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While the presence of a Factor VIII inhibitor does not increase the frequency of bleeding, it does make treatment of bleeding episodes difficult. Over the past decade prothrombin complex concentrates (PCC) have been used in an attempt to bypass the need for Factor VIII. While their precise mechanism of action is still not known, PCC do seem to be moderately effective in controlling bleeding in hemophiliacs with inhibitors. In each of three controlled double blind studies a single dose of non-activated PCC was found to be effective in controlling acute hemarthroses in approximately 50% of episodes. While FEIBA was found to be somewhat more effective (64%) than non-activated PCC (52%) in the Dutch trial, in the only controlled trial in which a single dose of Autoplex was compared to a single dose of non-activated PCC there was no difference between the two products. Nonetheless a number of independent observers have noted beneficial effects when activated PCC have been used in serious, life threatening types of bleeding. Thus, until a more predictably effective therapeutic modality becomes available, PCC, both non-activated and activated, have a definite role in the management of patients with inhibitors.

In view of reports of less than labelled F VIII:C content in some lots of commercially available f VIII concentrates, a multi-center prospective study of f VIII concentrate potency was organized in collaboration with the United States Bureau of Biologics (BoB). Phase one of the study was aimed at evaluating the reproducibility of F VIII:C assays (one stage) in the participating laboratories, using: 1) A uniform assay method, and 2) Each lab's in-house method. Reproducibility was better with the latter. Phase two consisted of: 1),In vitro assays of currently available F VIII concentrates, and 2) In vivo F VIII:C recovery studies in two severe hemophilia A subjects. Three different lots of concentrate from each of eight different products were used for these studies. Lots were randomly selected from those available in spring-summer 1982. Each lab used its in-house F VIII:C method, with lyophilized standards provided by BoB. All values were read against three standards: In-house, BoB A (concentrate standard) and BoB s (plasma standard). Baseline, 15 and 45 minute samples from the in vivo recovery studies were snap-frozen and stored at -70°C, then shipped in dry ice. All plasma samples were assayed as unknowns in each of nine participating labs (the authors‘, Hyland, Cutter and BoB). Statistical analysis of data for 24 lots of concentrate (three lots each from Cutter, Hyland, Alpha, Armour, N.Y. Blood Center, American Red Cross-Cutter, American Red Cross-Hyland, Michigan Department of Health) revealed the following: Inter-lab values of in vitro assays of concentrate compared best when BoB A (concentrate standard) was used. Mean values corresponded to those on the manufacturers' labels, and in some instances were higher. In vivo studies revealed better than “expected” F VIII:C recovery with each product tested. In the in vivo studies inter-lab values (for f VIII:C assays of the plasma samples) compared very well when BoB 5 (plasma standard) was used. In both in vitro and in vivo studies there was much greater inter-laboratory variation in results when in-house standards were used.

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.

Children other than neonates infected with human immunodeficiency virus type 1 (HIV-1) have low rates of progression to acquired immunodeficiency syndrome (AIDS). Through 1989, 5.3% of 95 infected hemophiliacs aged 5 to 13 years developed AIDS, compared with 20.3% of 364 aged greater than or equal to 25 years. We asked whether the HIV-1 impact on peripheral blood mononuclear cell subpopulations differed with age using pairwise comparisons of uninfected and infected male children and adult hemophiliacs. Infected children had lesser reductions of total lymphocytes than adults, but proportionately lower numbers of CD2+, CD4+, CD2+CD26+, and CD4+CD29+ counts. CD4+CD45RA+ cell counts were greater than twofold higher in uninfected and infected children than adults; with infection, the CD4+CD45RA+/CD4+ proportion increased by 1.4-fold in adults, but was unchanged in children. Infected adults had highly significantly increased total CD8+ counts; both age groups had elevated CD8+HLA-DR+ counts. Infected children had significantly higher total B-cell counts than infected adults, with a disproportionately lower number of resting B cells (CD20+CD21+). During 2 years of follow-up, infected children and adults had lymphocyte changes in the same directions and these were proportionately equal. The lower rate of HIV-1 progression in children may be partly associated with differences in lymphocyte populations compared with adults; functional properties of immune cells may be equally or more important.

OBJECTIVE--To examine the CD4 count and its near term changes relative to progression to AIDS within 30 months and to subsequent CD4 counts. DESIGN--Longitudinal clinical and laboratory study. SETTING--Haemophilia treatment centres in six large American cities. PATIENTS--555 people with congenital clotting disorders who were infected with HIV, initially without AIDS, and seen at follow up for 6-30 months in 1986-9. MAIN OUTCOME MEASURES--Absolute CD4 counts and incidence of AIDS. RESULTS--Outset CD4 count and age were independently related to progression to AIDS (p less than 0.0001 and p less than 0.005 respectively). Patients with CD4 counts of 0.30-0.49 x 10(9) cells/l had an age adjusted risk of AIDS within 30 months of only 9% that of patients with counts less than 0.20 x 10(9)/l. Children under 10 years old had only 16% of the CD4 adjusted risk of AIDS of people aged greater than or equal to 45 years. Analysis of 149 patients' CD4 counts at the beginning and end of two successive six month intervals showed an average decrease of 11% in each six months regardless of the outset count (greater than or equal to 0.20 x 10(9)/l). For individual patients the decrease in the second six month period was unaffected by the decrease in the first six month period. CONCLUSIONS--Antiviral treatment of asymptomatic people, particularly children, with CD4 counts greater than or equal to 0.3 x 10(9)/l is questionable if predicted on near term progression to AIDS. Because of individual CD4 count variability and the low rate of progression to AIDS near term declines in individual CD4 counts are a poor index for identifying people who will rapidly progress to AIDS.

Objectives: We undertook an international, multicenter study to describe the clinical picture and to estimate the bleeding risk in a group of obligatory carriers of type 3 von Willebrand disease (VWD). Patients and methods: Obligatory carriers (OC) of type 3 VWD were identified by the presence of offspring with type 3 VWD or by being an offspring of a type 3 patient. Normal controls were age- and sex-matched with the obligatory carriers. A physician-administered standardized questionnaire was used to evaluate hemorrhagic symptoms at presentation. A score system ranging from 0 (no symptom) to 3 (hospitalization, replacement therapy, blood transfusion) was used to quantitate bleeding manifestations. Odds ratios were computed for each symptom. Results: Ten centers participated to the study, enrolling a total of 35 type 3 VWD families, with 70 OC. A total of 215 normal controls and 42 OC for type 1 VWD were also included. About 40% of type 3 OC had at least one bleeding symptom compared to 23% of normal controls and 81.8% of type 1 OC (P < 0.0001 by chi-squared test), showing that type 3 OC clearly represent a distinct population from type 1 OC. The clinical situations associated with an increase of bleeding risk in type 3 OC were epistaxis [odds ratio 3.6; 90% confidence intervals (CI) 1.84-21.5], cutaneous bleeding (odds ratio 5.5; 90% CI 2.5-14.1) and postsurgical bleeding (odds ratio 16.3; 90% CI 4.5-59). The severity of bleeding score correlated with the degree of factor (F) VIII reduction in plasma. Conclusions: OC for type 3 VWD represent a distinctive population from type 1 OC. These patients, however, present with more frequent bleeding symptoms in comparison to normal controls, especially in case of significantly low FVIII. Desmopressin and/or tranexamic acid might be useful to prevent or treat bleeding in these cases. (Less)

To the Editor: We congratulate the ASH for wishing to develop practice guidelines, but we believe that it may not have been a wise decision to choose ITP as the focus of its initial effort.[1][1] There are very few randomized controlled studies of ITP that provide firm data to guide the clinician

The aim of this retrospective review was to assess the overall effectiveness of prophylaxis when compared with on-demand treatment of haemophilic patients. Twenty-five children (22 with severe haemophilia A and three with severe haemophilia B) were evaluated. Five haemophilia A patients received primary prophylaxis (instituted before the onset of any joint bleed) while the other 17 haemophilia A and all three haemophilia B patients were on secondary prophylaxis. We compared factor usage, number of bleeding episodes, emergency room (ER) visits and hospitalizations while on prophylaxis to those while on demand therapy. All subjects were male, the median age at time of review was 11.4 years and at start of prophylaxis was 4.5 years. Thirteen of the 25 patients (52%) required indwelling venous catheters for access, seven of these had one or more (one-six) episodes of line sepsis. Haemophilia A patients received an average of 23.8 U kg(-1) (20-30 U kg(-1)) of recombinant factor VIII three times a week while haemophilia B patients received 50 U kg(-1) recombinant FIX twice weekly. There was a significant reduction in the mean number of major bleeds on prophylaxis from 15.5 to 1.9 per year and a significant decrease in target joints, ER visits and hospitalizations. Although factor usage per year was higher on prophylaxis, there was an overall reduction in number of bleeds and resultant decrease in hospitalizations and ER visits. By preventing new target joints, prophylaxis can lead to reduction in long-term morbidity and a better quality of life despite increased central lines and higher factor usage.

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

During the late 1980s, short-term hepatitis safety trials with certain new high purity, virally attenuated plasma derived factor VIII (FVIII) concentrates showed a higher than anticipated percentage of inhibitors in previously untreated patients (PUPs). Thus, the design of prelicensure dinical trials with each of the recombinant (r) FVIII products included prospective evaluations for inhibitors at well-defined time points, to see whether treatment with rFVIII resulted in a higher incidence of inhibitors.Each of several prospective clinical trials with rFVIII preparations is described and analyzed in terms of inhibitor development, patient demographics, and current prevalence of inhibitors in the cohort.In prospective trials with rFVIII preparations (both full length and B domain deleted rFVIII), the percentage of PUPs with severe hemophilia A who developed FVIII inhibitors has varied between 28.3 and 30.6%. Many of the inhibitors have been transient, disappearing while the patient was receiving episodic (on demand) treatment with rFVIII, while others have responded to immune tolerance induction regimens with rFVIII alone. However, many other have persisted. Genetic influences (underlying gene defect and race) were shown to play a role in inhibitor development. In contrast to the experience in the PUPs, in trials with rFVIII preparations in previously treated patients (PTPs), only 0-1 subject per trial developed an inhibitor.While the percentage of PUPs developing inhibitors in each of the prospective clinical trials with rFVIII preparations appears high, published data from similarly conducted studies with plasma-derived FVIII products show very similar results. Additionally, only an occasional PTP on rFVIII developed an inhibitor. Thus, none of the rFVIII preparations studied to date appears to be more immunogenic than plasma-derived FVIII.

The development of persistent, high titer inhibitors represents a serious complication of the treatment of patients with severe hemophilia A. Elimination of these inhibitory antibodies is usually attempted through repeated administration of high doses of factor VIII. Such regimens are costly, time-consuming and often fail when the inhibitor is of very high titer or of longstanding duration. A potential alternative approach to inhibit the production of antifactor VIII antibodies is blockade of the T-cell/B-cell collaboration that is required to generate humoral responses. One cognate receptor pair that is required for T-cell-dependent B-cell activation consists of CD40, which is expressed on B-lymphocytes and other antigen presenting cells, and CD40 ligand (CD40L, CD154), which is transiently expressed on activated T-cells. To determine whether blockade of the CD40-CD40L pathway can inhibit the production of anti-factor VIII antibodies, a clinical study has been designed in which patients with hemophilia A and a high titer inhibitor (10 BU) receive monthly exposures to factor VIII in the presence of a humanized mouse monoclonal antibody to human CD40L (hu5c8*). Subjects must be between the ages of 5 and 60 years old and be HIV seronegative. To date, three subjects have received at least three doses of hu5c8 at the initial protocol dose of 10 mg/kg. Preliminary results suggest that anti-CD40L inhibition may be effective in blocking anamnestic responses to factor VIII in some patients. It remains to be determined whether this effect will persist and whether patients may eventually become tolerant to factor VIII in the absence of hu5c8 co-administration.

The development of an inhibitor to transfused factor VIII (FVIII) is a serious treatment-related problem in haemophiliac children. The management of patients with high titre FVIII inhibitors is difficult, and immune tolerance induction (ITI) is the only method available for the eradication of these inhibitors. The results of the ITI regimen used at the Children's Hospital of Michigan Haemophilia Treatment Center are described and discussed. ITI was attempted in 14 children with severe haemophilia A (13 high responders, one low responder), with daily doses of FVIII alone. FVIII dosage was chosen according to the patient's historical peak inhibitor titre. ITI included three phases; induction phase, dose reduction phase and maintenance phase. During the first phase, the starting dose was 50 or 100 U kg-1 d-1; during the second phase the FVIII dosage was reduced gradually to 25 U kg-1 every other day according to the inhibitor titre, FVIII recovery and/or half-life study. In the third (maintenance) phase, the children received either prophylactic therapy or episodic therapy for 12 months. The inhibitor elimination was defined as the time taken to achieve a negative inhibitor assay with no anamnestic response and normal FVIII recovery and/or normal half-life. Immune tolerance was achieved in 11 of 14 patients (79%) patients within a median time of 6 months; two children are still on therapy, three failed ITI. We observed either failure or prolongation of immune tolerance if the historical peak titre or the maximum titre during ITI was200 BU. The success rate of our low dose ITI regimen is not different from that reported by other investigators and the inhibitor elimination time is similar to some of the studies reported previously.

Individuals with Haemophilia are at risk from hepatitis A virus (HAV) infection through exposure to blood products. Havrix(R), an intramuscular hepatitis A vaccine, is currently recommended for the prevention of disease caused by hepatitis A virus. Because bleeding may complicate intramuscular injections in those with bleeding disorders, we conducted a randomized, Phase IV clinical trial to compare the safety and immunogenicity of Havrix(R) given by the subcutaneous (s.c) vs. intramuscular (i.m.) route. A total of 45 children with Haemophilia were vaccinated subcutaneously, while their 41 nonhaemophlic siblings were vaccinated intramuscularly, at a dose of 720 Elisa units (EL.U.) at time 0 and 6 months. All children were anti-HAV and anti-HIV negative at baseline, and the haemophilic group did not differ from their siblings in alanine aminotransferase (ALT; 25 IU L-1 vs. 22 IU L-1), or in age; 8.5 years vs. 8.7 years. The vaccine was well tolerated, with minor adverse events being similar between groups; 21 (47%) vs. 24 (58%), P0.05. Local symptoms included soreness in 39 (45%), erythema in 25 (29%), swelling in 21 (24%), and bruising in six (7%), with no differences between groups. The proportion seroconverting to anti-HAV IgG positive did not differ between groups; 98% vs. 97% at month 1; 82% vs. 93% at month 6; and 100% vs. 100% at month 8, respectively. The HAV geometric mean titre was lower in those with Haemophilia, 185 vs. 233 mIU mL-1 at month 1; 68 vs. 94 mIU mL-1 at month 6; and 584 vs. 1082 mIU mL-1 at month 8, respectively. We conclude that Havrix(R) is safe and immunogenic when administered s. c. in children with Haemophilia.

In assessing a patient with excessive uterine bleeding, the clinician should consider systemic causes in the differential diagnosis. Both hereditary and acquired conditions can result in mucous membrane bleeding, including menorrhagia, epistaxis, and gum bleeding, as well as excessive bruising. Among hereditary conditions, von Willebrand disease (vWD) is by far the most common, affecting an estimated 1% of the population worldwide. It is important to consider the possibility of vWD, and to establish the proper diagnosis (including subtype), as safe, effective, and easy-to-use treatment is available for most persons with this disorder. This review also covers a number of other systemic conditions that can be manifested by excessive uterine bleeding, including congenital deficiency of factor XI, idiopathic thrombocytopenic purpura and other acquired platelet disorders, acquired autoantibodies against factor VIII (FVIII), and vitamin K deficiency states.

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.

Haemophilia B is an X-linked recessive coagulopathy due to mutations in the factor IX gene. Occasionally, patients receiving factor IX replacement therapy develop inhibiting antibodies to the factor IX protein, and it has been recently documented that a subset of these patients have had anaphylactic responses to factor IX replacement therapy in association with the development of inhibiting antibodies. To determine the relationship between mutation type and the risk of anaphylaxis, eight unrelated patients from families in whom anaphylaxis had occurred were genotyped. The mutations were compared to those in 550 haemophilia B patients and to those in 276 patients with clinically severe disease. Individuals with complete gene deletions were found to be at greatest risk for anaphylaxis, with an estimated risk of 26% or greater. Anaphylaxis was less likely to occur in patients with protein truncation mutations or partial gene deletions and least likely to occur with missense mutations. Genotypes can help physicians and patients anticipate the likelihood of anaphylaxis, a potentially life-threatening complication of factor IX replacement therapy. The very high risk of anaphylaxis associated with a complete gene deletion suggests that the lack of expression of a partial protein product may predispose to anaphylaxis and/or that the absence of a closely linked, codeleted gene enhances the anaphylactic immune response.

While certain plasma-derived factor VIII/von Willebrand factor (FVIII/vWF) concentrates have proven to be quite useful in preventing or controlling bleeding in persons with von Willebrand disease who are not candidates for DDAVP, most of the information concerning dosage and effectiveness has been anecdotal. Additionally, the laboratory tests used to quantify vWF (the vWF:RCoF assay and collagen binding assay) are not well standardized. Thus, the US Food and Drug Administration (FDA) has been reluctant to grant licensed indication for use of these products in von Willebrand disease. This brief report describes a survey of non-US physicians (from major centres) who are recognized experts in haemophilia and von Willebrand disease. Twenty-four of 27 questionnaires were completed, returned and analysed. Products thought to be effective in von Willebrand disease included Haemate P, Facteur von Willebrand, Alphanate, and the UK's BPL '8Y'. In calculating dosage to stop or prevent bleeding, most aim for a certain level of both FVII and vWF:RCoF. Postoperatively, 16/24 respondents follow both of these laboratory tests once daily. Twenty-two of 24 would follow FVIII levels once daily. It is noteworthy that FVIII assay results are generally the only test results readily available to guide the respondents' clinical decisions. For treatment of significant mucous membrane bleeding, respondents often individualize dosage and monitoring, depending on the type, location and extent of bleeding. Gastrointestinal bleeding is generally treated more aggressively. Patient monitoring varies between merely looking for cessation of bleeding, to a battery of laboratory tests, including haemoglobin and haematocrit. Seven out of 24 would monitor BT as well. In addition to FVIII content, 22/24 respondents noted that they would find it helpful to have vWF:RCoF listed on the label, while 15/24 would like to know the vWF multimeric composition.

Summary. In view of reports of FVIII assay discrepancies in post-infusion plasma samples depending on methods used, we compared FVIII results run by each of four different methods following infusion of rFVIII (Kogenate®). Nine persons with haemophilia A were infused with each of two lots of product. Plasma samples were obtained at baseline, and at 10 min, 30 min, 1, 2, 4, 8, 12, 14, 30 and 48 h post-infusion for measurement of FVIII. FVIII assay methods were chromogenic, and one-stage APTT using three different types of activators: micronized, silica, ellagic acid, and kaolin. The same reference plasma standard was used throughout. Results demonstrated a consistent difference in FVIII values, with chromogenic assays being considerably higher than those run by one-stage assays. The discrepancy was greatest when kaolin was the activator. These results point out the problems in attempting to determine the “correct” FVIII level in patient plasma samples following infusion of high purity FVIII preparations. Potential “pitfalls” include the standard used for defining product potency, the methods, reagents, instrumentation and standards used in assaying plasma samples and, in some instances, the characteristics of the product itself. This situation has considerable cost implications, potential impact on patient care, and makes it difficult to compare results between laboratories.

In the compassionate-use protocols, treatment with recombinant activated factor VII (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark) was almost always instituted quite late, after the patient's bleeding had failed to respond to other forms of treatment. In the case of intramuscular haemorrhages, this resulted in worsening of the haemorrhage by the time treatment with rFVIIa was started. The mean number of doses given was 13.6 (64.8 for tense muscle and compartment syndrome), and 62% of episodes were judged to have an excellent or effective response. In the dose-finding study protocol, patients were required to come to the haemophilia centre for treatment, thus resulting in some delay (of at least a few hours and often longer) before rFVIIa was given. In the dose-finding study, the average time from onset of bleeding to the first dose of rFVIIa was 9 h. The average number of doses given was 3.6 for the 70 microg/kg dosage group and 3.5 for the 35 microg/kg dosage group. In contrast, patients on the US home treatment study with rFVIIa could be treated quite soon after the onset of bleeding. We have analysed the response to treatment of intramuscular haemorrhages, based on the time interval from onset of bleeding to initiation of treatment with rFVIIa. Our analysis includes cases of full-blown 'compartment syndrome', as well as other less severe peripheral intramuscular haemorrhages. The mean number of doses given was 13.6 (64.8 for tense muscle and compartment syndrome, response rated as excellent or effective in 62% of bleeding episodes) in the compassionate use study; 3.6 and 3.5 for the 70 microg/kg (72% effective) and 35 microg/kg dosage groups, respectively, in the dose-finding study, and 2.3 (92% effective) in the home treatment study. The findings clearly indicate a greater success rate, and with fewer doses, when rFVIIa was started early.

The development of inhibitor antibody is a serious complication of haemophilia in young children. The incidence of factor IX (FIX) inhibitors in haemophilia B patients is five- to 10-times less common (1.5-3%) than the incidence of FVIII inhibitors in haemophilia A (15-30%). Inhibitors are commonly associated with the total absence of FIX antigen due to total deletions or other major derangements of the FIX gene. Unlike those with haemophilia A, patients with haemophilia B often experience anaphylactic reactions to FIX concentrates at the time of inhibitor development. Although the reasons for anaphylaxis at the time of inhibitor development are not yet clear, several hypotheses can be considered. One relates to the smaller molecular size of FIX compared with FVIII. With a molecular size of 55000, FIX diffuses into extravascular spaces more readily. Secondly, since the normal plasma FIX concentration is much higher compared with FVIII (5 microg/ml versus 0.1 microg/ml), haemophilia B patients are exposed to higher amounts of exogenous protein when a standard dose of 40-80 units/kg FIX is used. The routine exposure of haemophilia B patients to such large amounts of exogenous protein without any endogenous FIX antigen may contribute to the development of hypersensitivity. A third reason to consider is the absence of tolerance. Whether the lack of tolerance is due to the total absence of any FIX antigen or co-deletion of neighbouring genes that modulate the immune system is unknown. Management of bleeding in patients with inhibitors and anaphylaxis is complicated because the only readily available products for treatment are the FIX-containing prothrombin complex concentrates or activated prothrombin complex concentrates, the very same products that induce anaphylaxis. Recently, recombinant activated factor VII (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark) has been used effectively in several of these children, but in the USA rFVIIa is only available on a compassionate basis for the treatment of life- or limb-threatening bleeding. Eradication of the inhibitor by immune tolerance induction (ITI) has only been minimally successful in haemophilia B patients with inhibitors and anaphylaxis. Despite initial successful desensitization, the majority of these patients have had recurrent allergic reactions to FIX requiring administration of antihistamines and steroids. Recently, the development of nephrotic syndrome has been reported as a serious complication of ITI in these patients. Since inhibitor antibody is seen in association with complete gene deletions or major derangements of the FIX gene, it may be possible to select those patients with the highest risk for close monitoring during the early period of treatment by obtaining molecular diagnosis at the time of presentation.

Nine patients (10 infusions) with a confirmed diagnosis of type 3 VWD were infused with von Willebrand factor (human), a preparation of von Willebrand factor (VWF) with a very low factor VIII content. Each patient was infused with one dose of approximately 50 or 100 iu ristocetin cofactor activity (VWF:RiCoF) per kg body weight. Bleeding times were performed during the 24 h period after infusion. Plasma samples were obtained over the 96 h period after infusion and were analysed for factor VIII coagulant activity (FVIIIC), VWF:RiCoF, von Willebrand factor antigen (VWF:Ag), and multimers. The FVIIIC data were analysed by non-linear least-squares analysis assuming constant FVIIIC 'synthesis' and exponential decay. The VWF data were fitted for exponential decay. The average decay rates for FVIIIC, VWF:RiCoF and VWF:Ag were 0.041, 0.061 and 0.056 respectively. The average calculated 'synthesis' rate for FVIIIC was 6.4 u/dl/h. The synthesis of FVIIIC was slightly faster and the decay slightly slower following the infusion of 100 iu VWF:RiCoF/kg than of 50 iu VWF:RiCoF/kg. Correction of the bleeding time was strongly dose dependent. At 4 h post infusion the median bleeding time was 9 min following a dose of 50 iu VWF:RiCoF/kg versus 3 min with a dose of 100 iu VWF:RiCoF/kg. There was no decrease in the bleeding time until the level of VWF:Ag or VWF:RiCoF reached100 u/dl.

Six brands of normal reference plasma produced in the United States, with assigned assay values for factor VII and IX and, in four instances, ristocetin cofactor and van Willebrand antigen, were assayed in nine coagulation laboratories in academic institutions in the same country. Differences in mean assays of reference plasmas, as a percent of labelled potency, were significant and were greater than differences among laboratories. Standard methods of assigning potency to commercial reference plasmas are recommended.

Transfusion therapy for the congenital coagulopathies has changed considerably in recent years. Improved donor screening, purification, and virucidal methodologies have resulted in much safer plasma-derived clotting factor concentrates. Additionally, synthetic products such as rF VIII and DDAVP are licensed and available. For persons with hemophilia B, nonthrombogenic coagulation F IX concentrates are available. Treatment recommendations for each of the congenital coagulopathies are discussed.

The synthetic agent, 1-deamino-8-D-arginine vasopressin (DDAVP), is generally regarded to be the treatment of choice for persons with type I von Willebrand disease (vWD), and may be useful in type IIA vWD as well. Several formulations of the drug are available, including a highly concentrated intranasal spray formulation which is ideal for home use. The degree of F VIII and vWF response to DDAVP varies among individuals, but is generally consistent in individual patients over time. Some have tachyphylaxis while others do not. While side effects are uncommon, DDAVP is a potent antidiuretic agent. Thus one should be aware of the possibility of hyponatremia and water intoxication if certain precautions are not observed.

In summary, PCCs and APCCs are moderately effective in controlling bleeding in inhibitor patients. However, they are not as effective in controlling or preventing bleeding as factor VIII (or factor IX) concentrates in hemophiliacs who do not have inhibitors. Their precise mechanism of action is still poorly understood, and there is no readily available laboratory test for monitoring patient response. While viral safety is far less of an issue with PCCs than it was a few years ago, and while thrombogenicity is far less of a problem in using PCCs and APCCs in inhibitor patients than it is in persons with hemophilia B, one must keep in mind the risk of acute myocardial infarction. Frequent, repetitive doses may be hazardous. PCCs and APCCs represent a valuable part of one's therapeutic armamentarium in managing bleeding in inhibitor patients. However, one must be aware of their limitations and potential complications, and use them appropriately.

Among the adverse events that have been associated with the use of F IX CC in inhibitor patients, the likelihood of transmission of blood-borne pathogens is now greatly reduced. However, one must be aware of the possibility of thrombotic complications and acute myocardial infarction when using large, repetitive doses of F IX CC. A greater awareness of such potentially life-threatening complications, and avoidance of frequent, repetitive large doses, should decrease the risk. F IX CC are not always effective in achieving or maintaining hemostasis in hemophiliacs with inhibitors. Thus, in subjects who are responding suboptimally, in those in need of surgical intervention, or in those who have large intramuscular hemorrhages and/or will require a prolonged period of treatment, alternative therapeutic approaches should be considered.

Although methods of viral attenuation in plasma-derived clotting-factor concentrates have improved, there is still a possibility that such concentrates may transmit certain blood-borne viruses. For this reason, the use of recombinant DNA-derived factor VIII (which is virus-free) to treat hemophilia A has generated considerable interest.We conducted a multicenter trial in previously untreated children with hemophilia A. They received recombinant factor VIII for all treatment or for prophylaxis and were evaluated at their respective clinics at intervals of no more than three months.Between January 1, 1989, and July 1, 1992, 95 patients who could be evaluated received recombinant factor VIII. By September 1, 1992, they had received the concentrate exclusively for 2.4 months to 3.5 years (median, 1.5 years). All responded well, with no treatment failures. A total of 3315 infusions were administered; there were three reports of minor adverse reactions. Inhibitor antibodies to factor VIII developed in 16 of 81 patients tested for them, after a median of nine days of exposure to factor VIII treatment. Inhibitor titers were or became low in 9 of the 16 patients despite continued episodic treatment with the concentrate. Inhibitors disappeared completely in 4 patients and remained at a low level (10 Bethesda units) in 5 patients receiving episodic treatment.Transient or low levels of inhibitor, as observed in this study, may represent part of the natural history of hemophilia in infants. In view of the transient nature and lower concentration of the inhibitors detected and the generally satisfactory response to treatment, the benefits of recombinant factor VIII for the treatment of hemophilia seem to outweigh the risks.

Over the past few years considerable progress has been made in elucidating the molecular genetics of hemophilia A, in carrier detection and prenatal diagnosis, and in the production of safer clotting factor concentrates. Recombinant FVIII, shown to be safe and effective in ongoing prelicensure clinical trials that began in the spring of 1987, should soon be licensed and commercially available. There is now considerable interest in beginning prophylactic therapy regimens at 1 or 2 years of age, in an attempt to prevent chronic joint disease and other complications of serious bleeding episodes. The possibility of gene insertion therapy for persons with hemophilia now seems to be a realistic one--perhaps achievable in the 1990s. Although many problems remain--major problems resulting from HIV, HCV, and HBV infections; how to deal with existing musculoskeletal problems; how to pay for the higher-priced new technologies; high titer inhibitors; just to name a few--the many recent scientific advances and their clinical applications make this an exciting time. This is truly, as indicated in the title of the proceedings of the XIX Congress of the World Federation of Hemophilia, a new decade of hopes and challenges.

Children other than neonates infected with human immunodeficiency virus type 1 (HIV-1) have low rates of progression to acquired immunodeficiency syndrome (AIDS). Through 1989, 5.3% of 95 infected hemophiliacs aged 5 to 13 years developed AIDS, compared with 20.3% of 364 aged greater than or equal to 25 years. We asked whether the HIV-1 impact on peripheral blood mononuclear cell subpopulations differed with age using pairwise comparisons of uninfected and infected male children and adult hemophiliacs. Infected children had lesser reductions of total lymphocytes than adults, but proportionately lower numbers of CD2+, CD4+, CD2+CD26+, and CD4+CD29+ counts. CD4+CD45RA+ cell counts were greater than twofold higher in uninfected and infected children than adults; with infection, the CD4+CD45RA+/CD4+ proportion increased by 1.4-fold in adults, but was unchanged in children. Infected adults had highly significantly increased total CD8+ counts; both age groups had elevated CD8+HLA-DR+ counts. Infected children had significantly higher total B-cell counts than infected adults, with a disproportionately lower number of resting B cells (CD20+CD21+). During 2 years of follow-up, infected children and adults had lymphocyte changes in the same directions and these were proportionately equal. The lower rate of HIV-1 progression in children may be partly associated with differences in lymphocyte populations compared with adults; functional properties of immune cells may be equally or more important.

Inhibitors develop in approximately 15% of persons with severe hemophilia A and in 1%–2% of those with hemophilia B. While a great deal is known about these inhibitors — their antibody nature, reaction kinetics and natural history — management has remained somewhat frustrating and controversial [1, 2]. Management considerations can be divided into attempts to stop or prevent bleeding, and attempts to suppress or eradicate the inhibitor.

Heat treatment of lyophilized factor VIII and factor IX concentrates has been found to eliminate HIV virus infectivity in plasma-derived products. Pasteurization of factor VIII in solution has recently been used to reduce the risk of hepatitis transmission in concentrates prepared by standard fractionation methods. This report presents early experience with factor VIIIC prepared by monoclonal antibody immunoaffinity chromatography following pasteurization of the factor VIIIC/von Willebrand factor complex (Monoclate-P). Twelve patients were treated in three centers with Monoclate-P. Recovery and survival of factor VIII clotting activity were determined and patients were closely monitored for infusion safety. The mean half-life was 14.2 +/- 5.0 while recovery in predicted plasma volume was 72 +/- 12% corresponding to a response of 1.99 +/- 0.66 U/dL for every U/kg administered. These values are very similar to those found for Monoclate in previous studies indicating that pasteurized factor VIIIC purified by immunoaffinity chromatography retains satisfactory pharmacokinetic properties with an added margin of viral safety.

The Transfusion Safety Study monitored susceptible persons for human immunodeficiency virus type 1 (HIV-1) infections transmitted by plasma products and blood components. Through December, 1988, 6 subjects without antibody to HIV-1 (anti-HIV-1) became seropositive after receiving dry-heated factor VIII concentrate. The preparations implicated in 3 cases were derived entirely from anti-HIV-1-screened donors. In all instances, HIV-1 infection could be explained by concentrates heated at 60 degrees C for 24-30 h. Limiting consideration to concentrates and components administered after study entry showed that 4 of the seroconversions occurred among 122 subjects given 10 million units of factor VIII concentrates. No seroconversions occurred among 84 subjects given 5 million units of factor IX concentrates, or 83 who received components from over 26,000 unpaid donations. Serologic surveillance of anti-HIV-1-negative subjects provides important information, and should be routine in the management of persons receiving clotting factor concentrates.

Following the initial studies of the St. Jude group (1), high dose (2400 rad) cranial irradiation plus intrathecal (IT) methotrexate (MTX) or craniospinal irradiation given shortly after remission induction has become the ‘standard’ form of CNS prophylactic therapy. This form of CNS prophylactic therapy, based on the CNS sanctuary theory, has been widely used and the results obtained with this approach have been discussed by D’Angio (2), Mauer (3), Bleyer (4) and Hardisty (5) elsewhere in this volume.