bluuebunny/crossref_metadata_2025 huggingface dataset:
Linkage analysis in haemophilia A: simultaneous genotyping of two polymorphisms of the human factor VIII gene using induced heteroduplex formation
Authors: Howarth  , Bowen
Published: March 2003

Linkage analysis is currently the most widely used approach to genetic testing in families affected by haemophilia A. Among the polymorphisms of the factor VIII gene which can be used in such studies, a T/A polymorphism affecting a BclI restriction site in intron 18 and a G/A polymorphism in intron 7 are potentially useful. Both may be analysed by polymerase chain reaction (PCR) amplification followed by restriction endonuclease digestion and gel electrophoresis (the intron 7␣polymorphism does not directly affect a restriction site but a minor sequence change in one PCR primer introduces an AlwNI site if the ‘G’ allele is present). We have developed a novel approach for the analysis of these two polymorphisms which uses induced heteroduplex formation to distinguish their allelic forms. Heteroduplex analysis eliminates the restriction endonuclease step and reduces the analysis for both loci to PCR followed directly by gel electrophoresis. Additionally, the new test has been designed to permit both loci to be analysed in the same PCR (multiplex heteroduplex analysis). Multiplex analysis was used to determine the allele frequencies of these polymorphisms in 105 factor VIII genes in the local (South Wales) population: BclI ‘T’/BclI ‘A’ = 0.80/0.20 ± 0.08 (95% confidence interval), intron 7 ‘G’/intron 7 ‘A’ = 0.88/0.12 ± 0.06 (95% confidence interval). The polymorphisms were found to be in strong linkage disequilibrium. The utility of multiplex heteroduplex analysis for linkage studies in haemophilia A was demonstrated by its application to carrier status investigation for an at risk female in a haemophilia A family.
Newer concepts of blood coagulation
Authors: Lee C. A. , Kessler C. M. , Varon D. , Martinowitz U. , Heim M. , ROBERTS H. R. , MONROE D. M. , OLIVER J. A. , CHANG J.‐Y. , HOFFMAN M.
Published: March 2003

Summary. In this report we describe an in vitro model of blood coagulation reactions that mimics as closely as possible the in vivo condition. Our model indicates that the tissue factor—factor VIIa complex initiates coagulation by activating small amounts of both factor IX and factor X in the environment of the tissue factor bearing cell. Factor Xa and factor IXa formed in the initial reaction then play very distinct roles in the subsequent interactions of the clotting mechanism leading to a burst of thrombin generation on the platelet surface. Our results also indicate that factor XI can be activated by thrombin in the absence of factor XII and that the function of factor XI is simply to enhance conversion of factor IX to factor IXa resulting in enhanced thrombin generation on the platelet surface.
Prion diseases
Authors: Lee C. A. , Kessler C. M. , Varon D. , Martinowitz U. , Heim M. , AGUZZI A. , WEISSMANN C.
Published: March 2003

Summary. Although the nature of the infectious agent causing prion diseases is still debated, several of its molecular characteristics have been clarified in remarkable detail. The transmissibility of bovine spongiform encephalopathy to humans dramatically highlights the need for research focused at interference with prion replication and spread, and at prevention of brain damage. Precondition to achieving these goals is a thorough understanding of prion biology, and in particular of its protein chemistry.
Tolerance induction using the Malmö treatment model 1982–1995
Authors: FREIBURGHAUS  , BERNTORP  , EKMAN  , GUNNARSSON  , KJELLBERG  , NILSSON
Published: March 2003

The ultimate goal in the treatment of haemophilia patients with inhibitors is to eradicate permanently the inhibitor and induce tolerance. Here we summarize our experience at the Malmö centre regarding tolerance induction according to the Malmö Treatment Model. The protocol includes immunoadsorption if needed, neutralization of inhibitor and replacement with factor concentrates, cyclophosphamide intravenously for 2 days (12–15 mg kg−1bw) and then orally (2–3 mg kg−1bw) for an additional 8–10 days and intravenous gammaglobulin daily at dosages of 0.4 g kg−1 bw for 5 days. This protocol has been applied in 23 haemophilia patients with inhibitors, 16 haemophilia A patients and seven haemophilia B patients. Altogether 36 attempts have been made to induce tolerance. Ten of the 16 haemophilia A (62.5%) and 6/7 patients with haemophilia B (86%) became tolerant after the treatment. The chances of success or failure are roughly equal, if the series is considered in a historical perspective. The data showed that the chances of success in tolerance induction with the Malmö protocol were best in those patients with low inhibitor titres, with relatively low historical inhibitory peak and with a long interval since the previous replacement therapy. This was especially true where no inflammatory state was present at the start or during tolerance induction. The advantage with this method compared to the high‐dose regimen is that in the successful cases tolerance can be achieved within 3–4 weeks.
Health status and satisfaction of asymptomatic HIV‐positive haemophiliacs in Kyushu, Japan
Authors: TANAKA  , HACHISUKA  , OKAZAKI  , SHIRAHATA  , OGATA
Published: March 2003

The purpose of this study was to elucidate the effects of human immunodeficiency virus (HIV) on haemophiliacs with physical functional disabilities induced by haemophilia in Kyushu, Japan. The subjects were 38 adult haemophiliacs who were selected from 129 patients registered with the North Kyushu Haemophilia Centre. They were divided into 21 asymptomatic HIV‐positive and 17 HIV‐negative adult haemophiliacs. Coagulation factor levels, modified DePalma classification, Arthritis Impact Measurement Scale 2 (AIMS 2), and a satisfaction in daily life (SDL) questionnaire were used to investigate the clinical severity of their haemophilia and arthropathy, physical functional disabilities, and satisfaction. Although there were no significant differences in the objective assessments of health status between the HIV‐positive and ‐negative haemophiliacs, the HIV‐positive haemophiliacs were significantly more dissatisfied with their social activities and mood, according to AIMS 2, and with social intercourse, job, self‐development, and social security and pension according to SDL assessment. These dissatisfactions were due to the effects of HIV, in addition to the physical functional disabilities that were caused by haemophilia. Dissatisfaction with social security and pension may be a specific feature in HIV‐positive haemophiliacs in Japan resulting from the origin of HIV infection.
Recombinant factor VIIa for patients with inhibitors to factor VIII or IX or factor VII deficiency
Authors: Scharrer
Published: March 2003

Inhibitors to factor VIII (FVIII) or IX (FIX) in patients with haemophilia A or B create a challenging problem for the treatment of these patients. Recombinant FVIIa (rFVIIa; NovoSeven®, Novo Nordisk A/S, Bagsvaerd, Denmark) is a realistic treatment option, owing to its specific mode of action and lack of immunogenicity.

This was a multicentre, open‐label, compassionate‐use trial in patients with severe haemophilia A (FVIII:C < 1%) or B (FIX:C < 1%) with inhibitors, acquired antibodies to FVIII or FIX, or FVII deficiency (FVII:C < 5%), for whom alternative therapies had failed or were contraindicated. Patients received rFVIIa treatment for life‐ or limb‐threatening bleeding episodes or for coverage during essential surgery. The mean rFVIIa dose was approximately 90 μg kg−1for haemophilia A/B and acquired inhibitor patients, and 25 μg kg−1for FVII‐deficient patients. Efficacy data for 67 treatment episodes (45 bleeding episodes, 22 surgical procedures) are presented; seven patients were treated for a concurrent serious bleeding episode and surgical procedure. At the end of treatment, rFVIIa was effective or partially effective in 85% of serious bleeding episodes. During surgery, bleeding was assessed as none or less than or equivalent to normal in 91% of surgical procedures; postoperatively, 91% of procedures were associated with no or minimal oozing.

During 60 separate treatment episodes, 26 adverse events (22 nonserious, four serious) were reported in 15 patients, during 17 bleeding episodes or surgical procedures. Only 10 were considered as having a possible, probable, or unknown relationship with rFVIIa; of these, fever (n=2) and thrombophlebitis (n=3) were the most common. There was no evidence of disseminated intravascular coagulation. In conclusion, rFVIIa is an effective, well‐tolerated treatment for serious bleeding episodes and bleeding associated with surgical procedures in patients with severe haemophilia A/B with inhibitors, acquired inhibitors, or FVII deficiency.
Teaching parents advanced clinical skills
Authors: Vidler
Published: March 2003

The management of haemophilia, in common with many other inherited, chronic disorders, has witnessed enormous advances and improvements. The quality of life enjoyed by children with haemophilia is excellent. To realize these benefits, however, expectations are placed on parents to administer intravenous treatment at home. The frequency of required treatment can be as often as alternate days.

The role of implantable venous access devices has made venous access in young children at home a realistic procedure. This is a highly complex skill for the lay person to undertake, and comprehensive parental teaching and standardized written information are necessary.

A teaching package has been created that commences with theoretical instruction and moves onto practical training. On‐going assessment is then carried out at regular intervals in the home environment.

Not only does this package provide a formal framework for instruction, it also facilitates emotional support for both the child and parents, which can be given in a planned manner.

Nurses are professionally accountable for the information and teaching they give. This package documents the process of training undertaken and standardizes the level of information given. Thereby providing reassurance to nurses that they have fulfilled the professional requirements placed on them.

Currently, there is no other source of information about implantable venous access devices for the lay carer. This package could be of value in other chronic conditions that incorporate an element of intravenous home care.
Guidelines on replacement therapy for haemophilia and inherited coagulation disorders in Italy
Authors: Santagostino  , Mannucci  , Bianchi Bonomi
Published: March 2003

In the last years, the availability in Italy of technologically advanced products for replacement therapy has produced significant changes in the management of haemophilia and of hereditary bleeding disorders in general. With the aim of a uniform approach to treatment, the Italian Association of Haemophilia Centres express in these guidelines a consensus on therapeutic strategies designed to ensure the highest degree of safety and efficacy for the treatment of inherited coagulopathies. The guidelines provide specific recommendations for the choice of the product according to updated scientific evidence, and advice on optimal dosages for the treatment of rare bleeding disorders. The system for haemophilia care and funding in Italy is briefly described.
Adverse events during use of intranasal desmopressin acetate for haemophilia A and von Willebrand disease: a case report and review of 40 patients
Authors: Dunn  , Powers  , Ribeiro  , Rickles  , Abshire
Published: March 2003

We report our experience with the incidence of adverse events during the use of Stimate® brand intranasal desmopressin acetate (IN DDAVP) for patients with haemophilia A (HA) or von Willebrand disease (vWD) after noting two severe adverse events in one adult patient.

All patients with documented vWD (type 1 or 2 A) or haemophilia A (mild, moderate or symptomatic carrier) from the Emory Comprehensive Hemophilia Center who had IN DDAVP challenge testing or were using Stimate® for treatment of bleeding were evaluated for adverse events by patient report or nursing observation of clinical signs and symptoms.

Forty patients were studied. Sixty‐eight per cent (27/40) experienced clinical signs and/or symptoms. The majority of these symptoms were mild, however several patients reported moderate to severe side‐effects and one adult patient required medical intervention for symptomatic hyponatraemia.

In our experience, two‐thirds of patients tested experienced adverse signs and/or symptoms with the use of Stimate®; considerably higher than that reported from preliminary results in the literature. Young age did not correlate positively with adverse reactions. Severe adverse events requiring medical intervention were rare, however symptoms such as moderate to severe headache, nausea, vomiting and weakness may necessitate evaluation for hyponatraemia. This is the first report of symptomatic hyponatraemia in an adult patient with recommended dosing of Stimate®. Side‐effects may be minimized if patients adhere to instructions regarding fluid intake and composition while using IN DDAVP.
Sensitivity of the reaction time of the resonance thrombogram for factor VIII:C and factor IX deficiencies in the blood of dogs with haemophilia A or B
Authors: Mischke
Published: March 2003

The sensitivity of the reaction time of the resonance thrombogram (RTG‐r) was examined for two instruments based on 105 canine samples with a reduced factor VIII:C activity and 26 samples with a reduced factor IX activity. These samples were taken from dogs suffering from haemophilia A (n=18) or B (n=3) before and at different times after the substitution therapy with fresh frozen plasma. The RTG‐r sensitivity was low; with reference to the total of all examined samples, it was between 0.39 and 0.65 for the factor VIII:C activity and between 0.46 and 0.62 for the factor IX activity, depending on the instrument and the testing procedure used. Low sensitivity was shown especially by the fact that even some of the samples with a factor VIII:C activity < 5% showed false negative results. Moreover, the correlation found between RTG‐r and factor VIII:C activity (Spearman’s rank correlation coefficient, rS=–0.556 to –0.700) as well as between factor IX activity and RTG‐r (rS=–0.380 to –0.612) was only moderate. The low sensitivity of the RTG towards a reduced activity of the haemophilia factors VIII:C and IX contradicts the exclusive use of the RTG for monitoring haemophilic dogs as well as a global screening test for the haemostasis of dogs.
Safety and efficacy of solvent/detergent‐treated antihaemophilic factor with an added 80 °C terminal dry heat treatment in patients with haemophilia A
Authors: Powell J. S. , Bush M. , Harrison J. , Abildgaard C. , Vosburgh E. , Thompson A. R. , Hurst D.
Published: March 2003

Plasma‐derived factor VIII concentrates remain an important resource for haemophilia A patients. To improve the safety of these preparations, various methods of viral removal and inactivation have been used that are designed to eliminate both enveloped and non‐enveloped viruses. There have been rare reports that some viral inactivation processes altered the immunogenicity of some concentrates, leading to the development of factor VIII inhibitors in previously treated haemophilia A patients. This study evaluated the safety, efficacy and lack of neo‐antigenicity of a highly purified factor VIII preparation which undergoes both solvent/detergent treatment and final dry heat treatment at 80 °C for 72 h. The study included: (i) a single blind, single‐dose crossover pharmacokinetic study in 18 previously treated patients, comparing sibling lots of the unheated preparation (Koate®‐HP) and the heat‐treated preparation (Koate®‐DVI), and (ii) an extended home treatment programme for 36 patients at two haemophilia treatment centres primarily to assess immunogenicity. Clinical parameters were assessed at regular intervals. The results confirm that Koate®‐HP and Koate®‐DVI are bioequivalent, and that Koate®‐DVI is safe and efficacious for treatment of acute bleeding episodes and for surgery. Furthermore, the heat‐treated preparation is not associated with the development of inhibitors in previously treated patients.
Disappearance of factor VIII autoantibodies preceding autoimmune haemolytic anaemia
Authors: Van Den Brink E. N. , Turenhout E. A. M. , Wijn‐Maas E. C. M. , Van Der Meer F. J. M. , Voorberg J. , Bosch L. J.
Published: March 2003

We describe a previously healthy woman who at the age of 44 years developed a factor VIII inhibitor, that over the years increased to a maximum level of 3600 Bethesda units (BU) mL–1 in 1978. The epitope specificity of the factor VIII inhibitor was investigated and antibodies directed against the A2 and C2 domains of factor VIII were detected. The majority of these antibodies were of subclass IgG4. Over the years, the inhibitor titre gradually decreased and in 1989, the inhibitor could no longer be detected. Shortly after, the patient developed autoimmune haemolytic anaemia. A possible link between the disappearance of factor VIII inhibitors and the development of other autoantibodies may be explained by concomitant development of anti‐idiotypic antibodies that neutralize the activity of factor VIII inhibitors. We were unable to detect anti‐idiotypic antibodies, which could explain the decline in factor VIII inhibitor titre in this patient.
The utility of the Dutch Arthritis Impact Measurement Scales 2 for assessing health status in individuals with haemophilia: a pilot study
Authors: Van Meeteren N. L. U. , Strato I. H. M. , Van Veldhoven N. H. M. J. , De Kleijn P. , Van Den Berg H. M. , Helders P. J. M.
Published: March 2003

The aim of this pilot study was to examine the usefulness of the Dutch version of the Arthritis Impact Measurement Scales 2 (D‐AIMS2)in assessing the health status of Dutch individuals with haemophilia. Sixty‐eight individuals with mild, moderate, and severe haemophilia attending our clinic for their annual check‐up participated. They first completed the Canadian Occupational Performance Measure (COPM). The D‐AIMS2 was filled in afterwards at home. With the COPM, individuals rated their specific problematic activities of daily life (ADL), as well as the severity and importance of each problem. The D‐AIMS2 is a comprehensive, self‐administered questionnaire that evaluates functional health status. Fifty‐seven individuals completed and returned the D‐AIMS2. Reliability analysis demonstrated good internal consistency for the scales (Cronbach’s α=0.76–1.00), as well as for the components (α=0.80–0.88), except for the component ‘social interaction’ (α=0.44). Criterion validity of the D‐AIMS2 was assessed by comparison with COPM outcomes; 80% of the problematic ADLs were included in the questionnaire, 20% were missing. Correlations between the D‐AIMS2 components ‘physical health’ and ‘symptoms’ with predicted scores of those individuals by a highly experienced physiotherapist (r=0.63 and 0.53, respectively) substantiated its concurrent validity. Based on these results we concluded that the D‐AIMS2, with minor adjustments, can be an appropriate tool for assessing the health status of Dutch haemophilia patients.
Frequency of inhibitor development in severe haemophilia A children treated with cryoprecipitate and low‐dose immune tolerance induction
Authors: El Alfy M. S. , Tantawy A. A. G. , Ahmed M. H. , Abdin I. A.
Published: March 2003

The frequency of factor VIII inhibitor development was evaluated in a hundred severe haemophilia A patients < 18 years of age (mean 10.4 ± 5.1 years); 25 were previously untreated patients (PUPs), with a mean age of 11.2 ± 2.9 months. All were followed up for 3 years from December 1996. Immune tolerance (IT) was induced with low‐dose factor VIII (FVIII); 25–50 IU kg–1 every other day for the 10 haemophiliacs who developed persistent inhibitors. The incidence of inhibitors for PUPs was 3/25 (12%; 95% confidence interval [CI], 0.7–24.7%) and were detected after 4, 15 and 20 exposure days (mean 13 ± 8.2 days; 95% CI, 3.7–22.2%). Children with maximum inhibitor levels of > 40 Bethesda units (BU) per mL (n=4) received IT therapy as 25 U kg–1 FVIII in the form of cryoprecipitate every other day for 1–4 months (mean 2.4 ± 1.6 months; 95% CI, 0.8–3.9%), which was successful in all of them. FVIII (50 U kg–1) was given every other day for six patients with maximum inhibitor level > 40 BU mL–1 for 3–9 months (mean 5.4 ± 3.2 months; 95% CI, 2.9 –7.9%) with success in 4/6 (66.6%; 95% CI, 28.8–104.3%). Patients who showed a good IT response had an inhibitor level ≤ 30 BU mL–1, were ≤ 9 years of age at inhibitor development with few exposure days to FVIII and had an early immune tolerance. In conclusion, inhibitor development in severe haemophilia A children exclusively treated with cryoprecipitate is low. Early low‐dose IT induction for high responders may be achieved successfully if inhibitor level is ≤ 50 BU mL–1.
The pelvi‐femoral incomplete bone bridge in a patient with mild haemophilia
Authors: Aydogdu S. , Memis A. , Kavakli K. , Balkan C.
Published: March 2003

A 15‐year‐old boy with mild haemophilia who regularly participates in contact sports presented with right hip pain radiating to the groin and buttock areas and difficulty in walking. Conventional radiography disclosed a heterotopic new bone formation in the adductor region. The reformatted and three‐dimensional reconstructed images of computerized tomography (CT) scans detailed an incomplete pelvi‐femoral bone bridge formation in the quadratus femoris muscle, which was located very close to the sciatic nerve but did not cause any clinical symptoms. Postural exercises and clinical survey were selected as the primary treatment.
Blunt abdominal trauma with delayed rupture of splenic haematoma in a haemophiliac patient
Authors: Samaiya A. , Gupta S. , Chumber S. , Kashyap R. , Dewanda N. K. , Vashisht S. , Choudhry V. P.
Published: March 2003

A 13‐year‐old haemophilia A patient presented with pain in the abdomen, 4 days after a blunt abdominal trauma. The computed tomography scan of the abdomen showed a large splenic haematoma. The patient was initially managed with factor VIII replacement therapy, but 4 weeks later he had a delayed rupture of the splenic haematoma with haemoperitoneum and shock. An elective splenectomy under factor VIII therapy was successfully performed.
Pseudotumour in von Willebrand disease
Authors: Wexler S. , Edgar M. , Thomas A. , Learmonth I. , Scott G.
Published: March 2003

Pseudotumour is a rare complication of haemophilia; it has previously been reported in patients with moderate or severe haemophilia and rarely in mild disease. We report a case of a proximal pseudotumour occurring in a 36‐year‐old patient with mild von Willebrand disease (vWD) who made a good recovery with conservative management. Surgery has been advocated as the optimal treatment for proximal pseudotumours due to the risk of continued bleeding and progression. However, in mild haemophilia or vWD, where the risk of spontaneous bleeds is low, conservative management may be an appropriate alternative.
Rationale for the use of high dose rFVIIa in a high‐titre inhibitor patient with haemophilia B during major orthopaedic procedures
Authors: Cooper H. A. , Jones C. P. , Campion E. , Roberts H. R. , Hedner U.
Published: March 2003

Inhibitor development is a serious complication in patients with haemophilia A and B. Historically, a lack of optimal therapies and factor products for treating inhibitor patients resulted in many patients developing chronic haemophilic arthropathies and flexion contractures of the involved joints. The introduction of immune‐tolerance protocols to eradicate high‐titre inhibitors has greatly diminished the incidence of these types of complications but as in the case reported here, immune tolerance is not always successful. Various elective surgical procedures were often delayed or not even considered in patients with inhibitor because of the variability in achieving adequate haemostasis and the thrombotic risks involved with the use of activated prothrombin‐complex concentrates (APCCs) over extended periods of time. The development of recombinant factor VIIa (rFVIIa; NovoSevenTM) and its demonstrated safety and efficacy in treating inhibitor patients has opened new possibilities for addressing severe arthropathy with flexion contracture. This case report demonstrates that the use of rFVIIa in such a situation must include dosing flexibility that is both patient‐specific and related to the potential for bleeding; the ability to maintain clinical haemostasis with a prophylactic dose of rFVIIa given as little as once daily; and the capacity for higher doses of rFVIIa, particularly in children because their kinetic profiles differ from adults.
Use of Protein‐A column and porcine factor VIII
Authors: Rivard G.E.
Published: March 2003

Extracorporeal immunoadsorption of factor VIII (FVIII) antibodies using Sepharose matrix columns coupled with staphylococcal Protein‐A was reported two decades ago. The efficiency of this technique for removing FVIII antibodies of the IgG subtypes was clearly demonstrated. The recent widespread use of a variety of apheresis techniques for the management of a multitude of haematological and oncological conditions has made this technology more accessible and affordable. For the treatment of patients with FVIII inhibitors, the use of porcine FVIII makes it possible to control haemostasis with a therapeutic product for which in vitro testing can help predict the in vivo efficacy. By lowering the level of FVIII inhibitors, immunoadsorption can make the use of pFVIII concentrate possible in situations otherwise untreatable with FVIII preparations. Moreover, lowering the level of FVIII inhibitors by immunoadsorption allows adequate haemostasis to be achieved with much lower doses of FVIII leading to significant saving. Our preliminary data suggest that immunoadsorption combined with the use of pFVIII should be considered early in the treatment plan for controlling haemostasis in patients with FVIII inhibitors.
Porcine factor VIII: pharmacoeconomics of inhibitor therapy
Authors: Ewenstein B.M. , Avorn J. , Putnam K.G. , Bohn R.L.
Published: March 2003

The treatment of acquired haemophilia is characteristically exceedingly expensive and thus a cost‐benefit analysis of the several available treatment strategies is urgently needed. To address this issue, decision‐analysis techniques were used to construct a cost‐minimization model to compare the cost of treatment with porcine factor VIII (pFVIII), human FVIII (hFVIII) or an activated prothrombin complex concentrate (APCC). This model was based upon the results of a comprehensive literature search of all relevant clinical studies and case series. To supplement these data, a panel of haemophilia specialists was presented with a clinical scenario describing an acquired haemophilia patient with an acute haemorrhage in whom the human and porcine inhibitor titres were initially unknown. Based on this scenario and on their own clinical experience, the expert panel assessed the applicability of the model as initially constructed, assigned probabilities of success to each treatment and recommended appropriate initial dosing and follow‐up regimens. This information was incorporated into the model and a simulation was conducted from which the costs of care were calculated. Sensitivity analyses were then conducted on all parameters. The results of the model show that treatment initiated with pFVIII would be more cost effective compared with treatment sequences initiated with an APCC or hFVIII, respectively. The model indicates that initial treatment with pFVIII in this scenario may be the preferred strategy clinically, as well as on economic grounds.
Orthopaedic surgery in haemophilic patients with inhibitors: an overview
Authors: HVID I. , RODRIGUEZ‐MERCHAN E. C.
Published: March 2003

Our experience and a review of the literature on inhibitors have shown that, with the availability of recombinant factor VIIa (rFVIIa), haemophilic patients with high inhibitor titres requiring elective orthopaedic surgery can undergo such surgery with a high expectation of success. The advent of rFVIIa has made major elective orthopaedic surgery possible in haemophilic patients with high‐titre inhibitors, resulting in an improved quality of life. Recombinant FVIIa appears to be an efficient haemostatic product for surgery in patients suffering from haemophilia A and B with inhibitors. The series of major elective orthopaedic surgical procedures using rFVIIa (n=53) is the largest ever reported in haemophilic patients with inhibitors, despite the long‐standing presence of other treatment modalities, such as high‐dose human factor VIII (FVIII), porcine FVIII (n=8), and prothrombin complex concentrates/activated prothrombin complex concentrates (n=9). Thorough analysis of each case as part of a multidisciplinary team will allow us to perform elective orthopaedic procedures in patients with inhibitors.
Menorrhagia from a haematologist's point of view. Part II: management
Authors: SIEGEL J. E. , KOUIDES P. A.
Published: March 2003

The management of menorrhagia has until recently been the domain of the gynaecologist. As haematologists, we are now addressing the issue of optimal management of menorrhagia in our patients with bleeding disorders. Addressing three life periods, the menarche, reproductive years, and postchildbearing years, this review will discuss the use of oral contraceptive agents, antifibrinolytics, non‐steroidal anti‐inflammatory drugs, intranasal DDAVP and the new levonorgestrel‐impregnated IUD. Management of specific bleeding disorders will also be reviewed for von Willebrand disease, haemophilia A and B carriers, women with factor XI deficiency and PAI‐1 deficiency.
Pathophysiology of inhibitors to factor VIII in patients with haemophilia A
Authors: LACROIX‐DESMAZES S. , MISRA N. , BAYRY J. , ARTAUD C. , DRAYTON B. , KAVERI S. V. , KAZATCHKINE M. D.
Published: March 2003

The occurrence of factor VIII (FVIII) inhibitors is one of the major complications of the treatment of haemophilia A. We present this review as a description of the major players of the antiFVIII immune response, with particular emphasis on the nature and properties of the different antiFVIII antibodies, their mechanisms of action in inhibiting FVIII activity, their potential neutralization by anti‐idiotypic antibodies, and the importance of the T cell in participating in the induction of FVIII inhibitors. We briefly conclude on the avenues that remain to be explored in order to establish efficient therapeutic approaches aimed at eliminating FVIII inhibitors in patients with haemophilia A.
Inhibitors: resolving diagnostic and therapeutic dilemmas
Authors: DIMICHELE D.
Published: March 2003

The good quality of life now anticipated by individuals with haemophilia A and B can be drastically altered by the unpredictable development of an inhibitor, a polyclonal high‐affinity IgG antibody directed against factor VIII or IX. This paper discusses our current state of knowledge about inhibitors within the context of: (1) the extent and nature of the problem, including its incidence and prevalence, diagnostic options, and the characteristics of the individual immunologic response; (2) possible underlying aetiological factors, both inherited and situational; and (3) existing and future therapeutic options for both the interim treatment of haemorrhage and the ultimate restoration of normal clotting factor recovery and survival. Current and future strategies for immune tolerisation are also reviewed.
Experience of prophylaxis treatment in children with severe haemophilia
Authors: YEE T. T. , BEETON K. , GRIFFIOEN A. , HARRINGTON C. , MINERS A. , LEE C. A. , BROWN S. A.
Published: March 2003

The practice of prophylactic treatment of boys with severe haemophilia has been evaluated in our centre. Prophylaxis was started at the median age of 3.7 years (range 0.4–12.7 years) in 38/41 children (93%) under 17 years of age. Median follow‐up was 4.1 years (range 0.4–12.7 years). The criteria of primary prophylaxis according to the definition by the European Paediatric Network of Haemophilia Management was fulfilled by 9/38 (24%). Although a majority [76%, 29/38] of the children started prophylaxis after a median number of joint bleeds of 3.5, 70% of the children in this group had clinical joint scores of 0. Intravenous catheter insertion was required at a median age of 15.5 months (range 5–36 months) in 21% of the children, resulting in a catheter infection rate of 1.74 per 1000 catheter days. None developed an inhibitor on prophylaxis and three patients who had low‐titre inhibitors (< 5 Bethesda units) prior to prophylaxis had undetectable inhibitors after prophylaxis. The home‐treatment training programme required considerable time and cost. As a result, 87% of the children used peripheral venous access and hospital visits declined as prophylaxis became established. Parents' incentives for prophylaxis were that the children undertook many physical activities and sports previously not recommended, there was less parental anxiety and an overall improvement in the quality of life for the whole family.
Linking medicine and economics: health economics and quality of life in haemophilia care
Authors: Schramm W. , Berger K.
Published: March 2003

Summary.  Scarce resources in healthcare are a fact of life everywhere. Providing optimal healthcare for haemophilia means delivering the best possible clinical outcomes at an acceptable total cost, however that is defined by individual societies. Health economics helps us to do this. So far, economic evaluation has enhanced our understanding of some of the economic implications of haemophilia and has provided some guidance on the way forward to optimize efficient allocation of resources for this condition. Further advances and consensus on evaluation methods and standards for the economics of haemophilia are required, however. This need will continue in the face of new, more sophisticated and therefore more costly haemophilia therapies.
Radial artery mycotic pseudoaneurysm in a haemophiliac: a potentially fatal complication of arterial catheterization
Authors: Harkin D. W. , Connolly D. , Chandrasekar R. , Anderson M. , Blair P. H. , Hood J. M. , Barros D'Sa A. A. B.
Published: March 2003

Summary.  We present a case of radial artery pseudoaneurysm formation in a haemophiliac patient, which developed after radial artery cannulation. Haematologists and anaesthetists should be aware of this potentially fatal condition.
Cost related to replacement therapy during hospitalization in haemophiliacs with or without inhibitors: experience of six French haemophilia centres
Authors: Gautier P. , D'Alche‐Gautier M. J. , Coatmelec B. , Marques‐Verdier A. , Bertrand M. A. , Dieval J. , Berthier A. M.
Published: March 2003

Summary.  Replacement therapy in haemophiliacs has a major economic impact on health establishments. We assessed in this prospective study the cost of clotting factor concentrate therapy for haemophilia A or B patients. We compared the overall costs of treated patients with or without inhibitors. In six French haemophilia centres, 278 consecutive hospitalizations were collected and analysed between June 97 and June 99. Haemophilia must be considered as the main cost factor during hospitalization. The severity of bleeds and surgical procedures increase the total cost. Furthermore, the daily and total costs are closely linked to the presence or the absence of inhibitors. This study should enable the hospital administration to evaluate the necessary resources to the clotting factor therapy in haemophiliacs with or without inhibitors during hospitalization.
DDAVP nasal spray for treatment of menorrhagia in women with inherited bleeding disorders: a randomized placebo‐controlled crossover study
Authors: Kadir R. A. , Lee C. A. , Sabin C. A. , Pollard D. , Economides D. L.
Published: March 2003

Summary. To assess DDAVP (1‐deamino‐8‐d‐arginine vasopressin; desmopressin) nasal spray in the management of menorrhagia in patients with inherited bleeding disorders, 39 women (aged 18–50 years) with menorrhagia were recruited and were randomized to start 2 months' therapy with placebo or DDAVP (300 µg) spray in a double‐blind crossover study. Twenty‐eight and 24 completed first and second period of treatment, respectively. Menstrual loss was assessed using the pictorial blood assessment chart (PBAC) during each treatment period. The main outcome measure was comparison of PBAC scores following DDAVP and placebo treatments. The safety of DDAVP spray was also assessed by monitoring side‐effects. Overall, PBAC scores were significantly lower in the second treatment period than the first (P = 0.01). After adjusting for this differences, mean PBAC scores were slightly lower (mean difference 8; 95% confidence interval of − 15.5 to 31.6) in women receiving DDAVP than when receiving placebo, although this difference was not statistically significant (P = 0.51). In conclusion, although there was an indication that menstrual bleeding was less heavy when women received DDAVP than when receiving placebo, the small sample size meant that this difference was not significant.
Sequential treatment with bolus and continuous infusion of recombinant factor VIIa for hip arthroplasty in a patient with haemophilia A and inhibitor
Authors: Perez R. , Martinez M. L. , Piñero A. , Sosa R.
Published: March 2003

Summary. We describe a total arthroplasty of the hip in a 40‐year‐old male patient with haemophilia A and a high‐titre inhibitor to factor VIII, treated with rFVIIa. The patient received sequential therapy first as bolus in the early postoperative phase in order to obtain appropriate haemostasis and then as continuous infusion with lower doses to avoid frequent episodes of bleeding without a higher consumption of product. After an initial dose of 150 µg kg−1 for the first five days after surgery, we used bolus doses of 120–90 µg kg−1 every 2.5–3 h, achieving plasma FVII:C levels above 40 U mL−1. We then continued with continuous infusion at decreasing doses 15–7 µg kg−1 h−1 for 12 days (FVII:C 19–7 U mL−1). There were no bleeding complications nor signs of clotting activity. The rehabilitation programme was continued without prophylactic treatment. The total consumption of rFVIIa was 6.3 mg kg−1, implying a saving of at least 30% of the product with respect to previous publications.
A high‐purity double virus inactivated FVIII/vWF concentrate (Immunate) in the successful treatment of patients with von Willebrand disease
Authors: Auerswald G , Eberspächer B , Eifrid B , Engl W , Günther C , Koksch M , Kreuz W , Nitz A , Pindur G , Scharrer I , Scheel H , Schrieber JD , Siekmann J , Turecek PL , Wolf H‐H
Published: March 2003

Patients with severe forms of von Willebrand disease (vWD) most frequently require substitution of both factor VIII and von Willebrand factor (vWF). Immunate is a high‐purity, double‐virus inactivated FVIII/vWF concentrate derived from human plasma. The clinical efficacy of Immunate concerning the management of acute bleeding episodes and surgical prophylaxis in patients with von Willebrand disease (vWD) is being investigated and documented in a prospective, phase III, open‐label, single‐armed multicenter trial. Data on its pharmacokinetics are collected, and the product's safety with respect to adverse experiences is monitored.
Physical training increases isometric muscular strength and proprioceptive performance in haemophilic subjects
Authors: Hilberg T. , Herbsleb M. , Puta C. , Gabriel H. H. W. , Schramm W.
Published: March 2003

Summary. Sufficient muscular strength and proprioception lessen the risk of joint damage, however, both are impaired in haemophilic subjects. The aim of the study was to investigate proprioceptive performance and isometric muscular strength before and after a specialized training in haemophilic subjects (H) compared with two groups of control subjects (C). Nine subjects with severe haemophilia A, and eight ‘active’ C (AC) without haemophilia took part in a physical training programme over a 6‐month period. Eleven ‘passive’ C (PC) were requested to avoid any additional training during this period. Proprioceptive performance and isometric strength were determined before and after the training programme. The maximal isometric muscular strength in the legs, bilaterally measured by knee extensor (and leg press) was increased (P < 0.05) by 34% (29%) after training in the H and by 20% (28%) in the AC groups while remaining unchanged in the PC group. The performance in one‐leg‐stand tests after training was increased (P < 0.05) in the H and AC groups. An improvement of angle reproduction of 20° and 40° (P < 0.05) in the H compared with the PC groups was seen in the tests. Quantitative sensory testing by the tuning fork showed an increase (P < 0.05) in performance of both H and AC groups. The results of the present study confirm that specific sports therapy focused on proprioceptive function and accompanied by gentle strength training with low resistance and 20–25 repetitions is able to increase proprioceptive performance and muscular strength with a minimal stress to the joints. It is strongly recommended that specialized sports therapy be included as an integral component of the complete treatment regimen of haemophilic subjects.
Intra‐articular rifamycin in haemophilic arthropathy
Authors: Radossi P. , Baggio R. , Petris U. , Biasi E. De , Risato R. , Davoli P. G. , Tagariello G.
Published: March 2003

Synoviorthesis is the intra‐articular injection of chemical or radioactive substances able to produce fibrosis of hypertrophied synovium, which has proved effective in the treatment of chronic haemophilic synovitis. Between September 1999 and October 2001 we treated 28 outpatients (25 with haemophilia A, three with haemophilia B). Our treatment was focused on pain and functional limitation of joints. A schedule was adopted to treat each joint using intra‐articular rifamycin once a week, repeated five times. Patients were covered with factor replacement on demand. Oral analgesia was offered as required because of acute but transient painful inflammatory reaction. Their median age was 34 years (range 15–60 years). The indication for synoviorthesis was chronic synovitis characterized by recurrent haemarthroses, persistent pain and limited range of motion (ROM). Thirty‐five joints were treated with a total of 169 injections, including six joints (20%) in patients with inhibitors. In five patients two joints were treated in the same session. Thirty procedures were completed: 24 (80%) were considered effective (as excellent or good), while six were considered insufficient (20%). Pain was reduced in 96% of cases and in 70% the ROM was improved. In our experience intra‐articular infiltration with rifamycin appears to be effective in reducing joint pain and in improving the ROM. The procedure presents a low risk of bleeding, can be used for patients with inhibitors and multiple joints can be treated without any additional cost.
The safety and efficacy of B‐domain deleted recombinant factor VIII concentrate in patients with severe haemophilia A
Authors: Lusher J. M. , Lee C. A. , Kessler C. M. , Bedrosian C. L. ,   for the ReFacto Phase 3 Study Group
Published: March 2003

Background: B‐domain‐deleted recombinant factor VIII (BDDrFVIII) was developed when the B‐domain was found to be redundant for maintaining haemostasis. This allows formulation of the final product without albumin added as a stabilizer.

Methods: Three multicentre clinical studies and one pharmacokinetic study were conducted in 218 patients to evaluate the safety and haemostatic efficacy of BDDrFVIII.

Results: Previously treated patients (n = 113; median duration, 1711 days; median exposure days, 385; total 98 096 287 IU infused) rated 97–99% of all infusions as good or excellent efficacy. FVIII inhibitor was noted in one patient in the previously treated patient cohort after 113 exposure days. Among 101 previously untreated patients, responses to BDDrFVIII were rated as excellent or good in 92–95% of infusions (median duration, 1413 days; median exposure days, 148; total 12 636 458 IU infused). Thirty‐two previously untreated patients developed inhibitors after a median duration of 12 exposure days (range, 3–49). Sixteen of 32 (50%) patients had low levels (≤ 5 Bethesda units) and 16 had high levels of inhibitors. Inhibitors disappeared in six of 14 (43%) of the high‐level and six of eight (75%) of the low‐level patients who underwent immune tolerance induction therapy. A total of 42 patients underwent surgery and the overall efficacy of BDDrFVIII was rated as excellent or good for 99.6% of infusions.

Conclusions: The results of these clinical studies indicate that BBDrFVIII is safe and effective and has haemostatic activity similar to that of full‐length FVIII concentrates.
An evaluation of the stability of factor VIII inhibitors in plasma and plasma dried on filter paper discs stored at room temperature
Authors: Winikoff R. , Boulanger A. , St Louis J. , Lacroix S. , Rivard G.‐É.
Published: March 2003

Summary. The transportation of plasma specimens to specialized haemophilia centre laboratories for anti‐factor VIII inhibitor titre determination is often necessary. The routine method of transporting frozen specimens on dry ice is limited by its cost and need for special handling. The present study was undertaken to evaluate the effect of storing specimens at room temperature on the FVIII inhibitor titre determinations using the Bethesda assay. Specimens stored both in liquid phase as well as adsorbed onto filter paper discs were studied. The results of the present study demonstrate that plasma specimens stored for up to 2 weeks at room temperature, either in liquid phase or adsorbed onto filter paper, yield equivalent measures of FVIII inhibitor titres using the Bethesda assay to plasma specimens stored frozen at −70 °C. Plasma specimens dried on filter paper discs and stored at room temperature offers a reliable, more practical and less expensive alternative to frozen plasma as a means of transport to specialized referral laboratories for analysis of anti‐FVIII titres.
Distribution of edaphic‐endemic butterflies in the Sierra Nevada of California
Authors: Gervais* Bruce R. , Shapiro Arthur M.
Published: March 2003

Five edaphically‐restricted or ‐endemic butterflies, mostly associated with serpentine, are shown to be distributed in the western foothills of the Sierra Nevada in addition to their previously documented areas of occupancy in the California North Coast Ranges. Two species are absolutely limited by the edaphic restriction of their host plants, while the other three seemingly are not. The controversies concerning the origins of serpentine endemism in plants apply to butterflies as well. Long‐term relictualism can presumably apply only at the metapopulation level, not the local population level, due to the frequency of fire in these habitats. Development and habitat‐conversion trends pose a high risk to the long‐term survival of these species in the Sierra Nevada.