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Keywords:

  • haemophilia;
  • prophylaxis;
  • age;
  • arthropathy;
  • Port-A-Cath

Abstract

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. References

The frequency of joint bleeds and orthopaedic joint scores were evaluated in 121 patients with severe haemophilia who had started prophylactic treatment with clotting factor concentrates at least once weekly before the age of 10. 75 of the patients started before the age of 3, 31 at the age of 3–5 and 15 at the age of 6–9. Each subgroup was evaluated separately. In addition, a regimen of one infusion weekly was compared with that of two (haemophilia B) or three (haemophilia A) infusions weekly in each patient.

A significant decrease in the overall number of joint bleeds per year was found after shortening the infusion interval (P < 0.005), but the individual bleeding pattern varied. In survival analysis of the first pathologic joint score event, those who started prophylaxis before the age of 3 had a better outcome overall than those starting at later ages (P = 0.001). However, in subgroup analysis, no significant difference was seen in the annual number of joint bleeds and the development of arthropathy between those starting with, or shifting to, the more intensive regimen before the age of 3 and those that were put on this regimen at the age of 3–5. Age at start of prophylaxis was found to be an independent predictor for the development of arthropathy (P = 0.0002), whereas dose and infusion interval at start were not.

Our data emphasize the importance of starting replacement therapy during the first years of life. However, it seems that when beginning the regimen it can be individualized and adjusted according to the bleeding pattern. In this way, the need for a venous access system may be assessed on an individual basis.

Prophylactic treatment of patients with severe haemophilia has been practised in Sweden for three decades and the benefits of this treatment compared to the on-demand regimen have been described elsewhere (Petrini et al, 1991; Nilsson et al, 1992; van den Berg et al, 1994; Manco-Johnson et al, 1994; Aledort et al, 1994; Berntorp, 1995; Liesner et al, 1996; Löfqvist et al, 1997). Thanks to a better supply of plasma-derived factor concentrates, it has been possible to intensify treatment, with a shorter infusion interval and a higher dosage. In addition, the introduction of central venous access devices such as the Port-A-Cath has provided an alternative route of venous access for the younger boys (Ljung et al, 1998). Based on the Swedish experience, prophylaxis has been accepted as the optimal treatment modality for patients with severe haemophilia by the Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation in the United States (Lusher, 1997). The dose recommendations are 25–40 IU/kg, two (haemophilia B) or three (haemophilia A) times weekly, starting at the age of 1–2 years. The aim of this regimen is to keep the trough level of the deficient factor >1%, i.e. to convert severe haemophilia into a milder form (Ahlberg, 1965). However, the recommendations regarding age and dose at start of treatment continue to be a matter of debate, largely due to the side-effects associated with the use of a central venous line, which is often needed for frequent injections at an early age (Blanchette et al, 1997; Ljung et al, 1998). In order to examine how starting various prophylactic regimens influences the number of joint bleeds and the development of arthropathy, we correlated age at start of prophylactic treatment and dosage to clinical outcome in patients with severe haemophilia starting prophylactic treatment at least once weekly before the age of 10. As the infusion of clotting factor concentrates (CFCs) can be performed in most subjects at the age of 3 without the need for a central venous access device, we stratified the cohort into three groups: those starting before the age of 3, those starting at the age of 3–5, and those starting at the age of 6–9.

METHODS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. References

Subjects

121 boys with severe haemophilia (factor VIII or IX clotting activity <1 IU/dl) and no history of inhibitor development were included in the study (108 haemophilia A, 13 haemophilia B). The patients were born between 1963 and 1996 and all attended the Haemophilia Centres in Malmö, Stockholm or Gothenburg. All 121 patients started prophylactic treatment at least once weekly before the age of 10; 75 of them before the age of 3, 31 patients at the age of 3–5, and 15 patients at the age of 6–9. 108 subjects (89%) were treated according to our present standard regimen of 25–40 IU/kg, two (haemophilia B) or three (haemophilia A) times weekly during the course of the study, and 54 subjects (45%) reached the age of 15 or older. All patients had either prophylactic or on-demand treatment from the first years of life. The CFC used during the early 1970s for the haemophilia A patients was human fraction I-O (AHF, Kabi, Stockholm, Sweden), followed by CFCs of intermediate purity, predominantly Octonativ (Pharmacia, Stockholm, Sweden), until the late 1980s. During the last 10 years immunoaffinity-purified factor VIII concentrates, e.g. Octonativ-M (Pharmacia & Upjohn, Stockholm, Sweden) and Monoclate P (Centeon, Kankakee, Ill.), as well as recombinant products, e.g. Recombinate (Baxter, Los Angeles, Calif.) and Kogenate (Bayer, Berkeley, Calif.), have been given. The haemophilia B patients were treated with Preconativ (Kabi, Stockholm, Sweden) and Prothromplex (Immuno, Vienna, Austria) until recently, when the high-purity concentrates Nanotiv (Pharmacia & Upjohn, Stockholm, Sweden) and Immunine (Baxter-Immuno, Vienna, Austria) were introduced. All patients and/or parents were taught to give infusions at home and they reported on a monthly basis on bleeding episodes and the number of infusions given. A Port-A-Cath device was inplanted in some of the boys who were receiving prophylactic treatment two to three times weekly during the first years of life. A routine check-up was performed once or twice a year and the orthopaedic joint score evaluated, as recommended by the Orthopaedic Advisory Committee of the World Federation of Hemophilia (Löfqvist et al, 1997). According to this protocol, the elbows, knees and ankles are each given a score of 0–15 depending on the severity of the arthropathy, giving a maximum worst score of 90.

Assays

Analysis of factor VIII and IX clotting activities as well as inhibitor analyses were performed as described elsewhere (Rosén, 1984; Berntorp et al, 1996; Carlsson et al, 1998).

Statistical analysis

The two-tailed t-test for dependent samples was used to compare the average number of joint bleeds per year during infusions once weekly and two (haemophilia B) or three times weekly (haemophilia A). The non-parametric Mann-Whitney test was used for intergroup comparisons and the correlation coefficients were estimated using the Spearman rank test. Kaplan-Meier analysis was used to estimate the cumulative incidence of the development of arthropathy in terms of an orthopaedic joint score above zero. The Log-rank test was used for intergroup comparison. Cox's proportional hazards regression analysis was used to evaluate independent predictors of the development of arthropathy. All P-values are two-sided and a P-value < 0.05 was considered to indicate statistical significance.

RESULTS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. References

Mean age at start of prophylactic treatment at least once weekly was 2.8 ± 2.1 years (mean ± SD). The average annual dosage used at the start was 2610 ± 1910 IU/kg (range 370–8760). The correlation of the number of joint bleeds per year to the annual amount of CFCs (IU/kg/year) used at the start (rS = − 0.18, P = 0.062) as well as to the age at which prophylaxis was started (rS = 0.35, P < 0.001) are shown in Fig 1. Interestingly, several of those that consumed small amounts of CFCs or started at a relatively high age experienced few joint bleeds.

image

Figure 1. . Scattergram showing the correlation between the average number of joint bleeds per year and the annual dosages (IU/kg/year) used at the start of prophylactic treatment (A) as well as the age at the start of treatment (B). The shaded area in A indicates a starting dose corresponding to a regimen of 25–40 IU/kg three times weekly.

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As shown in Fig 2, there was a significant correlation between the amount of joint bleeds before and after shifting from one infusion weekly to the more intensified regimen of two or three times weekly (rS = 0.72, P < 0.001), indicating the importance of starting treatment before the patient suffers from frequent bleeding episodes, with subsequent development of target joints.

image

Figure 2. . Scattergram showing the correlation between the average number of joint bleeds per year in each patient during treatment with one and two (haemophilia B) or three (haemophilia A) infusions weekly.

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The average annual number of joint bleeds in all subjects during treatment once weekly was 2.6 ± 0.4 (mean ± SEM) (range 0–22.8), dropping to 1.6 ± 0.3 (range 0–15.4) after a shift to treatment two or three times weekly (P < 0.005). Comparison between the group starting prophylaxis before the age of 3 and that starting at the age of 3–5 revealed that in both groups the average amount of joint bleeds decreased significantly after a shift to the more intense treatment (Fig 3). There were also significantly fewer bleeds in the subgroup starting earlier, irrespective of the infusion interval (Fig 3). However, when only the 55 subjects who started prophylaxis according to the more intensive scheme at the age of 5 or earlier were considered, no significant difference was seen in the number of joint bleeds between those who were put on this regimen before the age of 3 and those who had to wait until the age of 3–5 (1.1 ± 0.3 v 2.1 ± 0.4, P = 0.108, during one infusion weekly, and 0.8 ± 0.2 v 1.2 ± 0.4, P = 0.600, during infusions two or three times weekly).

image

Figure 3. . Box plot showing the annual number of joint bleeds during prophylactic treatment once weekly as well as during a regimen of two (haemophilia B) or three (haemophilia A) infusions weekly in patients starting prophylactic treatment once weekly before the age of 3 and at the age of 3–5, respectively. The 10th, 25th, 50th, 75th and 90th percentiles are shown.

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At the age of 10 only 14/90 subjects had an orthopaedic joint score above zero (range 0–6). In Fig 4 the scores at the age of 15–18 are plotted against the dosage used at start of prophylaxis in 50/54 patients having reached this age (rS = − 0.27, P = 0.062). One of the remaining four subjects not yet given a score had a joint score above zero at a younger age. This subject used 1300 IU/kg/year at start of treatment whereas the other three used between 890 and 2350 IU/kg/year. It is worth noting that although there was a clear tendency towards a milder arthropathy the greater the amount of CFCs used, several of those using small amounts at a young age still have no arthropathy on reaching adulthood.

image

Figure 4. . Scattergram showing the correlation between annual dosage (IU/kg/year) used at start of prophylactic treatment and arthropathy at the age of 15–18 (n = 50). A starting dose corresponding to a regimen of 25–40 IU/kg three times weekly is shaded.

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In the Kaplan-Meier analysis we found that those starting prophylaxis before the age of 3 had a better clinical outcome in terms of arthropathy, i.e. there were significantly more subjects with an orthopaedic joint score of zero, than those starting at later ages (P = 0.001; Fig 5). No significant difference between those starting at the age of 3–5 and those starting at the age of 6–9 could be found (P = 0.275). It is also interesting to note that arthropathy seems to develop preferentially at school-age in most patients, even when therapy is started at a relatively high age and low dosage. Among the subgroup of patients (n = 55) whose treatment was intensified according to our present standard protocol with two or three infusions weekly before the age of 6, no difference was found concerning arthropathy between those starting this regimen at the age of 0–2 and those starting at the age of 3–5 (P = 0.566). In each subgroup there was only one subject with a joint score above zero.

image

Figure 5. . Kaplan-Meier plot of the development of arthropathy, i.e. an orthopaedic joint score above zero, in patients starting prophylactic treatment before the age of 3, at the age of 3–5, and at the age of 6–9. The difference between the latter two subgroups was not significant (P = 0.275).

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The subgroup of patients that had developed arthropathy during the course of the study (n = 28) had consumed significantly less CFCs annually than those with an unaffected orthopaedic joint score (1540 v 2970 IU/kg/year; P < 0.0001). In addition, age at the start of prophylaxis was an independent predictor of the development of arthropathy (P = 0.0002), whereas dose and dose interval did not reach statistical significance (P = 0.082 and P = 0.099, respectively).

DISCUSSION

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. References

Until a cure is developed, primary prophylaxis has to be considered the optimal treatment for patients with severe haemophilia. However, only a fraction of all haemophilia patients world-wide have access to this treatment. Instead, most patients are treated either on-demand or not at all, primarily because of the cost associated with the use of CFCs (Smith et al, 1996; Szucs et al, 1996; Bohn et al, 1998). Therefore it is of major importance to optimize treatment so that cost and clinical outcome are acceptable to both patients and care providers. In Sweden, prophylaxis was initiated in the 1960s and 1970s and has since then been intensified concomitantly with a better supply of CFCs. In addition, the introduction of central venous access systems such as the Port-A-Cath device has facilitated the start of treatment in the younger subjects, and nowadays prophylaxis is recommended at the age of 1–2 (Lusher, 1997). However, the use of central line devices has also been criticized because of side-effects, such as severe infections and bleeding episodes (Blanchette et al, 1997; Ljung et al, 1998). Therefore the importance of starting regular primary prophylaxis with a short infusion interval during the earliest years of life is still a matter of debate. In Sweden, we generally start treatment after the diagnosis has been established, either with infusions of 25–40 IU/kg every second (haemophilia A) or third (haemophilia B) day using a Port-A-Cath device, or with only one infusion weekly during the first year(s), after which the infusion interval is shortened. One of the benefits of this latter regimen is that in most subjects it is possible to infuse the CFCs into peripheral veins without the need for a surgical procedure and the implantation of a Port-A-Cath device. In addition, the time in hospital is minimized.

Previous reports have focused on the benefits of prophylaxis versus on-demand treatment, and it has been clearly shown that it is important to minimize the amounts of joint bleeds and to start treatment before arthropathy has developed (Petrini et al, 1991; Nilsson et al, 1992; van den Berg et al, 1994; Manco-Johnson et al, 1994; Aledort et al, 1994; Berntorp, 1995; Liesner et al, 1996). However, in the study by Aledort et al (1994) several of the subjects who had been treated with only small amounts of CFCs at a young age had no arthropathy. In this context it is also worth noting that arthropathy measured by physical examination in our cohort seems to develop preferentially at school-age, even though treatment at a younger age probably has been insufficient. Moreover, Liesner et al (1996) have pointed out that it is important to evaluate whether a severe haemophilia patient, in terms of the factor VIII or IX clotting activity, behaves as a severely ill subject clinically. Our data clearly emphasize the importance of starting prophylaxis at a young age before recurrent bleeding episodes have occurred, to prevent arthropathy. However, it is also obvious that, in agreement with previous findings, the clinical manifestations are quite different for different subjects. Several of the patients who used an annual starting dose of <1000 IU/kg and/or did not start prophylactic treatment until school-age, still did not suffer from frequent bleeding episodes or develop any arthropathy during childhood. In addition, there was no increase in the number of joint bleeds and the severity of the arthropathy in subjects who were given only one infusion each week during the first year(s) of life, followed by two (haemophilia B) or three (haemophilia A) infusions per week at the age of 3–5, compared to those starting with this latter, more intensive, regimen from the time of diagnosis.

The aim of haemophilia treatment should be to keep the baseline level of the deficient factor in each individual as high as possible. However, in reality, it is important to optimize the use of the resources available in most countries. Therefore, although the risk of fatal bleeding episodes has always to be considered, our data suggest that it might be possible to individualize treatment more than at present and that the bleeding pattern could be followed during the first year(s) with weekly infusions of CFCs. The infusion interval should then be shortened with or without the use of a central venous access system. In this way the need of a surgical implant might also be reduced.

Acknowledgements

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. References

The study was supported by grants from the Research Fund at Malmö University Hospital.

References

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. References
  • 1
    Ahlberg, Å. (1965) Haemophilia in Sweden. VII. Incidence, treatment and prophylaxis of arthropathy and other musculoskeletal manifestations of haemophilia A and B. Acta Orthopaedica Scandinavica, 77, (Suppl.), 198.
  • 2
    Aledort, L.M., Haschemeyer, R.H. & Pettersson, H. (1994) A longitudinal study of orthopaedic outcomes for severe factor VIII-deficient haemophiliacs. The Orthopaedic Outcome Study Group. Journal of Internal Medicine, 236, 391399.
  • 3
    Berntorp, E. (1995) Methods of hemophilia care delivery; regular prophylaxis vs. episodic treatment. Haemophilia, 1, (Suppl. 1), 37.
  • 4
    Berntorp, E., Ekman, M., Gunnarsson, M. & Nilsson, I.M. (1996) Variation in factor VIII inhibitor reactivity with different commercial factor VIII preparations. Haemophilia, 2, 9599.
  • 5
    Blanchette, V.S., Al-Musa, A., Stain, A.M., Ingram, J. & Fille, R.M. (1997) Central venous access devices in children with hemophilia: an up-date. Blood Coagulation and Fibrinolysis, 8, (Suppl. 1), S11S14.
  • 6
    Bohn, R.L., Avorn, J., Glynn, R.J., Choodnovskiy, I., Haschemeyer, R. & Aledort, L.M. (1998) Prophylactic use of factor VIII: an economic evaluation. Thrombosis and Haemostasis, 79, 932937.
  • 7
    Carlsson, M., Björkman, S. & Berntorp, E. (1998) Multidose pharmacokinetics of factor IX: implications for dosing in prophylaxis. Haemophilia, 4, 8388.
  • 8
    Liesner, R.J., Khair, K. & Hann, I.M. (1996) The impact of prophylactic treatment on children with severe haemophilia. British Journal of Haematology, 92, 973978.DOI: 10.1046/j.1365-2141.1996.420960.x
  • 9
    Ljung, R., Van Den Berg, M., Petrini, P., Tengborn, L., Scheibel, E., Kekomäki, R. & Effenberg, W. (1998) Port-A-Cath usage in children with haemophilia: experience of 53 cases. Acta Paediatrica, 87, 10511054.DOI: 10.1080/080352598750031365
  • 10
    Löfqvist, T., Nilsson, I.M., Berntorp, E. & Pettersson, H. (1997) Haemophilia prophylaxis in young patients: a long-term follow-up. Journal of Internal Medicine, 241, 395400.DOI: 10.1046/j.1365-2796.1997.130135000.x
  • 11
    Lusher, J. (1997) Prophylaxis in children with hemophilia: is it the optimal treatment? Thrombosis and Haemostasis, 78, 726729.
  • 12
    Manco-Johnson, M.J., Nuss, R., Geraghty, S., Funk, S. & Kilcoyne, R. (1994) Results of secondary prophylaxis in children with severe hemophilia. American Journal of Hematology, 47, 113117.
  • 13
    Nilsson, I.M., Berntorp, E., Löfqvist, T. & Pettersson, H. (1992) Twenty-five years' experience of prophylactic treatment in severe hemophilia A and B. Journal of Internal Medicine, 232, 2532.
  • 14
    Petrini, P., Lindvall, N., Egberg, N. & Blombäck, M. (1991) Prophylaxis with factor concentrate in preventing hemophilic arthropathy. American Journal of Pediatric Hematology/Oncology, 13, 280287.
  • 15
    Rosén, S. (1984) Assay of factor VIII:C with a chromogenic substrate. Scandinavian Journal of Haematology, 33, (Suppl. 40), 139145.
  • 16
    Smith, P.S., Teutsch, S.M., Schaffer, P.A., Rolka, H. & Evatt, B. (1996) Episodic versus prophylactic infusions for hemophilia A: a cost-effectiveness analysis. Journal of Paediatrics, 129, 424431.
  • 17
    Szucs, T.D., Öffner, A. & Schramm, W. (1996) Socioeconomic impact of haemophilia care: results of a pilot study. Haemophilia, 2, 211217.
  • 18
    Van Den Berg, H.M., Nieuwenhuis, H.K., Mauser-Bunchoten, E.P. & Rosendaal, G. (1994) Haemophilia prophylaxis in the Netherlands. Seminars in Haematology, 31, (Suppl. 2), 1315.