Showing papers on "Haemophilia published in 1999"

Primary prophylaxis in severe haemophilia should be started at an early age but can be individualized.

Abstract: The frequency of joint bleeds and orthopaedic joint scores were evaluated in 121 patients with severe haemophilia who had started prophylactic treatment with clotting factor concentrates at least once weekly before the age of 10. 75 of the patients started before the age of 3, 31 at the age of 3-5 and 15 at the age of 6-9. Each subgroup was evaluated separately. In addition, a regimen of one infusion weekly was compared with that of two (haemophilia B) or three (haemophilia A) infusions weekly in each patient. A significant decrease in the overall number of joint bleeds per year was found after shortening the infusion interval (P<0.005), but the individual bleeding pattern varied. In survival analysis of the first pathologic joint score event, those who started prophylaxis before the age of 3 had a better outcome overall than those starting at later ages (P=0.001). However, in subgroup analysis, no significant difference was seen in the annual number of joint bleeds and the development of arthropathy between those starting with, or shifting to, the more intensive regimen before the age of 3 and those that were put on this regimen at the age of 3-5. Age at start of prophylaxis was found to be an independent predictor for the development of arthropathy (P=0.0002), whereas dose and infusion interval at start were not. Our data emphasize the importance of starting replacement therapy during the first years of life. However, it seems that when beginning the regimen it can be individualized and adjusted according to the bleeding pattern. In this way, the need for a venous access system may be assessed on an individual basis.

Bleeding and thrombosis in 55 patients with inherited afibrinogenaemia

Abstract: Knowledge of the spectrum of symptoms in patients with inherited afibrinogenaemia is limited by the rarity of this coagulation defect. We compared a large series of 55 afibrinogenaemic patients from Iran with 100 patients with severe factor VIII deficiency. In afibrinogenaemia there was a higher frequency of mucosal-type bleeding symptoms but joint and muscle bleeding was less frequent and severe than in haemophilia. Umbilical cord bleeding was relatively frequent only in afibrinogenaemic patients. Two young patients developed spontaneous thrombotic episodes and three women had recurrent abortions. Overall, in afibrinogenaemia bleeding symptoms are qualitatively different and less severe than in haemophilia. Afibrinogenaemia can also be accompanied by thrombotic manifestations.

Incidence of inhibitors in haemophilia A patients – a review of recent studies of recombinant and plasma‐derived factor VIII concentrates

Abstract: 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 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.

Assessing health-related quality-of-life in individuals with haemophilia.

Abstract: The objectives of this study were to analyse current levels of health-related quality-of-life (HR-QoL) in individuals with severe haemophilia and to assess the scope for these levels to improve. To do this, 249 individuals with severe, moderate and mild haemophilia were asked to complete Medical Outcomes Study (MOS) Short-Form 36 (SF-36) and EuroQol (EQ-5D) questionnaires. Access was also gained to two appropriate normative data sets. The results from these questionnaires showed that HIV status, history of orthopaedic surgery and bleeding frequency in the previous calendar year were not strong predictors of HR-QoL for individuals with severe haemophilia. However, for the majority of scales, age was found to be a strong predictor of HR-QoL for this patient group. The results from the analysis also showed that compared to individuals with moderate/mild haemophilia and the UK male normative population, individuals with severe haemophilia generally recorded poorer levels of HR-QoL. These results suggest, therefore, that individuals with severe haemophilia have reduced levels of HR-QoL compared to individuals with moderate/mild haemophilia and the general population, irrespective of differences in age. The results also suggest that the scope for primary prophylaxis to increase HR-QoL in individuals with severe haemophilia is significant.

Assessment of menstrual blood loss and gynaecological problems in patients with inherited bleeding disorders.

Abstract: Menstrual blood loss and gynaecological problems in patients with inherited bleeding disorders were assessed in this study. One hundred and sixteen women, including 66 with von Willebrand's disease (vWD), 30 carriers of haemophilia and 20 with factor XI (FXI) deficiency were interviewed and their gynaecological history obtained. Their case records were also reviewed and menstrual loss was objectively assessed using a pictorial blood assessment chart (PBAC). Comparison with an age-matched control group (69 women) was performed. Menorrhagia (PBAC score> 100) was confirmed in 74%, 57% and 59% of women with vWD, carriers of haemophilia and FXI deficiency, respectively, in comparison with 29% in the control group (P = 0.001). PBAC scores were higher in vWD patients with a von Willebrand factor activity (vWF:Ac) of

Tolerance induction using the Malmö treatment model 1982–1995

Abstract: 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 Malmo centre regarding tolerance induction according to the Malmo 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-1 bw) and then orally (2-3 mg kg-1 bw) 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 Malmo 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.

Recombinant factor VIIa for patients with inhibitors to factor VIII or IX or factor VII deficiency.

Abstract: 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 microg kg-1 for haemophilia A/B and acquired inhibitor patients, and 25 microg kg-1 for 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.

Induction of immune tolerance in haemophilia A inhibitor patients by the 'Bonn Protocol': predictive parameter for therapy duration and outcome.

Abstract: The treatment of inhibitors is one of the most challenging fields in haemophilia care. The present study reports the results of 60 haemophilia A inhibitor patients treated according to the ‘Bonn Proto

When are children diagnosed as having severe haemophilia and when do they start to bleed? A 10-year single-centre PUP study.

Abstract: The aim of this single-centre study was to obtain data prospectively on when children are diagnosed as having severe haemophilia and when they start to bleed. Results of this 10-year PUP study suggest that severe haemophilia is nowadays diagnosed much earlier than in the Sixties. Patients with severe haemophilia (n = 37; FV III <0.01 U/ml) start to bleed at very different ages. While 44% of patients have their first bleeding episode within the first year of life, others do not bleed before the age of four. The onset of joint bleedings generally occurs about half a year later than other types of bleeding. While half our patients developed their first bleeding by the age of 1.22 years, the mean age for the first joint bleeding was 1.91 years.

When are children diagnosed as having severe haemophilia and when do they start to bleed? A 10-year single-centre PUP study : Haemophilia and von Willebrand disease

Abstract: The aim of this single-centre study was to obtain data prospectively on when children are diagnosed as having severe haemophilia and when they start to bleed. Results of this 10-year PUP study suggest that severe haemophilia is nowadays diagnosed much earlier than in the Sixties. Patients with severe haemophilia (n = 37; FV III < 0.01 U/ml) start to bleed at very different ages. While 44% of patients have their first bleeding episode within the first year of life, others do not bleed before the age of four. The onset of joint bleedings generally occurs about half a year later than other types of bleeding. While half our patients developed their first bleeding by the age of 1.22 years, the mean age for the first joint bleeding was 1.91 years. Conclusion Early-onset prophylactic therapy can prevent damage to the joints, but for rational therapy the age at onset of bleeding must also be taken into account. A non-bleeding child does not benefit from prophylactic treatment.

Use of prothrombin complex concentrates and activated prothrombin complex concentrates as prophylactic therapy in haemophilia patients with inhibitors

Abstract: 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.

Diagnostic importance of the two-stage factor VIII:C assay demonstrated by a case of mild haemophilia associated with His1954 Leu substitution in the factor VIII A3 domain

Abstract: Summary. In some families with mild haemophilia higher results are obtained for factor VIII activity (FVIII:C) determined by one-stage assay than by two-stage or chromogenic assays. Amino-acid substitutions in the A1, A2 and A3 domains of factor VIII have been described in affected individuals with this phenotype. We describe a case of mild haemophilia A in which FVIII:C measured by one-stage assay was normal at 106%. However, FVIII:C levels measured by two-stage and chromogenic assays were 18% and 35% respectively. DNA analysis revealed a novel mutation in the A3 domain of factor VIII, His 1954 ! Leu. In a molecular model of the FVIII A domains, His 1954 is placed in close proximity to two other mutations that have previously been shown also to be associated with one-stage/two-stage discrepancies. In this patient the diagnosis of haemophilia A would be missed if only the one-stage assay was used.

Hemophilia. Treatment of patients with inhibitors: cost issues.

Abstract: The management of bleeding episodes and surgery in haemophilia patients who develop inhibitors is specially difficult and also has major impact on therapeutic costs. We assessed the costs of coagulation factors in noninhibitor haemophilia A and B patients (0 Inh; n=103), patients with low responding inhibitors (LR; n=24), patients with high responding inhibitors (HR; n=17) in our centre between 1988 and 1998 during two periods: 1988-1995 and 1996-1998, before and after the introduction of recombinant factor VIIa in France (1996). From 1988 to 1995 the mean annual cost of 0 inh and LR patients was 43 234 and 49 422, respectively, with more than 90% as home treatment, whereas the mean cost of HR patients was 56 262 (1.3 time more than 0 Inh), half of this cost being related to treatment administered in hospital. From 1996 to 1998, the mean cost of HR patients was 186 482, approximately three times more than that of 0 Inh (59 887) and LR patients (54 226) with half of the cost due to treatment administered in hospital. So rFVIIa seems to exert a major economic effect on both the cost of home treatment and treatment administered in hospital. It must be pointed out that particularly severe bleeding episodes were effectively treated with rFVIIa during this period and that rFVIIa allowed surgery to be undertaken: including two elective orthopaedic surgeries. So there is no doubt that rFVIIa offers new perspectives in the therapeutic management of HR patients, but creates a new economic situation which needs further evaluation.

Prevalence and incidence of intracranial haemorrhage in a population of children with haemophilia. The Hemophilia Growth and Development Study.

Abstract: The prevalence of intracranial haemorrhage (ICH) in our population of haemophiliacs was 12%. The incidence of ICH was approximately 2% per year. At entry, 7% (21/309) had clinical histories of ICH without MRI evidence of old haemorrhage, indicating that either the haemorrhages had completely resolved, that routine MRI sequences are not particularly sensitive for the detection of old blood products, or a combination of both of these factors. One half (4/8) of the ICHs documented by entry MRI were clinically silent, and three of the 11 incident cases documented by MRI were clinically silent. HIV infection did not increase the risk of ICH.

Acquired von Willebrand syndrome--report of 10 cases and review of the literature.

Abstract: Acquired von Willebrand syndrome (AvWS) is a rare bleeding disorder with clinical and laboratory features closely resembling hereditary von Willebrand disease (vWD), arising in previously haemostatically normal individuals. We present a retrospective review of 10 cases with AvWS diagnosed over 17 years. The severity of the bleeding tendency varied from mild to severe forms. Multimers electrophoresis showed that 8/10 patients had a normal pattern similar to type 1 vWD, 1/10 had a type 2A vWD pattern (with absence of high and intermediate molecular weight multimers) and 1/10 had a type 3 vWD pattern. An inhibitor screen was performed in 6/10 patients and autoantibodies against von Willebrand factor were found in only two cases. The underlying cause/associated conditions were identified in 8/10 patients. Treatment of the bleeding diathesis was successfully achieved with desmopressin or clotting factor concentrates. Resolution of underlying hypothyroidism (in two cases) and multiple myeloma (in one case) led to normalization of the coagulation parameters. The report on this cohort of 10 patients with AvWS illustrates the complexity of AvWS and its multifactorial aetiology. A brief review of the recent literature on AvWS is also presented, with emphasis on the current opinions in pathogenesis and treatment. Acquired von Willebrand syndrome (AvWS) is an acquired bleeding disorder, characterized by a phenotype similar to the inherited von Willebrand disease (vWD), with a prolonged bleeding time and low plasma levels of factor VIII - von Willebrand factor (vWF) measurements. It occurs in patients with no family history of vWD, who present with recent onset of bleeding symptoms. AvWS appears to be associated mainly with lymphoproliferative disorders, immunological conditions and neoplasia. AvWS is a rare condition and it is difficult to conduct prospective studies, therefore it is important to document the experience with such cases. The aim of this paper is first, to report 10 cases of AvWS identified at our Haemophilia Centre during the past 17 years. Second, to present a brief review of the recent literature on AvWS - outlining the salient features, associated disorders, mechanisms of acquisition and the available options of treatment.

Human recombinant DNA-derived antihaemophilic factor (factor VIII) in the treatment of haemophilia A: conclusions of a 5-year study of home therapy. The KOGENATE Study Group.

Abstract: Fifty-eight previously treated haemophilic subjects were treated exclusively with the recombinant FVIII (rFVIII-KOGENATE) produced by Bayer Corporation (Berkeley, CA) in an international multicentre prospective study of more than 5 years duration. Fifty-four of the 58 had severe haemophilia (< 2% FVIII) and four had moderate haemophilia (2-5% FVIII); 23/58 (40%) were seropositive for HIV, while 35/58 (60%) were HIV seronegative. Patients were monitored for safety and efficacy over a median period of 4.7 years (range 0.9-5.9 years) and received 17 922 infusions totalling 25.7 million units of rFVIII. Of 7107 bleeding episodes reported in home diaries, 5831 (82%) required only one treatment with rVIII. Twenty-five invasive surgical procedures in 17 patients, including eight joint replacements, were successfully accomplished and 13 serious bleeding episodes in eight patients were successfully treated. FVIII recovery performed on 885 occasions using 39 different lots of rFVIII showed mean incremental recovery of 2.48% IU-1 kg-1 (+/- 0.64). Adverse events were associated with 42 infusions (0.2%); none caused discontinuation of therapy. Immunological parameters remained stable in HIV-seronegative subjects treated with rFVIII; a small decrease in CD4 counts was noted in HIV-seropositive individuals (mean - 37.2 cells mm-3 yr-1). No de novo formation of inhibitors to FVIII was noted; and no clinical allergic reactions occurred to murine or hamster proteins. These conclusions from the longest monitored safety study ever performed for a haemophilia treatment product (with more than 5 years of observation) confirm previous interim study reports that rFVIII is well tolerated over the long-term, has biological activity comparable to that of plasma-derived FVIII, and is safe and efficacious for the treatment of haemophilia A.

Current practices regarding newborn intracranial haemorrhage and obstetrical care and mode of delivery of pregnant haemophilia carriers: a survey of obstetricians, neonatologists and haematologists in the United States, on behalf of the National Hemophilia Foundation's Medical and Scientific Advisory Council.

Abstract: We undertook this survey to determine institutional practices of obstetricians, neonatologists and haematologists regarding care of pregnant haemophilia carriers and newborns with haemophilia and intracranial haemorrhage (ICH). Our purpose was also to determine whether institutions had written guidelines to manage such patients. Questionnaires were sent to 1000 obstetricians and through the Haemophilia Treatment Centres (HTC) to 180 paediatric haematologists and 180 neonatologists, each representing an institution. Twenty-three per cent of obstetricians, 22% of neonatologists and 16% of paediatric haematologists returned completed surveys. Over 94% of the respondents had no written guidelines for management of pregnant haemophilia carriers or their newborns or for neurologic assessment of newborns. For known haemophilia carriers, 57% of the obstetricians routinely preferred vaginal delivery and 11% preferred caesarean section. Availability of perinatal services influenced prenatal management (P < 0.05). In term newborns with documented ICH, only 23% of neonatologists would evaluate for haemophilia, whereas in pre-term newborns with ICH, this number dropped even further to 3%. For all newborns with haemophilia, 40% preferred routine administration of clotting factor concentrates (CFC) immediately following birth to offset the trauma of delivery and 89% of paediatric haematologists favoured early prophylaxis with CFC. Guidelines are needed for management of pregnant haemophilia carriers as well as newborns with haemophilia. Physicians need to be made aware that ICH may be a presenting sign of haemophilia in both term as well as pre-term newborns, so that appropriate therapy can be instituted early in the event of a bleed.

Therapeutic plasma concentrations of human factor IX in mice after gene delivery into the amniotic cavity: a model for the prenatal treatment of haemophilia B.

Abstract: Background Several groups including our own have reported gene delivery to fetal organs by vector administration into the amniotic cavity. Based on these studies we hypothesised that the large surface of the fetal skin may be exploitable for high level production of systemically required gene products to be released into the fetal circulation. Methods We administered E1/E3-deleted adenoviral vectors carrying a bacterial β-galactosidase gene or the human coagulation factor IX gene into the amniotic cavities of mid- to late-gestation mouse fetuses. The concentrations of human factor IX in the plasma of fetal or new-born mice were determined by ELISA. Reverse transcription PCR was used to identify sites of transgene expression. Results Application of 5×108 infectious units of the factor IX gene vector in utero resulted in plasma concentrations of human factor IX of up to 1.2 µg/ml without significant decrease in fetal survival. Transgenic protein was found to be produced in the fetal skin, mucosae and amniotic membranes and was shown to be present for several days after birth of healthy pups. Conclusion As ultrasound-guided amniocentesis in humans is a well-established diagnostic procedure, delivery of the factor IX gene into the amniotic cavity appears to be a safe route for prenatal treatment of haemophilia B and may prevent haemorrhagic complications such as intracranial bleeding during delivery. Our study allowed for the first time a quantification of the expression of a potentially therapeutic transgene in rodents after prenatal gene delivery. It thus provides a model for the prenatal treatment of haemophilia B, but may also serve as a pathfinder to gene therapy of inheritable skin disorders such as epidermolysis bullosa. Copyright © 1999 John Wiley & Sons, Ltd.

Physiotherapy for the treatment of articular contractures in haemophilia.

Abstract: Articular contractures in haemophilia are impairments that can not be cured by means of physiotherapy because of the pathophysiology of the joint. Rehabilitation, however, tries to diminish the disabilities and prevent handicaps caused by the impairments. Physiotherapy aims at pain reduction by means of manual traction. Next to manual traction the intensive physiotherapy programme includes mobilization techniques, muscle strengthening exercises and stretching, joint stability training, postural and gait, training, and functional training. In all 50 haemophilia patients have undergone this intensive 4-week clinical rehabilitation programme. Data of 20 of these severe haemophilia patients show that the mean range of motion at the start of the rehabilitation period, after 4 weeks and after 5 years do not differ. In spite of progressing arthropathy after 5 years the activities of daily living (ADL), walking range and pain are equal or better according to 13 of 15 patients.

German recommendations for immune tolerance therapy in type A haemophiliacs with antibodies.

Abstract: Haemophilia A is the most common X-chromosomal-linked congenital bleeding disorder and is caused by decreased activity of blood coagulation factor VIII. Affected individuals develop a variable phenotype of haemorrhages, mainly into joints and muscles depending on the amount of the residual factor VIII. The exogenous factor VIII-substitution by plasma-derived or recombinant products are the only treatments either on demand or prophylactically. The most important complication of treatment is the development of inhibitors that affect about 20%-50% of the severe cases. These antibodies neutralize the therapeutic effect of factor VIII-concentrates, leading to recurrent bleeding episodes, progredient joint damages and sometimes life-threatening situations. The only chance for a complete and permanent eradication of the inhibitors in these patients is the induction of Immune-Tolerance (ITT) to substituted factor VIII by the application of high-doses of factor VIII. The treatment demands a strict compliance of the patient and a much higher effort of the physician, to non-compared inhibitor patients. Requirements for a consistent realization of the ITT to increase the successful outcome was carried out by German Haemophilia Center Directors.

A rapid method for haemophilia B mutation detection using conformation sensitive gel electrophoresis

Abstract: Conformation sensitive gel electrophoresis (CSGE) was confirmed as an effective procedure for screening the factor IX (FIX) gene by detecting 10/10 previously known FIX gene mutations. The FIX genes of a further 11 haemophilia B patients with unknown mutations were then screened and an abnormal CSGE profile was identified in all cases. Subsequent DNA sequencing demonstrated one of these to be a novel mutation (31133insT, Arg338Fs), the remaining 10 having been previously reported on the haemophilia B database. Mutation screening of the FIX gene using CSGE was demonstrated to be a rapid and efficient means of carrier analysis in families with haemophilia B.

Haemophilia therapy: assessing the cumulative risk of HIV exposure by cryoprecipitate.

Abstract: Most of the world’s haemophilia population live in countries with developing or emerging economies. As such, they do not have access to viral inactivated clotting product. Many are treated with cryoprecipitate made from locally supplied blood. The rationale for using cryoprecipitate instead of viral inactivated products is based on an implicit 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 is cumulative, and haemophilia patients treated with cryoprecipitate or fresh-frozen plasma are exposed to hundreds or thousands of donors during their lifetime. The risk that an HIV-infected person will be a donor during the ‘window period’ is directly related to the incidence of HIV in the country where the donation occurs. To illustrate the extent of this problem, we devise a model for estimating the risk that a person with haemophilia will encounter HIV-contaminated cryoprecipitate as a function of years of treatment and the underlying incidence rate of HIV among blood donors. We apply the model to two countries with different incidence rates of HIV, Venezuela and the USA. Over a lifetime of treatment (60 years), the cumulative risk of HIV exposure for a person with haemophilia receiving monthly infusion of cryoprecipitate prepared from plasma of 15 donors is significant, 2% in the USA and 40% in Venezuela. Considering the cumulative risk for transmitting HIV to patients with haemophilia through cryoprecipitate treatment, medical care providers should carefully evaluate the use of cryoprecipitate in any but emergency conditions or when no virally inactivated products are available.

Central venous catheter-associated thrombosis in severe haemophilia.

Abstract: Significant subclavian vein thromboses associated with indwelling fully implanted (port-a-cath) devices are described in two boys with severe haemophilia A and factor VIII inhibitors. Investigations were prompted by prominent chest wall veins in one case, whereas the thrombosis was a chance finding in the other case during investigation of mechanical dislocation of the catheter tubing. Extensive collateral venous circulations were demonstrated by venography in both instances indicating that the thrombus had been present for some time. Possible contributing factors to the thromboses included desensitization therapy (both patients), high-dose FEIBA (in one patient) and use of lower doses of heparin for line flush than that recommended by some authors. Neither patient had a familial or non-familial predisposition to thrombosis.

Bleeding episodes in HIV-positive patients taking HIV protease inhibitors: a case series.

Abstract: In July 1996 the Food and Drug Administration (FDA) alerted healthcare providers about 15 case reports of spontaneous bleeding episodes in HIV-positive haemophiliacs taking HIV protease inhibitors. In order to characterize the bleeding associated with HIV protease inhibitor therapy, the FDA's spontaneous adverse event reporting system was searched through 28 February 1997. The bleeding episode reporting rate for persons with haemophilia was compared for HIV protease inhibitors and zidovudine, and the characteristics of haemorrhagic events were compared between individuals with and without haemophilia. There was a substantial predominance of bleeding episodes for haemophiliacs taking HIV protease inhibitors (39 of 67; 58%) as compared with zidovudine (two of 63; 3.2%). A comparison of 39 reports of bleeding in haemophiliacs with 28 in non-haemophiliacs revealed similarities in time to event and type of HIV protease inhibitor implicated, but differences were present concerning location of bleeding and outcome. A greater proportion of haemophiliacs had resolution of their bleeding following discontinuation of their HIV protease inhibitor and recurrence of bleeding following rechallenge, as compared with non-haemophiliacs. HIV-positive haemophiliacs appear to be at an elevated risk of bleeding while taking HIV protease inhibitors, but these medications may predispose all individuals to such complications.

Functional lymphocyte immunophenotypes observed in thalassaemia and haemophilia patients receiving current blood product preparations.

Abstract: Immune abnormalities have been reported in recipients of cellular and plasma blood products. To document the effect of current transfusion practices, we performed ex vivo lymphocyte immunophenotypic studies on patients with thalassaemia major who had received multiple (leucocyte-depleted) transfusions and patients with haemophilia A and B who had received heat viral-inactivated factor concentrates. Patients with thalassaemia major showed a significant lymphocytosis, with mainly B-cell changes consistent with ongoing B-cell stimulation associated with chronic exposure to red cell antigens. Reduced T-cell IL-2Rα expression would be consistent with inhibition by desferrioxamine chelation therapy. In contrast, patients with haemophilia showed predominantly T-cell changes. Patients with haemophilia A showed significantly elevated activated CD8+ cytotoxic T lymphocytes whereas those with haemophilia B showed an increase in CD8+CD11adim and CD4+CD45RA+ suppressor T cells. Several of the immune abnormalities found may be due to the presence of cytokines not removed by leucocyte filtration or destroyed by factor concentrate production (e.g. TGF-β) causing a T-helper-2-like response. The extensive lymphocyte characterization in this study has not previously been performed and has enabled a closer examination of the functional lymphocyte immunophenotypes seen in patients treated according to current transfusion practices.

Factor VIII inhibitors in haemophiliacs: a single‐centre experience over 34 years, 1964–97

Abstract: A retrospective study of the natural history of factor VIII inhibitors in haemophilia A patients experienced in a single comprehensive haemophilia centre over three decades is reported. 431 haemophilia A patients of all severities have been followed-up for a total of 5626 patient-years. The frequency of inhibitors was 10% in the severe haemophilia A patients and 37% occurred in children 5 BU). An 8-year (1987–95) inhibitor-free period was seen during which all previously untreated patients were treated with an intermediate-purity factor VIII concentrate. A moderate haemophiliac with a misense mutation that has not been described in association with inhibitor is reported. Six HIV-positive patients preserved their antibody response to factor VIII even at the advanced stage of their disease.

Origin of mutation in sporadic cases of haemophilia A

Abstract: The aim of this study was to define the origin of mutation in sporadic cases of severe haemophilia A. The series was composed of 31 families with sporadic severe haemophilia A in the geographical catchment area of the Malmo haemophilia centre. The mutation was characterized in 29/31 families: inversion type 1 (n = 11), inversion type 2 (n = 3), other inversion (n= 1), small or partial deletion (n = 6), insertion (n = 2), non-sense mutation (n = 4) and mis-sense mutation (n = 2). Of 29 probands, eight carried a de novo mutation, whereas the proband's mother was found to carry the mutation in 21/29 families. Of the 21 carrier mothers, 16 had de novo mutations (i.e. the proband's maternal grandfather and grandmother were non-carriers). Owing to the lack of samples from the grandparents, origin could not be determined in the remaining five families. Polymorphisms of the FVIII gene were used to determine whether the de novo mutation of the carrier mother was of paternal or maternal origin. In 15/16 cases the mutation was of paternal origin and in 1/16 cases of maternal origin. In the series as a whole, mutation frequency was 6-fold higher in males than in females, but no differences in the ratio of sex-specific mutations rates was found among different types of mutation.

Increased bleeding associated with protease inhibitor therapy in HIV-positive patients with bleeding disorders.

Abstract: The use of protease inhibitor (PI) drugs in treatment regimens for HIV-infected patients with hereditary bleeding disorders has been associated with an increased bleeding tendency To characterize the nature of this bleeding tendency, a retrospective case record analysis was performed on 67 HIV-positive patients with hereditary bleeding disorders who had been treated with PI therapy 34 patients (51%) developed an increased bleeding tendency on PI therapy, usually within the first few weeks of treatment As well as an increase in usual joint bleeds, patients developed spontaneous atypical small joint, soft tissue and muscle bleeds Haematuria was also common Bleeding episodes tended to respond suboptimally to factor concentrate replacement Ritonavir was most likely to be associated with bleeding Nine patients switched first-line PI therapy as a direct consequence of bleeding and seven had no further bleeding problem on their second PI Factor concentrate usage was significantly increased during the first 6 months of PI therapy compared to the 6 months preceeding treatment PI therapy is frequently associated with increased bleeding in patients with hereditary bleeding disorders The mechanism of the bleeding tendency remains to be elucidated

Assessing health-related quality-of-life in patients with severe haemophilia A and B

Abstract: Severe haemophilia is a chronically disabling and painful condition but treatment may modify progression of the disease and consequently health-related quality-of-life (HR-QoL) In order to assess HR-QoL in patients with severe haemophilia A and B, 99 patients received MOS Short Form 36 (SF-36) and EuroQol (EQ-5D) questionnaires The relationships between responses from both questionnaires, HIV status, age, orthopaedic history and the number of bleeds patients had experienced in the previous year were examined Scores from both questionnaires were also compared to appropriate UK normative data The final analysis was based on 70 and 71 SF-36 and Euroqol questionnaires, respectively Age aside, none of the clinical variables were found to be statistically significant predictors of health-related quality-of-life (HR-QoL) However, results from both questionnaires clearly showed that compared to the general population these patients with severe haemophilia are experiencing significantly lower levels of HR-Qo