BMS3021 Lecture Notes - Lecture 16: Helper Virus, Glycoprotein, Copii
30 May 2018
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Week 6. Lung and circulatory disease - Coagulation
and haemophilia
COAGULATION AND HAEMOPHILIA
• Initial injury -> break in integral blood vessel -> recruit platelets first -> surface has assembly of
factors that drive formation of fibrin clot -> thrombus -> stays while underlying endothelial cells
are repaired -> the lood lot is reoved a have troule if this does’t happe
-This is a finely tuned process
• Coagulation pathway:
o Vessel injury triggers stepwise activation of circulating inactive coagulation enzymes
o Extrinsic pathway: triggered by trauma/wounding that opens blood vessels
o Intrinsic pathway: not well understood
o Both pathways converge at factor 10
o Activated factors convert something to a biological reactive agent
• Coagulation factors:
o Most components (including IXa, Xa and IIa) are proteases
o VIIIa and Va are non-proteolytic cofactors involved in the activation of the proteases on
the surface of membranes
-presence accelerates a conversion process
o Cofactors themselves must be activated i.e. factor VIII is converted to VIIIa by proteolysis
find more resources at oneclass.com
find more resources at oneclass.com
• Haemophilia: disease manifested by uncontrolled bleeding due to dysfunction in a coagulation
factor
Major forms:
Haemophilia A
o Cofactor VIII deficiency
o Most common
o Normal plasma levels of factor VIII are 0.2nmol.L
o Severe haemophilia is less than 1% normal factor VIII
o Moderate haemophilia : 1-5% normal levels
o Have problems with internal bleeding
o Low plasma concentrations of factor VIII makes replacement therapy a good
option
o Lack of VIII means activation of X by factor IXa in the intrinsic pathway does
not occur – no cofactor
o Extrinsic pathway still operates
o Clinical description:
Bleeding episodes in joints, muscles, organs, brain
Bleeding into joints is most common
- leads to loss of joint mobility (intrinsic pathway defect)
No major problems with bleeding from membranes (extrinsic
pathway is unaffected)
o Acquired:
Commonly caused by autoantibodies (inhibitors) against factor VIII
(or factor V)
Affects mainly elderly
Bleeding tendency is severe, occasionally life threatening
Specific mechanism is unknown
o Bleeding may be caused by:
Lac of factor VIII protein – not synthesised or unstable
Dysfunctional factor VIII protein – synthesised normally but inactive
Presence of factor VIII inhibitors
o Diagnosis:
Measurement of circulating VIII protein levels by immunological
assay
Measurement of protein function via activated partial
thromboplastin time (measures intrinsic pathway function)
Genetic diagnosis: identification of causative mutation in VIII gene
o Genetics:
Occurs in all ethnic groups
High levels of spontaneous mutations i.e. 30% of patients have no
family history (can run in families)
X-linked, affects 1 in 5000 males
Mutation is mostly DNA rearrangement (>50% frequency) –
abolishes protein – no VIII circulation at all
o Treatment:
Bleeding can be managed by the injection of purified factor VIII
o dead – give only in response to bleeding episode
or
Prophylactic – give regularly as a preventative
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
Lung and circulatory disease - coagulation and haemophilia. This is a finely tuned process: coagulation pathway, vessel injury triggers stepwise activation of circulating inactive coagulation enzymes, extrinsic pathway: triggered by trauma/wounding that opens blood vessels. Presence accelerates a conversion process: cofactors themselves must be activated i. e. factor viii is converted to viiia by proteolysis, haemophilia: disease manifested by uncontrolled bleeding due to dysfunction in a coagulation factor. Bleeding episodes in joints, muscles, organs, brain. Leads to loss of joint mobility (intrinsic pathway defect) No major problems with bleeding from membranes (extrinsic pathway is unaffected: acquired: Commonly caused by autoantibodies (inhibitors) against factor viii (or factor v) Bleeding tendency is severe, occasionally life threatening. Specific mechanism is unknown: bleeding may be caused by: Lac of factor viii protein not synthesised or unstable. Dysfunctional factor viii protein synthesised normally but inactive. Presence of factor viii inhibitors: diagnosis: Measurement of circulating viii protein levels by immunological assay.
