bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical management of patients with von Willebrand’s disease with a VHP vWF concentrate: the French experience
Authors: Goudemand  , Negrier  , Ounnoughene  , Sultan
Published: March 2003

Part of the French clinical experience using the solvent/detergent (S/D) treated VHP von Willebrand factor (vWF) concentrate (LFB, Les Ulis, France) characterized by a high vWF:RCoF specific activity and a low factor VIII (FVIII) content is reported. Since 1989 this concentrate has been routinely used in clinical practice taking into account the vWF:RCoF given by the manufacturer. Seventy‐five patients with von Willebrand disease (type 1: 42, 2 A: 11, 2B: 5, 2N: 6, 3: 4, acquired: 7) were treated on 99 occasions either to control spontaneous bleedings (15) or to prevent haemorrhagic risks associated with minor (< 5 days of treatment) (48) or major (5 days of treatment) (36) surgery including seven knee or hip‐replacements. Forty lots of concentrate were used containing 58 ± 13 U mL–1 vWF:RCoF with less than 10 units of FVIII per 100 units vWF:RCoF. Patients with type 2N were analysed separately. With the exception of gastro‐intestinal bleedings, spontaneous bleedings were generally stopped after few infusions of 40–47 U kg−1 vWF:RCoF. Patients having more than 20 U dL−1 FVIII were treated on 54 surgical occasions with one preoperative infusion (51–55 U kg−1 vWF:RCoF) which allowed an increase in FVIII concentration to a mean level of 67–88 U dL−1. Patients with less than 20 U dL−1 were either treated with two preoperative infusions of vWF, 12 or 24 h apart (11 cases) or received a FVIII injection immediately after the preoperative infusion of vWF (10 cases). During the postoperative period vWF alone (30–35 U kg−1 vWF:RCoF) allowed FVIII to be kept at a mean level of 118–138 U dL−1 not exceeding 180 U dL−1. Patients with type 2N were treated taking in account only their baseline FVIII concentration. No haemorrhagic complications occurred in any of the patients. Thus it was found to be feasible and practical to manage replacement therapy in patients with von Willebrand disease (whatever the type or the circumstances) on the basis of the vWF:RCoF activity of the concentrate.
Nonviolent (empathic) communication for health care providers
Authors: Lee C. A. , Kessler C. M. , Varon D. , Martinowitz U. , Heim M. , ROSENBERG M. , MOLHO P.
Published: March 2003

Summary. The purpose of Nonviolent or Empathic Communication Training is to facilitate the flow of information necessary for people to work cooperatively and resolve differences effectively. Such training is widely used in medical communities where the communication with patients and the cooperation between team members are of critical importance for the effectiveness of the treatment. Communication skills are of particular importance for health care providers dealing with patients having chronic diseases such as haemophilia. In addition to the difficulties inherent to the chronicity of the disease, the HIV contamination has dramatically impaired the relationships between patients and health care providers, creating a lot of pain, still alive in both parties. The purpose of this presentation is to offer to health care providers and patients some tools to deal with their feelings and restore effective, compassionate and fulfilling communication.
Advances in carrier detection in haemophilia
Authors: Lee C. A. , Kessler C. M. , Varon D. , Martinowitz U. , Heim M. , GOODEVE A. C.
Published: March 2003

Summary.Increasing worldwide use of molecular genetic analysis is enabling accurate carrier detection for the haemophilias to be made more widely available. Use of DNA polymorphisms in linkage analysis is an accurate method for carrier detection applicable to the majority of families. For those families with severe haemophilia A, the inversion mutation can be sought by most molecular genetics laboratories. For families remaining uninformative by these procedures, a range of point mutation screening techniques is available. Dedicated electrophoresis equipment is enabling use of these techniques to become more widespread.
Combined factors V and VIII deficiency — the solution
Authors: Lee C. A. , Kessler C. M. , Varon D. , Martinowitz U. , Heim M. , GINSBURG D. , NICHOLS W. C. , ZIVELIN A. , KAUFMAN R. J. , SELIGSOHN U.
Published: March 2003

Summary. Combined deficiency of coagulation factor V and factor VIII is an autosomal recessive disorder which has been observed in a number of populations around the world. However, this disease appears to be most common in the Mediterranean basin, particularly in Jews of Sephardic and Middle Eastern origin living in Israel. We have taken a positional cloning approach toward identifying the gene responsible for this disorder. We initially studied 14 affected individuals from nine unrelated Jewish families using a panel of polymorphic genetic markers spaced throughout the human genome. The combined factors V and VIII deficiency gene was mapped to a locus on the long arm of chromosome 18 with a maximal LOD score of 13.22. A detailed genetic analysis identified two distinct haplotypes among these families, suggesting two independent founders or, alternatively, a single ancient founder with a more recent split of these subpopulations. Further work to identify and characterize the gene responsible for combined factors V and VIII deficiency should provide important insights into the biosynthesis of these homologous proteins.
Use of prothrombin complex concentrates and activated prothrombin complex concentrates as prophylactic therapy in haemophilia patients with inhibitors
Authors: Leissinger
Published: March 2003

Haemophilia patients with inhibitors are treated for acute bleeding with prothrombin complex concentrates (PCCs) or activated prothrombin complex concentrates (aPCCs). Despite this therapy, patients with high‐level inhibitors are at increased risk of developing devastating joint disease. This paper examines available information that supports the study of PCCs and/or aPCCs as prophylactic therapy for haemophilia patients with inhibitors. This strategy would require that PCCs or aPCCs be administered repetitively in a dose that is sufficient to prevent haemarthrosis without causing thrombogenic events, or causing anamnestic response in inhibitor titre. PCC doses ranging from 30 to 50 U kg−1 every other day for up to 8 months have resulted in subjective improvement both in bleeding associated with target joints and in the management of chronic joint inflammation. aPCC doses as low as 50–100 U kg−1 every other day have been useful in postsurgical prophylaxis. The risk of developing a myocardial infarction or clinically relevant disseminated intravascular coagulation is linked to total dosages of either PCCs or aPCCs greater than 200 U kg−1 day−1. It is uncertain what anamnestic response would result from prophylaxis, but with typical therapy the aPCCs cause such a response in only a small percentage of patients. Based on these findings, a clinical trial of these products used in doses of 50–100 U kg−1 every other day would appear to be warranted in patients who have permanent inhibitors and frequent joint bleeding.
Psychological aspects and coping of parents with a haemophilic child: a quantitative approach
Authors: SAVIOLO‐NEGRIN  , CRISTANTE  , ZANON  , CANCLINI  , STOCCO  , GIROLAMI
Published: March 2003

Although haemophilia is a relatively rare hereditary disease, and is curable by blood products, the psychological and social problems of haemophilic patients and of their families are always serious. Anxiety for the risks of bleedings and the fear for infections transmitted by blood products cause stress and difficulty in coping with the situation. The aim of this paper is to assess resources, stress, and coping in parents with a haemophilic child. In order to measure the dimensions related to family stress and resources, social desirability, tendency to depression, and anxiety, the subjects were administered the short‐form of the Questionnaire on Resources and Stress by Friedrich et al. revised by Saviolo & Cristante, along with the Social Desirability Scale, the Beck Depression Inventory, and the Ipat Anxiety Scale. The subjects of this study were 20 couples who were the parents of haemophilic sons. We analysed how the parents perceived the behavioural characteristics of their child, the differences between mothers and fathers in the questionnaire scores, and the correlation among the considered dimensions. The results show that the parents paid great attention to the problems of their sons, but mothers were more depressed and anxious about the disease of their child.
Incidence of inhibitors in haemophilia A patients – a review of recent studies of recombinant and plasma‐derived factor VIII concentrates
Authors: Scharrer  , Bray  , Neutzling
Published: March 2003

The development of inhibitors to factor VIII or IX is the most serious complication of haemophilia therapy. While early surveys revealed inhibitor prevalences of 3.6–25%, recent studies, especially those using recombinant DNA‐derived products, have prompted speculation as to whether ultrapurified products may cause a higher incidence of inhibitors. Although studies of ultrapure rFVIII in previously treated patients have not shown an increased inhibitor risk, in previously untreated patients (PUPs) with severe haemophilia A (factor VIII < 2%), cumulative incidences of approximately 30% have been reported. The majority of these inhibitors are low responders; many have disappeared spontaneously despite continued treatment with the study product (i.e. transient inhibitors), and were most probably detected as a consequence of frequent inhibitor testing. The mutation causing haemophilia has recently been shown to be a significant risk factor for developing an inhibitor; mutations leading to the absence of endogenous factor VIII protein (for example, large multidomain deletions, nonsense mutations, isochromosomal intron 22 inversions) are associated with the highest risk of inhibitor development. Furthermore, recent prospective studies of plasma‐derived products reveal inhibitor incidences (i.e. 21–52%) that are comparable to those obtained with recombinant products. When comparing the incidences of high‐responder inhibitors (> 10 BU) among recent prospectively studied severe haemophilia A cohorts (i.e. 11–41%), differences between plasma‐derived and recombinant products cannot be discerned. New studies of either recombinant or plasma‐derived products should consider all known parameters influencing inhibitor formation, thereby facilitating meaningful comparisons of inhibitor risk.
Induction of immune tolerance with recombinant factor VIII in haemophilia A patients with inhibitors
Authors: Batlle  , López  , Brackmann  , Gaillard  , Goudemand  , Humbert  , De Moerloose  , Maass  , Mauz‐Körholz  , Sultan  , Stieltjes
Published: March 2003

We report on 11 patients (nine unrelated and a brother pair) with severe haemophilia A and factor VIII (FVIII) inhibitor, in whom immune tolerance (IIT) was induced with recombinant FVIII (r‐FVIII). Their age ranged from 11 months to 47 years. The number of exposure days (ED) at inhibitor detection varied from 11 to 130. Nine of the 11 patients were high responders [>10 Bethesda units (BU)] with peak inhibitor levels ranging from 10 to 566 BU. The other two were low responders with peak levels between 0.7 and 2 BU. Before inhibitor detection, the patients had been receiving products of various purities. The IIT regimens were very heterogeneous, and the treatment schedule varied from a short period with 50 IU kg–1 every 2 days, followed by 100 IU kg–1 every 2 days and then 220 IU kg–1 daily. The outcome was considered successful when the inhibitor level fell to 0.6 BU or lower after IIT treatment. The outcome overall was successful in nine out of 11 patients (81.8%), with the nine successful cases comprising seven of the nine high responders (77.8%) and the two low responders. Definite failure of IIT was observed in one high responder after two different IIT regimens. A second high responder is still on IIT treatment. All patients in whom IIT was successful are currently receiving r‐FVIII on demand or prophylactically at various dosages. Despite the variability of the patient characteristics and the IIT schedules, this study demonstrates that r‐FVIII represents an effective alternative for the eradication of inhibitors through IIT.
Acquired von Willebrand disease
Authors: Petrini P.
Published: March 2003

Acquired von Willebrand disease (AvWD) is a syndrome that has clinical and laboratory features similar to hereditary vWD. In contrast to the latter it occurs in patients without a family history of previous bleeding tendency.
Postoperative use of rFVIIa by continuous infusion in a haemophilic boy
Authors: LORENZO J. I. , MONTORO J. M. , AZNAR J. A.
Published: March 2003

Continuous infusion of coagulation factor concentrates has proved to be safe and effective. Because rFVIIa (NovoSeven®) is a very expensive product and very frequent doses are needed, continuous infusion is expected to be highly cost‐effective. The postoperative use of continuous infusion of rFVIIa in a haemophilic boy with a high titre FVIII inhibitor is reported. He presented with a large right knee haemarthrosis and was treated with intermittent doses of rFVIIa. After a transient improvement the haemarthrosis became worse and an open evacuation of the joint had to be made under treatment with bolus injections of rFVIIa for 3 days (120 μg kg−1 every 2 h). A previous pharmacokinetic evaluation in this patient had showed that FVIIa recovery and half‐life were less than expected. Continuous infusion of rFVIIa (20 μg kg−1h−1), with added low molecular heparin to prevent local thrombophlebitis, was started on the fourth postoperative day and maintained unchanged for 7 days. Four additional single bolus injections were given for early joint mobilization. The intervals between replacements of the pump syringes were progressively increased from 6 to 12 h and then up to 24 h. FVIIa plasma levels during continuous infusion ranged between 6.3 and 10.4 IU mL−1. Although FVIIa assays seemed to show good stability, we observed the formation of precipitates inside the syringes. The precipitates seemed to contain FVIIa. We concluded that FVIIa plasma levels of 6–10 IU mL−1 were safe and effective to prevent postoperative haemorrhage in this patient. The addition of heparin to the rFVIIa concentrates, however, may cause precipitation and should be avoided. Individual pharmacokinetic evaluation may be useful to select the appropriate initial doses, especially in young patients.
Factor XI deficiency and its management
Authors: Bolton‐Maggs
Published: March 2003

Factor XI deficiency has a more variable bleeding tendency than haemophilia A or B. Individuals with severe deficiency have only a mild bleeding tendency, which is typically provoked by surgery, but the risk of bleeding is not restricted to individuals with severe deficiency. The bleeding tendency varies between individuals with similar factor XI levels, and sometimes the bleeding tendency of an individual may vary. The reasons for this are not fully understood, although in cases of severe deficiency there is some correlation between phenotype and genotype.

Factor XI is activated by thrombin. The role of factor XI in physiological processes has become clearer since this fact was discovered, and the discovery has contributed to a revised model of blood coagulation. Factor XI deficiency occurs in all racial groups, but is particularly common in Ashkenazi Jews. The factor XI gene is 23 kilobases long. Two mutations are responsible for most factor XI deficiency in the Ashkenazi population, but a number of other mutations have now been reported in other racial groups.

Individuals with factor XI deficiency may need specific therapy for surgery, accidents, and dental extractions. Several therapies are available which include fresh frozen plasma, factor XI concentrates, fibrin glue, antifibrinolytic drugs, and desmopressin. Each has advantages and risks to be considered. Factor XI concentrate may be indicated for procedures with a significant risk of bleeding especially in younger patients with severe deficiency, but its use in older patients has been associated with thrombotic phenomena. If fresh frozen plasma is to be used it is preferable to obtain one of the virally inactivated products. Fibrin glue is a useful treatment which deserves further study.
Predicting the long‐term risk of HIV exposure by cryoprecipitate
Authors: Evatt  , Austin  , Leon  , Ruiz‐Sáez  , De Bosch
Published: March 2003

Most of the world’s haemophilia population lives in countries with few medical or financial resources. As such, they cannot easily obtain viral‐inactivated clotting product. Many patients are treated with cryoprecipitate made from locally supplied blood. The reasoning for using cryoprecipitate, instead of viral‐inactivated products, is based on an unspoken belief that because blood banks can provide reasonably safe products by using modern testing procedures, transmission of HIV and other blood‐borne viruses is rare. However, the risk of acquiring a blood‐borne infection increases with every exposure, and haemophilia patients treated with cryoprecipitate or fresh‐frozen plasma are exposed to hundreds or thousands of donors during their lifetime. The risk that a person infected with HIV will donate blood during the ‘window period’ is directly related to the incidence of HIV in the country where the donation occurs. To demonstrate the extent of this problem, we devised a model for estimating the risk that a person with haemophilia will encounter HIV‐contaminated cryoprecipitate based on the years of treatment and the underlying incidence rate of HIV among blood donors. We applied the model to two countries with different incidence rates of HIV: Venezuela and the United States. We found that a person with haemophilia who receives monthly infusions of cryoprecipitate prepared from plasma of 15 donors over a lifetime of treatment (60 years) is at significant risk of being exposed to HIV. In the United States there is a 2% risk of being exposed to HIV‐contaminated blood product, and in Venezuela, the percentage of risk is 40%. Given this degree of risk, medical care providers should carefully evaluate the use of cryoprecipitate except in emergencies or when no viral‐inactivated products are available.
Epidemiological survey of the orthopaedic status of severe haemophilia A and B patients in France
Authors: Molho  , Rolland  , Lebrun  , Dirat  , Courpied  , Croughs  , Duprat  , Sultan  ,   THE FRENCH STUDY GROUP
Published: March 2003

One hundred and 16 patients contributed to an analysis of the impact of the consequences of severe haemophilia A or B (factor levels < 2%) on orthopaedic status, resources consumed in relation to this status and resultant cost, and quality of life as perceived by the patient, using the MOS 36‐Item‐Short‐Form Health Survey (SF‐36). This French cross‐sectional study involved outpatients regularly attending a haemophilia treatment centre. Data were collected retrospectively over a period of 1 year by the physician of the haemophilia treatment centre. Patients had a mean age of 23, and consisted of 50% students, 25% salaried workers, 17.2% with no professional activity and 7.8% physically impaired; 82.8% of them had type A haemophilia. Mean pain score was 2.5 per patient for the six main joints; 7.7 for the clinical score and 18.8 for the radiological score, with a mean number of bleeds of 16.3 per year per patient. During the year prior to inclusion, and because of their orthopaedic status, 22.4% of patients were hospitalized, 76.7% attended for an outpatient visit and 76.7% required at least one special investigation; 97.4% received replacement therapy, 41.4% required treatment for joint pain and 42.2% orthopaedic equipment. The less affected dimensions were the physical function (76.8 ± 22.2) and the social relations (76.1 ± 23.1). Least good quality of life scores concerned the pain (60.2 ± 25.2), perception of general health (59.3 ± 23.1) and vitality (57.8 ± 19.5) dimensions. The age was a discriminant criterion since quality of life was better in patients of the 18–23 age group for five dimensions. Mean annual treatment costs of a patient with severe haemophilia were determined as 425 762 French francs ($73 029). Loss of production was estimated at a mean of 4609 French francs ($791) per active patient over the course of the year. Results showed indirect evidence of the usefulness of early home treatment.
Intron 22 factor VIII gene inversions in Argentine families with severe haemophilia A
Authors: De Brasi  , Candela  , Cermelj  , Slavutsky  , Larripa  , Bianco  , De Tezanos Pinto
Published: March 2003

Intron 22 factor VIII gene inversion (Inv22) is the most common mutation causing severe haemophilia A (SHA). We studied Inv22 in 34 SHA affected families by Southern blotting. Data from the familial history of the disease and the inhibitor status were also included. We found Inv22 in 41 % of SHA Argentine families (35 % with type 1 and 6 % with type 2), in close agreement with previously reported series. No significant correlation between the inheritance (familiar or sporadic disease) and the presence of inversions was found. Our population showed 24 % of families included at least one hemophiliac with inhibitor. In families positive for Inv22, 29 % of patients developed inhibitor but this increased frequency was not statistically significant. In conclusion, analysis of Inv22 in SHA patients should be used as a first line method because it provides useful and secure information for carrier detection and prenatal diagnosis in a high percentage of cases.
Bell’s palsy during interferon therapy for chronic hepatitis C infection in patients with haemorrhagic disorders
Authors: Ogundipe  , Smith
Published: March 2003

Two adult patients with life‐long severe haemorrhagic disorders commenced on interferon‐α2b therapy for chronic hepatitis C infection. Both developed Bell’s palsy several weeks after commencing therapy, They were started on steroids and, in addition, the first patient discontinued interferon‐α2b therapy while the second patient elected to continue with therapy. In both cases facial paralysis improved over the ensuing weeks. Bell’s palsy is often idiopathic but has been reported. in association with herpesviruses. It is not a recognised complication of chronic hepatitis B or C infection, or interferon‐α2b therapy. However, the interferons are associated with numerous adverse reactions including various neuropsychiatric manifestations and neurological syndromes. There are several reports of nerve palsies, including optic tract neuropathy, occurring during interferon therapy, and immune‐based mechanisms are thought to play a role in the aetiopathogenesis. No reports of Bell’s palsy in association with interferon therapy were identified in our literature search, although one possible case has been reported to the Committee of Safety in Medicine. Although Bell’s palsy in our patients may have occurred by chance, a neuropathic effect of interferon‐α2b on the facial nerve cannot be excluded and we urge physicians using interferons to be aware of this potential side‐effect.
The orthopaedic status of severe haemophiliacs in Spain
Authors: Aznar J. A. , Magallón M. , Querol F. , Gorina E. , Tusell J. M.
Published: March 2003

This paper provides an outline of the results obtained in a cross‐sectional study conducted primarily with the aim of ascertaining orthopaedic complications in a group of young severe A and B haemophiliacs, the effects which these complications have on the medical resources used with these patients, and the impact of severe haemophilia on their quality of life. Its secondary aim was to link their current orthopaedic status to the type of treatment they had received prior to the study. Eleven Spanish hospitals took part in this study, monitoring 70 severe haemophiliacs (FVIII:C <2%) without inhibitors who had a mean age of 21.6 years and a median age of 22. Retrospective data collected from birth to the conclusion of the study were used and, for certain variables, data from the last 12 months. The type of treatment given had been on‐demand treatment, together with prophylaxis of variable time periods, which in 32 cases (45.7%) were prolonged (>6 months). In 40 cases (57.1%) the patients underwent one or more periods of prophylaxis. Thirty‐three patients (47.8%) had over 1000 days of administration of factors VIII and IX. The analysis of the total study group reveal an average of 348 bleeding episodes per patient. The findings of this study revealed that 84.3% of these patients suffer from articular complaints on the Gilbert scale, and 85.7% on the Pettersson scale. In addition, pain was reported in 16.1% of the joints, the most frequently affected being the ankle joints. Twenty‐six patients (37%) had undergone orthopaedic surgery from the time of birth to the conclusion of the study. The quality of life of the severe haemophiliacs reviewed seems to have been affected. During the last 12 months, there were 216 outpatient haematological visits and 176 orthopaedic‐rehabilitation visits, as well as 12 radiological explorations and two hospitalizations. During these 12 months, medical expenditure totalled $55 473 per patient per year, the most important item being factor concentrates VIII/IX ($54 119 per patient per year). The type of treatment given to these patients (on‐demand and/or as secondary prophylaxis) was found to be incapable of preventing haemophilic arthropathy or guaranteeing an acceptable quality of life, although both the administration of coagulant factor concentrate to such patients and the financial resources dedicated to their treatment was very high. Consequently, a strategic change is to be considered for the prevention of haemophilic arthropathy, based on the introduction of replacement treatment involving continuous administration of factors VIII and IX in primary prophylaxis regimens from the first years of life.
Cardiac tamponade due to post–cardiac injury syndrome in a patient with severe haemophilia A and HIV‐1 infection
Authors: Theodossiades  , Tsevrenis  , Bellia  , Avgeropoulou  , Nomikos  , Kontopoulou‐Griva
Published: March 2003

An 18‐year‐old man with severe haemophilia A (FVIII:C < 1%) and human immunodeficiency virus 1 (HIV‐1) infection was admitted to the hospital with fever and chest pain for 7 days. Eight weeks prior to his admission he had an accident for which he underwent, at another hospital, clinical and laboratory examination that revealed bone fractures of the nose cavity, and he was given factor VIII concentrates for seven days due to nasal bleeding. On admission, chest roentgenogram showed a large cardiac silhouette and echocardiography confirmed the presence of a large quantity of pericardial fluid. A presumptive diagnosis of the post‐cardiac injury syndrome was made and he was given anti‐inflammatory drugs plus infusion of recombinant factor VIII concentrate (35 units kg–1 b.i.d.). On the seventh day he exhibited cardiac tamponade for which he underwent subxiphoid pericardiotomy with drainage of approximately 1500 mL of bloody exudate. He had an uncomplicated recovery and 10 days later he left hospital. He was given a continuous prophylactic treatment of 15 units kg–1 of recombinant FVIII every 2 days for 6 months, and 30 months after this episode the patient is free of any symptom.
Nursing roles in orthopaedic joint correction in haemophiliac patients
Authors: Kuhathong K. , Chuansumrit A. , Keorochana S. , Pornpipatpong N. , Pitakjaroen M. , Suwannurak M. , Angchaisuksiri P. , Isarangkura P.
Published: March 2003

The roles of nurses in 16 orthopaedic joint corrections of 14 haemophilia A patients (eight severe, six moderate) are described. The patients’ ages ranged from 10 to 37 years with a mean age of 17 years and 4 months. The nursing tasks could be divided into three stages. The first is preoperation, the nurse acting as care provider on a team of experts involved in planning the corrective surgery for the affected joints; and as a counsellor for preparing the patients and family members to cope with the challenging operation. The second is intraoperation, the nurse having the role of care provider, giving factor concentrate either by bolus injection (seven episodes) or continuous infusion (nine episodes). The third is postoperation, as a comprehensive care provider, giving cryoprecipitate and/or factor concentrate and monitoring bleeding doses, and as a trainer, teaching the patients how to dissolve blood components and self‐venepuncture with aseptic technique. Home treatment for early bleeding was given for 11 episodes, while 6‐month prophylaxis was given for five. The accomplishment of these different roles required good communication and nurturing skills, a well‐adjusted personality and a warm and positive attitude. The successful performance of nursing roles allows the haemophiliac patients to have a near‐normal quality of life.
Treatment of children with haemophilia in Europe: a survey of 20 centres in 16 countries
Authors: Ljung R. , Aronis‐Vournas S. , Kurnik‐Auberger K. , Van Den Berg M. , Chambost H. , Claeyssens S. , Van Geet C. , Glomstein A. , Hann I. , Hill F. , Kobelt R. , Kreuz W. , Mancuso G. , Muntean W. , Petrini P. , Rosado L. , Scheibel E. , Siimes M. , Smith O. , Tusell J.
Published: March 2003

A survey was made of the current status of treatment of haemophilic boys at 20 centres in 16 European countries and includes approximately 1500 of the estimated 6500 haemophiliacs in the participating countries. Many mild haemophiliacs are not seen, or seen infrequently, at haemophilia centres and this requires study. Nine of 18 centres provide continuous prophylaxis to 80–100% of their patients, five centres provide it to 55–80% and the remaining four centres to 15–40% of the boys. The median dose given was 6240 U kg−1 year−1 (range 3120–7800). Four centres administered only recombinant concentrates to children with severe haemophilia A, while seven centres administered recombinant concentrates to 75–90% and the remaining centres to less than 50% of the boys (two centres < 10%). When asked for the choice of concentrate for a newly diagnosed boy with severe haemophilia A, all but one centre preferred recombinant concentrate. Most boys below 6 years received concentrates via a peripheral vein but three centres preferred a central venous line for 80–100% of the boys. Thirteen of 18 centres applied home treatment to 84–100% of the boys and the remaining five centres to 57–77% of the boys.
Pharmacokinetics of recombinant factor IX in relation to age of the patient: implications for dosing in prophylaxis
Authors: Björkman S. , Shapiro A. D. , Berntorp E.
Published: March 2003

The aims of this study were to investigate possible age‐related changes in the disposition of factor IX procoagulant activity (FIX:C) after administration of recombinant factor IX (rFIX) and to translate the pharmacokinetic findings into suggestions for dosing of rFIX during prophylactic treatment of haemophilia B. Pharmacokinetic data were available from a previous study on 56 patients, aged 4–56 years (one of whom was excluded from analysis). FIX:C curves during prophylactic dosing were computer‐simulated from the single‐dose data. Clearance and volume of distribution at steady state of FIX:C increased linearly with body weight of the patients, consequently increasing during childhood and adolescence but remaining fairly constant during adulthood. The terminal half‐life of FIX:C showed no correlation with age, while in vivo recovery (in U dL–1 per U kg–1 given) tended to increase. Computer‐predicted trough levels of exogenous FIX:C during repeated doses of rFIX (50 U kg–1) and, conversely, doses (in U kg–1) needed to maintain a 1‐U dL–1 trough level showed little or no dependence on age. There was considerable interindividual variation in disposition and required doses of rFIX, emphasizing the need for individual dose titration. Dosing of rFIX according to lean body mass instead of body weight did not reduce this variability. During prophylaxis a 1‐U dL–1 trough level can normally be maintained by dosing every 2–3 days, the former schedule resulting in, on average, a 45% lower consumption of rFIX.
Immune tolerance treatment in haemophilia patients with inhibitors: the Spanish Registry
Authors: Haya S. , LÓpez M. F. , Aznar J. A. , Batlle J. ,   THE SPANISH IMMUNE TOLERANCE GROUP
Published: March 2003

We present a retrospective study of immune tolerance treatment (ITT) carried out in 42 Spanish haemophiliac patients. Most of the patients were high responders (39/42), with a median maximum titre of 67 Bethesda units (BU) (range 6–2984). The median inhibitor titre at the start the ITT was 11 BU (range 1–256 BU) and the median age of the patients was 7 years (range 0–57). The mean factor dosage was 140 IU kg bodyweight−1 day−1 (range 25–500). In most of the ITTs, plasma‐derived factor concentrate of intermediate and high purity was used. The inhibitor was eradicated in 26/38 (68%) of the patients who completed the treatment and two patients changed their status from high to low responders. Multivariate logistic regression analysis showed that three significant variables were associated with the highest probability of success: (i) the use of low factor doses for ITT (≤ 100 IU kg−1 day−1; P=0.0106; 95% CI 0.000289–0.342); (ii) a titre of < 10 BU at start of ITT (P=0.0286; 95% CI 0.00253–0.7189) and (iii) a lower maximum titre (P=0.0214; 95% CI 0.98–0.9994).
Laboratory diagnosis of von Willebrand disorder (vWD) and monitoring of DDAVP therapy: efficacy of the PFA‐100® and vWF:CBA as combined diagnostic strategies
Authors: Favaloro E. J. , Kershaw G. , Bukuya M. , Hertzberg M. , Koutts J.
Published: March 2003

We have coevaluated a combination of test processes for diagnosing von Willebrand disease (vWD) and monitoring deamino‐δ‐D‐arginine vasopressin (DDAVP) therapy. Using normal controls (n=23), closure time (CT) ranges measured by PFA‐100® were (mean ± 2SD): (i) collagen/ADP cartridge (C/ADP): 67–127 s (ii) collagen/epinephrine (C/Epi): 94–162 s. From a panel of 125 patients undergoing evaluation for clinical haemostatic defects, 29/30 samples from patients with vWD [17/18 type 1, 1/1 type 3, 3/3 type 2A, 7/7 type 2B and 1/1 pseudo‐vWD] gave prolonged CTs using C/Epi. The C/ADP was less sensitive, being normal in 7/18 of the type 1 vWD individuals, with higher sensitivity to more severe vWD. Individuals with haemophilia (six factor VIII‐deficient, one factor XI‐deficient) gave normal CTs, while those with clinical thrombocytopenia (n=13) gave normal or prolonged CTs, somewhat dependent on platelet count. The PFA‐100® was also evaluated as a part of the laboratory monitoring procedure in patients with either vWD or haemophilia undergoing a DDAVP trial as a therapeutic management process. For vWD, correction of an initially prolonged CT by DDAVP, accompanied by normalization of von Willebrand factor (vWF) measurable by von Willebrand factor antigen, vWF collagen binding activity and vWF ristocetin cofactor assays (vWF:Ag, vWF:CBA and vWF:RCof), was achieved in type 1 vWD (n=5). In an individual with type 2A vWD, DDAVP normalized vWF:Ag and vWF:RCof, but had no apparent effect on the baseline maximally prolonged CT. In an individual with type 2B vWD, factor VIII/vWF concentrate also normalized vWF:Ag and vWF:RCof, but similarly had no apparent effect on the baseline maximally prolonged CT. vWF:CBA did not normalize for either of these individuals, potentially suggesting that normalization of vWF:CBA might be required for normalization of CT. This concept is supported by correlation analysis undertaken between CT and various vWF parameters. Among these, vWF:CBA held the strongest relationship in our data set, which showed an inverse progressive rise in CT for falling vWF:CBA. Based on these results, we would conclude that the PFA‐100® is highly sensitive to the presence of vWD, and may thus provide a valuable screening test for vWD. Furthermore, the combined utility of the PFA‐100® and vWF:CBA as markers of DDAVP responsiveness may prove to be simple, quick but powerful, predictors for its clinical efficacy.
High‐dose DDAVP intranasal spray (Stimate®) for the prevention and treatment of bleeding in patients with mild haemophilia A, mild or moderate type 1 von Willebrand disease and symptomatic carriers of haemophilia A
Authors: Leissinger C. , Becton D. , Cornell C. , Cox Gill J.
Published: March 2003

An open‐label multicentre trial was conducted to evaluate high‐dose DDAVP (desmopressin acetate) intranasal spray (Stimate®; 1.5 mg mL–1), for the control of bleeding in 333 patients with mild haemophilia A, mild or moderate type 1 von Willebrand disease, or symptomatic carriers of haemophilia A. Overall, 278 patients received 2170 doses of high‐dose DDAVP intranasal spray (1.5 mg mL–1). Using study‐defined guidelines, patients evaluated the efficacy of high‐dose DDAVP intranasal spray (1.5 mg mL–1) as ‘excellent’ or ‘good’ in 743 (95%) of 784 bleeding episodes. It demonstrated ‘excellent’ results in 384 (93%) of 413 administrations for prophylaxis and in eight of eight uses prior to acute surgical or dental procedures. When used for the treatment of menorrhagia, the efficacy of high‐dose DDAVP intranasal spray (1.5 mg mL–1) was rated as ‘excellent’ after 655 (92%) of 721 daily uses. Of 2170 doses of high‐dose DDAVP intranasal spray (1.5 mg mL–1), 172 (8%) were associated with adverse events. A total of 272 adverse events were reported among 80 patients. Of these, 239 (88%) were mild or moderate in intensity and only one patient was removed from the study due to an adverse event. These results demonstrate the safety and efficacy of high‐dose DDAVP intranasal spray (1.5 mg mL–1) for control of bleeding episodes in patients with mildly decreased levels of factor VIII, von Willebrand factor, or both.
Proprioception and isometric muscular strength in haemophilic subjects
Authors: Hilberg T. , Herbsleb M. , Gabriel H. H. W. , Jeschke D. , Schramm W.
Published: March 2003

Haemophilia is characterized by intra‐articular bleeding, often requiring immobilization, which may result in muscle atrophy and impaired proprioception. The aim of the study was to investigate differences in proprioceptive performance and isometric muscular strength of the lower limbs in haemophilic subjects compared with control subjects. Twelve subjects with severe haemophilia (11 haemophilia A; one haemophilia B) vs. 12 control subjects were matched for anthropometric data and tested for differences of proprioception (one‐leg‐stand, posturomed, angle‐reproduction, and tuning fork tests) and isometric strength (leg press, knee extensor). The static proprioceptive performance of the haemophilic group, as measured by the one‐leg‐stand test (on hard or soft ground, with open or closed eyes; P < 0.05) was demonstrably impaired (by 41–363%). In contrast, the dynamic proprioceptive perfomance measured by the posturomed test did not show any difference between the groups. The local proprioceptive performance (angle‐reproduction test) of the knee, (the most commonly affected joint in haemophiliacs) showed a trend to impaired function but was not distinctly different from that of controls. The quantitative sensory function (tuning fork) showed significant (P < 0.05) impairment of 9–10% in the haemophilic subjects. Additionally, the isometric muscular strength of the leg extensor was weaker (32–38%) in the haemophilic group when the limbs were tested individually as well as bilaterally (P < 0.05). In conclusion, the results suggest that global proprioceptive performance is impaired and that the isometric strength of the leg extensors is weaker in the haemophilic subjects. Therefore, specialized training for global proprioception would be helpful in order to compensate for proprioceptive deficits. This exercise regimen should also include safe strength‐training for an optimal stabilization of the joints, but must be adapted to the individual needs and situations of the haemophilic subjects.
Successful use of recombinant factor VIIa in a patient with inhibitor secondary to severe factor XI deficiency
Authors: LAWLER P. , WHITE B. , PYE S. , HERMANS C. , RIDDELL A. , COSTELLO C. , BROWN S. , LEE C. A.
Published: March 2003

Factor XI (FXI) inhibitors are a rare complication of inherited FXI deficiency. We report the successful use of recombinant factor VIIa (FVIIa) in a patient with a high‐responding inhibitor undergoing cataract extraction. At the time of surgery there were limited available data on the optimal management of patients with FXI deficiency. A 62‐year‐old Ashkenazi Jewish woman had a lifelong history of excessive bleeding secondary to severe FXI deficiency (2 U dL−1), and received FXI concentrate (FXI:C) when she underwent a colposuspension procedure. She was subsequently diagnosed with a FXI inhibitor of 16 Bethesda units (BU) when she developed a poor response to FXI:C at the time of total hip replacement. Two months later she was admitted for cataract extraction. The FXI level was < 1 U dL−1 with an inhibitor titre of 48 BU. She received 90 μg kg−1 of FVIIa immediately preoperatively followed by continuous infusion at a rate of 20 μg kg−1 h−1 for 24 h. The cataract extraction was successful and there was no excess bleeding during surgery or in the postoperative period. Mutation analysis of the FXI gene showed that the patient was homozygous for the type II genotype [exon 5, Glu117→Ter]. The reason for the low prevalence of inhibitor formation in patients with FXI deficiency is unclear but may reflect a number of factors including reporting bias, the rarity of absent circulating FXI:C activity, and the infrequent use of FXI replacement therapy.
Concentrate safety and efficacy
Authors: KASPER C. K.
Published: March 2003

Safety from transmission of infections through plasma‐derived clotting factor concentrates is assured by improved donor screening, serological testing of individual donations and direct viral testing of small plasma pools. Modern viral‐inactivation techniques are highly effective. Recombinant concentrates stabilized in human albumin are being superaeded by those with other stabilizers. Recently reported discrepancies between estimates of concentrate potency from in vitro assays versus in vivo recovery, depending upon type of assay and reference standard used, are not fully resolved.
Haemophilic cysts (pseudotumours)
Authors: RODRIGUEZ‐MERCHAN E. C.
Published: March 2003

It is very likely that with the advent of widespread maintenance therapy, pseudotumours will be less common in the future. It is important that they are diagnosed early, and prevention of muscular haematomas is the key to reducing their incidence. There are a number of therapeutic alternatives for this dangerous condition: surgical removal, percutaneous management, exeresis and filling of the dead cavity, irradiation, and embolization. The management of a patient with a haemophilic pseudotumour is complex, with a high rate of potential complications. Surgical excision is the treatment of choice but should only be carried out in major haemophilia centres by a multidisciplinary surgical team. The main postoperative complications are death, infection, fistulization, and pathological fractures (even requiring amputations of affected limbs). Pelvic pseudotumours can even become complicated by fistulization to the large bowel and by obstruction of the ureters. Untreated, proximal pseudotumours will ultimately destroy soft tissues, erode bone, and may produce neurovascular complications.
Current concepts in electrotherapy
Authors: WATSON T.
Published: March 2003

Electrotherapy has an established role in the management of a wide range of musculoskeletal and neurological problems. Used in conjunction with other therapeutic interventions, it can make a positive contribution to patient care. The means by which a range of different exogenous energy forms can influence the physiological state of the tissue is well documented. Different therapeutic modalities achieve their effects in different tissues, and the clinical decision‐making process should employ the available evidence in order to maximize the potential benefit for each patient.

The applied energy essentially acts as a trigger that is responsible for stimulating, enhancing or activating particular physiological events, which in turn are utilized to achieve therapeutic benefit. There appear to be windows of opportunity related to the magnitude of the applied energy, the amplitude of the stimulus and the frequency of application. Tissues appear to vary in their responsiveness to these factors, and thus an appropriate modality applied in an inappropriate manner will fail to achieve the anticipated effect. This paper aims to review the current concepts of electrotherapy intervention, taking into account various theories which support the principles. Application of various energies in this way can result in significant benefit for the patient.
Rare coagulation deficiencies
Authors: Peyvandi F. , Duga S. , Akhavan S. , Mannucci P. M.
Published: March 2003

Summary.  Deficiencies of coagulation factors (other than factor VIII and factor IX) that cause a bleeding disorder are inherited as autosomal recessive traits and are generally rare, with prevalences in the general population varying between 1 : 500 000 and 1 : 2 000 000. In the last few years, the number of patients with recessively transmitted coagulation deficiencies has increased in European countries with a high rate of immigration of Islamic populations, because in these populations, consanguineous marriages are frequent. Owing to the relative rarity of these deficiencies, the type and severity of bleeding symptoms, the underlying molecular defects and the actual management of bleeding episodes are not as well established as for haemophilia A and B. This article reviews these disorders in terms of their clinical manifestations and characterization of the molecular defects involved. The general principles of management are also discussed.Keywords: afibrinogenaemia, autosomal recessive disorders, factor VIII, factor XI, factor XIII.
Haemorrhage into a popliteal cyst: an unusual complication of haemophilia A
Authors: Rodriguez V. , Shaughnessy W. J. , Schmidt K. A. , Slaby J. A. , Gilchrist G. S. , Pruthi R. K.
Published: March 2003

Summary.  A 7½‐year‐old boy with severe haemophilia A had increasing discomfort and pain in his left knee after sledding on ice and landing on his knees. Left knee pain persisted for days despite recombinant factor VIII replacement. Imaging studies showed that by day 10 a popliteal cyst had ruptured, with diffusion of blood into the calf muscles. This case illustrates another possible bleeding complication in patients with a bleeding disorder and a popliteal cyst.
Assessment of the carrier status by pedigree analysis in some families from India
Authors: Singh M. , Kaur H.
Published: March 2003

Summary.  Pedigree analysis is an important tool to assess the carrier status of the females in the families of haemophiliac patients. A study was conducted on 85 families, of which 75 were of haemophilia type A and 10 of haemophilia type B. The probability values of the females being carriers were calculated by the Bayesian method. The results revealed that 45 mothers were genetic obligate carriers and the remaining 40 probable, hence the transmission was of familial nature in 45 families, whereas the remaining 40 were categorized as isolated cases. The probability values of 425 females were calculated and a wide range of probability values ranging from 0.0295 to 1 was observed.