Haemophilia Wk3 Flashcards
Clotting cascade
Intrinsic pathway _extrinsic pathway
Final common pathway - thrombin
Joint bleeds
Spontaneous - not always from trauma
Normally large weight bearing joints
Associated with pain, swelling, warmth and restricts movement
Muscle bleed
Less common than joint bleeds
Cause damage by compressing local blood vessels and nerves
Cerebral bleed
Potentially life threatening
Mouth + mucosal bleeds
Small amount can go a long way
Prolonged bleeding
After surgery + invasive procedures
Excessive bleeding
Usually in arms and legs “thumbprint bruising”
Haemophillia A
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)
Haemophilia B
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
Classification of HAEMOPHILLIA
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)
Inherited-affected male
Inheritance-carrier
Acquired haemophilia (big purple bruising)
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)
Von Willebrand’s Disease (vWD)
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
Von Willebrand’s Disease variation
Normal range = high variation = link between vWF level and ABO blood group of patient
Significant variation in bleeding
VWD subtypes quantitative defects
Type 1- moderate deficiency
Type 3- severe deficiency
Acquired haemophilia
Qualitative defects
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)
Typical vWD results
Acquired vWD
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
Laboratory diagnosis
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?
Lab diagnosis
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
Lab diagnosis Ristocetin co-factor (activity)
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
Fibrinogen defects. Activity < 1.5g/ltr
Dysfibrinogenemia
Detected by discrepancy between functional and quantitative assay
Afibrinogenemia
Absent production (rare, approx. 1 in 1,000,000)
Hypofibrinogenemia
Reduced production
Factor II deficiency
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)
Factor V deficiency (owrens parahaemophilia
Rare 1 in 1,000,000
Autosomal recessive
Leads to Strong bleeding tendency
Excessive bruising
Epistaxis (bleeding from nose)
Gum + muscle bleeds after trauma
Factor VII deficiency (pro convert in deficiency)
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
Factor X deficiency
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
Factor XI deficiency
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
Other defects
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
Replacement product - prevent damage + reduce morbidity
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
FVIII concentrates
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.
Development of inhibitors
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
Fresh frozen plasma (FFP) - all clotting factors contained
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 -
Cryoprecipitate prepared by slow thawing of fresh frozen plasma (FFP) at 4°C for 10–24 hours.
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.
Desmopressin 1-deamino-8-arginine vasopressin DDAVP
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
Tranexamic acid
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
NovoSeven ® (rVIIa) - promotes haemostasis by activating extrinsic pathway of clotting cascade
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
Home treatment available 1993-1996 for HAEMOPHILLIA patients receiving on demand or prophylactic treatment
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
Cost of treatment
2012-13 Haem-A
£30,000,000 of FVII concentrates
Home delivery 28p per unit (+VAT) 90,000,000 units
PEGylation PEG
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
Advantages of PEGylation technology
Increased bioavailability
Optimized pharmacokinetics
Decreased immunogenicity
Decreased frequency of administration
Disadvantages of PEGylation technology are
“I forget to take my medication when its not every day”
FVIII mimic - EMICIZUMAB
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
emizicumab trail licenced for use in patients with long standing high inhibitors
Untreated for bleeds for 24 months
Bleeding prevented, APTT normalised with weekly injections
Gene therapy
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
Recommended reading
www.ukhcdo.org
www.bcshguidelines.com
www.practical-haemostasis.com
