Function of Factor VIII (FVIII)

FVIII is a protein that plays an essential role in blood clotting1

There has been recent interest in other roles of FVIII beyond blood clotting2

FVIII has been implicated in:

antigenic-img antigenic-img antigenic-img

Bone and Joint Health Impacts bone mineral
density (BMD)2

Vascular function Influences blood vessel
formation and permeability6-9

Platelets Affects platelet function
and adhesion3-5

Bone and Joint Health Impacts bone mineral
density (BMD)2

Vascular function Influences blood vessel
formation and permeability6-9

Platelets Affects platelet function
and adhesion3-5

Bone and joint health in haemophilia A

Haemophilia A is associated with reduced bone mineral density (BMD), even in children2
Osteoporosis reported in
of adults with haemophilia6
of men >50 years in the general population (EU)11

Replacing the missing FVIII via prophylaxis may preserve bone health in haemophilia A patients12,13

People with haemophilia A have a higher rate of bone fracture than the general population14
Fractures per 1000 subject years
0 20 40 60 80 0 <16 16–30 31–45 ≥46
  • Haemophilia A
  • General population
Age (years)
Arthropathy is a frequent and serious complication of repeated joint bleeding in people with haemophilia A, resulting in pain, deformity and disability15

Right

Left

Illustrative example of patient with severe haemophilia A with arthropathy in the right knee16

In a long-term joint outcomes study17(n=33),

of haemophilia A patients had joint damage by age 18

Factor VIII prophylaxis can protect against
development of arthropathy and preserves joint
function18-20

Median Haemophilia Joint Health Score
8
7
6
5
4
3
2
1
0
3
Low-dose
prophylaxis
n=35
7
On-demand
n=15
p = 0.022
Higher score indicates worse joint condition with on-demand

In people with already established joint damage, FVIII
prophylaxis can improve joint function, quality of life,
activity level and pain21

Patients with negative bone deformity (%)
100
80
60
40
20
0
23/35
Low-dose
prophylaxis
5/15
On-demand
p = 0.022
Lower score indicates more bone deformity with on-demand

FVIII interactions with platelets

Platelets are critical throughout all steps of the blood clotting process, preventing excessive blood loss22,23

Haemophilia A severity correlates with FVIII activity levels

But also...

FVIII is known to directly interact with platelets4,5, and seems to influence platelet function3

Haemophilia A

FVIII

Platelet function

Low FVIII might also result in low platelet function, exacerbating bleeding symptoms

Altered platelet function has been observed in patients with haemophilia A3

FVIII products with different modifications, used to extend the circulation half-life of FVIII, show reduced binding to platelets24

Role of FVIII on Endothelial Cell Function

FVIII interactions with endothelial cells

Endothelial cells form the lining of blood vessels, and multiple types of endothelial cells have been shown to express FVIII25,26
In addition to its well-known role in the coagulation cascade, FVIII might have a role regulating endothelial cells, i.e. influencing the formation of blood vessels
People with haemophilia have defects in endothelial function7,8

Joints damaged in haemophilia A patients show

abnormal formation of blood vessels

which is not observed in joints damaged by other conditions like rheumatoid arthritis6

Emerging research27,28 indicates that without FVIII, blood vessels do not heal properly

This might promote re-bleeds, with further damage to blood vessels

References

  • 1

    Franchini M and Mannucci PM. Orphanet J Rare Dis 2012; 7:24;

  • 2

    Samuelson Bannow B et al. Blood Rev 2019; 35:43-50;

  • 3

    Riedl J et al. Thromb Res 2017; 155:131-9;

  • 4

    Obergfell A et al. Platelets 2006; 17:448-53;

  • 5

    Ahmad SS et al. J Biol Chem 2000; 275:13071-81;

  • 6

    Bhat V et al. Am J Hematol 2015; 90:1027-35;

  • 7

    Sartori MT et al. Haemophilia 2008; 14:1055-62;

  • 8

    Böhmert S et al. Hämostaseologie 2019; 39:195-202;

  • 9

    Barnes RFW et al. Int J Hypertension 2016; 2016:2014201;

  • 10

    Gerstner G et al. Haemophilia 2009; 15:559-65;

  • 11

    Vilaca T et al. Lancet Diabetes Endocrinol 2022; 10:273-83;

  • 12

    Khawaji M et al. Haemophilia 2009; 15:261-6;

  • 13

    Liel MS et al. Br J Haematol 2012; 158:140-3;

  • 14

    Gay ND et al. Br J Haematol 2015; 170:584-586;

  • 15

    Valentino LA. J Thromb Haemost 2010; 8:1895-902;

  • 16

    Lobet S et al. J Blood Med 2014; 5:207-18;

  • 17

    Warren BB et al. Blood Adv 2020; 4:2451-9;

  • 18

    Manco-Johnson MJ et al. J Thromb Haemost 2017; 15:2115-241;

  • 19

    Fischer K et al. Blood 2002; 99:2337-41;

  • 20

    Gamal Andrawes N et al. Haemophilia 2020; 26:325-32;

  • 21

    Pasi J et al. Ther Adv Hematol 2022; 3:20406207221079482;​

  • 22

    Periayah MG et al. Int J Hematol Oncol Stem Cell Res 2017; 11:319-27;​

  • 23

    Nechipurenko DY et al. Arterioscler Thromb Vasc Biol2019; 39:37-47;​

  • 24

    Strebel A et al. Blood 2024; 144(Suppl.1): 5462;​

  • 25

    Shahani T et al. J Thromb Haemost 2014; 12:36-42;​​

  • 26

    Pan J et al. Blood 2016; 128:104-9;​

  • 27

    Sun H et al. Haemophilia 2017; 23:777-83;​

  • 28

    Cooke EJ et al. J Thromb Haemost 2019; 17:1815:26.

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