Haemostasis and inherited bleeding disorders Flashcards
(78 cards)
1
Q
What are the key components of clotting?
A
- Platelets
- Von Willebrand factor
- Clotting proteins
2
Q
Describe primary haemostasis
A
- Platelets adhere to the margins of the lesions
- Platelets aggregate forming a primary platelet plug
3
Q
What are platelets?
A
- Non-nucleated cytoplasmic fragments derived from bone marrow megakaryocytes
4
Q
How large are platelets?
A
1 to 4 micrometres in diameter
5
Q
How long do platelets live for?
A
8 - 14 days
6
Q
What system removes platelets?
A
Reticuloendothelial system removes them from circulation
7
Q
What are the most abundant glycoprotein molecules?
A
- GpIIb / IIIa heterodimer complex
- GpIb
8
Q
What are the glycoprotein molecules on platelets receptors for?
A
- Agonists
- Adhesive proteins
- Coagulation factors
- Other platelets
9
Q
What are the 2 main components of the platelet cell membrane?
A
- Glycoprotein molecules
- Phospholipids
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
11
Q
What are some platelet specific granules?
A
- Dense bodies
- Nucleotides (ADP)
- Alpha-granules (VWF, platelet factor 4 etc.)
12
Q
What does VWF bind to?
A
Connects collagen to platelets and platelets to each other
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
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
15
Q
What glycoprotein on the platelet binds to VWF on the collagen?
A
GpIb
16
Q
What does GP IIb/IIIa do?
A
- Forms a second binding site for VWF
- Fibrinogen bound to promote platelet aggregation
17
Q
In what condition do patients lack GpIb?
A
Bernard Soulier syndrome
18
Q
In what condition do patients lack GpIIb/IIa?
A
Glanzmann’s syndrome
19
Q
What do patients with serious inherited platelet disorders (such as Bernard Soulier or Glanzmann’s syndrome) require?
A
- Platelets or Novoseven
20
Q
Whaat is the most common bleeding disorder?
A
Von Willebrand disease (deficient or defective vWF)
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
22
Q
How is Von Willebrand disease inherited?
A
Autosomal dominant (equal in males and females)
23
Q
What is Von Willebrand disease treated with?
A
- DDAVP
- Tranexamic acid
- VWF containing concentrate
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
25
Describe secondary haemostasis?
- 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'
26
Coagulation pathway
LEARN
27
What is the main protein responsible for clotting?
Fibrin
28
What enzyme converts fibrinogen into fibrin?
Thrombin
29
What factors does thrombin activate?
- 11
- 5
- 8
These then increase indirectly the amount of fibrin
30
What is Disseminated Intravascular Coagulopathy?
Rare but serious condition that causes abnormal blood clotting throughout the body's blood vessels
31
What part of the coagulation pathway is affected in haemophilia A?
- Factor 8
- Acceleration step of coagulation pathway is lacking
- Tissue factor and factor 7 are ok
32
How can haemophilia be classified?
- A or B (factor 8 or 9)
| - Severe (<1%), Moderate (2-5%) or Mild (5-40%)
33
What factor is affected in haemophilia b?
Factor 9
34
Where can bleeds occur in severe haemophilia?
- Soft tissue
- Joints (knees, ankles, elbows)
- Psoas
- Intracranial
- Operative sites (haematomas may become compromising)
35
How is severe haemophilia treated?
- 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
What is mild and moderate haemophilia treated with?
- DDAVP (for haemophilia A)
| - Factor replacement (usually in times of emergency)
37
What does antithrombin inhibit?
- Thrombin and Xa
| - (also VII, IX and XI)
38
How does heparin affect coagulation?
Increases activity of antithrombin 5 - 10,000 fold
| - Works by binding to heparin sulfate on the surface of the vascular endothelium
39
What do protein C and S do?
- Anticoagulation
- Vitamin K dependent glycoprotein synthesised in the liver
- Act on actor 8 and 5
40
Describe the fibrinolytic pathway
- Plaminogen is converted to plasmin through tissue plasminogen activator (tPA)
- Plasmin dissolves fibrin into soluble products
41
By how much does consanguinity increase the incidence of rare bleeding disorders?
10 - 20 times
42
Give examples of rare bleeding disorders
- 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
What is Menorrhagia?
- Heavy periods
| - Periods that last more than 7 days
44
What are some common smptoms of rare bleeding disorders?
- Mucosal bleeding
| - Mennorhagia in 50%
45
What time is reduced in a factor 7 deficiency?
Prothrombin (PT)
| - APTT is normal
46
What time is reduced in a factor VIII, IX, XI deficiency?
APTT
| - PT is normal
47
If a patient has an abnormal PT and APTT what factor deficiency could be responsible?
- Fibrinogen, 2, 5, 5+8, 10
48
What is a classic presentation for someone to be diagnosed with a rare bleeding disorder?
Prolonged bleeding post dental extraction
49
What specific population has a predisposition for factor XI deficiency?
Ashkenazi Jewish population
50
Do the levels of factor XI correlate with how much the patient bleeds?
No - 30% of severes do not bleed
| - In contrast haemophilia is related
51
What sites are mostly affected by factor XI deficiency?
- Mucosal and urogenital areas
| - Closed spaces and the spine
52
How is factor XI deficiency treated?
- 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
How do levels of factor VII correlate to bleeding tendency?
Poorly correlated (factor VII deficiency can often be a coincidental finding)
54
How is factor VII deficiency treated?
Low dose recombinant factor VIIa (15-30ug/kg)
55
How is Factor V deficiency treated?
Plasma - solvent detergent FFP (octoplas) as no concentrate fV available
56
How much factor V do you need for haemostasis?
Small amount (>15iu/dl)
57
Is fV deficiency severe?
- Generally mild
- Some children have early severe presentation
- Check VIII level
58
When is factor V + VIII deficiency severe?
- Generally has a mild phenotype
| - Surgery and injuries can cause severe bleeding
59
Where is the genetic abnormality in fV and VIII deficiency?
- VIII and V genetics are normal
| - Abnormality of cellular transport (ERGIC)
60
How is fV and VIII deficiency treated?
- VIII concentrate
- DDAVP
- Plasma
61
How can fibrinogen deficiency be broken down?
- Quantitative (too little or none)
- Qualitative (dysfibrinogenaemia)
- Coexist (hypodysfibrinogenaemia)
62
When can fibrinogen deficiency often be diagnosed?
- After birth (umbilical cord bleeding)
- Potential severe bleeding phenotype
- Often causes recurrent miscarriages and PPH
63
How can fibrinogen deficiency be treated?
- Cryoprecipitate or fibrinogen concentrate
- Both plasma derived
- Cryo. not pathogen inactivated
- Fibrinogen concentrate (heat inactivated)
64
How much fibrinogen is aimed for in replacement when a patient is during pregnancy?
- > 1g/L during pregnancy
| - > 2g/L for delivery
65
What is used in factor II deficiency menorrhagia?
Combined pill
66
Is there a bleeding correlation with severity level for factor X deficiency?
Yes
67
Explain factor XIII deficiency
- 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
What factors are affected by vitamin K dependent factor deficiency?
II, VII, IX and X (if one is found to be deficienct look for the others)
69
What is Vit K deficiency treated with?
- Prothrombin complex concentrate
- Plasma
- All neonates given vit K in case of haemorrhage in brain
70
What rare bleeding disorders' mutations are not in the corresponding clotting factor gene?
- Combined V and VIII deficiency
| - Vit K dependent factor deficiency
71
Are most rare bleeding disorders recessic=ve or dominant?
Autosomal recessive
72
What are severe platelet disorders?
- Glanzmann thrombasthenia
| - Bernard-Soulier
73
What is absent in Glanzmanns?
- Absent IIb/IIIa receptor on platelet surface (therefore looks normal under microscope and also normal count in FBC)
74
How can Glanzmanns be detected?
- PFA grossly abnormal
- Platelet aggregometry (absent response to all except ristocetin)
- Flow cytometry (demonstrate absent IIb/IIIa)
75
What is absent is Bernard-Soulier?
- Absent Ib/IX/V receptor on platelet surface (vWF receptor)
76
How can Bernard-Souliers be detected?
- 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
What are the treatment options in Glanzmanns and Bernanrd soulier?
- 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
How must rare bleeding disorders be managed (outwith medical management)
- Education
- Travel insurance
- Dental (post brushing or shaving bleeds - topical tranxemaic acid)
- Family screening and genetic counselling
- Hepatitis vaccination relevant
