Prophylaxis the journey to date 1960 s 1990

Prophylaxis : the journey to date 1960 s 1990 s 2000 s 2020 and beyond

History of prophylaxis in haemophilia Original observation • Patients with moderate haemophilia (1 - 5%) have fewer haemarthroses and less arthropathy than patients with severe haemophilia • Patients with severe haemophilia – treat with regular factor to maintain trough levels above 1% • Convert “severe” haemophilia into “moderate” haemophilia

Does prophylaxis work? Swedish experience 1 • Commenced 1958; boys 1 -2 years • Significantly improved joint outcomes • Leading normal lives 1. Nilsson et al. J Intern Med. 1992.

Does prophylaxis work? • Orthopaedic outcomes study 1 • Longitudinal 6 -year study group • Physical exam and X-ray of ankles/knees/elbows • Prophylaxis significantly reduced rate of joint deterioration and number of days lost from work / school 1. Aledort et al. J Intern Med. 1994.

Superiority of Prophylaxis Over On-Demand − Prospective Randomized Study • US Joint Outcomes Study • Open-label / multicenter • Age <2. 5 years • Baseline FVIII ≤ 2% (88% severe) • History of ≤ 2 joint bleeds 1. Manco Johnson 2007.

Prophylaxis Versus On-Demand – US Joint Outcomes Study results Manco Johnson. NEJM 2007.

Prophylaxis Versus On-Demand – US Joint Outcomes Study results

Prophylaxis Versus On-Demand – US Joint Outcomes Study results

Prophylaxis Versus On-Demand – US Joint Outcomes Study results

Prophylaxis Versus On-Demand – US Joint Outcomes Study results

• Current prophylaxis regimens work

• Current prophylaxis regimens work …. . or do they?

Prophylaxis regimens • Twice/week Factor IX • Three/week Factor VIII • Only concession to personalisation = weight • 25 -40 IU/kg

Deciding on the optimal dose • Start prophylaxis regimen; frequency; weight based dosing

Deciding on the optimal dose • Start prophylaxis regimen; frequency; weight based dosing

However clearly not everyone is the same…. .

However clearly not everyone is the same…. .

However clearly not everyone is the same…. .

However clearly not everyone is the same…. . • How long clotting factor replacement works for • Bleeding • Joint damage

However clearly not everyone is the same…. . • How long clotting factor replacement works for • Bleeding • Joint damage

Half life of treatment • How long clotting factor replacement works for • 100% 50% 25% 12. 5%. . . .

Half-life of treatment • How long clotting factor replacement works for • 100% 50% 25% Time taken = half-life 12. 5%. . . .

Marked differences exist in Factor VIII half-life between different people • 6 -29 hours • Fijnvandraat et al, 1995 • 7 -20 hours • Van Dijk et al, Haematologica 1995 • 6 -25 hours • Bjorkman et al, JTH 2010

Prophylaxis to keep factor VIII level > 1% 25 IU/kg FVIII > 1%

Prophylaxis to keep factor VIII level > 1% 25 IU/kg FVIII 12 hr half life > 1%

Marked differences exist in Factor VIII half-life between different people • 6 -29 hours • Fijnvandraat et al, 1995 • 7 -20 hours • Van Dijk et al, Haematologica 1995 • 6 -25 hours • Bjorkman et al, JTH 2010

So, if you clear quickly…. . Fast FVIII clearance (Half-life = 6 hours) FVIII

So, if you clear quickly…. . FVIII level falls below 1%

What if you clear slowly? Slow FVIII clearance (Half-life = 18 hours) FVIII > 6%

Does this matter ? • YES • Risk of bleeding in both children and adults is dependent upon the time per week an individual spends with FVIII levels below 1% 1 1. Collins, JTH 2009

However clearly not everyone is the same…. . • How long clotting factor replacement works for • Bleeding • Joint damage

• All people with severe haemophilia – factor <1% • Bleeding patterns are not the same • Reasons unknown

However clearly not everyone is the same…. . • How long clotting factor replacement works for • Bleeding • Joint damage

Manco Johnson. NEJM 2007.

Joint bleeds MRI evidence of joint damage

No joint bleeds No MRI damage

Joint bleeds No MRI damage

NO Joint bleeds BUT MRI damage

• Subclinical joint bleeding? • Management? • Optimise prophylaxis?

• Subclinical joint bleeding? • Management? • Optimise prophylaxis? Could we identify susceptible individuals?

However clearly not everyone is the same…. . • How long clotting factor replacement works for • Bleeding • Joint damage

Prophylaxis : the journey to date 1960 s 1990 s 2000 s Weight based, bleed until optimal dose found

Prophylaxis : the journey to date 1960 s 1990 s 2000 s 2020 and beyond