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BII > Lecture 10, 12 - clotting cascade > Flashcards

Lecture 10, 12 - clotting cascade Flashcards

1
Q

Primary haemostasis

Secondary haemostasis

A

Primary - damaged endothelium, platelets adhere, and recruit more

Secondary - series of enzymatic reactions that form firbin then result in a fibrin mesh (clot) to trap the plug

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2
Q

Clotting cascade diagram

A

…

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3
Q

Where is tissue factor found? can you live without it?

A

Is expressed on sub endothelial tissue, and cannot survive without it

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4
Q

What makes up the initiation complex and what inhibits this

A

Tissue factor, 7a, 10a, 2a

Tissue factor pathway inhibitor

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5
Q

What makes up complex 2

A

On activated platelet surface

8, 9, 10, 5

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6
Q

what makes up complex 3

A

5, 10

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7
Q

What does protein C inhibit?

what molecule does it need? what is it activated by?

A

inhibits factor 8, 5

  • needs cofactor protein S
  • is activated by thrombin
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8
Q

What does antithrombin do?

A

most important inhibitor
-switches of activated 9, 11, and thrombin

-requires natural heparin like compounds as cofactor

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9
Q

Functions of thrombin

A 
!  Converts)fibrinogen)to)fibrin)
!  Activates)factor)VIII)
!  Activates)factor)V)
!  Activates)XI)(feedback)loop)to)IXa)) !  Activates)XIII:)cross)links)fibrin)
!  Activates)protein)C)
!  Other)roles)in)inflammation)
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10
Q

What does factor 13 do?

A

this can further cross link fibrin

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11
Q

what are the cofactors of complex 2 and 3?

A

5and 8 are both cofactors

8 helps 9, and 5 helps 10

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12
Q

What are vitamin K dependent proteins?

Why do we need vit K?

A

Prothrombin, 7, 9, 10, protein C and protein S

Why - need vit K because i carboxylates glutamate resitues on GLA domain of vit K depenedent protiens,

  • needs this to be folded properly so it can stick to lipid bilayer of platelet, and requires vit K to do this

This means the platelets cannot stick onto the lipid bilayer and thats why this layer is important

-is a fat soluble vitamin, needs bile to be absorbed , also made by bacteria in the gut

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13
Q

Newborns and relevance of Vit K

A

Newborns are relatively deficient in Vit K, so get an intramuscular injection or orally
-can prevent haemorrhagic disease of newborn

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14
Q

Contact pathway (intrinsic pathway)

A

Links to common factor pathway by factor 9

  • factor 12
  • this is activated by a surface e.g if in lab tests will be activated by a glass surface
  • factor 12 activates factor 11, which will activate factor 9 (which then goes onto activate 10 to 10a)

This will only occur in lab, and needs a surface

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15
Q

What happens if you have a factor 12 deficiencey

A
  • not associated with bleeding
  • however important in lab test - have odd clotting tests so although they are not affected in life, these may produce odd results we need to be aware off
  • also has a role in inflammation
  • can cause clots around needles due to surface activation
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16
Q

What does antithrombin do?

A
  • It inhibits thrombin
  • inhibits factor 10
  • also can slightly inhibit factor 9, 11
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17
Q

How does fibrin work with clotting?

A

thrombin chops of part of fibrinogen molecuels which allows them to attatch together

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18
Q

What is fibrinolysis

A

Is bodys way of breaking down clots, and keeping coagulation from becomign excessive

Plasminogen get converted to plasmin by tissue plasminogen activator

Plasmin will break down the stable insoluble fibrin clot and also breaks down some fibrinogen

-can measure d Dimer - as this is a result when the fibrin clot is broken down

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19
Q

APPT - activated partial thromboplastin time

  • How does this physiologically work
  • what factors can it test and not test
  • what does it mean if PR are normal and unnormal with an unnormal APPT test?
A
  • This is to do with the intrinsic pathway
  • supply an activator to activate factor 12 being activated to 12a

Can look at all factors except factor 7 *this is part of extrinsic pathway

Looks at - 12, 11, 9, 8

How to interpret results - if only APPT is off, then we know that something is wrong in the intrinsic pathway
-If PR is normal, then something in intrinsic pathway, if PR is not normal then something in common pathway

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20
Q

APPT in a lab

-what does citrate do?

A
  • Collected into citrate, this will stop blood from clotting as it removes calcium (this is required for clotting)
  • then spin the sample down to collect the plasma
  • add phospholipid as an activator
  • add calcium to overcome citrate
  • and then test the length till clot formation
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21
Q

How does it work with the machine absorbing light?

A

If we watch the clotting - there will be less light absorbed over time because when the clotting factors get soaked up, the plasma becomes clearer because the clot is forming

22
Q

Prothrombin time

  • what does this test?
  • what does it mean if we have a normal or abnormal APPT alongside
A
  • Activating the extrinsic pathway
  • and then moves down through the common pathway
  • we are adding Tissue Factor to trigger this (and calcium)
  • done need intrinsic factor, so cannot test 8 or 9 in intrinsic pathway
  • If have a prolonged prothrombin
  • could be factor 7, 10, 5, prothrombin or fibrinogen

-If something is wrong with common pathway - will have slow APPT and Prothrombin time

23
Q

Prothrombin time or ratio

  • what do we use?
  • why?
  • what is a normal ratio?
A

prothrombin time is often converted to prothrombin ratio
-this standardises the test to account for different lab methods and different normal ranges
Ratio - normally around 1

24
Q

Thrombin clotting time

  • what is this testing?
  • how can this test for inhibitors?
A
  • Occurs right at the bottom (doesn’t require intrinsic or extrinsic pathway)
  • add thrombin to plasma to make a clot
  • is looking at change from fibrinogen to fibrin
  • is used to work out amount of fibrinogen a patient has
  • also use this to look at the effect of inhibitors
  • if we dilute the plasma, and then add thrombin, the test becomes more sensitive to the presence of inhibitors (major inhibitors are drugs)
  • heparin interferes
25
Q

Mixing studies

A
  • First do APPT
  • mixing studies - determine sensitivity of this assay is
  • if a person has no clotting factor - will be very prolonged
  • if a person has 40-50% of normal, the APPT will be almost or completely normal
  • if u ad 50% normal plasma to sample, then you will supply 50% of the clotting factors and depending on how much clotting factor the patient has, will result in how much there is in total)
  • so if we mix in 50% normal plasma, and the sample corrects to normal - then this means there is a factor deficiencey

This is determining weather there is a factor deficiencey of something to do with inhibitors

-If sample does not fully correct, then an inhibitor is present

26
Q

Inhibitors in coagulation

-EXAM Q - maybe, understand well

A

Natural inhibitors - protein C, S, antithrombin

  • These do NOT affect ATTP
  • must be different inhibitors
27
Q

What does it mean when there is a prolonged APTT and a prolonged 1 + 1
-what are the 3 things it could be?

A
  1. lupus anticagulant
    - found in disease called antiphospholipid syndrome (autoimmune disease where people clot too much)
    - Can get this if someone is sick, but doesn’t cause bleeding , this is because the antibodies in plasma interfere with the APTT assay
  2. (rare) Autoimmune disease, making an inhibitor bind onto a clotting factor (usually 8) - causes “aquired haemophilia” - gives them a bleeding disorder
    - can be life threatening
  3. Heparin (drugs), these are inhibitors of coagulation system
    - can cause bleeding
    - upregulates the affect of anti-thrombin
    - so it blocks activated thrombin
    - because it is w the activated protein, it doesnt overcome the effect of the inhibitor and this is why 1 + 1 is prolonged

Also - Dibigatran

28
Q

When is heparin used?

A

-when put in central lines to stop the clotting

29
Q

Dibigatran

A

Is used to treat blood clotting problems (venous thrombosis and atrial fibrillation)

  • works by directly inhibiting thrombin
  • prolonged 1 + 1 because even when you give more clotting factors, these will be inhibited
30
Q

How can you distinguish between dibigatran and heparin

A

-both have prolonged APPT, and 1 + 1, however if you add protamine this will correct heparin but not dibigatran

31
Q

How can you have deficiencey with common pathway factors, with a normal APPT ? (but have an abnormal PT)

A
  • because APPT is less sensitive that prothrombin time
  • prothrombin will be prolonged if factors are reduced to 40-50%
  • but APPT is less sensitive then that, so if have mild common factor deficiencies, the APPT can be normal with a mild prolongation of PT time
32
Q

How to interpret test?

  • APTT Prolonged, PT Normal
  • PT Prolonged, APTT Normal
  • Both PT and APTT Prolonged
A

Interpretation of tests
• APTT Prolonged, PT Normal
– Deficiencies of factor(s) VIII, IX, XI, XII (intrinsic)
• PT Prolonged, APTT Normal
– Deficiency of factor VII (extrinsic)
– Occasionally mild deficiencies of II, V, X, I
• Both PT and APTT Prolonged
– Deficiency of factor(s) II, V, X and I (common) – Multiple factor deficiencies

33
Q

When is TCT prolonged

A
  • deficiencey of fibrinogen

- thrombin inhibitor (dabigatran or heparin)

34
Q

Other tests

A
  • When have figured out which factors it could be, can do further test to figure out individual factors
  • similar to APPT, however supply plasma each time that is deficient in one of the clotting factors to see which one is abnormal
  • Can also work out platelet function (primary haemostasis)
  • And can work out D-dimers, (broken down fibrin)
35
Q

Multiple factor deficiencies

Most common senario
-and causes

A
  • multiple factor deficiencies
    1. Vit K deficiencey - prothrombin,7,9, 10
  • wafarin can interfere with metabolism of vit K
    2. Bleeding patient
  • loss of coagulation factors ect. and dilution with fluids
    3. DIC - disseminated intravascular coagulation
  • widespread activation of coagulation which causes thrombis followed by bleeding as clotting factors and platelets are used up
    4. Liver disease - lack of production of coagulation factors and inhibitors (except 8) - all are made in liver except 8
  • prothrombin assay most sensitive to liver disease, because vit K factors get used up first and billary system is most common in this disease
36
Q

What is most sensitive test for liver disease?

A

Liver disease - lack of production of coagulation factors and inhibitors (except 8) - all are made in liver except 8

-prothrombin assay most sensitive to liver disease, because vit K factors get used up first and billary system is most common in this disease

37
Q

Prolonged PT causes

A
  • extrinsic pathway
  • wafarin - 2,7,9,10
  • vit K deficiencey
  • liver disease
  • low factor 7 (but this is only if APPT is normal)
38
Q

How to monitor wafarin

A
  • Using PT ratio
  • use INR - international normalised ratio
  • this standardises the prothrombin ratio, so that if you measure the INR in any lab it will be the same
  • APPT also prolonged with warfarin, but not to the same extent and dont routinely measure it
39
Q

What does wafarin do?

  • when is it used?
  • how to reverse?
A
  • inhibits recycling of vit K
  • cannot get coagulation factors to stick onto platelets
  • if give a big dose of Vit K - can overcome wafarin
  • used in atrial fibriliation, venous thromboembolism, other thrombotic disorderss
40
Q

What do we see with trauma? (blood loss)

A

APPT - long, PT - long, fibrinogen - low

  • due to loss from blood, and increase fluid dilution
  • clue is that fibrinogen is low - so everythign has been used up
41
Q

Haemophilia A

A
  • Most commonly factor 8 deficiencey
  • X linked ressive- men affected more
  • mild moderate or severe
42
Q

Haemophilia B

A
  • Factor 9 deficiencey
  • X linked recessive
  • cannot tell the difference in clinical symptoms compared to A
43
Q

Haemophilia clinical symptoms

A

-bleeding

  Spontaneous joint bleeds •  Chronic arthropathy •  Joint destruction
•  Deformity
•  Arthritis
• Soft tissue bleeds • Tissue damage
• nerve damage • deformity
44
Q

Treatment

A
  • replace the missing factor
  • prophylaxis in childrens and teenagers when severe
  • normal lives and joitn oucomes unless patients develop inhibitors
45
Q

What does haemophilia test come out with?

A
  • Prolonged APTT with normal PR
  • single factor assay - low 8, 9 levels
  • genetic analysis - can sequence factor 8,9 gene
46
Q

What else can cause low factor 8 level?

A

Von Willebrand Factor

  • plays a role in both primary and secondary haemostasi as it carries factor 8
  • so without VWB factor will lack 8, as needs this to bring it in stably
  • most common inherited bleeding disorder
  • autosomal dominant
47
Q

Test for low VWB factor

A
  • will have abnormal platelet function screen
  • marginally prolonged APTT
  • low factor 8
  • low level and function of VWB factor
48
Q

Symptoms of VWB disease

A
  • mucosal bleeding
  • epistaxis
  • heavy periods
  • heavy bleeding during pregnancy
49
Q

Lack of factor 12

A
  • APTT - slow

- APPT with 1 + 1 - normal

50
Q

Meningitis

  • due to meningococcal septicaemia
  • and DIC
A

-rash
-has thrombocytopenia (low platelets)
-low APT, PT
-normal fibrinogen
-toxins going into blood causing lots of clots
DIC - get breakdown of red blood cells

BII (50 decks)

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