Heritable bleeding disorders Flashcards
What are the primary and secondary stages in haemostatic plug formation?
Primary - platelet aggregation
Secondary - coagulation cascade forming a fibrin clot which stabilises the platelet plug
What are the 3 basic steps in platelet adhesion and activation?
1) Sight of vascular injury which platelets adhere to (via vWF which sticks to collagen in vessel wall)
2) As they adhere to the damaged endothelium they become activated
3) Activated platelets activate other platelets and they aggregate into a thrombus
How are clotting screen tests carried out?
Get rid of the cells from the blood so you are left with just plasma and activate the plasma by adding a reagent - time from when reagent added to fibrin clot formation (also add calcium as many of the reactions are calcium dependent)
What does the thrombin time measure?
The time taken for thrombin to cleave fibrinogen to fibrin
Which clotting factor cleaves pro-thrombin?
Factor 10a along with 5a which acts as a co factor
On what 2 surfaces does a lot of the clotting cascade take place?
1) Tissue factor bearing cells
2) Activated platelets
In vivo what is the role of the intrinsic pathway?
More of an amplification process
What is the sequence of the intrinsic pathway?
12-11-9-8
Common pathway 5 and 10 cleave prothrombin to thrombin which cleaves fibrinogen to fibrin
How is the extrinsic pathway activated?
TF activates 7 and TF-7a complex combine to cleave 10 to 10a
Platelets and clotting factors are the 2 procoagulants, name the 4 anti-coagulants?
1) Protein C
2) Protein S
3) Anti-thrombin 3
4) Fibrinolytic system
Which enzyme breaks down fibrin?
Plasmin (from plasminogen)
Which enzyme cleaves plasminogen?
Tissue plasminogen activator - an enzyme from the tissues
Name an enzyme involved in mopping up extra plasmin?
alpha 2 anti plasmin
Do congenital bleeding disorders often involve a single defect or multiple?
A single defect
Do acquired bleeding disorders often involve a single defect or multiple?
Multiple
People with defects in the primary coagulation pathway (platelets) tend to have what sort of bleeding pattern?
Bleeding into mucosa/skin, GI bleeding, menorrhagia, epistaxis, easy bleeding
People with defects in the secondary coagulation pathway (clotting factors) tend to have what sort of bleeding pattern?
Deep muscular and joint bleeds and bleeding following trauma
What are the 4 types of platelet/vessel wall defects (all of which give rise to a prolonged bleeding time)?
1) Reduced number of platelets (thrombocytopenia)
2) Abnormal platelet function (nb, drugs/aspirin)
3) Abnormal vessels wall
4) Abnormal interaction between platelets and vessel wall (von willebrand disease)
What is a petechial rash?
Small red dots in the skin which don’t blanch when you press them caused by bleeding into the skin
‘Petechiae and superficial bruises’ v ‘deep spreading haematoma’ - which is likely to be a coagulation defect and which a wall/platelet defect?
Petechiae and superficial bruises - platelets
Deep spreading haematoma - coagulation
‘skin and mucous membranes bleeding’ v ‘haemarthrosis’ - which is likely to be platelets/wall and which coagulation?
Skin and mucous membranes - vascular/ platelet
Haemarthrosis - coagulation
‘Spontaneous bleeding’ v ‘retroperitoneal bleeding’ which is likely to be platelets/wall and which coagulation?
Spontaneous bleeding - platelets
Retroperitoneal bleeding - coagulation
‘Bleeding prolonged and often recurrent’ v ‘bleeding immediate, prolonged and non recurrent’ - which is likely to be platelets/wall and which is coagulation?
Bleeding prolonged and recurrent - coagulation
Bleeding immediate, prolonged and non recurrent - wall/platelets
Are petechiae palpable?
No
What is the role of vWF?
Facilitates adhesion of platelets to vessel wall and under high shear conditions promotes platelet aggregation
Where is VWF synthesised?
Endothelial cells
How many types of von willebrand disease exist?
3
What is the structure of vwf?
Multimeric protein (made up of many multimers)
What are the 3 types of VW disease, what is the defect in each?
1) Mild type 1 - reduced production of normal molecule (less severe)
2) Type 2 - normal amount of abnormally structured vWF (likely missing the high molecular weight multimers important in adhesion)
3) Type 3 - complete absence of vWF (very severe)
Do people with VW disease always have a genetic abnormality?
People may have reduced VWF due to increased clearance of the protein, this is not referred to as VW disease as no genetic abnormality exists, instead it is referred to as reduced VWF which is a risk factor for bleeding
Aswell as platelet adhesion what is the other important function of VWF?
Carries factor VIII around the blood stream, without VWF factor 8 has a short half life in the bloodstream
Due to the effect on Factor 8 do patients with VW disease present with the symptoms of coagulation defects?
This is very rare
What is the most common heritable bleeding disorder?
VW disease
What is the pattern of inheritance of VW disease?
Mainly autosomal dominant
Do patients with VW disease have reduced factor 8 levels?
Some do but the levels are variable between patients
Which blood group has lower levels of VW disease?
Group O
What type of bleeding occurs in VW disease? 2
1) Mucocutaneous bleeding including menorrhagia
2) Post operative and post partum bleeding
Why is diagnosis of mild types VW disease difficult?
There is variable penetrance for mild types and presentations vary greatly
What is the treatment for VW disease? 5
1) Anti-fibrinolytics: tranexamic acid
2) DDAVP (desmopressin) for type 1 vWD - releases vWF from cells causing a temporary rise in vWF in mild disease
3) Factor concentrates containing vWF
4) Vaccination against hepatitis
5) COCP for menorrhagia
What is haemophilia A?
Deficiency of factor 8
What is haemophilia B?
Deficiency of factor 9
What is the inheritance pattern of haemophilia A and B?
Sex linked recessive
Aswell as the haemophilias, what 2 factors is it more common to become deficient in and what is the pattern of inheritance?
12 and 11
Autosomal
Is it common to become deficient in factors 1,2,5,7,10 and 13?
No, its very rare
Which clotting test would you expect to be prolonged in the haemophilias and why?
Prolonged APTT as both 8 and 9 are part of the intrinsic pathway which affects the APTT
Which is more common haemophila A or B?
A - affects 1 in 5000 males
B - only affects 1 in 30,000 males
Does haemophilia affect males and females?
As it sex linked recessive it is typically expressed in males and carried by females
How predictable is the severity of haemophilia when it is passed on?
Severity level is consistent between family members
What percentage of cases of haemophilia are new mutations?
30%
How are mild, moderate and severe haemophilia classified?
Mild - factor 8 or 9 level = 6-50%
Moderate - factor 8 or 9 level = 1-5%
Severe - factor 8 or 9 level =
What are the 5 types of bleed which can occur in haemophilia?
1) Spontaenous/ post traumatic
2) Joint bleeding = haemarthrosis
3) Muscle haemorrhage
4) Soft tissue
5) Life threatening bleeding
What are the 6 treatments for haemophilia?
1) Replacement of missing clotting protein - on demand or prophylaxis
2) DDAVP (desmopressin) - for mild/moderate Haemophilia A
3) Factor concentrates - recombinant are products of choice
4) Antifibrinolytic agents
5) Vaccination v hep A and B
6) Supportive measures - icing, immobilisation, rest
What are the 4 possible transfusion transmitted infections which are potential compications of haemophilia treatment?
Transfusion transmitted infection:
1) Hepatitis
2) HIV
3) Parvovirus
4) vCJD
What is one of the biggest complications of haemophilia treatment?
Development of an inhibitor - Ab against factor 8 or 9 which renders treatment with recombinant factors useless
What is the incidence of inhibitor development, is it more common in haemophilia A or B?
Haemophilia A
Occurs in 25% of haemophilia A patients
Can inhibitor development be treated?
A potential treatment is eradication of the inhibitor using immune tolerance
When in the course of treatment does inhibitor development tend to occur?
Early in exposure - within the first 10 days
What are the 9 possible investigations in a patient with a suspected bleeding disorder?
1) FBC and blood film
2) Coagulation screen and Clauss fibrinogen
3) Mixing studies if abnormal results
4) VW profile
5) Coagulation factor assays
6) Inhibitor assays in some cases
7) Platelet function tests
8) In all normal and suspicion remains then factor 8 assays and assay of alpha2 antiplasmin
If a patient has a normal coagulation screen but experiencing bleeding, what are the 7 possible diagnoses?
1) Thrombocytopenia
2) Disorder of platelet function
3) vWD
4) Factor 8 deficiency
5) Mild coagulation factor deficiency
6) Vascular disorder
7) Disorder of fibrinolysis: rare
