Current Practice in Management of Muscle Haematomas in Patients with Severe Haemophilia Rikke Beyer, Jørgen Ingerslev, Benny Sørensen

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Rikke Beyer, Jørgen Ingerslev, Benny Sørensen. Current Practice in Management of Muscle Haematomas in Patients with Severe Haemophilia. Haemophilia, Wiley, 2010, 16 (6), pp.926. 10.1111/j.1365-2516.2010.02275.x. hal-00552624

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Current Practice in Management of Muscle Haematomas in Patients with Severe Haemophilia

For Peer Review Journal: Haemophilia

Manuscript ID: HAE-00049-2010.R1

Manuscript Type: Original Article

Date Submitted by the 28-Mar-2010 Author:

Complete List of Authors: Beyer, Rikke; Bispebjerg Hospital, Department of Physical Therapy, Musculoskeletal Rehabilitation Research Unit Ingerslev, Jørgen; Skejby University Hospital, Centre for Haemophilia andThrombosis Sørensen, Benny; Haemostasis Research Unit, Centre for Haemostasis and Trombosis, Centre for Haemophilia and Thrombosis, Guy's and St Thomas' NHS Trust; Aarhus University Hospital Skejby, Centre for Haemophilia and Thrombosis

Haemophilia, Muscle haematoma, Haemostatic intervention, keywords: Physiotherapy, Diagnosis, Hhysical examination

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R Beyer et al. Management of Muscle Haematoma in Haemophilia 1 2 3 4 5 6 7 8 Current Practice in Management of Muscle Haematomas in 9 10 Patients with Severe Haemophilia 11 12 Rikke Beyer 1,3 , Jørgen Ingerslev 2, Benny Sørensen 1,2 13 14 15 1Haemostasis Research Unit, Centre for Haemophilia and Thrombosis, Department of 16 Haematology and Oncology, Guy’s and St Thomas Hospital & NHS Foundation Trust & King’s 17 College London School of Medicine, London, UK 18 19 2Center for Haemophilia and Thrombosis, Department of Clinical Biochemistry, Aarhus 20 University Hospital, Skejby,For Denmark Peer Review 21 3 22 Department of Physical Therapy, Musculoskeletal Rehabilitation Research Unit, Bispebjerg 23 Hospital, Copenhagen, Denmark 24 25 26 Key words : Muscle bleeding, muscle haematoma, diagnosis, physical 27 examination, haemostatic intervention, physiotherapy 28 29 30 31 Running title : Management of Muscle haematoma in Haemophilia 32 33 34 35 Word count : Abstract: 250, Main text: 2123 (excluding refereces) 36 37 38 39 Disclosure 40 41 Novo Nordisk kindly supported the study by providing an unrestricted 42 43 educational grant supporting the questionnaire e-survey. 44 45 46

47 48 49 50 Contact 51 52 Benny Sørensen, MD, Ph.D, Assoc. professor 53 54 Senior Clinical Research Fellow & Honorary Lecturer 55 56 Haemostasis Research Unit 57 58 Center for Haemophilia and Thrombosis, Guy’s and St Thomas Hospital & NHS Foundation Trust 59 Email: [email protected] 60

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R Beyer et al. Management of Muscle Haematoma in Haemophilia 1 2 3 4 5 Abstract 6 7 Muscle haematomas (MH) represent 10-25% of all bleeds in patients with severe 8 9 Haemophilia. We performed a cross sectional survey on current practice in 10 11 management of MH with participation from 22 consultants. The respondents 12 13 reported 492 MH/year, corresponding an average of 25/centre, most associated 14 15 with trauma. Iliopsoas (55%), calf (18%), and thigh (18%) bleeds were scored as 16 most serious. Half of respondents distinguished between contusion and strains, 17 18 whereas the majority (68.2%) did not categorise bleedings as intra- or 19 20 intermuscular, althoughFor 77.3% Peer routinely Review used ultrasound. Half of respondents 21 22 used a standard protocol for management of MH. A total of 20 of 22 (90.9%) 23 24 offered physiotherapy in the hospital following MH, with no clear consensus on 25 timing and type of treatment. In a theoretical case, 70 kg patient with a soleus 26 27 triceps haematoma, the average initial dose was 2730 U (range: 1750-4000) 28 29 twice daily for 3-5 days. In a similar case of a patient with inhibitors, 31.8% 30 31 reported first line and only use of either rFVIIa or aPCC, while 36.4% switched 32 33 between bypassing agents. Using rFVIIa the median dose was 100 µg/kg (range: 34 85 - 270) and with aPCC the median dose was 70 U/kg (range: 50 - 100). The 35 36 majority (68.2%) did not use antifibrinolytics. Resolution of pain (81.8% & 37 38 77.3%) was regarded the key clinical marker of arrest of bleeding as compared 39 40 to diminished swelling and improved range of motion. The survey outlines 41 42 limited consensus in management of MH in patients with Haemophilia and 43 highlights potential topics for future studies. 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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R Beyer et al. Management of Muscle Haematoma in Haemophilia 1 2 3 4 5 Introduction 6 7 Muscle bleedings in patients with Haemophilia often cause considerable pain 8 9 and compromise overall physical capacity. Intramuscular haemorrhages are 10 11 reported to represent approximately 10% -25% of all bleedings in patients with 12 13 haemophilia [1]. In patients with severe Haemophilia, bleeds may become limb 14 15 threatening. Recovery and rehabilitation may be protracted and insufficient. In 16 contrast to spontaneous joint haemarthrosis, muscle bleeds are mostly 17 18 associated with trauma [1]. In general, muscle haematomas in patients with 19 20 haemophilia areFor often considered Peer as Review difficult-to-treat bleeds. Insufficiently 21 22 treated muscle bleeds may result in several complications such as e.g. 23 24 irreversible damage to the muscles, including compartment syndrome, reduced 25 range of motion, loss of function, myositis [2], damage to tendons (Volkman’s 26 27 ischemic contractures) [3], as well as excessive blood loss, infection, peripheral 28 29 nerve complications, and development of haemophilia pseudo tumor [4]. 30 31 Unfortunately, the majority of research and development within Haemophilia are 32 33 focused on mechanisms related to preventing haemarthrosis and maintaining a 34 good functional joint status. Only very few publications have reported on aspects 35 36 of muscle haematoma in patients with severe Haemophilia [1;5]. Predominantly, 37 38 reports have focused on management of m. psoas major bleeds [6;7] and 39 40 haemophilia pseudo tumors [8-10]. As of today, limited consensus exists 41 42 regarding choice of factor concentrate, dosages of factor substitution utilised, 43 frequency of dosing, and duration of the haemostatic treatment. In particular, in 44 45 patients with severe Haemophilia and inhibitors, studies supporting various 46 47 approaches to treatment regimens do practically not exist. Finally, important 48 49 information on concomitant and adjuvant treatment such as physiotherapy are 50 51 rarely specified or described in detail. 52 53 The aim of the present study was to conduct a cross-sectional study on current 54 55 practice in management of muscle bleeds in patients with severe Haemophilia A 56 57 amongst haemophilia comprehensive care centres from UK, Denmark, Ireland, 58 59 and Australia based on an electronic mail questionnaire. 60

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R Beyer et al. Management of Muscle Haematoma in Haemophilia 1 2 3 4 5 Materials and Methods 6 7 8 Definition and classification of a muscle haematoma 9 10 In the present study, a muscle haematoma was defined as a bleeding in any 11 12 anatomical skeletal muscle group. Clinical classification and differentiation 13 14 between different types of muscle haematoma are described in a recent review 15 (ref). 16 17 18 Questionnaire on current practice of muscle haematoma 19 20 An electronic questionnaireFor Peer was developed Review addressing evolvement of muscle 21 22 haematoma, diagnosis of muscle haematomas, haemostatic intervention of 23 24 muscle bleeds in patients with severe haemophilia without and with inhibitors, 25 use of concomitant or adjuvant haemostatic intervention, diagnostic procedures, 26 27 and physiotherapy (See Appendix 1). The questionnaire was emailed to 28 29 consultant haematologists from 50 registered Haemophilia comprehensive care 30 31 centres (CCC) in the United Kingdom (UK), Ireland (IR), Denmark (DK), and 32 33 Australia (AUS). We advised that the questionnaire was answered by the 34 consultant haematologist and not by junior doctors or nurses. Centres were 35 36 asked to answer questions regarding adults only. Respondents reported 37 38 estimated figures rather than actual measured data. Each participant was offered 39 40 £100 for the effort and time spent filling out the questionnaire. All e-survey was 41 42 circulated by June 2008. We allowed a period of 1 month for answering the 43 44 questionnaire. Gentle reminders were emailed once a week. Following closure of 45 the study period, results from the questionnaire were organized, analyzed and 46 47 interpreted by the authors. In order to ensure the validity and quality of data, 48 49 two of the investigators (RB and BS) independently listed the results in a 50 51 preformed excel spreadsheet, using a predetermined checklist. In case of doubt 52 53 or disagreement of the meaning of the responses, the third investigator (JI) 54 evaluated the questionnaire. 55 56 57 58 59 60

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R Beyer et al. Management of Muscle Haematoma in Haemophilia 1 2 3 4 5 Data analysis and statistical considerations 6 7 Quantitative data and categorical data are presented using descriptive statistics. 8 9 Qualitative statements are organized in tables, whereas quantitative measures 10 11 are listed as figures and graphically illustrated. 12 13 Ethical considerations 14 15 The data from each participant are anonymous; hence, none of the results can be 16 17 referred back to a specific centre. The questionnaire did not include specific 18 19 patient data. 20 For Peer Review 21 22 Results 23 24 Frequency and aetiology of muscle bleeding 25 26 In total 22 consultants representing 20 comprehensive haemophilia care centres 27 28 in UK (17), IR (1), DK (2), and AUS (2) responded to the questionnaire. The 29 30 respondents reported an estimated number of 492 muscle haematomas/year, 31 32 corresponding an average of 25/CHCC. Using a score system ranging from 0-10 33 34 (0 representing never , 10 representing always ) the aetiology of muscle 35 haematomas was predominantly assessed as associated with trauma (score 7.1 36 37 of 10) rather than spontaneous development (4.0 of 10). Amongst a list of 38 39 different anatomic localisations of muscle haematomas, Iliopsoas (55%), calf 40 41 (18%), and thigh (18%) bleeds were scored as the most serious (Figure 1). 42 43 Diagnostic procedures 44 45 Half of the respondents stated they distinguish between contusion and strains, 46 47 whereas the majority (68.2%) did not categorise bleedings as intra- or 48 49 intermuscular, although 77.3% routinely used diagnostic ultrasound. 50 51 52 Haemostatic intervention 53 54 Only 50 % of respondents reported using a standard protocol for management of 55 muscle haematomas. 56 57 58 59 60

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R Beyer et al. Management of Muscle Haematoma in Haemophilia 1 2 3 4 5 The questionnaire outlined a theoretical case: “An objectively verified muscle 6 7 haematoma in the soleus triceps of a lower limb of a 29 year old patient, 8 9 weighing 70 kilos with severe Haemophilia A.” followed by questions addressing 10 11 i) initial dosages of factor, ii) subsequent dosages of factor, iii) duration of 12 therapy, iv) tapering of dosages or dose frequency, as well as v) addition of an 13 14 anti-fibrinolytic. 15 16 17 Haemostatic intervention in patients with severe Haemophilia A without 18 19 inhibitor 20 For Peer Review 21 The average initial dose of factor VIII was 2730 U (range: 1750-4000). 22 23 Treatment was continued for a mean of 3-5 days (range: 1-10). Subsequent 24 25 dosages were similar to the initial dosage, although the majority of respondents 26 27 indicated they were tapering the dosage and dose frequency based on daily 28 29 assessment of each individual case. The majority (77.3%) of consultants did not 30 distinguish recombinant factor VIII from plasma derived factor VIII concentrate 31 32 containing von Willebrand factor. The total amount of factor VIII used ranged 33 34 from minimum=4500 U to maximum=50000 U (median=10750 U, mean=17103 35 36 U) depending on the severity, type and anatomical localisation of the 37 38 haematoma. 39 40 Haemostatic intervention in patients with severe Haemophilia A with 41 42 inhibitors 43 44 45 In a similar case of a patient with inhibitors, 31.8% reported first line and only 46 47 use of either recombinant factor VIIa (rFVIIa) or plasma derived activated 48 prothrombin complex concentrate (pd-aPCC), while 36.4% switched between 49 50 bypassing agents. Using rFVIIa the median starting dose was 100 µg/kg (range: 51 52 85 - 270) and with aPCC the median dose was 70 U/kg (range: 50 - 100). 53 54 Subsequent dosages ranged from 85-270 µg/kg for rFVIIa (mean=110) and 50- 55 56 75 U/kg (mean=63) for pd-aPCC. Dosing interval was 2-3 hrs for rFVIIa and 12- 57 58 24 hrs for pd-aPCC. The average duration of treatment was 2.3 – 4.4 days, longer 59 for pd-aPCC (4.1 days) than rFVIIa (2.8 days). 60

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R Beyer et al. Management of Muscle Haematoma in Haemophilia 1 2 3 4 5 For both patients with and without inhibitors, physicians generally expected 6 7 haemostasis to be achievable within 6 hours, although up to 18% of centres 8 9 allowed > 12 hrs to obtain haemostasis (Figure 2). 10 11 12 Adjuvant haemostatic intervention 13 14 The majority (68.2%) did not use concomitant antifibrinolytic treatment. The 15 16 consultant reporting to use tranexamic acid, dosage regimens varied from 1g 17 18 daily to 25mg/kg qds 6 hourly. The antifibrinolytic treatment was most often 19 20 continued for 5-7For days. Peer Review 21 22 Clinical marker of arrest of bleeding and maintaining haemostasis 23 24 Resolution of pain (patients without inhibitors: 18 out of 22 haemophilia 25 26 treaters=81.8% & patients with inhibitors: 17 out of 22 haemophilia 27 28 treaters=77.3%) was regarded the key clinical marker of arrest of bleeding and 29 30 maintenance of haemostasis as compared to diminished swelling and improved 31 range of motion. Figure 3, Panels A and B illustrates the scoring of importance (1 32 33 important to 4 less important) amongst patients without and with Haemophilia, 34 35 showing that pain was scored as the most important marker. 36 37 38 Physiotherapy 39 40 A total of 20 of 22 (90.9%) offered physiotherapy in the hospital following 41 muscle haematomas. As outlined in Table 1, there was limited consensus on 42 43 timing and type of treatment. RICE-treatment (rest-ice-compression-elevation) 44 45 was recommended in most centres. All centres offered therapeutic ultrasound in 46 47 the hospital setting, although there was limited agreement on the optimal timing 48 49 of the intervention. 50 51 Grading of importance of further research and studies in management of muscle 52 53 haematoma in patients with Haemophilia 54 55 The overall importance of further research and studies in management of muscle 56 57 haematomas scored 7 and 8 (out of 10) for haemophilia patients without and 58 59 with inhibitors. 60

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R Beyer et al. Management of Muscle Haematoma in Haemophilia 1 2 3 4 5 Discussion 6 7 Muscle haematomas represent difficult to treat bleeds in patients with severe 8 9 Haemophilia. Multiple anatomical targets and various trauma mechanisms 10 11 complicate the clinical evaluation, diagnosis, treatment and rehabilitation. 12 13 Currently, limited consensus exists on the comprehensive management of 14 15 muscle haematomas in Haemophilia patients. 16 17 The present survey verified that the majority of muscle haematomas has a 18 19 traumatic aetiology. It may be speculated whether patients with inhibitors are 20 For Peer Review 21 more prone to develop muscle haematomas than patients without inhibitors. 22 23 Some studies suggest that muscle haematomas represent 10% of all bleeds in 24 patients with severe Haemophilia [1]. However, the data from the US home 25 26 treatment study of rFVIIa suggest that up to 23% of bleeds in patients with 27 28 inhibitors are muscle haematoma [11]. These questions were not explored in 29 30 further detail in the present study, however, should be kept in mind for future 31 32 investigations. 33 34 Not surprisingly, iliopsoas muscle bleeds were reported as the most severe type 35 36 of muscle haematoma. Likewise, the majority of previous reports and studies 37 38 have focused on the iliopsoas bleeds [6;7]. 39 40 41 The study revealed sparse consistency regarding diagnostic procedures. Only 42 half of the respondents distinguished contusions from strains. The majority of 43 44 centres listed the use of ultrasound for diagnosis. However, only few 45 46 differentiated between intra- vs. inter-muscular localisation of the haematoma. 47 48 Diagnostic classification of muscle haematomas is a complicated clinical 49 50 discipline and in the current issue of Haemophilia we have reviewed 51 classification and strategies for optimised diagnosis of muscle haematomas [12]. 52 53 54 Moreover, the questionnaire highlighted limited agreement regarding dosing 55 56 regimens and duration of the pharmacological therapy. Only half of respondents 57 58 stated to have a specific written protocol on recommendations for coagulation 59 60 factor treatment of muscle bleeds. Thus, the total amount of factor VIII used

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R Beyer et al. Management of Muscle Haematoma in Haemophilia 1 2 3 4 5 varied considerably. The lack of consensus was even more pronounced with 6 7 Haemophilia patients with inhibitors. A potential explanation for the variation in 8 9 treatment regimens could be the markers of arrest of bleeding and achieved 10 11 haemostasis. The respondents of the survey predominantly used pain rather 12 than reduced swelling and improved range of motion as the marker for arrest of 13 14 bleeding as well as achieved haemostasis. It is noteworthy that, even in 15 16 professional athletes the entire repair process and rehabilitation period 17 18 following muscle injuries may take more than 30 days [13]. Pain may be 19 20 considered a physiologicalFor Peer response toReview muscle damage and present despite 21 22 arrest of bleeding and normal haemostasis. Hence, it seems that optimised 23 measures for assessing ongoing bleeding and achieved haemostasis are essential 24 25 for optimising treatment regimens. 26 27 28 The majority of participants indicated a time period of less than 6 hrs as the 29 30 preferred / accepted time to arrest of bleeding. There was a slight tendency to 31 accept of longer time to arrest of bleeding in patients with inhibitors. This may 32 33 be due to less predictability regarding haemostatic response as well as 34 35 difficulties in monitoring and dosing the bypassing agents. 36 37 38 Recently investigations have shown that patients with severe Haemophilia not 39 40 only suffer from compromised thrombin generation, but also insufficient clot 41 stability caused by delayed and incomplete activation of FXIII [14] and increased 42 43 susceptibility toward accelerated fibrinolysis [15]. Clinical studies have 44 45 suggested a potent effect of concomitant antifibrinolytic treatment with 46 47 tranexamic acid [15]. However, the majority of responders in the survey stated 48 49 not to use adjuvant tranexamic acid for muscle haematoma. The study did not 50 explore reasons for limited use of tranexamic acid. Lack of clinical studies may be 51 52 one reason, whereas theoretical speculations on thrombotic risk may be another 53 54 explanation. Further mechanistic as well as clinical studies would be desirable. 55 56 57 The timing and type of adjuvant physiotherapy recommended revealed 58 considerable discrepancy. The RICE principle and therapeutic ultrasound was 59 60

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R Beyer et al. Management of Muscle Haematoma in Haemophilia 1 2 3 4 5 commonly recommended. However, a series of other interventions were 6 7 mentioned and recommended. Obviously, it would be interesting to develop a 8 9 series of systematic studies challenging various physiotherapy regimens. The 10 11 current issue of Haemophilia lists some experiences from Sports Physiotherapy 12 that may prove useful for improving overall rehabilitation and prevention of 13 14 muscle injuries in patients with severe Haemophilia [12]. Recent publications 15 16 have proposed a beneficial and potentially protective effect of regular exercise in 17 18 patients with severe Haemophilia [16]. Optimized muscular function may protect 19 20 against joint bleedingsFor and Peerimproved fitness Review was associated with a higher rating 21 22 of quality of life [17-19]. Likewise, a recent study describe a conservative and 23 non-operative physiotherapeutic regime for the management of chronic 24 25 haematomata and pseudotumors in patients suffering from haemophilia [20]. 26 27 28 The study contains a series of important limitations. This cross sectional study 29 30 only provides a random sample of current management of muscle haematomas. 31 The nature of the study design does not provide valid data on causality, neither 32 33 on actual measured frequencies and dose regimens. Respondents may have 34 35 reported on their preferred/wished treatment modality, with no assurance that 36 37 the data reflect actual practice. As an example, the numerous types of 38 39 physiotherapy may reflect what consultant haematologists would like to offer, 40 rather than what is actually available. The questionnaire was sent to 50 random 41 42 comprehensive haemophilia care centres, however, only centres from UK, 43 44 Ireland, DK, and Australia were enrolled. Thus, selection and information bias 45 46 may be present and the data has reduced external validity. 47 48 49 In conclusion, the present survey suggests the need for further studies on the 50 pathology, diagnosis, and importance of early treatment to achieve rapid control 51 52 of bleeding, as well as rehabilitation following muscle haematomas in patients 53 54 with Haemophilia. A prospective international multicentre registry of current 55 56 management of muscle haematomas seems desirable to get more data. 57 58 Optimised and systematic diagnosis may facilitate a better strategy regarding 59 type and timing of physiotherapy. 60

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R Beyer et al. Management of Muscle Haematoma in Haemophilia 1 2 3 4 5 Acknowledgement 6 7 We are grateful to colleagues at comprehensive haemophilia care centres in UK, 8 9 DK, Ireland, and Australia for their time and effort in responding to our 10 11 questionnaire. 12 13 14 Appendix 15 16 A pdf-copy of the questionnaire can be obtained by emailing the corresponding 17 author. 18 19 20 References For Peer Review 21 22 Reference List 23 24 25 26 27 1. Alcalay M, Deplas A. Rheumatological management of patients with 28 29 hemophilia. Part II: Muscle hematomas and pseudotumors. Joint Bone 30 Spine 2002; 69 (6): 556-9. 31 32 2. Brukner P, Khan K. Clinical sports medicine. 3rd ed. Australia ed. McGraw- 33 Hill; 2006. 34 35 36 3. Lancourt JE, Gilbert MS, Posner MA. Management of bleeding and 37 associated complications of hemophilia in the hand and forearm. J Bone 38 Joint Surg Am 1977; 59 (4): 451-60. 39 40 4. Ahlberg AK. On the natural history of hemophilic pseudotumor. J Bone 41 Joint Surg Am 1975; 57 (8): 1133-6. 42 43 44 5. Aronstam A, Browne RS, Wassef M, Hamad Z. The clinical features of early 45 bleeding into the muscles of the lower limb in severe haemophiliacs. J 46 Bone Joint Surg Br 1983; 65 (1): 19-23. 47 48 6. Dauty M, Sigaud M, Trossaert M, Fressinaud E, Letenneur J, Dubois C. 49 50 Iliopsoas hematoma in patients with hemophilia: a single-center study. 51 Joint Bone Spine 2007; 74 (2): 179-83. 52 53 7. Heim M, Horoszowski H, Seligsohn U, Martinowitz U, Strauss S. Ilio-psoas 54 hematoma--its detection, and treatment with special reference to 55 hemophilia. Arch Orthop Trauma Surg 1982; 99 (3): 195-7. 56 57 58 8. NELSON MG, MITCHELL ES. Pseudo-tumour of bone in haemophilia. Acta 59 Haematol 1962; 28 : 137-44. 60

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R Beyer et al. Management of Muscle Haematoma in Haemophilia 1 2 3 4 5 9. Grauthoff H, Hofmann P, Lackner K, Brackmann HH. [Haemophilic 6 pseudo-tumours and iliac haematomas: radiological and clinical findings 7 8 (author's transl)]. Rofo 1978; 129 (5): 614-20. 9 10 10. Chakal F, Viso R, Fernandez PF. Percutaneous treatment of haemophilic 11 digital pseudo tumours. Int Orthop 2005; 29 (3): 197-8. 12 13 11. Key NS, Aledort LM, Beardsley D, Cooper HA, Davignon G, Ewenstein BM, 14 15 et al. Home treatment of mild to moderate bleeding episodes using 16 recombinant factor VIIa (Novoseven) in haemophiliacs with inhibitors. 17 Thromb Haemost 1998; 80 (6): 912-8. 18 19 12. Beyer R, Ingerslev J, Sørensen B. Muscle Bleeds in Professional Athletes - 20 Diagnosis, For Classification, Peer Treatment, Review and Potential Impact for Patients with 21 22 Haemophilia . Haemophilia 2010; (Manuscript in submission). 23 24 13. Mason DL, Dickens V, Vail A. Rehabilitation for hamstring injuries. 25 Cochrane Database Syst Rev 2007; (1): CD004575. 26 27 14. Brummel-Ziedins KE, Branda RF, Butenas S, Mann KG. Discordant fibrin 28 29 formation in hemophilia. J Thromb Haemost 2009; 7(5): 825-32. 30 31 15. Hvas AM, Sorensen HT, Norengaard L, Christiansen K, Ingerslev J, 32 Sørensen B. Tranexamic acid combined with recombinant factor VIII 33 increases clot resistance to accelerated fibrinolysis in severe hemophilia 34 35 A. J Thromb Haemost 2007; 5(12): 2408-14. 36 37 16. Buzzard BM. Physiotherapy, rehabilitation and sports in countries with 38 limited replacement coagulation factor supply. Haemophilia 2007; 13 39 Suppl 2 : 44-6. 40 41 17. Wittmeier K, Mulder K. Enhancing lifestyle for individuals with 42 43 haemophilia through physical activity and exercise: the role of 44 physiotherapy. Haemophilia 2007; 13 Suppl 2 : 31-7. 45 46 18. VON MS. Quality of life and sports activities in patients with haemophilia. 47 Haemophilia 2007; 13 Suppl 2 : 38-43. 48 49 19. van der Net J, Vos RC, Engelbert RH, van den Berg MH, Helders PJ, Takken 50 51 T. Physical fitness, functional ability and quality of life in children with 52 severe haemophilia: a pilot study. Haemophilia 2006; 12 (5): 494-9. 53 54 20. D'Young AI. Conservative physiotherapeutic management of chronic 55 haematomata and haemophilic pseudotumours: case study and 56 57 comparison to historical management. Haemophilia 2009; 15 (1): 253-60. 58 59 60

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1 2 3 4 5 6 Figures 7 8 9 Figure 1 10 11 12 Anatomical localisation of most severe muscle haematoma 13 14 15 16 17 18 19 20 For Peer Review 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Haemophilia Page 14 of 18

1 2 3 4 Figure 2 5 6 7 Accepted time to arrest of bleeding 8 9 10 11 12 13 14 15 16 17 18 19 20 For Peer Review 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 15 of 18 Haemophilia

1 2 3 4 Figure 3 5 6 7 Markers of arrest of bleeding and maintaining haemostasis 8 9 10 11 12 13 14 15 16 17 18 19 20 For Peer Review 21 22 23 24 25 26 27 28 29 30 Panel A: Haemophilia patients without inhibitors 31 32 Panel B: Haemophilia patients with inhibitors 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Haemophilia Page 16 of 18

1 2 3 4 5 Legends 6 7 8 Figure 1 9 10 11 Anatomical localisation of most severe muscle haematoma 12 13 14 Illustrates frequency data (%) on the anatomical localisation of the most severe 15 16 muscle haematoma. 17 18 19 20 Figure 2 For Peer Review 21 22 Accepted time to arrest of bleeding 23 24 25 26 Depicts the accepted time to arrest of bleeding in patients without and with 27 inhibitors. 28 29 30 31 Figure 3 32 33 34 Markers of arrest of bleeding and maintaining haemostasis 35 36 37 Illustrates the results of score of importance of the three clinical markers: 38 reduced pain, reduced swelling, improved range of motion as defined by 39 40 subjective reported relief of pain, reduced circumferential measure, and 41 measurement of the achievable distance between the flexed position and the 42 extended position of a particular muscle group, respectively. The score 1 43 corresponds most important, whereas the score 3 corresponds least important. 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 17 of 18 Haemophilia

1 2 3 4 5 6 7 8 Tables 9 10 11 12 Table 1 13 For Peer Review 14 Timing and type of physiotherapy 15 16 SUPER ACUTE PHASE (0- ACUTE PHASE (24-72 SUB ACUTE PHASE (4-21 POST ACUTE PHASE (>21 17 24 HOURS) HOURS) DAYS) DAYS) 18 19 RICE 10/22 – 45.5% 9/22 – 40.9% 2/22 – 9.0% 1/22 – 4.5% 20 Megapulse Ultrasound 1/22 – 4.5% 2/22 – 9.0% 0 0 21 Passive movement 2/22 – 9.0% 2/22 – 9.0% 0 0 22 Walking aids 2/22 – 9.0% 3/22 – 13.6% 2/22 – 9.0% 4/22 – 18.2% 23 24 Mobilisation 0 2/22 – 9.0% 4/22 – 18.2% 3/22 – 13.6% 25 Isometric strengthening 0 2/22 – 9.0% 2/22 – 9.0% 0 26 Strengthening 0 0 2/22 – 9.0% 5/22 – 22.7% 27 Exercise 0 3/22 – 13.6% 3/22 – 13.6% 5/22 – 22.7% 28 Ultrasound 0 0 9/22 – 40.9% 2/22 – 9.0% 29 30 PSWD 0 2/22 – 9.0% 3/22 – 13.6% 0 31 Hydrotherapy 0 0 3/22 – 13.6% 1/22 – 4.5% 32 Active muscle contraction 0 0 1/22 – 4.5% 0 33 ROM exercise 0 1/22 – 4.5% 3/22 – 13.6% 2/22 – 9.0% 34 35 Massage 0 0 1/22 – 4.5% 0 36 Functional training 0 0 0 2/22 – 9.0% 37 Stretching 0 0 6/22 – 27.3% 4/22 – 18.2% 38 Re-assessment 0 0 0 3/22 – 13.6% 39 40 No intervention 10/22 – 45.5% 7/22 – 31.8% 4/22 – 18.2% 7/22 -31.8% 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Haemophilia Page 18 of 18

1 2 3 4 5 Legends 6 7 8 Table 1 9 10 11 12 Timing and type of physiotherapy 13 For Peer Review 14 Lists the recommended type of physiotherapy at various time intervals: 0-24hrs, 24-72hrs, 4-21 days, and >21 days. Data show number of 15 responders as well as the frequency in percentages. 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60