Haemophilia Wk3

Question 1

Clotting cascade

Answer 1

Intrinsic pathway _extrinsic pathway
Final common pathway - thrombin

Question 2

Joint bleeds

Answer 2

Spontaneous - not always from trauma
Normally large weight bearing joints
Associated with pain, swelling, warmth and restricts movement

Question 3

Muscle bleed

Answer 3

Less common than joint bleeds
Cause damage by compressing local blood vessels and nerves

Question 4

Cerebral bleed

Answer 4

Potentially life threatening

Question 5

Mouth + mucosal bleeds

Answer 5

Small amount can go a long way

Question 6

Prolonged bleeding

Answer 6

After surgery + invasive procedures

Question 7

Excessive bleeding

Answer 7

Usually in arms and legs “thumbprint bruising”

Question 8

Haemophillia A

Answer 8

X linked chromosomal disorder

1 in 10,000 live male births

Deficiency or defect in Factor VIII

Factor VIII acts as a cofactor in the activation of Factor X and circulates attached to Von Willebrand Factor (vWF)

Question 9

Haemophilia B

Answer 9

X linked chromosomal disorder
1 in 35,000 live male births
Factor IX acts as an activator for Factor X in presence of factor FVIII and phospholipid

Question 10

Classification of HAEMOPHILLIA

Answer 10

SEVERE HAEMOPHILLIA MODERATE HAEMOPHILLIA MILD HAEMOPHILLIA
<1% Factor level. 1 to 5% Factor level. 6-30% Factor level
Spontaneous bleeding. Can bleed with slight injury. Bleeding only occurs with surgery, invasive procedures and severe injury
Characteristic
May bleed 1 to 2 times a week May bleed once per month. May never experience a bleeding problem
Characterised by joint bleeding. May have joint bleeding. Rarely have joint bleeds.
(haemarthrosis)

Question 11

Inherited-affected male

Question 12

Inheritance-carrier

Question 13

Acquired haemophilia (big purple bruising)

Answer 13

Due to development of an autoimmune inhibitor
Inhibitor usually targets factor VIII
Inhibitors against others factors and Von willebrand’s disease (VWF) are rare but possible.
Affect both males and females
Most cases occur spontaneously- can be associated with drug therapy and pregnancy.
Approx. 75% of acquired inhibitors destroy the Factor VIII molecule (Type 1)
The other 25% inhibit the molecule but do not destroy it (Type II)

Question 14

Von Willebrand’s Disease (vWD)

Answer 14

Adhesive glycoprotein, circulating in large multimers 800-20,000KDA
Synthesised in endothelial cells and megakaryocytes
Initiates platelet adhesion to exposed collagen at sites of vascular damage and between platelets themselves
Transports and protects factor VIII in circulation
Effects both males and females and approx 1% WWP

Question 15

Von Willebrand’s Disease variation

Answer 15

Normal range = high variation = link between vWF level and ABO blood group of patient
Significant variation in bleeding

Question 16

VWD subtypes quantitative defects

Answer 16

Type 1- moderate deficiency
Type 3- severe deficiency

Question 17

Acquired haemophilia
Qualitative defects

Answer 17

Type 2a- functional, absence of high molecular weight multimers
Type 2b- spontaneous binding to platelets
Type 2M- reduced platelet binding
Type 2n- reduced binding to factor VIII (underdiagnosed)

Question 18

Typical vWD results

Question 19

Acquired vWD

Answer 19

Type 1,2 or 3
Result of 1 of 3 mechanisms
Mild form associated with hypothyroidism
Mechanical removal, associated with aortic stenosis + replacement of heart valves (Hyde’s syndrome)
Autoantibody to vWF
Labs unable to quantitate inhibitor in vitro

Question 20

Laboratory diagnosis

Answer 20

Prolonged PT/APTT
Anticoagulated?
Liver disease, low factor II, VII, IX X and fibrinogen
Malignant conditions with paraproteins
Disseminated intravascular coagulation (DIC)
Family history- characteristic bleeding tendency’s
Pregnancy - some factors increased = masking underlying disorder?

Question 21

Lab diagnosis

Answer 21

Factor assays
Ability of plasma to correct known deficiency in reagent plasma relative to standard
100% correction = 100% factor

VWF assays
VWF antigen (latex immunoassays)
Latex particles coated with IgG monoclonal antibody specific for human vWF
Latex particles aggregate around vWF molecules in patient plasma

Question 22

Lab diagnosis Ristocetin co-factor (activity)

Answer 22

Testing ability of the vWF mol to bind to GP1b platelet receptors
Collagen binding-
Testing vWF mol ability to bind to collagen (GP2b/3a)
VWF multimers distribution -
Electrophoresis of vWF determines physical size of vWF molecule

Question 23

Fibrinogen defects. Activity < 1.5g/ltr

Answer 23

Dysfibrinogenemia
Detected by discrepancy between functional and quantitative assay

Afibrinogenemia
Absent production (rare, approx. 1 in 1,000,000)

Hypofibrinogenemia
Reduced production

Question 24

Factor II deficiency

Answer 24

Produced in liver
Genetic mutation leading to reduced factor II very rare 1 in 2,000,000
Autosomal recessive (pattern of inheritance)
Acquired factor II deficiency associated with lupus anticoagulant (15 cases worldwide per year)

Question 25

Factor V deficiency (owrens parahaemophilia

Answer 25

Rare 1 in 1,000,000
Autosomal recessive
Leads to Strong bleeding tendency

Excessive bruising
Epistaxis (bleeding from nose)
Gum + muscle bleeds after trauma

Question 26

Factor VII deficiency (pro convert in deficiency)

Answer 26

Produced in liver
1 in 400,000
Strong bleeding history = high mortality + morbidity (condition of being diseased)
50% with severe <1% experience serious CNS bleed

Question 27

Factor X deficiency

Answer 27

Produced in liver
Rare 1 in 1,000,000
Autosomal recessive
Associated with joint bleeds, epistaxis and GI bleeds (gastrointestinal tract)
Diagnosed neonatally due to excessive bleeding from umbilical stump

Question 28

Factor XI deficiency

Answer 28

Autosomal recessive
Prolonged bleeding from minor wounds
Milder bleeding history, mild epistaxis and menorrhagia
Rare 1 in 1,000,000
1 in 8 Ashkenazi Jews are carriers of FXI mutation

Question 29

Other defects

Answer 29

Factor XII, pre-Kallikrein + height mol weight kininogen deficiencies cause prolongation of the APTT DO NOT LEAD TO BLEEDING HISTORY
Liver disease can cause decreased production of clotting factors 11, VII, IX, X and fibrinogen
Vitamin K deficiency (Dietary and anticoagulant) causes a decrease in production of functional forms of factors II, VII, IX, X
FXIII and ⍺2Antiplasmin – Associated with delayed onset bleeding

Question 30

Replacement product - prevent damage + reduce morbidity

Answer 30

With Haemophilia (cant make blood clots) can be treated for bleeding prophylactically / demand
Complications of replacement products (development of antibodies) + exposure to viruses. Hep B, Hep C, HIV, vCJD Creutzfeldt-Jacob syndrome)

Prophylactic more expensive than on demand treatment.
Lower numbers than demand
Reduced risk of arthropathies
Optimal

Question 31

FVIII concentrates

Answer 31

Recombinant ultra-high-purity products:
Kogenate (Bayer) - Cultured BHK cells
Advate (Baxter) – Cultured CHO cells
Xyntha (Pfizer) – Cultured CHO cells, β domain deleted
Helixate NexGen (CSL Behring) - Cultured BHK cells

Typically require human albumin = stabilising protein or utilise human albumin during cell culture step.

Question 32

Development of inhibitors

Answer 32

25% of severe + moderate haemophilia A patients develop inhibitor - pre-teenage
Treatment with bypassing agents (FEIBA) or activated recombinant factor VII (rFVIIa)
Interest-patient variability complicates dosing and prevents optimal response
Develop treatment treatment strategies for both dose and choice in individual patients

Remove stimulus (switch product)
Immunosuppression
Immune tolerance

Question 33

Fresh frozen plasma (FFP) - all clotting factors contained

Answer 33

Fluid portion of 1 unit human blood that’s been centrifuged, separated, and stored frozen at -18 °C (or colder) within 6 hours of collection.
Post massive blood transfusion- replace clotting factors after red cells been replaced
Cannot be used for replacement of isolated factor deficiencies -

Question 34

Cryoprecipitate prepared by slow thawing of fresh frozen plasma (FFP) at 4°C for 10–24 hours.

Answer 34

Contains FVIII 5 IU/ml, von Willebrand’s factor (vWF), fibrinogen, XIII
Coagulation factor content is variable + not controlled in each pack
Cryoprecipitate not subject to viral inactivation procedures, = repeated exposure comes with risk.

Question 35

Desmopressin 1-deamino-8-arginine vasopressin DDAVP

Answer 35

Synthetic analogue of antidiuretic hormone ADH
Used in mild Haemophilia A + type 1 VWD
Triggering release of VWF stored in endothelial cells
Single IV infusion 0.3mg/kg of body weight = boost FVII level 3 fold
DDAVP cheaper than replacement products. No viral exposure
Concentrated nasal spray

Question 36

Tranexamic acid

Answer 36

Antifibrinolytic (helps blood clot) competitively inhibits activation of plasminogen to plasmin
Promotes clot stability - used in some bleeding disorders
Good controlling bleeding from mucosal surfaces
Cover minor dental, gynae + urological surgery

Question 37

NovoSeven ® (rVIIa) - promotes haemostasis by activating extrinsic pathway of clotting cascade

Answer 37

1952 discovery of role of factor VIIa (FVIIa) in coagulation initiation
1988 1st haemophilia patient treated with recombinant FVIIa (rFVIIa)
1996 rFVIIa is approved for marketing in Europe
2008 ^ room temperature

Question 38

Home treatment available 1993-1996 for HAEMOPHILLIA patients receiving on demand or prophylactic treatment

Answer 38

Advantages
Access to treatment quicker if bleeding occurs
Fewer visits to doctors and haemophilia centres
Cheaper
Helps children accept treatmentment and responsibilities - fitten with portacath

Question 39

Cost of treatment

Answer 39

2012-13 Haem-A
£30,000,000 of FVII concentrates
Home delivery 28p per unit (+VAT) 90,000,000 units

Question 40

PEGylation PEG

Answer 40

Polyethylene glycol - chemical compound composed of repeating ethylene glycol units
Covalent attachment of Polyethylene glycol polymer chains to another molecule,
Incubation of reactive derivative of PEG with target macromolecule
Intended to lengthen time a substance redials in bloodstream without being metabolized + excreted

Question 41

Advantages of PEGylation technology

Answer 41

Increased bioavailability
Optimized pharmacokinetics
Decreased immunogenicity
Decreased frequency of administration

Question 42

Disadvantages of PEGylation technology are

Answer 42

“I forget to take my medication when its not every day”

Question 43

FVIII mimic - EMICIZUMAB

Answer 43

Bispecific antibody - common light chain, Anti FIXa, Anti FX heavy chain immunoglobulins
Binds to FIXa and FX, hold in spatially appropriate orientation for activation of FX to Fxa

Question 44

emizicumab trail licenced for use in patients with long standing high inhibitors

Answer 44

Untreated for bleeds for 24 months
Bleeding prevented, APTT normalised with weekly injections

Question 45

Gene therapy

Answer 45

Replacing mutated gene which causes disease with healthy copy of gene
Adenosine-associated virus (AAV) non-pathogenic + doesn’t integrate into chromosomal DNA
Haemophilia B. Functional part of gene small enough to fit into modified virus vector
Small amounts of Factor IX is synthesized + released into blood
Large difference observed in bleeding tendencies

Question 46

Recommended reading

Answer 46

www.ukhcdo.org
www.bcshguidelines.com
www.practical-haemostasis.com