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Barts year 3 semester 1 > Haemostasis and inherited bleeding disorders > Flashcards

Haemostasis and inherited bleeding disorders Flashcards

1
Q

What are the key components of clotting?

A
  • Platelets
  • Von Willebrand factor
  • Clotting proteins
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2
Q

Describe primary haemostasis

A
  • Platelets adhere to the margins of the lesions

- Platelets aggregate forming a primary platelet plug

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3
Q

What are platelets?

A
  • Non-nucleated cytoplasmic fragments derived from bone marrow megakaryocytes
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4
Q

How large are platelets?

A

1 to 4 micrometres in diameter

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5
Q

How long do platelets live for?

A

8 - 14 days

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6
Q

What system removes platelets?

A

Reticuloendothelial system removes them from circulation

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7
Q

What are the most abundant glycoprotein molecules?

A
  • GpIIb / IIIa heterodimer complex

- GpIb

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8
Q

What are the glycoprotein molecules on platelets receptors for?

A
  • Agonists
  • Adhesive proteins
  • Coagulation factors
  • Other platelets
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9
Q

What are the 2 main components of the platelet cell membrane?

A
  • Glycoprotein molecules

- Phospholipids

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10
Q

What is the phospholipid membrane on the platelet associated with?

A
  • Prostaglandin synthesis
  • Calcium mobilization
  • Localisation of coagulant activity to the platelet surface
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11
Q

What are some platelet specific granules?

A
  • Dense bodies
  • Nucleotides (ADP)
  • Alpha-granules (VWF, platelet factor 4 etc.)
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12
Q

What does VWF bind to?

A

Connects collagen to platelets and platelets to each other

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13
Q

What does VWF bind to?

A

Connects collagen to platelets and platelets to each other (glue between platelets)
- Captures platelets to form plug

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14
Q

What does VWF bind to?

A

Connects collagen to platelets and platelets to each other (glue between platelets)
- Captures platelets to form plug

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15
Q

What glycoprotein on the platelet binds to VWF on the collagen?

A

GpIb

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16
Q

What does GP IIb/IIIa do?

A
  • Forms a second binding site for VWF

- Fibrinogen bound to promote platelet aggregation

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17
Q

In what condition do patients lack GpIb?

A

Bernard Soulier syndrome

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18
Q

In what condition do patients lack GpIIb/IIa?

A

Glanzmann’s syndrome

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19
Q

What do patients with serious inherited platelet disorders (such as Bernard Soulier or Glanzmann’s syndrome) require?

A
  • Platelets or Novoseven
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20
Q

Whaat is the most common bleeding disorder?

A

Von Willebrand disease (deficient or defective vWF)

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21
Q

What are the 3 types of Von Willebrand disease

A
  • Type 1 - mild to moderate deficiency
  • Type2 - protein present but defective
  • Type3 - total absent proetien
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22
Q

How is Von Willebrand disease inherited?

A

Autosomal dominant (equal in males and females)

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23
Q

What is Von Willebrand disease treated with?

A
  • DDAVP
  • Tranexamic acid
  • VWF containing concentrate
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24
Q

How is tissue factor activated?

A
  • Present on subendothelial cells which are not normally exposed to flowing blood
  • Physical injury exposes TF to flowing blood
  • Initiates coagulation via factor VII
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25
Q

Describe secondary haemostasis?

A
  • Tf activates coagulation factors in the blood at the site of injury
  • Coagulation factors adhere to the platelet surfaces and form catalytic complexes
  • Complexes cause formation of thrombin
  • Thrombin converts fibrinogen to fibrin
  • Fibrin polymers form long chains between platelets in the platelet plu, are crossed linked and form a stable ‘clot’
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26
Q

Coagulation pathway

A

LEARN

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27
Q

What is the main protein responsible for clotting?

A

Fibrin

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28
Q

What enzyme converts fibrinogen into fibrin?

A

Thrombin

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29
Q

What factors does thrombin activate?

A
  • 11
  • 5
  • 8
    These then increase indirectly the amount of fibrin
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30
Q

What is Disseminated Intravascular Coagulopathy?

A

Rare but serious condition that causes abnormal blood clotting throughout the body’s blood vessels

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31
Q

What part of the coagulation pathway is affected in haemophilia A?

A
  • Factor 8
  • Acceleration step of coagulation pathway is lacking
  • Tissue factor and factor 7 are ok
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32
Q

How can haemophilia be classified?

A
  • A or B (factor 8 or 9)

- Severe (<1%), Moderate (2-5%) or Mild (5-40%)

33
Q

What factor is affected in haemophilia b?

A

Factor 9

34
Q

Where can bleeds occur in severe haemophilia?

A
  • Soft tissue
  • Joints (knees, ankles, elbows)
  • Psoas
  • Intracranial
  • Operative sites (haematomas may become compromising)
35
Q

How is severe haemophilia treated?

A
  • Patients learn from a young age to moderate factor 8 levels by IV infusion of factor 8
  • Infusions are used as prophylaxis and also targeted around activity (e.g sport)
36
Q

What is mild and moderate haemophilia treated with?

A
  • DDAVP (for haemophilia A)

- Factor replacement (usually in times of emergency)

37
Q

What does antithrombin inhibit?

A
  • Thrombin and Xa

- (also VII, IX and XI)

38
Q

How does heparin affect coagulation?

A

Increases activity of antithrombin 5 - 10,000 fold

- Works by binding to heparin sulfate on the surface of the vascular endothelium

39
Q

What do protein C and S do?

A
  • Anticoagulation
  • Vitamin K dependent glycoprotein synthesised in the liver
  • Act on actor 8 and 5
40
Q

Describe the fibrinolytic pathway

A
  • Plaminogen is converted to plasmin through tissue plasminogen activator (tPA)
  • Plasmin dissolves fibrin into soluble products
41
Q

By how much does consanguinity increase the incidence of rare bleeding disorders?

A

10 - 20 times

42
Q

Give examples of rare bleeding disorders

A
  • Prothrombin (factor XI, VII, V, X, II) deficiency
  • Factor XIII and fibrinogen
  • Combined V and VII, Vit K dep factors deficiency
  • Platelet disorders (Glanzmanns, Bernard-Soulier)
43
Q

What is Menorrhagia?

A
  • Heavy periods

- Periods that last more than 7 days

44
Q

What are some common smptoms of rare bleeding disorders?

A
  • Mucosal bleeding

- Mennorhagia in 50%

45
Q

What time is reduced in a factor 7 deficiency?

A

Prothrombin (PT)

- APTT is normal

46
Q

What time is reduced in a factor VIII, IX, XI deficiency?

A

APTT

- PT is normal

47
Q

If a patient has an abnormal PT and APTT what factor deficiency could be responsible?

A
  • Fibrinogen, 2, 5, 5+8, 10
48
Q

What is a classic presentation for someone to be diagnosed with a rare bleeding disorder?

A

Prolonged bleeding post dental extraction

49
Q

What specific population has a predisposition for factor XI deficiency?

A

Ashkenazi Jewish population

50
Q

Do the levels of factor XI correlate with how much the patient bleeds?

A

No - 30% of severes do not bleed

- In contrast haemophilia is related

51
Q

What sites are mostly affected by factor XI deficiency?

A
  • Mucosal and urogenital areas

- Closed spaces and the spine

52
Q

How is factor XI deficiency treated?

A
  • Factor concentrate - plasma derived
  • Avoid concurrent tranexamic acid (only for simple procedures)
  • Aim for low normal levels (thrombotic potential)
  • Alternate day dosing (due to long half life)
  • Consider thromboprophylaxis when replacing factor 11
53
Q

How do levels of factor VII correlate to bleeding tendency?

A

Poorly correlated (factor VII deficiency can often be a coincidental finding)

54
Q

How is factor VII deficiency treated?

A

Low dose recombinant factor VIIa (15-30ug/kg)

55
Q

How is Factor V deficiency treated?

A

Plasma - solvent detergent FFP (octoplas) as no concentrate fV available

56
Q

How much factor V do you need for haemostasis?

A

Small amount (>15iu/dl)

57
Q

Is fV deficiency severe?

A
  • Generally mild
  • Some children have early severe presentation
  • Check VIII level
58
Q

When is factor V + VIII deficiency severe?

A
  • Generally has a mild phenotype

- Surgery and injuries can cause severe bleeding

59
Q

Where is the genetic abnormality in fV and VIII deficiency?

A
  • VIII and V genetics are normal

- Abnormality of cellular transport (ERGIC)

60
Q

How is fV and VIII deficiency treated?

A
  • VIII concentrate
  • DDAVP
  • Plasma
61
Q

How can fibrinogen deficiency be broken down?

A
  • Quantitative (too little or none)
  • Qualitative (dysfibrinogenaemia)
  • Coexist (hypodysfibrinogenaemia)
62
Q

When can fibrinogen deficiency often be diagnosed?

A
  • After birth (umbilical cord bleeding)
  • Potential severe bleeding phenotype
  • Often causes recurrent miscarriages and PPH
63
Q

How can fibrinogen deficiency be treated?

A
  • Cryoprecipitate or fibrinogen concentrate
  • Both plasma derived
  • Cryo. not pathogen inactivated
  • Fibrinogen concentrate (heat inactivated)
64
Q

How much fibrinogen is aimed for in replacement when a patient is during pregnancy?

A
  • > 1g/L during pregnancy

- > 2g/L for delivery

65
Q

What is used in factor II deficiency menorrhagia?

A

Combined pill

66
Q

Is there a bleeding correlation with severity level for factor X deficiency?

A

Yes

67
Q

Explain factor XIII deficiency

A
  • Doesnt sit within conventional pathways of APTT or PT
  • It is a post fibrin generated factor that cross-links fibrin strands
  • Often diagnosed after prolonged umbilical stump bleeding
  • Conventional bleeding tests will not detect
  • Concentrate is being trialed (used in cardiothoracic surgery)
68
Q

What factors are affected by vitamin K dependent factor deficiency?

A

II, VII, IX and X (if one is found to be deficienct look for the others)

69
Q

What is Vit K deficiency treated with?

A
  • Prothrombin complex concentrate
  • Plasma
  • All neonates given vit K in case of haemorrhage in brain
70
Q

What rare bleeding disorders’ mutations are not in the corresponding clotting factor gene?

A
  • Combined V and VIII deficiency

- Vit K dependent factor deficiency

71
Q

Are most rare bleeding disorders recessic=ve or dominant?

A

Autosomal recessive

72
Q

What are severe platelet disorders?

A
  • Glanzmann thrombasthenia

- Bernard-Soulier

73
Q

What is absent in Glanzmanns?

A
  • Absent IIb/IIIa receptor on platelet surface (therefore looks normal under microscope and also normal count in FBC)
74
Q

How can Glanzmanns be detected?

A
  • PFA grossly abnormal
  • Platelet aggregometry (absent response to all except ristocetin)
  • Flow cytometry (demonstrate absent IIb/IIIa)
75
Q

What is absent is Bernard-Soulier?

A
  • Absent Ib/IX/V receptor on platelet surface (vWF receptor)
76
Q

How can Bernard-Souliers be detected?

A
  • Platelets morphologically large and reduced in number
  • PFA abnormal
  • Platelet aggregometry (absent response to ristocetin, others normal)
  • Flow cytometry (demonstrate absent Ib/IX/V)
77
Q

What are the treatment options in Glanzmanns and Bernanrd soulier?

A
  • Platelets (ideally HLA matched donor)
  • Recombinant VIIa (90mcg/Kg)
  • Tranexamic acid
  • Combined pill
  • Bone marro transplantation
  • Recipient can form HLA and anti receptor ab (immune response to donor)
78
Q

How must rare bleeding disorders be managed (outwith medical management)

A
  • Education
  • Travel insurance
  • Dental (post brushing or shaving bleeds - topical tranxemaic acid)
  • Family screening and genetic counselling
  • Hepatitis vaccination relevant

Barts year 3 semester 1 (7 decks)

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