Week 5 Coagulation Lecture 1 - Haemophilias & Rare Coagulation Disorders Flashcards
Haemophilia A & Haemophilia B
Haemophilia A is an X-linked hereditary disorder that is due to defective and/or deficient factor FVIII molecule
Haemophilia B is an X-linked hereditary disorder that is due to defective and/or deficient factor IX molecule
Haemophilia A & Haemophilia B - Clinical Features
Lack of excessive bleeding from minor cuts and abrasion
- reflects ‘normal’ platelet function
Easy bruising
Soft tissue haematomas
Haemarthrosis and subsequent joint dysfunction
Prolonged and potentially fatal postoperative haemorrhage
Types of Bleeds - Haematomas and Pseudotumours
Haematoma
- haemorrhage into connective tissue or muscle
- have a tendency to progressively enlarge and to dissect in all directions
Pseudotumour
- occur in 1-2% of patients with severe haemophilia
- usually present as a painless expanding mass growing slowly
- start as a simple cyst, following a bleed into a muscle or soft tissue
- as it increases in size it compresses and destroys the adjacent muscle, nerve, bone etc
Types of Bleeds - Haemarthrosis
It is a bleed into the joints
Accounts for ~75% of bleeds
Haemophilic arthropathy is usually multiarticular
Ankles are commonly affected in children
Knees, elbows and ankles in adolescents and adults
Repeated bleeds leads to joint damage
Chronic toxic effects of blood and an inflamed synovium result in eroding into cartilage and subchondral bone, causing subarticular cyst formation
Types of Bleeds - Neurologic Conditions
The most dangerous haemorrhagic event in haemophiliac patients
Accounts for 25% of the deaths in haemophiliacs
Bleeding may be subdural, epidural, subarachnoid, intracerebral or rarely intraspinal
Classification of Haemophilia (Severe, Moderate, Mild)
Severe
- less than 1% FVIII:C/FIX
- bleeding occurs without known trauma
- haemarthrosis becomes frequent at about the time the patient begins to walk and chronic haemophilic arthropathy by early adulthood
- soft tissue haemorrhages dissect tissue planes and compromise vital organs
Moderate
- 1%-5% FVIII:C/FIX
- occasional haemarthrosis and haematomas, usually, but not always associated with trauma
- haemarthropathy is less disabling than in the severe patients
Mild
- 6%-30% FVIII:C/FIX
- infrequent bleeding episodes
- excessive haemorrhage following surgery or injury
Laboratory Aspects - Haemophilia A
General:
- BT = normal
- PFA = normal
- [platelet] = normal
- platelet function = normal
Screening assays:
- PT = normal
- aPTT = abnormal (prolonged)
Specific assays:
- FVIII:C = abnormal
- aPTT 50:50 mix with normal plasma shows sustained correction
- FVIII.Ag distunguishes deficiency from dysfunctional proteins
- VWF.Ag = normal/increased
- VWF function = normal
Laboratory Aspects - Haemophilia B
(Same as lab aspects of Haemophilia A)
General:
- BT = normal
- PFA = normal
- [platelet] = normal
- platelet function = normal
Screening assays:
- PT = normal
- aPTT = abnormal (prolonged)
Specific assays:
- FIX:C = abnormal
- aPTT 50:50 mix with normal plasma shows sustained correction
- FIX.Ag distinguishes deficiency from dysfunctional proteins
- VWF.Ag = normal
- VWF function = normal
Haemophilia in Females
Rarely may affect females
Inherit two copies of affected F8 gene
- extremely rare - affected father and carrier mother
May also occur in female with other X-chromosomal abnormalities
- e.g. Turner syndrome (X0) or X mosaicism
Symptomatic carriers can occur:
- with factor levels as low as 20%
- due to extreme Lyonisation ‘normal’ X chromosome /F8 gene
FVIII Protein Structure
The molecule is organised into six domains
They are arranged from the amino to the carboxy-terminus in the order (NH2)A1-A2-B-A3-C1-C2(COOH)
FVIII consist of a light chain comprising the A3-C1-C2 domains, and a heavy chain comprising the A1-A2 domains and a variable amount of the B domain
Thrombin and FXa both activate FVIII
After thrombin activation a portion of the B domain is removed
FVIII is a very labile and decays spontaneously in the absence of further proteolysis
FVIII Complex
FVIII and vWF circulate in blood as a complex
Deficiency of FVIII (FVIII:C) leads to Haemophilia A
Deficiency/abnormality of VWF leads to Von Willebrand Disease
VWF ‘protects’ FVIII from proteolysis in circulation
Haemophilia A Variant - Inversion Intron 22
~497 kb distal to 3’ end of the F8 gene
Interrupts F8 mRNA at intron 22
Makes up ~50% severe cases; 36% all cases
Haemophilia A Variant - Inversion Intron 1
Int1h-1; 15.26 kb downstream of exon 1
Int1h-2; 125 kb upstream of exon 1
=> altered mRNA; short F8 mRNA, incl. exon 1 only
Uncommon; ~ 1%
Haemophilia A Variant - Point Mutations
Affects all exons
‘Hot-spots’
- CpG sites (70)
- spontaneous deamination of methyl-cytosine
May produce missense or nonsense proteins
=> Range of clinical manifestations (mild, moderate, severe)
May affect splice sites
Haemophilia A Variant - Insertions
Affect most exons
Largest number of mutations affecting exon 14 (54/109)
‘Hotspots’ within exon 14
- 9As; codons 1191-1194
- 8As; codons 1439-1441
- 6As; codons 1588-1590
None reported for exons 10, 15, 23, 26