CP7-4 heritable bleeding disorders Flashcards
What is balanced in the hemostatic balance?
Bleeding and clotting
How are hemostatic plugs formed?
primary hemostasis of aggregation of platelets and secondary hemostasis of coagulation with thrombin and fibrin combines to form a clot
What does factor X become when it is activated (I.e. becomes factor Xa)?
A protease enzyme that cleaves factor II
Which clotting cascade is tissue factor involved in?
The extrinsic pathway
How does tissue factor contribute to the extrinsic clotting pathway?
Factor VII becomes activated and then activates factor X with calcium
When does factor XII become activated in the intrinsic pathway?
When it comes in contact with a foreign surface
What tests can be done to look at how quick clotting pathways work?
Prothrombin time - speed of extrinsic pathway
Activated partial thromboplastin time - speed of intrinsic pathway
Thrombin clotting time - adding thrombin to plasma and seeing how long a clot takes to form
Euglobulin lysis time
What are two procoagulant components?
Platelets
Clotting factors
What are 4 anti-coagulant components?
Protein C
Protein S
Anti+thrombin III
Fibrinolytic system
How many defects are usually caused by congenital bleeding disorders?
Usually 1
How many defects are usually caused by acquired bleeding disorders?
Usually multiple
What defect is usually caused by disorders affecting platelets/vessel wall?
Mucosal and skin bleeding
What can coagulation defects cause?
Deep muscular and joint bleeds and bleeding following trauma
What investigations can be done into potential bleeding dirsorders?
FBC and blood film
Coagulation screen and Clauss fibrinogen screen
D-dimer if suspicious of acquired disorder
Von Willebrand profile
Coagulation factor assays including FVIII and FIX
Inhibitor assays
Platelet function tests
What are further non-routine investigations into bleeding disorders if other tests are normal but suspicion remains?
FXIII assay
Assay of alpha2antiplasmin
What are examples of bleeding disorders?
Thrombocytopenia
Disorders of platelet function
Von Willibrand disease
Factor XIII deficiency
Mild coagulation factor deficiency
Vascular disorders
(Rarely) disorder of fibrinolysis
What are some defects that can lead to prolonged bleeding times?
Reduced number of platelets
Abnormal platelet function
Abnormal vessel wall
Abnormal interaction between platelets and vessel wall
What are petechiae rashes?
Rashes as a result of bleeding into the skin which do no blanch with pressure and are non palpable
What is the most common mild bleeding disorder?
Von willibrand disease
What is the function of Von Willebrand factor?
Helps platelets stick to the vessel wall by interacting with collagen in the wall
Type 1 and most type 2 Von Willebrand disease is inherited through which inheritance pattern?
Autosomal dominant
Type 3 Von Willebrand disease is inherited through what inheritance pattern?
Autosomal recessive
What clotting factor is Von Willebrand factor part of?
Factor VIII
What care complications of VWD?
Defective haemostasis
Variable reduction in VIII levels
Mucocutaneous bleeding including menorrhagia in women
Increased postoperative and postpartum bleeding
Who is more symptomatic with VWD? Men or women?
Women - both affects by VWD but women usually have more symptoms
What are confounding factors which affect diagnosis of mild VWD?
Contraceptive pill
Increased exercise
Psychological stress
Which blood group has lower vWF levels?
Group O
How is VWD treated?
With antifibrinolytics like tranexamic acid
With DDAVP if type 1
With factor concentrates containing vWF (either derived from plasma or recombinant)
Vaccination against hepatitis
In women combined oral contractile pill or inuterine system to increase progesterone hormones for menorrhagia
What clotting factors have hereditary deficiencies? How common are each?
XII - relatively common
XI - rare
IX haemophilia B - uncommon
VIII haemophilia A - uncommon
VIII vWD- common
VII, X, V, II, I & XIII - very rare
Why is factor XII deficiency common but not usually a problem?
Deficiency of factor XII doesn’t usually cause clinical bleeding problems
What factor deficiencies are inherited autosomally?
XII
XI
What factor deficiencies are inherited in a sex linked recessive inheritance pattern?
IX and VIII haemophilia A&B respectively
Who is more likely to be affected by haemophilia?
Men as women have two X chromosomes which acts as a protective factor although they are still carriers
What is the epidemiology in men of haemophilia A and B?
A = 1 in 5000
B = 1 in 30,000
What factor deficiency/defect is inherited autosomal dominantly?
vWD - factor VIII
What factor deficiencies/defects are inherited in an autosomal recessive inheritance pattern?
I, II, V, VII, X, XIII
What is the pattern of severity between family members?
Severity is consistent
What percentage of haemophilia cases are due to de novo mutations?
Around 30%
What percentage of factor VIII or IX, compared to normal levels, are found in each severity of haemophilia? (Mild/moderate/severe)
Mild = 6-50% of normal
Moderate = 1-5% of normal
Severe = <1% of normal
What are symptoms of mild haemophilia?
Won’t usually have spontaneous bleeds but will have increased bleeding after surgery or trauma
What type of bleeds occur in people with haemophilia?
Spontaneous bleeds
Post traumatic bleeds
Joint bleeding aka haemarthrosis
Muscle haemorrhage
Soft tissue bleeding
Life threatening bleeding
How is haemophilia treated/managed?
Replacement of missing clotting protein either in demand or by prophylaxis
DDAVP if mild/moderate haemophilia A
Factor concentrates (usually recombinant)
Anti fibrinolytic agents
Vaccination for hepatitis A and B
What are some transfusion transmitted infections that can complicate haemophilia?
Hepatitis A, B and C (and G)
HIV
Parvovirus
vCJD
How does inhibitor development complicate treatment of haemophilia?
Shortens half life of factor replacement therapy leading to poorer clinical response and poor recovery
How is inhibitor development in haemophilia treated/prevented?
With specialised management of bleeds
Emicizumab prophylaxis
Eradication of inhibitor e.g with immune tolerance
What is emicizumab?
A SC injected humanised bispecific monoclonal antibody which bridges FIXa and FX to restore function of missing FVIIIa and is not expected to be affected by or induce inhibitors/inhibition to help treat haemophilia A
What are some new haemophilia treatments being developed?
Gene therapy
EHL products
AntiTFPI antibodies
AT mRNAi
