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Z YEAR 2 BRS CARDIO > Haemostasis 2 > Flashcards

Haemostasis 2 Flashcards

1
Q

What is the role of coagulation?

A

generate thrombin (IIa)

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2
Q

What does thrombin (IIa) do?

A

convert fibrinogen to fibrin

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3
Q

What does deficiency of any coagulation factor result in?

A

failure of thrombin generation and hence fibrin formation

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4
Q

What does prothrombin (PT) time measure?

A

Extrinsic pathway (tissue factor 7)

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5
Q

What does the activated partial thromboplastin time (APTT) measure?

A

Intrinsic pathway (trigger this with contact acitvation e.g. glass, silica)

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6
Q

What could cause normal PT but high APTT?

A
  1. Haemophilia A (8)
  2. Hamophilia B (9)
  3. Factor XI deficiency
  4. Factor XII deficiency
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7
Q

What could cause normal APTT but prolonged PT?

A

Factor VII deficiency

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8
Q

What could cause prolonged APTT and PT?

A
  1. Liver disease
  2. Anticoagulant drugs e.g. warfarin
  3. DIC (platelets and D dimer)
  4. Dilution following red cell transfusion
  5. Deficiency in common pathway so deficiency in factor 5,10,2
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9
Q

How do you treat failure of production/function in abnormal haemostasis?

A

-Replace missing factor/platelets
i) Prophylactic
ii) Therapeutic
-Stop drugs e.g. aspirin/NSAIDs

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10
Q

How do you treat immune destruction in abnormal haemostasis?

A
  • Immunosuppression (e.g. prednisolone)

- Splenectomy for ITP

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11
Q

How do you treat increased consumption in abnormal haemostasis?

A
  • Treat cause

- Replace as necessary

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12
Q

What are some options for factor replacement therapy?

A
  1. Fresh frozen plasma (FFP)
  2. Cryoprecipitate
  3. Factor concentrates
  4. Recombinant forms of FVIII and FIX
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13
Q

What is FFP?

A

Contains all coagulation factors

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14
Q

What is cyroprecipitate?

A

Rich in Fibrinogen, FVIII, VWF, Factor XIII

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15
Q

What are factor concentrates?

A
  • Concentrates available for all factors except factor V.

* Prothrombin complex concentrates (PCCs) Factors II, VII, IX, X

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16
Q

What are recombinant forms of FVIII and FIX?

A
  • ‘On Demand’ to treat bleeds

- Prophylaxis to prevent bleeds

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17
Q

What is the evolution of haemophilia treatment?

A
  1. plasma derived clotting factors (Widespread viral contamination)
  2. Recombinant clotting factors FVIII and FIX (eliminated potential for transmission of blood borne pathogens)
  3. Investigational therapies
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18
Q

What are some investigation therapies?

A
  1. Prolonged half life (FVIII/FIX): Fc fusion, PEG, albumin fusion
  2. Gene therapy (A and B)
  3. Novel agents:
    -Bispecific antibody (emicizumab)
    -Anti TFPI antibody
    -Anti thrombin RNAi
    (reduce antithrombin means a procoagulation effects)
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19
Q

What does emicizumab do?

A

-Just A
-Bi-specific anitbody
•Binds to FIXa and FX
•Mimics procoagulant function of FVIII

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20
Q

What does RNA silencing do?

A

-A and B

•Targets natural anticoagulant - antithrombin

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21
Q

What are some additional treatments for abnormal haemostasis?

A
  1. Desmopressin (DDAVP)
    -Vasopressin analogue
    -2-5 fold increase in VWF (and FVIII)
    releases endogenous stores (so only useful in mild disorders)
  2. Tranexamic acid
    Antifibrinolytic
  3. Fibrin glue/spray
  4. Other approaches e.g hormonal (oral contraceptive pill for menorrhagia)
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22
Q

When can bleeding result from increased fibrinolytic factors and anticoagulant proteins?

A
  • Very rare except when induced by drugs
    1. tPA (stroke) Increasing fibrinolysis
    2. Heparin increases antithrombin
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23
Q

How does pulmonary embolism (PE) present?

A
  1. Tachycardia
  2. Hypoxia
  3. Shortness of breath
  4. Chest pain
  5. Haemopysis
  6. Sudden death
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24
Q

How does deep vein thrombosis (DVT) present?

A
  1. Painful leg
  2. Swelling
  3. Red
  4. Warm
  5. May embolise to lungs
  6. Post thrombotic syndrome
    - Can cause damage to valves
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25
Q

What is thrombosis?

A
  • Intravascular coagulation
  • Inappropriate coagulation
  • Venous (or arterial)
  • Obstructs flow
  • May embolise to lungs
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26
Q

What is Virchow’s triad?

A

three contributory factors to thrombosis

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27
Q

What are the three factors? When are each dominant?

A
  • Blood: dominant in venous thrombosis
  • Vessel wall:dominant in arterial thrombosis
  • Blood flow: contributes to both arterial and venous thrombosis
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28
Q

What is thrombophilia?

A

Increased risk of venous thrombosis

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29
Q

How may thrombophilia present?

A
  • Thrombosis at young age
  • ‘spontaneous thrombosis’
  • Multiple thromboses
  • Thrombosis whilst anticoagulated
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30
Q

How can venous thrombosis happen?

A
  1. Decrease in anticoagulant factors
  2. Increase in coagulant factors
  3. Increase in platelets
31
Q

Which anticoagulant proteins are decreased?

A
  1. Antithrombin
  2. Protein C
  3. Protein S
32
Q

Which coagulant factors and platelets are increased?

A
  1. Factor VIII
  2. Factor II
  3. Factor V Ledien (increase activity due to activated protein C resistance)
  4. Myelloproliferative disorders e.g. essential thrombocythemia (increased platelets)
33
Q

What does protein C and its cofactor protein S do?

A
  1. Activates factor 5a and 8a
  2. As soon as activated need to be inactivated by protein C helped by protein S
  3. Antithrombin inactivates thrombin factor 2a and factor 10a
34
Q

How does the vessel wall contribute to venous thrombosis?

A

Many proteins active in coagulation are expressed on the surface of endothelial cells and their expression altered in inflammation (TM, EPCR, TF)

35
Q

How does blood flow contribute to venous thrombosis?

A

Reduced flow (stasis) increases the risk of thrombosis e.g. surgery, long haul flight, pregnancy

36
Q

How do you prevent venous thrombosis?

A
  • Assess and prevent risks

* Prophylactic anticoagulant therapy

37
Q

How do you reduce the risk of reccurence/extension?

A

• lower procoagulant factors
e.g warfarin, DOACs
• increase anticoagulant activity
e.g: heparin

38
Q

How can anticoagulants be used therapeutically for venous thrombosis?

A
  • Initial treatment to minimise clot extension/embolisation (< 3 months)
  • Long term treatment to reduce risk of recurrence
39
Q

How can anticoagulants be used therapeutically for atrial fibrillation?

A
  • 800 per 100 000 population potentially eligible in 1 year

- To reduce risk of embolic stroke

40
Q

How else can anticoagulants be used therapeutically?

A

Mechanical prosthetic heart valve

41
Q

How can anticoagulants be used in a preventative way

A

(Thromboprophylaxis)

•E.g. following surgery, during hospital admission, during pregnancy

42
Q

What is heparin?

A
  • Naturally occurring glycosaminoglycan
  • Produced by mast cells of most species
  • Porcine products used in UK
43
Q

What are the chains like in heparin?

A

•Varying numbers of saccharides in chains – differing lengths

  1. Long chains - Unfractionated (UFH) – intravenous administration, short half life
  2. Low molecular weight (LMWH) – subcutaneous administration
44
Q

How does unfractionated heparin work?

A

•Enhancement of Antithrombin

  1. Inactivation of thrombin (Hep binds AT + Thrombin)
  2. Inactivation of FXa (Hep binds AT only)
  3. (Inactivation of FIXa, FXIa, FXIIa)
45
Q

How does LMW heparin work?

A
  • Contain pentasaccharide sequence for binding AT

* Predictable dose response in most cases so does not require monitoring (cf UFH)

46
Q

How does LMW heparin affect APTT?

A
  • Not useful for monitoring so if need to measure use Anti-Xa
  • No monitoring required as predictable effect
47
Q

How does unfractioned heparin affect APTT?

A

Prolongation, used to monitor effect

48
Q

How does Warfarin work?

A
  1. Blocks recycling of VitK
  2. So VitK dependent clotting factors 2,7,9,10 and anticoagulant factors proteins C and S
  3. VitK cannot be reduced back down to hydroquinone state and reused for gaba carboxylation
49
Q

Why is it bad that warfarin competes with Vit K?

A

– complicated metabolism
•Many dietary, physiological and drug interactions
•Narrow therapeutic index and requires monitoring

50
Q

What is the effect of warfarin?

A
  • Reduces production of functional coagulation factors

* Induces an anticoagulated state slowly

51
Q

Is warfarin reversible? How is it reversed slowly?

A
  • Reversible

- Reversed slowly by Vit K administration – takes several hours to work

52
Q

How is warfarin reversed rapidly?

A

infusion of coagulation factors:

  1. PCC (Prothrombin Complex Concentrate- contains Factors II, VII, IX and X)
  2. FFP (Fresh Frozen Plasma)
53
Q

What are warfarin side effects?

A 
-Bleeding
•Minor 5% pa
•Major 0.9 – 3.0% pa
•Fatal 0.25% pa
-Skin Necrosis
-Purple toe syndrome
-Embryopathy – Chondrodysplasia punctata
54
Q

What is skin necorsis?

A
  • Severe protein C deficiency
  • 2-3 days After starting warfarin
  • thrombosis predominately in adipose tissues
  • Can start on heparin instead - need overlap
55
Q

What is purple toe syndrome?

A
  • Disrupted atheromatous plaques bleed

- Cholesterol embolI lodge in extremities

56
Q

What is chondrodysplasia?

A
  • Early fusion of epiphyses

- Warfarin teratogenic in 1st trimester

57
Q

How do you monitor warfarin?

A
  • ISI = International Sensitivity Index
  • Indicates sensitivity of particular thromboplastin for warfarin
  • Unanticoagulated normal INR = 1.0
  • Target INR usually 2-3
58
Q

Why can there be resistance to warfarin?

A
  1. Lack of patient compliance
    •Measure warfarin levels
    •Proteins Induced by Vitamin K Absence (PIVKA)
  2. Diet, Increased Vit K intake
  3. Increased metabolism Cyt P450 (CYP2C9)
  4. Reduced binding (VKORC1)
59
Q

Which DOAC’s work as a direct inhibitor of factor Xa?

A
  1. Rivaroxaban
  2. Apixaban
  3. Edoxaban
60
Q

Which DOAC’s work as a direct inhibitor of factor IIa?

A

Dabigatran

61
Q

What is the difference between DOACs and warfarin with onset/offset?

A
  • Warfarin: slow

- DOACs: rapid

62
Q

What is the difference between DOACs and warfarin with dosing?

A
  • Warfarin: variable

- DOACs: fixed

63
Q

What is the difference between DOACs and warfarin with food effect?

A
  • Warfarin: yes

- DOACs: No

64
Q

What is the difference between DOACs and warfarin with interactions?

A
  • Warfarin: many

- DOACs: few

65
Q

What is the difference between DOACs and warfarin with monitoring required?

A
  • Warfarin: yes

- DOACs: no

66
Q

What is the difference between DOACs and warfarin with renal dependence?

A
  • Warfarin: no

- DOACs: some

67
Q

What is the difference between DOACs and warfarin with reversibility?

A
  • Warfarin: vitamin K / PCCs

- DOACs: specific antidotes available for dabigatran and in development for FXa inhibitors

68
Q

Which anticoagulant do you use for intial treatment to minimise clot extension/embolism (<3 months) for a therapeutic effect in venous thrombosis?

A

-DOAC or LMWH for first few days followed by DOAC or warfarin

69
Q

Which anticoagulant do you use for long term treatment to reduce risk of reccurence for a therapeutic effect in venous thrombosis?

A

-DOAC or warfarin

70
Q

What anticoagulant do you give for a therapeutic effect in atrial fibrillation to reduce risk of embolic stroke?

A

-DOAC or warfarin

71
Q

Which anticoagulant do you give in a therapeutic effect for those with mechanical prosthetic hear valve?

A
  • Warfarin (DOACs not effective and should be avoided)
72
Q

Which anticoagulant do you give for a preventative effect following surgery?

A
  • lower doses used

- LMWH or DOAC

73
Q

Which anticoagulant do you give for a preventative effect during hospital admission?

A
  • lower doses used

- (DOACs not effective for use as medical thromboprophylaxis

74
Q

Which anticoagulant do you give for a preventative effect during pregnancy?

A
  • lower doses used

- LMWH (DOACs not safe in pregnancy)

Z YEAR 2 BRS CARDIO (18 decks)

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