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Keywords:

  • adults;
  • cost-effectiveness;
  • FVIII consumption;
  • haemophilia A;
  • inhibitor development;
  • prophylaxis

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Bleeding in women with VWD
  5. Age-related FVIII consumption in patients with severe haemophilia A
  6. Inhibitor treatment in patients who failed at first attempt. Poor prognosis patients: RES.I.ST study
  7. Current experience using plasma-derived VWF-containing FVIII concentrates
  8. Rationale for using pdVWF/FVIII concentrates for ITI therapy
  9. RES.I.ST studies
  10. Long-term prophylaxis with highly purified plasma-derived VWF/FVIII concentrates in VWD. Pro.Will study
  11. Therapeutic options for the treatment of haemophilic patients with inhibitors: a cost-effectiveness approach
  12. How much does it cost to treat patients with inhibitors?
  13. The PROFIT study
  14. Musculoskeletal complications in patients with severe bleeding disorders
  15. Disclosures
  16. References

Summary.  Development of FVIII inhibitors is currently the most severe and challenging complication of haemophilia A treatment and represents a very large economic burden for a chronic disease. As a result, clinical research is making major efforts to optimize the therapeutic approaches for this condition. In this section we will review some important aspects of the management of haemophilia in adults, including an overview of bleeding in women with von Willebrand disease, an analysis of FVIII consumption in patients with severe haemophilia A, an update of the ongoing RES.I.ST study, long-term prophylaxis and experience from the Pro.Will study, current evidence relating to economic aspects of the treatment of haemophilic patients with inhibitors (based on the PROFIT study), and an overview of musculoskeletal complications in adults with severe bleeding disorders.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Bleeding in women with VWD
  5. Age-related FVIII consumption in patients with severe haemophilia A
  6. Inhibitor treatment in patients who failed at first attempt. Poor prognosis patients: RES.I.ST study
  7. Current experience using plasma-derived VWF-containing FVIII concentrates
  8. Rationale for using pdVWF/FVIII concentrates for ITI therapy
  9. RES.I.ST studies
  10. Long-term prophylaxis with highly purified plasma-derived VWF/FVIII concentrates in VWD. Pro.Will study
  11. Therapeutic options for the treatment of haemophilic patients with inhibitors: a cost-effectiveness approach
  12. How much does it cost to treat patients with inhibitors?
  13. The PROFIT study
  14. Musculoskeletal complications in patients with severe bleeding disorders
  15. Disclosures
  16. References

The overall life expectancy of persons with haemophilia has increased in the last years. In addition, quality of life has also improved, mainly as a result of prophylaxis. However, unfortunately, many adult patients still suffer from musculoskeletal complications such as chronic synovitis, fixed-joint flexion contractures and arthropathy. These complications result in the need for various surgical procedures (arthrocentesis, synoviorthesis and joint arthroplasty). In addition to these musculoskeletal problems, adult haemophilic patients are not immune to the usual diseases of ageing seen in the general male population. Among these co-morbidities cardiovascular diseases, prostatic hypertrophy and various cancers (in particular gastrointestinal [GI] and prostate) are the most relevant. An important group of adults with haemophilia are those with inhibitors to factor VIII (FVIII) or factor IX (FIX). Significant advances in inhibitor treatment [i.e. immune tolerance induction (ITI) and bypassing agents] have occurred over the past few decades and have led to improved clinical outcomes in these patients. Despite these advances, patients with inhibitors still have much poorer clinical outcomes than patients without inhibitors. Prophylaxis in haemophilia is now being implemented in many countries but in von Willebrand disease (VWD), the situation is somewhat different. The rationale for long-term prophylaxis in patients with severe forms of VWD (e.g. type 3) who bleed frequently seems obvious, but studies are lacking. The few studies that have been performed in this area suggest that the most frequent indications for prophylaxis in patients with VWD are joint bleeding (all ages), epistaxis (in children), GI bleeding (in older patients) and menorrhagia (in women). Optimal prophylaxis regimens for patients with VWD suffering from frequent bleeding need to be established and long-term studies need to be undertaken to evaluate the outcomes (including quality of life) of such regimens.

Bleeding in women with VWD

  1. Top of page
  2. Abstract
  3. Introduction
  4. Bleeding in women with VWD
  5. Age-related FVIII consumption in patients with severe haemophilia A
  6. Inhibitor treatment in patients who failed at first attempt. Poor prognosis patients: RES.I.ST study
  7. Current experience using plasma-derived VWF-containing FVIII concentrates
  8. Rationale for using pdVWF/FVIII concentrates for ITI therapy
  9. RES.I.ST studies
  10. Long-term prophylaxis with highly purified plasma-derived VWF/FVIII concentrates in VWD. Pro.Will study
  11. Therapeutic options for the treatment of haemophilic patients with inhibitors: a cost-effectiveness approach
  12. How much does it cost to treat patients with inhibitors?
  13. The PROFIT study
  14. Musculoskeletal complications in patients with severe bleeding disorders
  15. Disclosures
  16. References

Patients affected by bleeding disorders present a wide range of clinical symptoms, varying from a mild or moderate bleeding tendency to significant bleeding episodes. Women with inherited bleeding disorders are particularly disadvantaged as, in addition to suffering from general bleeding symptoms, they also have more opportunities to experience bleeding complications from regular haemostatic challenges during menstruation, pregnancy and childbirth. Furthermore, such disorders pose important problems for affected women due to the associated reduction in quality of life caused by limitations in daily activities and work, and alteration of their reproductive life [1]. These latter problems include excessive menstrual bleeding or menorrhagia, miscarriage, bleeding complications during pregnancy and during/after delivery, and related complications such as acute or chronic anaemia. Consequently, the management of these women is complicated due to considerable inter-individual variation. Moreover, reliable information on clinical management is relatively scarce with only a limited number of available long-term prospective studies of large cohorts providing evidence-based guidance relating to diagnosis and treatment.

Menorrhagia is defined as total blood loss exceeding 80 mL per cycle or menses lasting longer than 7 days [2]. Recent estimates from the World Health Organisation are that 18 million women worldwide experience menorrhagia [2], although this estimate may represent a very heterogeneous group of women and it is important to ensure correct diagnosis and treatment options. Menorrhagia is a common presenting symptom among female patients with VWD and FIX deficiency, and carriers of haemophilia [1]. In carriers of haemophilia, the reported prevalence of menorrhagia has been estimated to be 10–57% [3]. From a historical perspective, it is interesting to note that the first patient identified with this disorder by Erik von Willebrand in 1926 eventually died of uncontrollable menstrual bleeding at age 13 years. Using the pictorial blood assessment chart (PBAC), women affected with VWD were shown to have significantly higher menstrual scores than their healthy peers. Published data point out that in type 1 VWD, it occurs in 79–93% of women [4,5], whereas, in women with type 2 and type 3 VWD, the prevalence ranges from 32% to 63% and 56–69% respectively [6,7]. Whether this difference is attributed to methodological limitations or has an underlying pathophysiological basis remains to be clarified. Following hysterectomy, women with VWD are also more likely to require blood transfusion and are less likely to be free of any bleeding complications than controls [8].

The management of menorrhagia requires the combined expertise of gynaecologists and haematologists, and needs to consider the age of the patient and whether or not the preservation of fertility is a requirement. It is now established that in women with VWD, therapy should start on the first or second day of menses, with the specific therapeutic choice, dose, duration of therapy, and therapeutic monitoring. Haemostatic therapy includes antifibrinolytic agents (tranexamic acid and aminocaproic acid) and/or DDAVP or desmopressin (1-desamino-8-d-arginine vasopressin), a synthetic vasopressin that stimulates the release of von Willebrand factor (VWF) from endothelial cells, in addition to replacement treatment.

Case-control studies also report that women with VWD have significantly higher rates of heavy bleeding that ended the pregnancy compared with controls. Two different series of women with VWD reported a lower prevalence of primary postpartum haemorrhage (PPH) and a higher prevalence of the secondary PPH compared with haemophilia carriers. The most recent data documenting and comparing the incidence of PPH in women with VWD and controls come from a US discharge database, reporting that 6% of pregnancies in such women were complicated by PPH compared to 4% of controls [9]. Peripartum management of women with VWD at the beginning requires a laboratory evaluation for VWD that includes a basic coagulation panel, VWF antigen (VWF:Ag) assay, VWF ristocetin cofactor (VWF:RCo) assay and FVIII levels. Treatment should be instituted if the levels of VWF:RCo and FVIII are <50 IU dL−1 before any invasive procedure and delivery. The mainstays of therapy are desmopressin (DDAVP) and plasma concentrates that contain VWF. DDAVP may be used in women with type 1 VWD; recent data indicate that some individuals have accelerated clearance of VWF; therefore, even patients with type 1 may benefit from a test dose of DDAVP and subsequent measurement of VWF:RCo to document treatment efficacy [10]. In women with type 2, the main problem is that, despite an increase in secretion of VWF after treatment with DDAVP, the VWF secreted retains its intrinsic molecular dysfunction. As a result, the use of VWF concentrates is the preferred therapy for type 2 VWD [11]. However, a small subset of women with type 2 VWD respond to DDAVP and identification of those individuals requires a test dose of DDAVP and subsequent measurement of VWF:RCo 1 and 4 h after infusion. If the VWF:RCo corrects postdose, DDAVP is an acceptable treatment for this subset of women. Flushing, headache, GI complaints and transient hypo or hypertension are minor adverse effects of DDAVP. Repeated dosing is discouraged as it may lead to water retention and hyponatremia. DDAVP is safe for the foetus because it does not cross the placenta in detectable amounts [11]. According to previous reports, women with type 3 VWD lack the physiological rise in VWF during pregnancy. Only a few reports exist regarding the management of pregnancy and delivery in women with VWD type 3, hence few data about the clinical problems and their appropriate management are available. These patients could particularly be considered for prophylactic treatment with DDAVP. However, clinical experience suggests that bleeding at delivery and early postpartum is frequent without DDAVP replacement therapy [12].

After realizing the current gaps in knowledge regarding bleeding in women with VWD, the Angelo Bianchi Bonomi Thrombosis and Haemophilia Centre, University of Milan, established a data collection scheme, through collaboration with centres in the UK, Germany, Serbia and Iran, to evaluate the epidemiology and clinical characteristics of bleeding episodes in women affected with different types of VWD. Preliminary data from 193 patients show that menorrhagia occurred in 70% of patients compared with 46% of controls, and 81% of patients required treatment. In addition, acute bleeding episodes occurred at least once in all women, sufficient to require a blood transfusion. These preliminary data should help to identify the optimal management approach for this patient population.

In conclusion, despite the relatively small sample sizes and the type of data collection in studies reported to date, women with VWD are at increased risk of bleeding; however, it is necessary to increase the sample size of different types of VWD and to include controls. Appropriate treatment could significantly improve the quality of life (academic, social and professional) of these patients.

Age-related FVIII consumption in patients with severe haemophilia A

  1. Top of page
  2. Abstract
  3. Introduction
  4. Bleeding in women with VWD
  5. Age-related FVIII consumption in patients with severe haemophilia A
  6. Inhibitor treatment in patients who failed at first attempt. Poor prognosis patients: RES.I.ST study
  7. Current experience using plasma-derived VWF-containing FVIII concentrates
  8. Rationale for using pdVWF/FVIII concentrates for ITI therapy
  9. RES.I.ST studies
  10. Long-term prophylaxis with highly purified plasma-derived VWF/FVIII concentrates in VWD. Pro.Will study
  11. Therapeutic options for the treatment of haemophilic patients with inhibitors: a cost-effectiveness approach
  12. How much does it cost to treat patients with inhibitors?
  13. The PROFIT study
  14. Musculoskeletal complications in patients with severe bleeding disorders
  15. Disclosures
  16. References

The low incidence of haemophilia in the general population necessitates close cooperation among haemophilia treatment centres (HTC) to optimize treatment strategies. To achieve this goal, the Kompentenznetzwerk Hämorrhagische Diathesen Ost (Network for Coagulation Disorders) was founded in the eastern part of Germany. All HTCs in this region were requested to participate in the network. Of the 37 known haemophilia treatment centres in the area, 31 (83%) actively participated.

Unlike patients in other countries, those in Germany resist travelling long distances for treatment. Most patients prefer to visit local clinicians rather than attend comprehensive centralized treatment clinics such as the eastern region’s only large centre in Berlin. Some centres treat very few patients: in the eastern part of Germany there are 17 centres where clinicians see only 1–10 patients with severe haemophilia.

The aim of the network is therefore to collect epidemiological data, deliver knowledge to practitioners in these small centres to provide standardized treatment regardless of town size or location and, in turn, to acquire data on treatment practice and regimens. The present project undertook the collection of data in patients with severe haemophilia A according to treatment modalities and annual FVIII consumption in the eastern part of Germany.

Data from 224 patients with severe haemophilia A were analysed, with a focus on findings obtained in 2007 and 2009. Results demonstrate that the incidence of severe haemophilia A is highest in the age group 40–49 years (n = 71) and declines thereafter (Fig. 1).

image

Figure 1.  Average FVIII consumption per year in different age groups of patients with haemophilia.

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A total of 65% of adult patients (20 years and older) received prophylactic treatment with FVIII. Average FVIII consumption was similar in the different age groups, with a yearly maximum of 172 000 IU FVIII (2293 IU kg−1 bodyweight) for all patients in the age group 40–49 years (n = 71) and a minimum of 145 000 IU FVIII (2013 IU kg−1 bodyweight) in those aged 30–39 years (n = 39).

There was no marked reduction of the annual FVIII consumption in older patients.

The average annual FVIII consumption from year to year is relatively constant in patients with severe haemophilia A. Adults receive about 150 000 IU per patient which translates to approximately 2000 IU kg−1 bodyweight in adults: values were 2065 IU kg−1 bodyweight in 2005 vs. 2141 IU kg−1 bodyweight in 2009. The attitude of clinicians to plasma-derived and recombinant products in eastern Germany is reflected in the pattern of FVIII consumption (Fig. 2).

image

Figure 2.  Proportion of FVIII plasma-derived and recombinant products used by patients with severe haemophilia A.

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In 2005, approximately 80% of adults were treated with plasma-derived products, whereas more than 40% of adults received recombinant products in 2009, indicating a slow uptake of newer agents. This is explained by historical practice. Until German reunification in 1991, patients with haemophilia in the eastern region of Germany were mainly treated with cryoprecipitate, so the shadow of the HIV catastrophe bypassed that region. In adults, the switch from cryoprecipitate to plasma-derived FVIII products was so successful that clinicians and patients were satisfied with this approach.

In the eastern part of Germany, 64% of patients undergo individualized prophylactic treatment. These regimens differ from those in other countries: [13] prophylaxis in our cohort was defined as at least one FVIII infusion per week without a bleed.

To put our data in context we compared them to findings from the United Kingdom Haemophilia Centres Doctors’ Organisation [14]. The FVIII consumption in the UK varies widely across different regions and does not increase in specific age groups but is increasing per year in all age groups [14]. Overall consumption of FVIII from 2005 to 2009 in eastern parts of Germany was relatively constant, at approximately 44 million IU year−1. The rate of consumption in eastern regions of Germany appears broadly comparable to that in the UK, although it should be noted that in the UK recombinant FVIII is used more frequently [14].

Several conclusions can be drawn from these data. First, at least in the eastern part of Germany, consumption of FVIII was similar from 2005 to 2009, suggesting no trend towards its increased use. Second, individualized prophylactic treatment in adult patients is common, with nearly two-thirds of patients receiving this strategy. Lastly, in our cohort there was no reduction in FVIII consumption in higher age groups, in contrast to reports from the UK.

These findings raise yet more questions. Is the approach of using individualized low-dose prophylactic regimens beneficial to the patient? Our preliminary unpublished data show that all patients with existing joint disease who receive low-dose FVIII prophylaxis experience 2–3 joint bleeds per year on average. Is this level of bleeds acceptable? Furthermore, can intensive prophylactic treatment reduce bleed rate and avoid joint bleeds entirely? These important questions remain to be answered.

Inhibitor treatment in patients who failed at first attempt. Poor prognosis patients: RES.I.ST study

  1. Top of page
  2. Abstract
  3. Introduction
  4. Bleeding in women with VWD
  5. Age-related FVIII consumption in patients with severe haemophilia A
  6. Inhibitor treatment in patients who failed at first attempt. Poor prognosis patients: RES.I.ST study
  7. Current experience using plasma-derived VWF-containing FVIII concentrates
  8. Rationale for using pdVWF/FVIII concentrates for ITI therapy
  9. RES.I.ST studies
  10. Long-term prophylaxis with highly purified plasma-derived VWF/FVIII concentrates in VWD. Pro.Will study
  11. Therapeutic options for the treatment of haemophilic patients with inhibitors: a cost-effectiveness approach
  12. How much does it cost to treat patients with inhibitors?
  13. The PROFIT study
  14. Musculoskeletal complications in patients with severe bleeding disorders
  15. Disclosures
  16. References

For individuals with haemophilia who develop inhibitors to FVIII concentrates, ITI therapy is often employed as a means of eradicating the inhibitor. In terms of candidate patients, there are two main categories: those with ‘good’ and those with ‘bad’ prognostic features for a successful outcome (Table 1).

Table 1.   Risk features for a successful outcome with immune tolerance induction (ITI) therapy in patients with haemophilia.
Good risk featuresPoor risk features
  1. BU, Bethesda units.

Maximum inhibitor <200 BUMaximum inhibitor ≥200 BU
Inhibitor titre <10 BU at startInhibitor titre ≥10 BU at start
Inhibitor present <2 yearsInhibitor present >2 years
Age <8 years at startAge ≥8 years at start
 Others: African American (not a criterion for the RES.I.ST studies)

The International Immune Tolerance Study, which was prematurely stopped because of futility and safety considerations [15], indicated that successful outcomes can be achieved in approximately two-thirds of ‘good risk’ patients treated with conventional ITI therapy [generally recombinant FVIII (rFVIII) concentrate without immunosuppressive agents]. But what can be done for the one-third of patients who fail or for those `bad risk’ patients?

Over the years, several approaches for treating patients who fail ITI therapy have been reported (Table 2). Among these various approaches, cyclosporine and mycophenolate mofetil tend not to be regarded as viable options because of insufficient data, and the long-term success rate with rituximab appears low. Moreover, there is a general reluctance nowadays by clinicians to use cyclophosphamide especially in children who have no malignant conditions. The field of options for treating patients who fail conventional ITI therapy is thus narrowed to plasma-derived VWF-containing FVIII concentrates (pdVWF/FVIII).

Table 2.   Approaches to inhibitor eradication in patients who have failed previous immune tolerance induction (ITI) therapy.
  1. VWF, von Willebrand factor.

Cyclosporine
High-dose cyclophosphamide
ITI therapy with plasma-derived VWF-containing FVIII concentrates
 Malmo-ITI therapy protocol
 Mycophenolate mofetil
 Rituximab

Current experience using plasma-derived VWF-containing FVIII concentrates

  1. Top of page
  2. Abstract
  3. Introduction
  4. Bleeding in women with VWD
  5. Age-related FVIII consumption in patients with severe haemophilia A
  6. Inhibitor treatment in patients who failed at first attempt. Poor prognosis patients: RES.I.ST study
  7. Current experience using plasma-derived VWF-containing FVIII concentrates
  8. Rationale for using pdVWF/FVIII concentrates for ITI therapy
  9. RES.I.ST studies
  10. Long-term prophylaxis with highly purified plasma-derived VWF/FVIII concentrates in VWD. Pro.Will study
  11. Therapeutic options for the treatment of haemophilic patients with inhibitors: a cost-effectiveness approach
  12. How much does it cost to treat patients with inhibitors?
  13. The PROFIT study
  14. Musculoskeletal complications in patients with severe bleeding disorders
  15. Disclosures
  16. References

The bulk of experience using pdVWF/FVIII concentrates for ITI therapy in patients with haemophilia derives from three retrospective studies and one prospective study.

Two German studies reported much higher success rates in terms of inhibitor eradication during the years when ITI therapy had been conducted exclusively with pdVWF/FVIII concentrates (up to the early 1990s) compared with later years when it was substituted with rFVIII (Fig. 3) [16–18]. Importantly, both studies indicated that the majority of patients who had failed initial ITI therapy with a recombinant product achieved successful immune tolerance when their treatment was subsequently switched to a pdVWF/FVIII product.

image

Figure 3.  Data from a retrospective German study indicate that the incidence of a successful outcome with immune tolerance induction therapy is higher with pdVWF/FVIII concentrate than with rFVIII concentrate [18].

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Another of the retrospective studies involved patients who were treated with high-dose pdVWF/FVIII concentrate (100–200 IU kg−1 day−1) as part of their ITI therapy at five different institutions in the US [19]. All 25 patients were considered as having a poor prognosis on the basis of their clinical and laboratory characteristics. Overall, complete success (Bethesda negative, normal FVIII recovery and half-life) was achieved in 32% of patients. Another 40% of patients were described as having partial success which was defined in this study as an inhibitor titre of <10 Bethesda units (BU) and the ability to use FVIII concentrate to treat bleeds. Although suggestive of a good success rate, most clinicians would consider partial success to be failure and the results can therefore be stated simply as a complete success rate of 32% and a failure rate of 68%.

Lastly, experience with the use of pdVWF/FVIII concentrate is also available from a prospective, naturalistic study conducted in haemophilia centres in Italy (n = 9) and Spain (3) [20]. Between 1999 and 2005, 17 patients received ITI therapy with pdVWF/FVIII concentrate (Fanhdi®; Grifols S.A., Barcelona, Spain). All patients had poor risk features for successful treatment: all were aged 7 years or older at the start of therapy, including 10 adults; only one patient had an inhibitor for less than 2 years; two patients had peak inhibitor titres of >200 BU. At the start of treatment, four patients had inhibitor titres of >10 BU, and four patients had failed previous ITI therapy.

Nine patients were initiated on a low-dose regimen [50 IU kg−1 (three times a week)] and eight on a high-dose regimen (100 or 200 IU kg−1 day−1). Patients received ITI for anywhere from 4 to 33 months.

In terms of patient outcomes, 9 of 17 patients (53%) achieved complete success after a median of 24 months (Table 3), including two of the four patients who had failed previous ITI therapy. Seven patients achieved a partial success (Table 3), with sustained low inhibitor titres (median 1.5 BU, range 1.1–2.8) but with abnormal FVIII recovery and/or half-life, while the remaining patient withdrew from treatment after 12 months when the inhibitor titre was still 70 BU.

Table 3.   Criteria for complete and partial success in patients receiving immune tolerance induction (ITI) therapy in the RITS-FITNHES study [19].
Complete success (must meet all three variables)Partial success
  1. BU, Bethesda units.

Bethesda negativeInhibitor ≤3 BU
Normal FVIII recovery (>66% of expected)and/or
Normal FVIII half-life (>6 h)Reduced FVIII recovery or half-life

Based on the evidence available to date, it is not possible to state with confidence that pdVWF/FVIII is the product of choice when initiating patients on ITI therapy. Of the few published studies, all have their limitations: patient numbers were small, none of the studies was randomized, and all used different ITI therapy protocols. Although the 53% complete response rate reported by Gringeri and colleagues appears promising [20], this is counteracted to some extent by the 32% complete response rate reported by Kurth et al. [19]. Despite this uncertainty, recommendations published by European [21] and International [22] consensus panels state that ‘FVIII concentrates containing VWF should be considered for patients who fail ITI using high purity FVIII’.

Rationale for using pdVWF/FVIII concentrates for ITI therapy

  1. Top of page
  2. Abstract
  3. Introduction
  4. Bleeding in women with VWD
  5. Age-related FVIII consumption in patients with severe haemophilia A
  6. Inhibitor treatment in patients who failed at first attempt. Poor prognosis patients: RES.I.ST study
  7. Current experience using plasma-derived VWF-containing FVIII concentrates
  8. Rationale for using pdVWF/FVIII concentrates for ITI therapy
  9. RES.I.ST studies
  10. Long-term prophylaxis with highly purified plasma-derived VWF/FVIII concentrates in VWD. Pro.Will study
  11. Therapeutic options for the treatment of haemophilic patients with inhibitors: a cost-effectiveness approach
  12. How much does it cost to treat patients with inhibitors?
  13. The PROFIT study
  14. Musculoskeletal complications in patients with severe bleeding disorders
  15. Disclosures
  16. References

Some reasons have been postulated as to why pdVWF/FVIII concentrates may enhance ITI therapy compared with recombinant products.

In brief, one of these postulates centres around a potential protective effect of the presence of VWF. The VWF binds to different epitopes in the A3 and C2 domains of FVIII which may offer it protection against degradation by proteinases. Similarly, most inhibitors are also directed at epitopes on the A3 and C2 domains along with the A2 domain. As such, the presence of VWF on the FVIII molecule leads to (i) masking of epitope sites by VWF thereby preventing inhibitors (neutralizing antibodies) from binding to the FVIII molecule and (ii) increased stability (i.e. reduced clearance) of the FVIII molecule. Both processes result in longer presence of the FVIII molecule when infused into patients with inhibitors. It is postulated that this longer exposure of FVIII to the immune system may result in improved immune tolerance.

Another postulate relates to substances such as anti-idiotypic antibodies, cytokines and ‘other’ (as yet unidentified) proteins which may be present in pdVWF/FVIII concentrate but not in recombinant products. These other substances may have a role in affecting the immune system and conferring an advantage over recombinant products for purposes of immune tolerance.

RES.I.ST studies

  1. Top of page
  2. Abstract
  3. Introduction
  4. Bleeding in women with VWD
  5. Age-related FVIII consumption in patients with severe haemophilia A
  6. Inhibitor treatment in patients who failed at first attempt. Poor prognosis patients: RES.I.ST study
  7. Current experience using plasma-derived VWF-containing FVIII concentrates
  8. Rationale for using pdVWF/FVIII concentrates for ITI therapy
  9. RES.I.ST studies
  10. Long-term prophylaxis with highly purified plasma-derived VWF/FVIII concentrates in VWD. Pro.Will study
  11. Therapeutic options for the treatment of haemophilic patients with inhibitors: a cost-effectiveness approach
  12. How much does it cost to treat patients with inhibitors?
  13. The PROFIT study
  14. Musculoskeletal complications in patients with severe bleeding disorders
  15. Disclosures
  16. References

The RES.I.ST studies commenced in 2009 with the primary objective of determining whether pdVWF/FVIII concentrate is more effective than rFVIII concentrate for use in ITI therapy for patients with haemophilia [23]. Two studies are ongoing, which have been labelled ‘RES.I.ST-naïve’ and ‘RES.I.ST-experienced’.

Patients eligible for inclusion in the RES.I.ST-naïve study are those with high-titre inhibitors who have not previously received ITI therapy and have poor prognostic risk features for treatment success. In this study, patients are being randomly allocated to receive either pdVWF/FVIII or rFVIII, in both cases at a dose of 200 IU kg−1 day−1. Patients are followed on a monthly basis to monitor response (Fig. 4). Treatment success is defined in the same manner as in the International ITI Study [15]. Treatment can extend for up to 33 months after which a patient will be declared to have failed if an inhibitor is still present. Patients with successful outcomes will have their ITI therapy dose tapered to a prophylaxis regimen of 25–40 IU kg−1 (three times a week).

image

Figure 4.  RES.I.ST-naïve study design.

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The RES.I.ST-experienced study involves patients with high-titre inhibitors who have previously failed conventional ITI therapy with rFVIII. The design of this study is similar to that in RES.I.ST-naïve patients with the exception that patients are not randomized. Patients, as a cohort, will receive pdVWF/FVIII at the dose of 200 IU kg−1 day−1.

The primary question these studies are trying to answer is: which is the most effective factor concentrate for ITI therapy? This is an important clinical question. Despite the importance of the question, multicentre studies on immune tolerance therapy in inhibitor patients are difficult to perform due to the small number of potential patients within any one centre and the difficulties with instituting studies including the process of obtaining institutional ethics approval. So far the RES.I.ST studies have enrolled 16 patients in centres in four countries (Italy, Spain, USA, Canada) (personal communication, A. Gringeri, December 2011). Given the importance of determining the ‘best’ factor for immune tolerance, clinicians are encouraged to enrol their patients into the RES.I.ST study to find the answer.

Long-term prophylaxis with highly purified plasma-derived VWF/FVIII concentrates in VWD. Pro.Will study

  1. Top of page
  2. Abstract
  3. Introduction
  4. Bleeding in women with VWD
  5. Age-related FVIII consumption in patients with severe haemophilia A
  6. Inhibitor treatment in patients who failed at first attempt. Poor prognosis patients: RES.I.ST study
  7. Current experience using plasma-derived VWF-containing FVIII concentrates
  8. Rationale for using pdVWF/FVIII concentrates for ITI therapy
  9. RES.I.ST studies
  10. Long-term prophylaxis with highly purified plasma-derived VWF/FVIII concentrates in VWD. Pro.Will study
  11. Therapeutic options for the treatment of haemophilic patients with inhibitors: a cost-effectiveness approach
  12. How much does it cost to treat patients with inhibitors?
  13. The PROFIT study
  14. Musculoskeletal complications in patients with severe bleeding disorders
  15. Disclosures
  16. References

At present there are two main weapons in the treatment of VWD. One is DDAVP, which releases endogenous VWF from vascular endothelial cells. DDAVP is appropriate in mild to moderate forms of the disease (VWD1 and VWD2). When endogenous VWF is abnormal (VWD2B) or insufficient (as in severe VWD1), DDAVP is contraindicated or ineffective. Commercially available exogenous VWF concentrate is indicated in these patients (VWD3, severe VWD1). pdVWF/FVIII concentrates are indicated in patients with VWD3 and in VWD2A, VWD2M, VWD2N and VWD1 who do not respond to DDAVP, and in those with VWD2B, the latter because DDAVP may induce thrombocytopenia.

There are three main determinants when selecting appropriate treatment in patients with VWD. The first of these is patient type. Patients present with different abnormalities: in some patients plasma VWF is reduced whereas others may also have low plasma FVIII (e.g. VWD3). The second determinant is the type of VWF concentrate per se, which can contain a variable VWF:FVIII ratio. The third determinant is the clinical setting: patients with acute bleeding or undergoing surgery are difficult to manage, and this setting is where we would like to propose long-term prophylaxis.

The double virus-inactivated pdVWF/FVIII concentrate Alphanate® was the first product tested prospectively in VWD patients with bleeding or undergoing surgery [24]. Recently, we retrospectively re-evaluated the use of the high-purity pdVWF/FVIII concentrates Alphanate® (Grifols S.A, Barcelona, Spain) and Fanhdi® in a large cohort of patients (n = 120) in Italy [25]. At the time of our decision to start a prospective prophylaxis study, we found that in Italy several clinicians had already provided a prophylactic regimen to their patients with severe VWD [26].

We consider the bleeding severity score to be the best approach to understanding clinical severity and this parameter was used in our analysis. In this retrospective study we could define the various VWD types according to bleeding severity scores of <5, 5–10 and >10. Patients with the highest bleeding severity scores, e.g. VWD3 patients, may be suitable for long-term prophylaxis. Our retrospective analysis of 15 patients who received secondary long-term prophylaxis as provided by their clinicians, not according to any standardized protocol, showed complete prevention in the majority of these patients [25].

The ongoing Pro.Will study began in 2008 and addresses the critical question: ‘Is secondary prophylaxis with VWF/FVIII concentrates (for at least 6 months) more effective than treatment on-demand to stop recurrent bleeding in patients with severe VWD?’

This is a prospective, multicentre, open-label, randomized trial conducted in Italy, the UK and Spain. The primary objective of the Pro.Will study is to evaluate whether secondary prophylaxis with highly purified pdVWF/FVIII concentrates, compared with the same treatment on-demand, prevents spontaneous bleeding in patients with VWD who are unresponsive to DDAVP and suffer frequent bleedings. Secondary objectives are to assess adverse effects/thrombotic events, global effects on hospitalization and transfusion requirements, cost minimization of prophylaxis vs. on-demand treatment, cost efficacy (€/bleeding episode prevented, and improvement in quality of life).

The aim is to enrol 24 patients, the minimum number needed to ensure meaningful evaluation. Inclusion criteria are male or female patients of any age with severe inherited VWD, as defined by ratios of VWF:RCo <10 IU dL−1 and FVIII:C <20 IU dL−1 and/or bleeding time >15 min. Patients must also have documented unresponsiveness or a contraindication to DDAVP treatment and have experienced spontaneous bleedings requiring pdVWF/FVIII in the previous 12 months. Informed consent is obtained.

Accurate bleeding histories are essential for patient selection. Inclusion criteria for patient bleeding are:

  • 1
     Five frequent spontaneous bleedings in the last 12 months severe enough to require treatment with pdVWF/FVIII concentrates.
  • 2
     Six spontaneous epistaxis or two gastrointestinal (GI) bleeds.
  • 3
     Three haemarthroses at the same joint.
  • 4
     Four uterine bleeds for >10 days in the previous 12 months.

Patients are excluded if they have a life expectancy <1 year, allo-antibodies to VWF or FVIII, acquired von Willebrand syndrome, comorbidity with other haemorrhagic diathesis, advanced liver cirrhosis, any known need for invasive procedures or elective surgery, causes of GI bleeding unrelated to the study, or GI bleeding due to trauma and invasive diagnostic or surgical procedures. Pregnant or lactating women are excluded, as are patients with concomitant autoimmune anaemia and/or autoimmune thrombocytopenia. Concomitant non-steroidal anti-inflammatory drugs (NSAIDs), steroidal drugs and other VWF concentrates are not allowed. Patients who require elective surgery that could not be postponed during the study are withdrawn from treatment.

Figure 5 illustrates the enrolment design of the Pro.Will. The randomization method is key to the study. Patients are randomized 1:1 and are balanced as per type of bleed (GI, joint, epistaxis, menorrhagia). Patients receive a loading dose of VWF:RCo 60 IU kg−1 body weight (Fanhdi®/Alphanate®, Grifols S.A., Barcelona, Spain) as on-demand or prophylactic treatment followed by dosages given according to clinical presentation and symptom type.

image

Figure 5.  Enrolment design of the Pro.Will study.

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The primary efficacy endpoint is defined as the prevention of spontaneous bleeding recurrence (‘success’). Patients with bleeding recurrence are classified as ‘failure’. The study assumes success rates of 65% for prophylaxis and 10% for the on-demand arm. Secondary endpoints include the incidence of spontaneous bleeding and number of infusions required, incidence of all bleeding, duration of spontaneous bleeding, time to first event, VWF:RCo and FVIII:C trough levels during prophylaxis and transfusional needs.

Compared with haemophilia patients, those with VWD are few in number. Patient enrolment is complete in Italy and is ongoing in Spain and the UK to hasten study progress. Figure 6 shows the enrolment status of the first 16 patients included in Pro.Will to date. There were three dropouts due to factors such as requirement for elective surgery. We anticipate completing our mid-study (6-month) interim analysis for the first 12 patients very soon.

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Figure 6.  Current enrolment status of the Pro.Will study.

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Therapeutic options for the treatment of haemophilic patients with inhibitors: a cost-effectiveness approach

  1. Top of page
  2. Abstract
  3. Introduction
  4. Bleeding in women with VWD
  5. Age-related FVIII consumption in patients with severe haemophilia A
  6. Inhibitor treatment in patients who failed at first attempt. Poor prognosis patients: RES.I.ST study
  7. Current experience using plasma-derived VWF-containing FVIII concentrates
  8. Rationale for using pdVWF/FVIII concentrates for ITI therapy
  9. RES.I.ST studies
  10. Long-term prophylaxis with highly purified plasma-derived VWF/FVIII concentrates in VWD. Pro.Will study
  11. Therapeutic options for the treatment of haemophilic patients with inhibitors: a cost-effectiveness approach
  12. How much does it cost to treat patients with inhibitors?
  13. The PROFIT study
  14. Musculoskeletal complications in patients with severe bleeding disorders
  15. Disclosures
  16. References

Patients with haemophilia (at least those in high-income countries) currently experience an effective and safe standard of care. The major challenge continues to lie with the one-third of patients who develop inhibitors to FVIII concentrates, as inhibitors reduce FVIII efficacy and are associated with high morbidity. A related issue concerns the high economic burden of treating patients with inhibitors, whereby the direct costs of replacement factor therapy account for nearly 99% of the total medical resources absorbed by care [27].

Immune tolerance induction therapy is the first choice of treatment in patients with inhibitors, especially those with high-responding inhibitors (Fig. 7). By current standards, success may be expected in about two-thirds of such patients who can subsequently return to their original FVIII treatment. Options available for the remaining one-third of patients include a move to bypassing agents either as prophylaxis or on-demand.

image

Figure 7.  Therapeutic options to treat patients with haemophilia A who develop inhibitors to FVIII.

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How much does it cost to treat patients with inhibitors?

  1. Top of page
  2. Abstract
  3. Introduction
  4. Bleeding in women with VWD
  5. Age-related FVIII consumption in patients with severe haemophilia A
  6. Inhibitor treatment in patients who failed at first attempt. Poor prognosis patients: RES.I.ST study
  7. Current experience using plasma-derived VWF-containing FVIII concentrates
  8. Rationale for using pdVWF/FVIII concentrates for ITI therapy
  9. RES.I.ST studies
  10. Long-term prophylaxis with highly purified plasma-derived VWF/FVIII concentrates in VWD. Pro.Will study
  11. Therapeutic options for the treatment of haemophilic patients with inhibitors: a cost-effectiveness approach
  12. How much does it cost to treat patients with inhibitors?
  13. The PROFIT study
  14. Musculoskeletal complications in patients with severe bleeding disorders
  15. Disclosures
  16. References

A few years ago our group attempted to analyse the economic impact of treating patients with inhibitors [28]. A brief overview of available data in this area highlights some of the issues involved in conducting an analysis of this nature (Table 4).

Table 4.   Limitations of available studies regarding haemophilia treatment in patients with inhibitors [28].
Few data 
 Few patients (rare complication of a rare disease)
 Lack of rigorous studies
 Analysis time- and region (country)- specific
Heterogeneous approaches to treatmentCost-effectiveness [DOWNWARDS ARROW] Cost-utility
 ITI: different protocols
 Bypassing agents: on-demand (type, doses), prophylaxis
Assumptions of outcomes
 Lack of prospective evidence
 Introduction of orthopaedic surgery
Need for a lifetime perspective
 Short-term evaluations in most studies
Quality of life assessment

Given that inhibitor formation is a rare complication of a rare disease, available data are limited; most stem from retrospective short-term evaluations that allow only for analysis of the direct costs of different treatment strategies (cost-effectiveness). The data are time and region specific and are therefore not directly transferable between countries. Another issue relates to the heterogeneity of the ITI therapy and bypassing agent strategies employed in various studies. The use of bypassing agents represents a lifetime decision and, as such, how does this compare economically with administering massive doses of FVIII concentrate in the hope of restoring original treatment over a 1- to 3-year period? Moreover, the introduction of orthopaedic surgery for patients with inhibitors has obviated any previous assumptions of outcomes and underscores the need for a lifetime perspective of the economic consequences of treating this patient group. A cost-utility analysis which takes into account the benefits of a given treatment/intervention on patients’ health-related quality of life is likely to be the most appropriate approach.

Briefly, some pertinent findings from studies which have attempted to quantify the costs of treating patients with inhibitors are as follows:

  • 1
     Average annual concentrate costs are 1.5- to 3-fold higher in patients with inhibitors vs. those without inhibitors, although ‘outliers’ account for a high proportion of these total higher costs [29–32].
  • 2
     The FVIII consumption and costs are approximately sixfold higher in patients with ‘bad’ vs. ‘good’ prognostic factors for successful ITI therapy [33].
  • 3
     Annual costs for ITI therapy are 15-fold higher than that for lifetime on-demand treatment protocols with FVIII concentrates, but are limited to 1–3 years – can costly be cheaper? [34].
  • 4
     In ‘good risk’ patients, success rates with ITI therapy were similar between high-dose (200 U kg−1 day−1) and low-dose [50 U kg−1 (three times a week)] FVIII regimens, but the twofold increased risk of bleeding episodes in patients on the low-dose regimen was associated with higher costs [35].

The PROFIT study

  1. Top of page
  2. Abstract
  3. Introduction
  4. Bleeding in women with VWD
  5. Age-related FVIII consumption in patients with severe haemophilia A
  6. Inhibitor treatment in patients who failed at first attempt. Poor prognosis patients: RES.I.ST study
  7. Current experience using plasma-derived VWF-containing FVIII concentrates
  8. Rationale for using pdVWF/FVIII concentrates for ITI therapy
  9. RES.I.ST studies
  10. Long-term prophylaxis with highly purified plasma-derived VWF/FVIII concentrates in VWD. Pro.Will study
  11. Therapeutic options for the treatment of haemophilic patients with inhibitors: a cost-effectiveness approach
  12. How much does it cost to treat patients with inhibitors?
  13. The PROFIT study
  14. Musculoskeletal complications in patients with severe bleeding disorders
  15. Disclosures
  16. References

Currently ongoing in Italy is the PROFIT (PROgnostic Factors in ITI of haemophiliacs A with inhibitors) study which has the aim of establishing an optimal regimen for ITI therapy. A total of 24 centres are participating in this retrospective-prospective registry study and, as of July 2011, 108 of 113 registered patients (71 retrospective, 52 prospectively followed) had completed their first course of ITI therapy. All patients have severe haemophilia A with high-responding inhibitors and 70% of the population has negative prognostic factors for a successful outcome. Of the 108 patients for whom data are available, at least one-third received FVIII concentrates at a dose of <95 U kg−1 day−1 and 29% did not receive FVIII concentrate on a daily basis [either three times weekly (= 12) or every other day (n = 19)]. Thirty-nine per cent of patients received a different FVIII concentrate than was in use at the time of inhibitor diagnosis. Twenty-seven per cent received a pdFVIII product, whilst the remaining 73% of patients received a rFVIII product at significantly higher amounts than in those treated with pdFVIII products.

As was reported in 2009, the overall success rate was good and a multivariate analysis indicated that significant predictors of success included an inhibitor titre of <5 BU at the start of ITI therapy, F8 genotype (non-null mutations), and a peak inhibitor titre of <100 BU while receiving ITI therapy [36].

Since then, the data have been re-analysed based on a number of pharmacoeconomic parameters. For analysis purposes, the patient population was split by age: <14 (n = 73) and ≥14 (n = 35) years of age. Significant differences emerged in terms of how younger vs. older patients are treated with regard to FVIII dose (P = 0.002), daily regimen (P = 0.003), use of rFVIII products (P < 0.0001) and whether or not the same concentrate is used as at the time of inhibitor diagnosis (P < 0.0001). Nevertheless, treatment success was similar in both age groups (Table 5) with the only significant differences being the time to inhibitor negative status (6 vs. 9 months in younger vs. older patients; P = 0.04) and the time to treatment success (8 vs. 12 months respectively; P = 0.04).

Table 5. PROFIT (PROgnostic Factors in Immune Tolerance induction of haemophiliacs A with inhibitors) study: outcomes according to age at start of ITI therapy.
 <14 years (n = 73)≥14 years (= 35)P-value
  1. *Median (range).

Inhibitor peak on ITI*(BU mL−1) 68 (6–16 384)31 (6–4096) 
 ≤100 BU mL−141 (60%)24 (69%)
Success39 (57%)16 (46%) 
Partial8 (12%)10 (28%)
Success22 (31%)9 (26%)
Failure
Time to inhibitor negative*(months)6 (1–35)9 (0.5–21)P = 0.04
Time to success*(months)8 (1.5–40)12 (2–33)P = 0.04

In terms of median consumption of FVIII concentrate required to achieve a successful outcome, the groups were virtually identical (24 690 vs. 24 840 U kg−1 for younger vs. older patients) as were the costs of a successful outcome (18 979 vs. 17 009 € kg−1).

Based on previous prices for FVIII concentrates in Italy, the cost of achieving a successful outcome with ITI therapy irrespective of age equates to € 2000 kg−1 or € 150 000 overall. Expressed in current prices, the overall cost of successful ITI therapy in patients with severe haemophilia A and high-responding inhibitors who have negative prognostic features for a successful outcome is € 200 000.

In conclusion, although the evidence for higher costs associated with the treatment of haemophilia in patients with inhibitors vs. those without inhibitors is unequivocal, in the absence of solid economic data from prospective controlled studies which take into account the lifetime perspective of various treatment strategies and employ a cost-utility approach, the ability to quantify the incremental difference remains elusive. It is imperative also that the positions of all parties involved – healthcare professionals, patients, caregivers and resource providers – are considered. Until such data become available, we are obliged to maintain our current position in stating that, at present, the only means of lowering the cost of haemophilia treatment is to prevent inhibitor development.

Musculoskeletal complications in patients with severe bleeding disorders

  1. Top of page
  2. Abstract
  3. Introduction
  4. Bleeding in women with VWD
  5. Age-related FVIII consumption in patients with severe haemophilia A
  6. Inhibitor treatment in patients who failed at first attempt. Poor prognosis patients: RES.I.ST study
  7. Current experience using plasma-derived VWF-containing FVIII concentrates
  8. Rationale for using pdVWF/FVIII concentrates for ITI therapy
  9. RES.I.ST studies
  10. Long-term prophylaxis with highly purified plasma-derived VWF/FVIII concentrates in VWD. Pro.Will study
  11. Therapeutic options for the treatment of haemophilic patients with inhibitors: a cost-effectiveness approach
  12. How much does it cost to treat patients with inhibitors?
  13. The PROFIT study
  14. Musculoskeletal complications in patients with severe bleeding disorders
  15. Disclosures
  16. References

The hallmark of severe bleeding disorder is joint bleeding, especially in patients with haemophilia, in whom 80% to 90% of bleeding episodes occur in the musculoskeletal system. The vicious cycle of joint bleeding begins with haemarthrosis leading to synovial hypertrophy and cartilage damage (chondrocyte apoptosis), which gradually destroys the joint, resulting in haemophilic arthropathy.

Prophylaxis is the gold standard treatment for haemophilic patients. However, some patients develop joint damage despite no clinically evident episodes of joint bleeding. Unfortunately, older patients have important musculoskeletal complications requiring several surgical procedures.

Management of haemarthrosis involves a multifaceted approach of haematological treatment, short-term rest of the involved joint, cryotherapy (local ice application), joint aspiration via arthrocentesis when haemoarthrosis is profuse and acute, rehabilitation with physiotherapy to improve range of movement and periarticular strength of muscles, and appropriate use of analgesic medications.

Radiosynovectomy is a good alternative in chronic synovitis and provides a 75% reduction in haemoarthroses on average. Ablation of the synovial membrane by injection of radioactive isotopes (e.g. Yttrium-90, Rhenium-186) is minimally invasive, very safe and easy to perform, although care must be taken to avoid radiation contamination.

If after three consecutive radiosynovectomies it is impossible to stop the bleeding, open or arthroscopic synovectomy may be attempted. This latter procedure is less invasive than the classic approach, with a similar success rate.

In patients with advanced severe arthropathy, the last resort is replacement of the affected joint. The main concern is the likelihood of infection after surgery. About 7% of patients with haemophilia develop postsurgical infection compared with 1–2% of the general population. It must be stressed that some patients may develop infection several months or a year after the procedure.

The pathogenesis of haemophilic joint disease involves changes in the synovial lining layer and synovial type A (macrophage) and type B (fibroblast) cell function. Fatty and fibrous tissue develops in the sublining layer. Blood vessels are the source of joint bleeds, as articular cartilage is avascular. Joint collagen entraps proteoglycans and, in the event of blood or trauma, excessive proteoglycan release contributes to long lasting cartilage damage.

A classic element in these synovial changes is the role of iron. Iron-loaded tissues synthesize proinflammatory cytokines [interleukin (IL)-6, IL-1β, tumour necrosis factor alpha (TNF-α)]. In synovial cells, iron increases human synovial cell proliferation and induces c-myc expression, and inducing mdm2 gene expression. This latter effect decreases p53 activity, resulting in abrogation of synovial apoptosis and/or increased cellular proliferation (Fig. 8) [37–39].

image

Figure 8.  Schematic illustration of the signalling pathway that is activated in the presence of iron in synovial cells, resulting in cell cycle arrest/apoptosis. Akt1, a serine-threonine kinase; C-Myc, a regulator gene encoding a transcription factor; ERK, extracellular signal regulated kinase; GTP, guanosine triphosphate; Mdm2, murine double minute oncogene; MEK, mitogen-activated protein kinase; p53, protein 53/tumour protein 53 (a tumour suppressor protein); Raf, a serine-threonine protein kinase; Ras, rat sarcoma protein (a membrane-associated GTPase).

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A study investigating the role of angiogenic mediators in synovial changes [40] identified several contributing factors. These investigators observed elevations in proangiogenic factors such as vascular endothelial growth factor A (VEGF-A) and stromal cell-derived factor 1, elevated levels of proangiogenic macrophages and monocytes, and increased numbers of endothelial and haematopoietic progenitor cells. Sera from patients with haemophilia and joint disease induced an angiogenic response in endothelial cells that was abrogated by blocking VEGF. Peripheral blood mononuclear cells from these patients stimulated synovial cell proliferation, which was blocked by the anti-VEGF antibody bevacizumab. Lastly, human synovial cells, when incubated with haemophilic sera, elicited upregulation of hypoxia-inducible factor 1-alpha (HIF-1α) mRNA, implicating hypoxia in the neo-angiogenesis process [40].

To summarize, blood and its breakdown products stimulates synovial proliferation, leading to hypoxia and the release of HIF-1α and producing active synovitis (Fig. 9).

image

Figure 9.  Factors contributing to synovial changes in haemophilic joint disease.

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Another interesting observation regarding musculoskeletal bleeding disorders is that some patients with haemophilia develop severe joint disease despite the lack of clinically identified bleeding into the joints. Conversely, other patients appear to be protected from the onset of arthritis despite many episodes of haemarthrosis.

Manco-Johnson and colleagues [41] examined the relationship between Magnetic Resonance Imaging (MRI) score (0 = normal, 7–10 = cartilage damage) and number of clinically evident joint haemorrhages. It is very interesting that some patients with high MRI scores have never experienced a clinically evident joint haemorrhage, whereas others with bleeding episodes have low MRI scores and no joint damage. One explanation is given by Rodriguez-Merchan and colleagues [42] and illustrated in Fig. 10. The authors proposed that the oval seen in the figure represents the normal distribution of patients and provides evidence for a correlation between bleeding and MRI score. The dotted line indicates the threshold for patients to develop arthropathy. Within the upper green rectangle are patients with a genetic propensity protecting them from haemarthrosis, while the lower red rectangle includes patients who suffer severe bleeding with no change in MRI score.

image

Figure 10.  Relationship between MRI score and joint haemorrhages [42].

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These results suggest that as yet unidentified genetic and environmental factors lead to arthropathy in patients with haemophilia. The ability to identify these factors may permit the rational design of therapies to target treatment and prevention of blood-induced joint disease.

In conclusion, advanced arthropathy remains a prominent clinical problem in adult patients with haemophilia. Despite the better outcome of patients receiving prophylaxis, some will still develop structural joint damage. The new role of angiogenic mediators in the pathogenesis of joint disease remains to be fully elucidated. In future, better understanding of the cause of discrepancies between patients in outcome of arthropathy and the role of the blockade of chemokine and proangiogenic signalling could hasten the development of effective strategies.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Bleeding in women with VWD
  5. Age-related FVIII consumption in patients with severe haemophilia A
  6. Inhibitor treatment in patients who failed at first attempt. Poor prognosis patients: RES.I.ST study
  7. Current experience using plasma-derived VWF-containing FVIII concentrates
  8. Rationale for using pdVWF/FVIII concentrates for ITI therapy
  9. RES.I.ST studies
  10. Long-term prophylaxis with highly purified plasma-derived VWF/FVIII concentrates in VWD. Pro.Will study
  11. Therapeutic options for the treatment of haemophilic patients with inhibitors: a cost-effectiveness approach
  12. How much does it cost to treat patients with inhibitors?
  13. The PROFIT study
  14. Musculoskeletal complications in patients with severe bleeding disorders
  15. Disclosures
  16. References