A

TENET

Twelve
Eleven
Nine
Eight
Ten (Final common pathway)
40
Q

When is aPTT prolonged

A
  1. Unfractionated heparin therapy (+ Antithrombin III)
    (NOT LMWH - too small to activate antithrombin III. It directly inhibits Xa and therefore aPTT is unchanged)
  2. Haemophilia (factor VIII deficiency)
  3. Christmas disease (factor IX deficiency)
  4. von Willebrand disease (vWF deficiency)
  5. DIC
41
Q

How is the Thrombin Time performed.

What does thrombin time test and when is it used

A

Thrombin is added to plasma and the clotting time measured
Thrombin time tests the interaction between thrombin and fibrinogen.

TT is prolonged in fibrinogen deficiency due to DIC

42
Q

What is bleeding time and why is it rarely performed

A

Standard incision is made and the time to stop bleeding measured –> time it takes for an effective platelet plug to form = platelet function.

It is rarely performed as it does not help to predict surgical bleeding.

43
Q

What is thromboelastography. What are its advantages?

A

Thromboelastography is a near-patient method of testing the entire haemostatic process. It assesses:

  1. Platelet function
  2. Coagulation
  3. Fibrinolysis in a single test

Advantages

  1. Quicker than standard coagulation tests
  2. Better representation of in vivo haemostasis
44
Q

Describe how thromboelastogram sampling works

A

Patient’s blood into Cuvette which is SLOWLY ROTATING to mimmic the low-shear environment of venous flow.

Plastic pin attached to torsion wire is lowered into the cuvette.

As the blood clots, fibrin strands form between the cuvette and the plastic pin and the torsion in the wire changes resulting in a cigar-shaped graph.

Detailed analysis of the graph can be made analysing various parameters

45
Q

What is plasminogen

A

A Beta globulin synthesized in the liver.

Plasminogen becomes interwoven into the clot as it is formed

46
Q

What is the function of t-PA secreted normally by endothelial cells

A

Keeps endothelial surface fibrin free and hence small vessels patent.

Physiology for Anaesthetists (61 decks)

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