Chronic pain as a hallmark of haemophilia. Remarkable, but true.   April 19th, 2021

​To date thousands of rare diseases have been described in medical literature and still every day researchers worldwide are working to discover and better understand new unique diseases. 

This is how “Haemophilia”, a rare genetic bleeding disorder was discovered, but it might be world’s best known rare disease. Or perhaps “the royal disease” will ring a bell, as Queen Victoria of England passed the trait on her descendants in the 19th and 20th centuries, spreading the disease through most European royal families as a result of princely alliances. Especially the male relatives, as it is an X-linked recessive genetic disorder typically affecting males, while females are carriers.  

Today, approximately 400 000 people worldwide are estimated to be living with haemophilia, a deficiency of clotting factors (Haemophilia A (i.e. Factor VIII) and Haemophilia B (i.e. Factor IX)).1 This disorder is manifested by recurrent spontaneous and trauma-related bleeding, with most bleeding occurring in muscles and synovial joints (i.e. hemarthrosis), mostly knee, ankle, and elbow (target joints).2 

However, thanks to tremendous scientific progress, patients in developed countries have excellent access to substitution therapy (i.e. clotting factors by intravenous injection) which is administered after a bleeding or as preventive prophylactic treatment, thereby significantly decreasing the risk of bleeding.3 As a result, life expectancy of treated patients has now become comparable to the general population. Despite this scientific progress, recurrent hemarthrosis still occur.3,4 These bleeding have devastating effects on joint components due to iron deposits, resulting in synovial inflammation, cartilage degeneration and bone damage, with as end-stage a very painful and invalidating hemophilic arthropathy2 affecting the majority of adult patients. Hereby, hemophilia in adults seems clinically more related to a chronic musculoskeletal disorder than a bleeding disorder with many patients reporting a clinical pain experience with an intensity exceeding 6/10 on a visual analogue scale.5,6 

Previously studies revealed that a sudden increase in pain intensity is believed to be the result of an acute bleed rather than chronic pain due to arthropathy.6 But, this association seemed wrong, as a bleeding was only confirmed in a minority of patients and fluctuations in pain intensity are extremely common in musculoskeletal pain conditions.6 

However, in contrast to literature in chronic pain conditions such as osteoarthritis, rheumatoid arthritis or low back pain, there is still a huge lack of studies investigating the (patho)physiology of pain in haemophilia, despite the high prevalence of (widespread) pain.7 So understanding the complexity of pain and its corresponding causal/or maintaining factors would allow us to better assess and manage pain in haemophilia.8 Because the treatment approach will be different according to the underlying predominant pain mechanism seen (i.e. nociceptive, neuropathic or nociplastic pain).

In conclusion, the enormous impact of chronic joint pain is remarkably not the first hallmark you would think of when you hear about haemophilia. Therefore, exploring the underlying pain mechanisms will drastically change the treatment strategy to improve patients’ quality of life. There is still some work to be done, but the future only looks promising. 

Anthe Foubert

Anthe is a doctoral researcher at the Department of Rehabilitation Sciences and Physiotherapy (REVAKI) at the Antwerp University (Antwerp, Belgium) and Université Catholique de Louvain (Brussels, Belgium). 

2021  Pain in Motion

References and further reading:  

1. Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al. Guidelines for the management of hemophilia. Haemophilia 2013; 19(1): e1-47.

2. Pulles AE, Mastbergen SC, Schutgens RE, Lafeber FP, van Vulpen LF. Pathophysiology of hemophilic arthropathy and potential targets for therapy. Pharmacological research 2017; 115: 192-9.

3. Manco-Johnson MJ, Lundin B, Funk S, et al. Effect of late prophylaxis in hemophilia on joint status: a randomized trial. J Thromb Haemost 2017; 15(11): 2115-24.

4. Khair K, Mazzucconi MG, Parra R, et al. Pattern of bleeding in a large prospective cohort of haemophilia A patients: A three-year follow-up of the AHEAD (Advate in HaEmophilia A outcome Database) study. Haemophilia 2018; 24(1): 85-96.

5. Tagliaferri A, Franchini M, Rivolta GF, et al. Pain assessment and management in haemophilia: A survey among Italian patients and specialist physicians. Haemophilia 2018; 24(5): 766-73.

6. Kruger S, Weitz C, Runkel B, Hilberg T. Pain sensitivity in patients with haemophilia following moderate aerobic exercise intervention. Haemophilia 2016; 22(6): 886-93.

7. Roussel N. Gaining insight into the complexity of pain in patients with haemophilia: State‐of‐the‐art review on pain processing. Haemophilia 2018; 24: 3-8.

8. Timmer MA, Pisters MF, de Kleijn P, de Bie RA, Fischer K, Schutgens RE. Differentiating between signs of intra-articular joint bleeding and chronic arthropathy in haemophilia: a narrative review of the literature. Haemophilia 2015; 21(3): 289-96.