Lecture 12 - Benefits And Complications Of Treating Hemophilia

Question 1

Hemophilia etiology

Answer 1

• most common severe inherited bleeding disorder
• X-linked congenital bleeding disorder caused by a deficieny of F8 (HA) or F9 (HB)
• 1:10000 births worldwide and 400000 people living with it
• no major geographical variances
• affects mostly man
• some carrier women manifest clinical symptoms of bleeding because of low clotting factor levels

Question 2

F8 and F9 in coagulation

Answer 2

• protease complexes form on cell membrane - requires phosphatidylserine - exposed on the surface of activated platelets, following granule release factors bind to membrane via Gla domains and calcium

Question 3

Hemophilia A genetics

Answer 3

• F8 gene is located at Xq28
• two principal sites of FVIII synthesis: liver and vascular endothelium
• F8 is secreted into the circulation, where it forms a tight non-covalent complex with VWF
• Majority of VWF in plasma is synthesised and secreted by vascular endothelial cells
• 30% of hemophilia A cases are caused by a sporadic mutation
• significant proportion of HA are the result of an inversion mutation involving sequences in intron 22
• remainder of the mutations responsible for HA involve more than 1000 different alterations

Question 4

Females with hemophilia A

Answer 4

• severe and moderately severe cases of HA are unusual
• inheritance of either homozygous or compounf heterozygous F8 mutations
• inheritance of a single F8 mutation together with a 46 XO karyotype (turner syndrome)
• rare: skewed inactivation of the X chromosome

Question 5

F9

Answer 5

• located on X chromosome
• synthezised exclusively in hepatocytes
• Vit K dependent factor: enables F9 to form calcium-dependent interactions with procoagulant phospholipid membranes

Question 6

Genetics - hemophilia B

Answer 6

• X linked
• approximately 75% of mutations in heam B are missense substitutions
• no common recurrent F9

Question 7

Initial diagnosis of haemophilia

Answer 7

• Families in which haemophilia has previously been identified. But 30% have no family Hx
• prenatal diagnosis by CV or amniocentesis
• should begin with evaluation of the fetal sex
• pathological bleeding can occur in the neonatal period
• severe disease manifests with easy bruising or soft tissue or joint bleeding between 6 and 18 months of age
• APTT

Question 8

APTT

Answer 8

• activated partial thromboplastin time
• how long it takes for the patient’s plasma to clot in the presence of phospholipids, activator and calcium ions
• FVIII/FIX specific assays

Question 9

Intracranial haemorrhage in babies with severe hemophilia

Answer 9

• 4%
• 1/3 present in the first week of life
• 3% for vaginal delivery, 15% for C/S and 64% for vacuum extraction
• recommend an autraumatic vaginal delivery
• avoid IM vit K

Question 10

Bleeding phenotype

Answer 10

• characteristic phenotype
• severity of bleeding usually correlated with clotting factor level
• majority of bleeds occur in joints (70-80%) or muscles (10-20%)
• more common in hinge joints

Question 11

Development of a target joint

Answer 11

• repeated bleeding into a single joint
• further bleeding episodes facilitated by previous events
• vicious cycle of joint damage
• joints become painful and less mobile
• immobility and muscle wasting of affected limb

Question 12

Pathophysiology of hemophilic arthropathy

Answer 12

1) repeated bleeding into joint
2) destruction of joint tissues by proteolytic enzymes
3) destruction of cartilage
4) destruction of subchondral bone
5) bone resorption and ossification
6) joint deformation and impaired joint funciton

Question 13

Determining haemophilic arthropathy

Answer 13

• plain radiographs are relatively inexpensive and widely available but are insensitive to soft tissue changes
• MRI is the most sensitive to early joint changes, no radiation, but high cost, and need for general anesthesia in very young children
• ultrasonography: no sedation in young children, less expensive than MRI, differentiates between synovium and hemosiderin, which is not always possible with MRI

Question 14

Treatment of acute bleeds

Answer 14

• stop the bleed ASAP
• clotting factor concentrates
• rest + physiotherapy

Question 15

Coagulation factor concentrates

Answer 15

• until the 1970 - plasma or cryoprecipitate
• plasma-derived clotting factor concentrates became available in the 1970: contaminated with HIV and hep C. Thousands of hemophilia patients worldwide exposed
• currently administered plasma-derived clotting factor concentrates are not associated with HIV, HepB or HepC

Question 16

REcombinant factor concentrates

Answer 16

• developped in late 1980
• first generation recombinant product: stabilized by inclusion of albumin
• seconf generation products: still exposed to human plasma-derived albumin during the manufacturing process
• third generation products: no exposure to human or animal proteins and are stabilized with sucrose

Question 17

Dose

Answer 17

• F8 concentrates: 1 U/kg of F8 increases F8 levels by 2%
• F8 level of a 100% in an individual with severe hemophilia requires a dose of 50U/kg
• F9 has a volume of distribution twice that of F8
• 1 U/kg increases the F9 level by 1%
• F9 level of 100% in an individual with severe hemophilia requires a dose of 100 U/kg

Question 18

Prophylactic therapy

Answer 18

• 25-40 IU/kg
• 3 times a week or 2nd daily for HA
• 2 times a week or 3rd daily for HB

Question 19

Prophylaxis issues

Answer 19

• joint and bleed protection
• IV access
• parental and social factors
• cost and funding
• inhibitor rates
• dosing
• compliance

Question 20

Individuality in Australian prophylaxis practice

Answer 20

• await first joint bleed
• start at a particular age
• increase to multiple weekly dosing as soon as feasible
• CVAD
• recombinant products
• inhibitor risk profiling

Question 21

Compliance to prophylactic therapy

Answer 21

• overalll adherance is high: 80%

- 18% of adults had an adherance of

Question 22

Factor VIII inhibitors: pathophysiology

Answer 22

• adverse immunologic responses to replacement products
• development of inhibitory antibodies to F8, termed inhibitors
• inhibitors bind F8 and prevent hemostatic action
• produced when a F8-specific memory B cell is stimulated to differentiate into an anti-F8 antibody secreting plasma cell
• not all patient with Heam A who are exposed to replacement F8 products develop inhibitors

Question 23

Goals of treatment

Answer 23

1) eradication of the inhibitor: immune tolerance therapy, immunosuppression
2) treatment of bleeds: treatment of acute bleeds, prevention of bleeds, bypass therapies (non F8 products

Question 24

Non factor 8 or 9 replacement therapies

Answer 24

• Emicizumab: FVIII mimetic
• ConcizumabL anti TFPI
• anti-thrombin II