J
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`britishjournalofhaematology
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`THE OFFICIAL JOURNAL OF THE
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`BRITISH SOCIETY FOR HAEMATOLOGY
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`IN THIS ISSUE
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`- Allogeneic haematopoietic cell transplantation
`conditioning for Fanconi anaemia
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`. Molecular and clinical aspects of pyruvate kinase
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`deficiency
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`- PFA testing for haemostatic defects in children
`
`‘- Results from UK acute lymphoblastic leukaemia
`
`R2 relapse trail
`
`- When can prophylactic therapy in haemophiliacs
`be stopped?
`
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`Blackwell
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`The official journal of the British Society for Haematology
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`Finbarr Cotter LondonIan Hann LondonEditors John Reilly Sheffield
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`2/11
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`2/11
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`

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`
`
`Volume 130, Issue 1, July-I 2005
`
`
`
`Images in Haematology
`
`Peritoneal haematopoiesis in acute panmyelosis with myelofibrosis
`G. Metzgeroth, A. Reiter, W. Back, M. Anders, R. Hehlmann and I. Hastka
`Disseminated Penicillium marneflei infection
`E. S. K. Ma and P. L. Ho
`
`Reviews
`
`The role of PFA—lOO® testing in the investigation and management of haemostatic
`defects in children and adults
`P. Harrison
`
`Red cell pyruvate kinase deficiency: molecular and clinical aspects
`A. Zanella, E. Fermo, P. Bianchi and G. Valentini
`
`Haematological Malignancy
`
`Prospective gene expression analysis accurately subtypes acute leukaemia in
`children and establishes a commonality between hyperdiploidy and t(12;21) in
`acute lymphoblastic leukaemia
`F. W. van Delft, T. Bellatti, Z. Luo, L. K. Jones, N. Patel, 0. Yiannikouris, A. S. Hill,
`M. Hubank, H. Kempski, D. Fletcher, T. Chaplin, N. Foot, B. D. Young, I. M. Hann,
`A. Gammerman and V. Saha
`
`Interphase fluorescence in situ hybridization with an IGH probe is important in the
`evaluation of patients with a clinical diagnosis of chronic lymphocytic leukaemia
`G. S. Nowakowski, G. W. Dewald, I. D. Hoyer, S. F. Paternoster, K. I. Stockero, S. R. Fink,
`S. A. Smoley, E. D. Remstein, R. L. Phyliky, T. G. Call, T. D. Shanafelt, N. E. Kay
`and C. S. Zent
`
`FLT3 inhibition in t(4;11)+ adult acute lymphoid leukaemia
`G. F. Torelli, A. Guarini, A. Porzia, S. Chiaretti, C. Tatarelli, D. Diverio, R. Maggie,
`A. Vitale, I. Ritz and R. Foa
`
`Engraftment of NOD/SCID/ycnull mice with multilineage neoplastic cells from
`patients with juvenile myelomonocytic leukaemia
`Y. Nakamura, M. Ito, T. Yamamoto, X. Y. Yan, H. Yagasaki, Y. Kamachi, K. Kudo
`and S. Kojima
`
`11
`
`26
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`36
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`43
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`51
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`119..lllllllllllllll Ill
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`PUbl'Sh'ng
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`0007—1048(200507) 130:01;1—x
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`3/11
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`3/11
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`

`

`Contents
`
`Short reports
`
`58
`
`67
`
`76
`
`83
`
`87
`
`92
`
`96
`
`99
`
`107
`
`113
`
`121
`
`Autocrine/paracrine involvement of insulin-like growth factor-1 and its receptor in
`chronic lymphocytic leukaemia
`R. Schillaci, A. Galeana, D. Becu—Villalabas, O. Spinelli, S. Sapia and R. F. Bezares
`Outcome after first relapse in childhood acute lymphoblastic leukaemia — lessons
`from the United Kingdom R2 trial
`A. Roy, A. Cargill, S. Love, A. V. Moarrn'an, S. Staneham, A. Lim, P. I. Darbyshire,
`D. Lancaster, I. Hann, T. Eden and V. Saha
`
`Osteosclerosis in advanced chronic idiopathic myelofibrosis is associated with
`endothelial overexpression of osteoprotegerin
`0. Back, G. Loch, U. Schade, G. Bilsche, R. van Wasielewski, B. Wiese and H. Kreipe
`CD344r cell selection is required to assess HOXA9 expression levels in patients with
`myelodysplastic syndrome
`S. Heinrichs, I. N. Berman, T. M. Ortiz, S. M. Kornblau, D. S. Neuberg, E. H. Estey
`and A. T. Look
`
`Severe and prolonged myeloid haematopoietic toxicity with myelodysplastic
`features following alemtuzumab therapy in patients with peripheral T—cell
`lymphoproliferative disorders
`S. D. I. Gibbs, D. A. Westerrnan, C. McCormaek, I. F. Seymour and H. M. Prince
`Downregulation of the major histocompatibility complex class I molecules by
`human herpesvirus type 8 and impaired natural killer cell activity in primary
`effusion lymphoma development
`M. C. Sirianni, F. Libi, M. Campagna, D. Rassi, D. Capella, G. Sciaranghella, A. Carbane,
`C. Simonelli, P. Martini, G. Gaidana and B. Ensoli
`
`Vaccination of patients with haematological malignancies with one or two doses of
`influenza vaccine: a randomised study
`P. Ljungman, H. Nahi and A. Linde
`
`Transplantation
`
`Low—dose cyclophosphamide conditioning for haematopoietic cell transplantation
`from HLA-matched related donors in patients with Fanconi anaemia
`I. Zanis—Neta, M. E. D. Flowers, C. R. Medeiras, M. A. Bitencaurt, C. M. Banfim,
`D. C. Setabal, V. Funke, I. Sanders, H. I. Deeg, H. P. Kiem, P. Martin, W. Leisenring,
`R. Storb and R. Pasquini
`
`Platelets, Haemostasis and Thrombosis
`
`Can long-term prophylaxis for severe haemophilia be stopped in adulthood?
`Results from Denmark and the Netherlands
`_
`K. van Dijk, K. Fischer, I. G. van der Barn, E. Scheibel, I. Ingerslev and H. M. van den Berg
`Impaired bradykinin response to ischaemia and exercise in patients with mild
`congestive heart failure during angiotensin—converting enzyme treatment.
`Relationships with endothelial function, coagulation and inflammation
`M. Cugna, P. Agastani, D. Mari, P. L. Merani, L. Gregorini, M. Bassatti, G. B. Anguissala,
`F. Donatelli and I. Nassberger
`
`Haemopoiesis and Leucocytes
`
`Co-operative signalling mechanisms required for erythroid precursor expansion in
`response to erythropoietin and stem cell factor
`M. O. Arcasoy and X. Iiang
`
`4/11
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`4/11
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`

`

`Contents
`
`130
`
`138
`
`145
`
`146
`
`147
`
`148
`
`150
`
`Red Cells and Iron
`
`A novel human CD32 mAb blocks experimental immune haemolytic anaemia in
`FcyRIIA transgenic mice
`A. van Royen—Kerkhof, E. A. M. Sanders, V. Walraven, M. Voorhorst—Ogink, E. Saeland,
`
`I. L. Tooling, A. Gerritsen, M. A. van Dijk, ‘W. Kuis, G. T. Rijkers, L. Vitale, T. Keler,
`S. E. McKenzie, J. H. W. Leusen and J. G. I. van de Winkel
`
`The measurement of urinary hydroxyurea in sickle cell anaemia
`R. N. Dalton, C. Turner, M. Dick, 8. E. Height, M. Awogbade, B. Inusa, I. Okpala,
`S. O’Driscoll, S. L. Thein and D. C. Rees
`
`Correspondence
`
`Efficacy and inhibitor development in previously treated patients with haemophilia A
`switched to a B domain-deleted recombinant factor VIII — clarification of Kogenate
`inhibitor data
`P. Larson
`
`Response to Larson
`A. Gringeri
`The NF-KB pathway and the successful application of anti-inflammatory and
`angiostatic therapy in Langerhans’ cell histiocytosis
`R. E. Brown
`
`Factors predicting development of chronic disease in Nordic children with acute
`onset of idiopathic thrombocytopenic purpura
`S. Rosthoj, I. Hedlund—Treutiger, I. Rajantie and B. Zeller on behalfof the Nordic Society
`for Paediatric Haematology and Oncology Idiopathic Thrombocytopenic Parpura Working
`Group
`Response to Rosthoj et al
`M. Bruin, M. Bierings, C. Uiterwaal, R. R. Tamminga and M. de Haas
`
`5/11
`
`5/11
`
`

`

`research paper
`
`Can long-term prophylaxis for severe haemophilia be stopped in
`adulthood? Results from Denmark and the Netherlands
`
`K. van Dijk,1,2 K. Fischer,1,3 J. G. van der
`Bom,1,4 E. Scheibel,5 J. Ingerslev6
`and H. M. van den Berg1,3
`1Van Creveldkliniek, UMC Utrecht, 2Julius Centre
`for Health Sciences and Primary Care, UMC
`Utrecht, 3Wilhelmina Children’s Hospital, UMC
`Utrecht, Utrecht, 4Department of Clinical
`Epidemiology, Leiden UMC, Leiden, The
`Netherlands, 5Juliane Marie Centre,
`Rigshospitalet, University of Copenhagen,
`Copenhagen, and 6Department of Biochemistry,
`Centre for Haemophilia and Thrombosis, A˚ rhus
`University Hospital, A˚ rhus, Denmark
`
`Received 20 February 2005; accepted for
`
`publication 21 April 2005
`
`Correspondence: K. van Dijk, MD, PhD, Van
`
`Creveldkliniek, UMCU,
`
`Room C01.425, PO Box 85500,
`
`3508 GA Utrecht, The Netherlands.
`
`E-mail: k_van_dijk@wanadoo.nl
`
`Summary
`
`Prophylaxis is the treatment of choice for children with severe haemophilia.
`As prophylaxis is especially important during the period of growth, the need
`for continued prophylaxis in adulthood should be considered. The aim of
`this study was to describe the incidence and outcome of stopping prophylaxis
`in patients with severe haemophilia who were offered prophylaxis during
`childhood. All patients with severe haemophilia (factor VIII/IX <0Æ01 IU/ml),
`born 1970–80, treated in two Danish and one Dutch treatment centre were
`studied. Data on discontinuation of prophylaxis, treatment,
`joint bleed
`frequency, clinical scores and radiological scores were collected. Eighty
`patients were studied. Median follow-up was 19 years (range 7–29). A total of
`35% of patients discontinued prophylaxis at a median age of 21Æ5 years
`[interquartile range (IQR) 18Æ4–24Æ4], experiencing only three joint bleeds
`per year (IQR 1Æ4–8Æ7). Median clinical scores were similar in patients who
`discontinued prophylaxis [4 points (IQR 0–6)] and those who continued [3
`points (IQR 1–6)], as were median Pettersson scores at 13 (IQR 1–24) vs. 13
`points (IQR 5–23) respectively. In conclusion one-third of young adults with
`severe haemophilia on a prophylactic regimen discontinued prophylaxis in
`early adulthood, while maintaining a low joint bleed frequency and similar
`arthropathy after 4 years.
`
`Keywords: prophylaxis, adherence, haemophilia, outcome, bleeds.
`
`Haemophilia is an X-linked recessive disease, characterized by
`a deficiency of
`factor VIII or IX. Spontaneous bleeds in
`muscles and joints occur in patients with the severest degree of
`the disease (<0Æ01 IU/ml of factor VIII or IX), while patients
`with moderate (0Æ01–0Æ05 IU/ml) and mild (>0Æ05 IU/ml)
`haemophilia rarely suffer spontaneous bleeds. This observation
`has prompted the introduction of prophylactic treatment in
`patients with severe haemophilia. Prophylaxis was first
`introduced in Denmark and the Netherlands in the early
`1970s. The objective of prophylaxis has been to convert the
`bleeding pattern of severe haemophilia into the bleeding
`pattern of moderate haemophilia, by preventing joint bleeds
`and subsequent arthropathy (Nilsson et al, 1992; Fischer et al,
`2002). Today, prophylactic administration of clotting factor in
`childhood is commonly used in many countries, and current
`debates about prophylaxis are related to the dose and how
`early to initiate this therapy. However, considering patient
`burden and costs, it is equally important to evaluate for how
`
`long prophylaxis is required. Should prophylaxis be adminis-
`tered during the entire lifetime of the patient or could it be
`safely discontinued in some patients? The discussions on the
`length of prophylactic treatment are increasing (Fischer et al,
`2001; Astermark, 2003; Berntorp et al, 2003; Carcao & Aledort,
`2004).
`Insight into patients’ ability to adhere to prophylaxis, and
`understanding the determinants that indicate which patients
`may safely stop prophylaxis, may assist us to individualize
`treatment and may therefore optimize the cost-effectiveness of
`treatment programmes. Recently, a study has been performed
`evaluating the incidence and outcome of discontinuation of
`prophylactic treatment in a single-centre cohort of severe
`haemophilia patients (Fischer et al, 2001). Adherence to
`treatment together with the long-term outcome should be
`studied in larger numbers of patients in order to more
`accurately evaluate the consequences of discontinuation. Since
`patients born after 1970 had access to early treatment and
`
`ª 2005 Blackwell Publishing Ltd, British Journal of Haematology, 130, 107–112
`
`doi:10.1111/j.1365-2141.2005.05546.x
`
`6/11
`
`

`

`K. van Dijk et al
`
`prophylaxis, we studied the cohort of patients born between
`1970 and 1980.
`The aim of the present study was to describe the incidence of
`discontinuation of prophylaxis and to assess its association
`with clinical outcome in a multicentre cohort of patients with
`severe haemophilia who had been offered a prophylactic
`treatment regimen during childhood.
`
`Methods
`
`Study population
`
`All patients with severe haemophilia A and B (factor VIII/IX
`<0Æ01 IU/ml), born between 1 January 1970 and 31 December
`1980, treated at Rigshospitalet, Copenhagen, A˚ rhus University
`Hospital, A˚ rhus and the Van Creveldkliniek, Utrecht were
`studied.
`From the Danish cohort, 22 patients were included in the
`study. Of the initial cohort of 32 Danish patients, 10 patients
`were excluded because of long-term inhibitor activity (longer
`than 1 year; n ¼ 4), significant other pathology (n ¼ 1), late
`access to treatment (n ¼ 1), insufficient information (n ¼ 3)
`or because patients were never treated with prophylaxis
`(n ¼ 1). The Dutch cohort comprised 58 patients. Of the
`initial cohort of 72 Dutch patients, 14 patients were excluded
`because of long-term inhibitor activity (n ¼ 5), significant
`other pathology (n ¼ 1), insufficient information (n ¼ 6) or
`because patients were never treated with prophylaxis (n ¼ 2).
`
`Treatment strategy
`
`Prophylaxis was defined as the administration of clotting
`factor at least twice a week for haemophilia A patients and at
`least once a week for haemophilia B patients.
`The Dutch treatment strategy has been described in detail
`elsewhere (Fischer et al, 2001). Briefly, patients started pro-
`phylaxis at an early age according to their bleeding pattern, but
`mostly after the occurrence of several joint bleeds (Van Den
`Berg et al, 2001). Prophylaxis was aimed at preventing joint
`bleeds and dosages were adjusted in case of breakthrough
`bleeds. Every patient was
`intended to be treated with
`prophylaxis.
`Intentionally, Danish patients were treated according to the
`Swedish regimen. Prophylaxis was started at an early age in
`those patients who attended the National Haemophilia
`Centres;
`in a few instances local paediatricians had not
`initiated regular early prophylaxis. In both cohorts, patients
`discontinued prophylaxis on their own accord, and reported
`this during their visits. Patients were not encouraged to
`discontinue prophylaxis.
`
`Data collection
`
`All patients visited their clinic at least once a year. Data
`on discontinuation of prophylaxis were obtained from the
`
`medical files. In addition, all patients were asked to complete a
`questionnaire on their adherence to prophylaxis. Data on age
`at start of prophylaxis, and the first treatment with factor VIII/
`IX were collected from the patients’ files. Data on bleeding
`frequency, weekly dose on prophylaxis, number of weeks on
`prophylaxis, annual clotting factor use and type of treatment
`(i.e. prophylactic or on-demand), were collected yearly from
`1972 until 2003. Joint bleeds were self-reported and were
`defined as all
`symptoms
`in the major
`joints
`requiring
`replacement therapy. For assessment of short-term outcome,
`the number of joint bleeds experienced during the previous
`3 years was recorded.
`joint scores according to
`To evaluate clinical outcome,
`Gilbert (1993) were performed in both the Dutch and the
`Danish cohorts. Knees and ankles were given 0 (i.e. a normal
`joint) to 15 points according to level of pain, swelling,
`atrophy, axial deformity, crepitus on motion, flexion con-
`tracture and instability. As axial deformity and flexion
`contracture were not considered in the elbows, these joints
`were given a maximum of 11 points, resulting in a maximum
`total score of 82 points.
`In the Dutch cohort, X-rays of knees, elbows and ankles
`were taken at 5-year intervals and scored using the Pettersson
`score for haemophilic arthropathy (Pettersson et al, 1980).
`Each joint was attributed 0 points (i.e. no arthropathy) to 13
`points, resulting in a maximum obtainable total score of 78
`points. Joints with arthrodeses, ankylosis or arthroplasty were
`given 13 points. All X-rays were scored by the same radiologist.
`The Medical Ethics Committee of the University Medical
`Centre Utrecht approved this study.
`
`Data analysis
`
`Patients were categorized according to adherence to prophy-
`lactic treatment: patients who continued prophylaxis (contin-
`ued), and patients who discontinued prophylaxis permanently
`and were treated on-demand at
`the last
`recorded visit
`(discontinued).
`In patients who discontinued prophylaxis
`and used prophylaxis for <1 year, the indication to start
`prophylaxis was studied. For comparison of patient and
`treatment characteristics between groups, independent sample
`t-tests were used. All analyses comparing joint bleed frequen-
`cies were performed using the Kruskal–Wallis-test. As Petters-
`son scores and clinical scores are dependent on the cumulative
`number of joint bleeds and therefore highly dependent on age,
`analyses of these parameters were adjusted for age using log-
`linear regression.
`For calculation of annual clotting factor use and joint bleed
`frequency on prophylaxis all available years on prophylaxis
`were included. As joint bleed frequency and factor use change
`considerably during childhood (Liesner et al, 1996), only the
`follow-up years after the age of 18 were used to compare
`treatment characteristics before and after discontinuation of
`prophylaxis.
`
`108
`
`ª 2005 Blackwell Publishing Ltd, British Journal of Haematology, 130, 107–112
`
`7/11
`
`

`

`Results
`
`Study population
`
`Twenty-two Danish and 58 Dutch patients were studied. A
`comparison of patient characteristics, treatment and outcome
`between the Danish and Dutch patients is shown in Table I.
`Age and follow-up were comparable between the Danish and
`the Dutch populations, as was age at start of prophylaxis. None
`of the patients started prophylaxis before their first joint bleed.
`Danish and Dutch patients had a median duration of
`prophylaxis of 12Æ5 years [interquartile range (IQR) 8Æ0–18Æ2]
`and 16Æ6 years (IQR 13Æ8–20Æ7) respectively. The percentage of
`lifetime on prophylaxis since its start tended to be lower in
`Danish patients, at 83% (IQR 40–100), compared with 97%
`(IQR 67–100) for Dutch patients, thus indicating longer or
`more frequent periods of discontinuation of prophylaxis in the
`Danish cohort. Annual clotting factor use on prophylaxis was
`higher in Danish patients (P < 0Æ01), resulting in a lower joint
`bleed frequency on prophylaxis (P < 0Æ01). Therefore, data on
`treatment are presented for Danish and Dutch patients
`separately.
`
`Discontinuation
`
`In the Danish cohort 10 patients discontinued prophylaxis
`(45%). In the Dutch cohort 18 patients discontinued prophy-
`laxis (31%). Danish and Dutch patients who discontinued
`prophylaxis did so at a similar age [21Æ4 years (IQR 18Æ5–23Æ3)
`and 21Æ5 years (IQR 18Æ1–25Æ1) respectively]. Treatment char-
`acteristics according to adherence to prophylaxis for both
`cohorts are shown in Table II.
`In contrast to our expectations, there were no indications
`that patients in the Danish cohort who permanently stopped
`taking prophylaxis had a milder bleeding pattern. Possibly the
`
`Stopping Prophylaxis in Haemophilia
`
`higher prophylactic dosages may have masked differences in
`bleeding patterns between patients with different phenotypes.
`In accordance with earlier findings, Dutch patients who
`discontinued prophylaxis started prophylaxis 1Æ9 years later
`(P ¼ 0Æ06), used a
`lower weekly dose of prophylaxis
`(P < 0Æ01), and experienced less joint bleeds on prophylaxis
`(P ¼ 0Æ03) compared with patients who continued prophy-
`laxis.
`
`Treatment
`
`Treatment characteristics on prophylaxis and on-demand were
`compared for adult patients in both countries. Danish patients
`used 2916 IU/kg/year (IQR 2469–3963) during prophylaxis
`and 1772 IU/kg/year (IQR 1531–1879) during on-demand
`treatment (P < 0Æ01). Median joint bleed frequency was lower
`during prophylaxis than during on-demand treatment [0 (IQR
`0–0Æ5) vs. 3Æ0 (IQR 0Æ5–11Æ0; P < 0Æ01)]. Dutch patients used
`1000 IU/kg/year less than Danish patients, both on prophylaxis
`(2035 IU/kg/year, IQR 1639–2497) and during on-demand
`treatment (659 IU/kg/year, IQR 234–1018). Median annual
`clotting factor use decreased with 1144–1376 IU/kg/year after
`switching to on-demand treatment: a decrease of 39% for
`Danish patients and 68% for Dutch patients. Dutch patients
`suffered two extra joint bleeds per year compared with Danish
`patients, both during prophylaxis and during on-demand
`treatment; their joint bleed frequency was 1Æ9 (IQR 0Æ7–4Æ2) on
`prophylaxis and 4Æ9 (IQR 2Æ4–8Æ6) during on-demand treat-
`ment. Overall, adult patients treated on-demand suffered three
`more joint bleeds per year compared with patients on
`prophylaxis in both countries. Danish patients using on-
`demand treatment generally had a tendency to adopt self-
`adjusted prophylactic concentrate use before sports activities
`and other major exercises that may provoke bleeding. This
`may explain the relatively higher consumption of concentrate
`
`Table I. Patient characteristics, treatment and outcome of the Danish and the Dutch cohort.
`
`Denmark
`
`The Netherlands
`
`P-value
`
`Number of patients
`Follow-up (years)
`Age at last visit (years)
`Treatment
`Age start prophylaxis (years)
`Percentage of lifetime on prophylaxis
`Annual clotting factor use (IU/kg/year)*
`Joint bleeds (per year)*
`Outcome
`Joint bleeds in the last 3 years (per year)
`Clinical score
`Discontinuation
`Continued (n)
`Discontinued (n)
`
`22
`18 (11–24)
`26Æ2 (23Æ8–29Æ1)
`
`5Æ6 (3Æ8–8Æ1)
`83 (40–100)
`2940 (2364–3779)
`1Æ6 (0Æ0–3Æ0)
`
`0Æ0 (0Æ0–3Æ5)
`3Æ0 (0Æ0–5Æ5)
`
`12 (55%)
`10 (45%)
`
`58
`20 (15–24)
`26Æ5 (23Æ9–29Æ5)
`
`6Æ0 (4Æ1–8Æ9)
`97 (67–100)
`1855 (1508–2286)
`3Æ5 (1Æ2–5Æ6)
`
`2Æ2 (1Æ0–5Æ5)
`3Æ0 (1Æ0–6Æ0)
`
`40 (69%)
`18 (31%)
`
`Values are expressed as median (interquartile range) or as n (%).
`*For all available years on prophylaxis.
`
`ª 2005 Blackwell Publishing Ltd, British Journal of Haematology, 130, 107–112
`
`0Æ35
`0Æ72
`
`0Æ57
`0Æ34
`<0Æ01
`<0Æ01
`
`0Æ04
`0Æ91
`
`0Æ30
`0Æ23
`
`109
`
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`

`K. van Dijk et al
`
`Table II. Treatment characteristics according to discontinuation of prophylaxis in the Danish and Dutch cohorts.
`
`Denmark
`
`Continued
`(n ¼ 12)
`
`The Netherlands
`
`Discontinued
`(n ¼ 10)
`
`P-value
`
`Continued
`(n ¼ 40)
`
`Discontinued
`(n ¼ 18)
`
`P-value
`
`Age at start of prophylaxis (years)
`Joint bleeds on prophylaxis (per year)
`Annual clotting factor use on
`prophylaxis (IU/kg/year)
`
`5Æ3 (3Æ8–9Æ2)
`1Æ0 (0Æ0–2Æ9)
`2791 (2523–3701)
`
`5Æ6 (3Æ9–7Æ3)
`2Æ0 (0Æ8–4Æ7)
`3101 (1970–3863)
`
`0Æ42
`0Æ14
`0Æ73
`
`5Æ2 (3Æ9–8Æ7)
`4Æ2 (1Æ4–8Æ8)
`1923 (1592–2365)
`
`7Æ1 (5Æ4–10Æ7)
`2Æ2 (0Æ9–3Æ9)
`1643 (1177–2133)
`
`0Æ06
`0Æ03
`0Æ28
`
`Values are expressed as median (interquartile range).
`
`for a slightly lower number of annual bleeds when compared
`with the Dutch on-demand cohort.
`
`Outcome
`
`The median follow-up since the last change in treatment
`strategy for patients who stopped prophylaxis permanently was
`3Æ6 years (IQR 1Æ4–7Æ9). Despite the lower number of joint
`bleeds during the last 3 years of observation in the Danish
`patients (P ¼ 0Æ04), the clinical score was similar between
`Danish and Dutch patients (Table I). As the proportions of
`Danish and Dutch patients who permanently stopped were
`similar, outcome is presented for both Danish and Dutch
`patients together.
`As expected, patients who permanently switched to on-
`demand treatment tended to have a slightly higher joint bleed
`frequency in the last 3 years than patients who remained on
`prophylaxis (Table III). However, clinical outcome, as meas-
`ured by the clinical score, was similar between patients who
`stopped and patients who remained on prophylaxis. For Dutch
`patients, the radiological joint status was similar between both
`groups.
`
`10 years. The proportion of Danish and Dutch patients was
`comparable with the whole cohort and a similar percentage of
`stopped taking prophylaxis permanently (n ¼ 8;
`patients
`23%).
`Outcome according to discontinuation was again similar.
`Joint bleed frequency in the last year was 0Æ0 (IQR 0Æ0–6Æ0) in
`patients who stopped permanently and 1Æ2 (IQR 0Æ0–5Æ1) in
`patients still on prophylaxis (P ¼ 0Æ51). Patients who perma-
`nently stopped had a clinical score of 2Æ0 points (IQR 0Æ0–4Æ5)
`compared with 3Æ0 points (IQR 1Æ0–4Æ0; P ¼ 0Æ27) in patients
`the age of 27Æ4 and 25Æ6 years
`still on prophylaxis at
`respectively. Median Pettersson scores were also similar, at
`7Æ0 (IQR 0Æ3–26Æ5) points in patients who switched to on-
`demand treatment compared with 7Æ5 (IQR 3Æ8–17Æ3) points in
`patients who remained on prophylaxis (P ¼ 0Æ11). As expec-
`ted, outcome in those patients with a history of more intensive
`treatment during their early years tended to be superior to the
`outcome of the whole cohort; the last Pettersson score and
`clinical score tending to be lower (P ¼ 0Æ40 and P ¼ 0Æ08) at a
`similar age.
`
`Discussion
`
`Discontinuation in patients who received prophylaxis
`during the period of growth
`
`Ideally, prophylaxis is started at an early age and continued
`until growth is completed. To evaluate outcome according to
`adherence to prophylaxis more precisely, we studied outcome
`in a subgroup of 35 patients who started prophylaxis before the
`age of 6 years and who were treated prophylactically for at least
`
`This study shows that permanent discontinuation of prophy-
`laxis is a common phenomenon among both Danish and
`Dutch patients with severe haemophilia who were intended to
`receive lifelong prophylaxis. At the age of 26 years, one-third
`of both the Danish and the Dutch patients with severe
`haemophilia had switched to on-demand treatment, and
`suffered only three joint bleeds per year. After 3Æ6 years, joint
`status, as assessed by radiological and clinical score, appeared
`
`Table III. Outcome according to discontinuation of prophylaxis.
`Continued (n ¼ 52)
`
`Joint bleeds in the last 3 years (per year)
`Clinical score
`Age at clinical score (years)
`Last Pettersson score*
`Age at Pettersson score (years)
`
`1Æ8 (0Æ0–3Æ0)
`3Æ0 (1Æ0–6Æ0)
`26Æ6 (23Æ9–29Æ9)
`13Æ0 (5Æ0–23Æ0)
`24Æ7 (21Æ7–26Æ9)
`
`Values are expressed as median (interquartile range).
`*Pettersson scores were only performed in the Dutch cohort.
`
`Discontinued (n ¼ 28)
`
`3Æ2 (0Æ9–6Æ0)
`4Æ0 (0Æ8–6Æ3)
`27Æ3 (24Æ3–29Æ8)
`13Æ0 (0Æ8–23Æ5)
`23Æ7 (21Æ6–27Æ6)
`
`P-value
`
`0Æ04
`0Æ72
`0Æ96
`0Æ84
`0Æ93
`
`110
`
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`
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`

`not to be affected by the switch to on-demand treatment. In
`order to interpret these findings correctly, some aspects of the
`study design need to be discussed.
`First, it may be argued that patients categorized as having
`permanently stopped prophylaxis may restart prophylaxis at
`any time. However, it is expected that patients who experience
`a substantial number of bleeds after discontinuing prophylaxis
`will restart prophylaxis quickly, whereas patients who experi-
`ence few bleeds will
`tend to remain on the on-demand
`regimen. This was confirmed by following-up our previous
`report on discontinuation of prophylaxis in 49 severe haemo-
`philia patients (Fischer et al, 2001). None of the patients who
`permanently stopped taking prophylaxis restarted prophylactic
`treatment and an additional five patients have stopped
`permanently as the previous study. These findings suggest
`that patients who discontinue prophylaxis permanently are
`those with a milder bleeding pattern, in contrast to patients
`who temporarily discontinue prophylaxis.
`Secondly, o