Inhibitors in patients with haemophilia A.

Inhibitor development is the most problematic and costly complication of haemophilia treatment. Inhibitor development depends on a complex multifactorial immune response that is influenced by patient- and treatment-related factors. Considerable research is focussed on inhibitor development as well as the mechanism of eradication through immune tolerance induction (ITI). Once an inhibitor develops, two general treatment options are available: to treat acute bleeds through bypassing agents, and to eradicate the inhibitor permanently through ITI. Previously untreated haemophilia A patients (PUPs) are at greatest risk of inhibitor development within the first 20 exposure days to factor VIII (FVIII). Inhibitor incidence in PUP studies ranges from 0% to as high as 52%. Plasma-derived FVIII concentrates have repeatedly been shown in cohort studies to be associated with a decreased inhibitor risk compared with recombinant FVIII concentrates, but results from randomized clinical trials are lacking; although one such trial is ongoing (SIPPET study). The occurrence of an inhibitor represents a major hardship for the patient and his family, and can result in high morbidity and a significant reduction in quality of life. Inhibitor eradication often requires the need for demanding and expensive treatment strategies aimed at inducing immune tolerance or bypassing the inhibitor. The role of von Willebrand factor (VWF) in immunoprotection is currently under review. The high-purity, pasteurized, plasma-derived FVIII concentrate, Beriate(®), contains sufficient amounts of VWF to not only bind all FVIII molecules but also provide additional FVIII binding sites, and may have additional beneficial effects that reduce the general immunogenicity of FVIII.

Pharmacokinetics of plasma-derived C1-esterase inhibitor after subcutaneous versus intravenous administration in subjects with mild or moderate hereditary angioedema: the PASSION study.

BACKGROUND: Hereditary angioedema (HAE) is a rare disease caused by C1-esterase inhibitor (C1-INH) deficiency, characterized by periodic attacks of acute edema affecting subcutaneous (SC) tissues and mucous membranes. Human C1-INH concentrate given intravenously (IV) is effective and safe, but venous access may be difficult. We compared SC and IV administration of human pasteurized C1-INH concentrate with respect to pharmacokinetics, pharmacodynamics, and safety. STUDY DESIGN AND METHODS: This was a prospective, randomized, open-label, crossover study. Twenty-four subjects with mild or moderate HAE were randomly assigned during an attack-free interval to receive 1000 units of human pasteurized C1-INH concentrate IV or SC. Plasma levels of C1-INH activity and antigen, C4 antigen, cleaved high-molecular-weight kininogen (clHK), and C1-INH antibodies were measured. RESULTS: The mean relative bioavailability of functional C1-INH after SC administration was 39.7%. Maximum C1-INH activity after SC administration occurred within 48 hours and persisted longer than after IV administration. C4 antigen levels increased and clHK levels decreased after IV and SC administration, indicating the pharmacodynamic action of C1-INH. The mean half-life of functional C1-INH was 62 hours after IV administration and 120 hours after SC administration (p=0.0595). C1-INH concentrate was safe and well tolerated when administered via both routes. As expected, SC administration resulted in a higher incidence of injection site reactions, all of which were mild. CONCLUSION: With a relative bioavailability of 39.7%, SC administration of human pasteurized C1-INH yields potentially clinically relevant and sustained plasma levels of C1-INH and is safe and well tolerated.

Inhibitors and prophylaxis in paediatric haemophilia patients: focus on the German experience.

Prophylaxis is now an established treatment standard in haemophilia in Western Europe and the US with multiple studies demonstrating the clinical benefits of prophylaxis over on-demand treatment. In Western Europe in particular, prophylactic use of factor VIII (FVIII) is high as a result of the findings from the early prophylaxis studies and adherence to national guidelines. Unfortunately, prophylaxis has not yet been implemented on a worldwide basis. The introduction of prophylaxis by haemophilia treatment centres in Bremen, Frankfurt and Munich, as recommended in German guidelines, has significantly improved outcomes for our young haemophilia patients. In the Frankfurt centre, a decreasing rate of inhibitors has been observed since prophylaxis was started early, dosing was individualized, and the importance of treatment continuity was recognized. The centres in Munich and Bremen have explored the possibility of further reducing inhibitor rates using early tolerization - a new prophylaxis regimen that introduces low FVIII doses administered once weekly as soon as a bleeding tendency is observed - with excellent results. All three centres avert the induction of immunological danger signals by avoiding the use of central venous catheters, postponing vaccination wherever possible and not undertaking elective surgery during the early FVIII exposure days. The benefits of using this approach have been confirmed by the remarkably low rates of inhibitors in previously untreated patients reported at these centres. Hopefully, as we and others explore new prophylaxis regimens for our paediatric patients, we can work towards the goal of one day overcoming this serious complication of haemophilia treatment.

Home therapy with intravenous human C1-inhibitor in children and adolescents with hereditary angioedema.

BACKGROUND: C1-esterase inhibitor (C1-INH) replacement therapy is the treatment of choice for acute edema attacks in patients with hereditary angioedema (HAE). STUDY DESIGN AND METHODS: Our retrospective, observational study assessed the efficacy and safety of home therapy with a human plasma-derived C1-INH concentrate (pC1-INH) in 20 pediatric patients with HAE who had previously been treated with physician-based therapy. While on home therapy, 15 patients received on-demand treatment and five received individual replacement treatment (IRT). RESULTS: The switch to home therapy did not involve a significant increase in the dose of pC1-INH administered, but there was a significant increase in dosing frequency. Although only two patients were affected, the frequency of laryngeal attacks appeared to decrease on home therapy. All attacks, including laryngeal edema, were treated successfully during home therapy with pC1-INH. The mean annual number of days hospitalized was reduced from 3.8 during physician-based therapy to 0.11 during home therapy. No side effects or injection site complications were reported. The median time from onset of attack to administration of pC1-INH was reduced from 67.5 minutes during physician-based therapy to 15 minutes after switching to home therapy. The corresponding median time to initial symptom relief for all types of attack was reduced from 60 to 40 minutes. CONCLUSION: As in adults, home therapy with pC1-INH is effective and safe in the treatment of HAE attacks in pediatric patients; a larger, randomized study should ideally confirm our findings before this approach can be considered the standard of care for pediatric patients.

Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema.

BACKGROUND: Hereditary angioedema is characterized by recurrent attacks of angioedema of the skin, larynx, and gastrointestinal tract. Bradykinin is the key mediator of symptoms. Icatibant is a selective bradykinin B2 receptor antagonist. METHODS: In two double-blind, randomized, multicenter trials, we evaluated the effect of icatibant in patients with hereditary angioedema presenting with cutaneous or abdominal attacks. In the For Angioedema Subcutaneous Treatment (FAST) 1 trial, patients received either icatibant or placebo; in FAST-2, patients received either icatibant or oral tranexamic acid, at a dose of 3 g daily for 2 days. Icatibant was given once, subcutaneously, at a dose of 30 mg. The primary end point was the median time to clinically significant relief of symptoms. RESULTS: A total of 56 and 74 patients underwent randomization in the FAST-1 and FAST-2 trials, respectively. The primary end point was reached in 2.5 hours with icatibant versus 4.6 hours with placebo in the FAST-1 trial (P=0.14) and in 2.0 hours with icatibant versus 12.0 hours with tranexamic acid in the FAST-2 trial (P<0.001). In the FAST-1 study, 3 recipients of icatibant and 13 recipients of placebo needed treatment with rescue medication. The median time to first improvement of symptoms, as assessed by patients and by investigators, was significantly shorter with icatibant in both trials. No icatibant-related serious adverse events were reported. CONCLUSIONS: In patients with hereditary angioedema having acute attacks, we found a significant benefit of icatibant as compared with tranexamic acid in one trial and a nonsignificant benefit of icatibant as compared with placebo in the other trial with regard to the primary end point. The early use of rescue medication may have obscured the benefit of icatibant in the placebo trial. (Funded by Jerini; ClinicalTrials.gov numbers, NCT00097695 and NCT00500656.)

Human protein C concentrate in the treatment of purpura fulminans: a retrospective analysis of safety and outcome in 94 pediatric patients.

INTRODUCTION: Purpura fulminans (PF) is a devastating complication of uncontrolled systemic inflammation, associated with high incidence of amputations, skin grafts and death. In this study, we aimed to clarify the clinical profile of pediatric patients with PF who improved with protein C (PC) treatment, explore treatment effects and safety, and to refine the prognostic significance of protein C plasma levels. METHODS: In Germany, patients receiving protein C concentrate (Ceprotin, Baxter AG, Vienna, Austria) are registered. The database was used to locate all pediatric patients with PF treated with PC from 2002 to 2005 for this national, retrospective, multi-centered study. RESULTS: Complete datasets were acquired in 94 patients, treated in 46 centers with human, non-activated protein C concentrate for purpura fulminans. PC was given for 2 days (median, range 1-24 days) with a median daily dose of 100 IU/kg. Plasma protein C levels increased from a median of 27% to a median of 71% under treatment. 22.3% of patients died, 77.7% survived to discharge. Skin grafts were required in 9.6%, amputations in 5.3%. PF recovered or improved in 79.8%, remained unchanged in 13.8% and deteriorated in 6.4%. Four adverse events occurred in 3 patients, none classified as severe. Non-survivors had lower protein C plasma levels (P < 0.05) and higher prevalence of coagulopathy at admission (P < 0.01). Time between admission and start of PC substitution was longer in patients who died compared to survivors (P = 0.03). CONCLUSIONS: This retrospective dataset shows that, compared to historic controls, only few pediatric patients with PF under PC substitution needed dermatoplasty and/or amputations. Apart from epistaxis, no bleeding was observed. Although the data comes from a retrospective study, the evidence we present suggests that PC had a beneficial impact on the need for dermatoplasty and amputations, pointing to the potential value of carrying out a prospective randomised controlled trial.

On demand treatment and home therapy of hereditary angioedema in Germany - the Frankfurt experience.

BACKGROUND: Manifestation of acute edema in hereditary angioedema (HAE) is characterized by interindividual and intraindividual variability in symptom expression over time. Flexible therapy options are needed. METHODS: We describe and report on the outcomes of the highly individualized approach to HAE therapy practiced at our HAE center in Frankfurt (Germany). RESULTS: The HAE center at the Frankfurt University Hospital currently treats 450 adults with HAE or AAE and 107 pediatric HAE patients with highly individualized therapeutic approaches. 73.9% of the adult patients treat HAE attacks by on-demand therapy with pasteurized pd C1-INH concentrate, 9.8% use additional prophylaxis with attenuated androgens, 1% of the total patient population in Frankfurt has been treated with Icatibant up to now. In addition adult and selected pediatric patients with a high frequency of severe attacks are instructed to apply individual replacement therapy (IRT) with pasteurized pd C1-INH concentrate. Improvement on Quality of Life items was shown for these patients compared to previous long-term danazol prophylaxis. Home treatment of HAE patients was developed in the Frankfurt HAE center in line with experiences in hemophilia therapy and has so far been implemented over a period of 28 years. At present 248 (55%) of the adult patients and 26 (24%) of the pediatric patients are practicing home treatment either as on demand or IRT treatment. CONCLUSIONS: In conclusion, the individualized home therapies provided by our HAE center, aim to limit the disruption to normal daily activities that occurs for many HAE patients. Furthermore, we seek to optimize the economic burden of the disease while offering a maximum quality of life to our patients.

HAE international home therapy consensus document.

Hereditary angioedema (C1 inhibitor deficiency, HAE) is associated with intermittent swellings which are disabling and may be fatal. Effective treatments are available and these are most useful when given early in the course of the swelling. The requirement to attend a medical facility for parenteral treatment results in delays. Home therapy offers the possibility of earlier treatment and better symptom control, enabling patients to live more healthy, productive lives. This paper examines the evidence for patient-controlled home treatment of acute attacks ('self or assisted administration') and suggests a framework for patients and physicians interested in participating in home or self-administration programmes. It represents the opinion of the authors who have a wide range of expert experience in the management of HAE.

2010 International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema.

BACKGROUND: We published the Canadian 2003 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema (HAE; C1 inhibitor [C1-INH] deficiency) and updated this as Hereditary angioedema: a current state-of-the-art review: Canadian Hungarian 2007 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema. OBJECTIVE: To update the International Consensus Algorithm for the Diagnosis, Therapy and Management of Hereditary Angioedema (circa 2010). METHODS: The Canadian Hereditary Angioedema Network (CHAEN)/Réseau Canadien d'angioédème héréditaire (RCAH) http://www.haecanada.com and cosponsors University of Calgary and the Canadian Society of Allergy and Clinical Immunology (with an unrestricted educational grant from CSL Behring) held our third Conference May 15th to 16th, 2010 in Toronto Canada to update our consensus approach. The Consensus document was reviewed at the meeting and then circulated for review. RESULTS: This manuscript is the 2010 International Consensus Algorithm for the Diagnosis, Therapy and Management of Hereditary Angioedema that resulted from that conference. CONCLUSIONS: Consensus approach is only an interim guide to a complex disorder such as HAE and should be replaced as soon as possible with large phase III and IV clinical trials, meta analyses, and using data base registry validation of approaches including quality of life and cost benefit analyses, followed by large head-to-head clinical trials and then evidence-based guidelines and standards for HAE disease management.

Characterization of acute hereditary angioedema attacks during pregnancy and breast-feeding and their treatment with C1 inhibitor concentrate.

OBJECTIVE: The objective of the study was to investigate the rates and characteristics of hereditary angioedema (HAE) attacks associated with pregnancy, delivery, and the postpartum period and their treatment with C1 esterase inhibitor (INH) concentrate. STUDY DESIGN: This was an observational study including 22 women with type I HAE, with data collected before, during, and after 35 pregnancies (37 children) based on patient diaries, interviews, and case report forms. RESULTS: In 83% of pregnancies, attack rates increased during pregnancy; highest mean rates occurred in the second and third trimesters. C1-INH concentrate effectively controlled attacks and was safe for mothers and children. Low-plasma C1-INH activity during pregnancy tended to be associated with an increased chance of giving birth to a child with HAE. CONCLUSION: Increased attack rates during pregnancy in women with HAE are well controlled with C1-INH concentrate, indicating the clear benefit of integrating the availability of C1-INH concentrate into the management plan for these women during pregnancy and delivery.

Association of ABO(H) and I blood group system development with von Willebrand factor and Factor VIII plasma levels in children and adolescents.

BACKGROUND: The modulation of Factor (F)VIII activity (FVIII : C), von Willebrand factor antigen (VWF : Ag), and von Willebrand factor ristocetin cofactor (VWF : RCo) by the ABO(H) blood group is well established in adults. Expression of ABH antigens on N-linked glycans of VWF protects plasma VWF from proteolysis and clearance. Protection by H antigens is less effective than by AB antigens, resulting in approximately 25% lower VWF plasma levels in adults with blood group O compared to non-O. Given the reduced branching of ABO(H) bearing structures (I blood group system) with lower numbers of H, A, and B antigen sites during the first 18 months of life, we reasoned that if the relationship between ABO(H) blood group and VWF levels were causal, the difference of ABO(H) blood group-dependent VWF levels should be marginal or not be observed in the first months of life. STUDY DESIGN AND METHODS: We undertook quantification of FVIII : C and VWF in 574 presumably healthy children aged 1 to 210 months and correlated the values with ABO(H) blood type. Moreover, we establish reference intervals for common coagulation variables for several pediatric age groups. RESULTS: Significant differences between blood group O versus non-O values of FVIII : C, VWF : Ag, and VWF : RCo were not observed in the first months of life, started to develop during childhood, and in adolescence reached adult values. CONCLUSION: In comparison to the levels for adults and adolescents, we report fundamental differences of VWF levels in the first year of life, which may be associated with the physiologic development of the ABO(H) and I blood group system.

Pharmacokinetic analysis of human plasma-derived pasteurized C1-inhibitor concentrate in adults and children with hereditary angioedema: a prospective study.

BACKGROUND: Hereditary angioedema (HAE) is a rare and potentially life-threatening disease presenting with acute edema of subcutaneous tissues and/or mucous membranes. Patients with HAE have abnormally low or dysfunctional C1-inhibitor (C1-INH). Preventing the progression of acute attacks is the main goal of C1-INH replacement therapy; knowledge of the C1-INH concentrate half-life is of crucial importance. This pharmacokinetic study was conducted to investigate the pharmacokinetics of pasteurized human plasma-derived C1-INH concentrate (pC1-INH). STUDY DESIGN AND METHODS: This was a prospective, single-center study of six children and 34 adults with an established diagnosis of HAE. On-demand treatment with pC1-INH was administered to all children, whereas adults received either pC1-INH on-demand treatment or individual replacement therapy (IRT). Functional C1-INH plasma levels were fitted to a single-compartment model with nonlinear regression, and the area under the curve was standardized to a dose equivalent of 15 U/kg body weight of pC1-INH concentrate. RESULTS: The median half-life of functional C1-INH plasma levels in pediatric patients receiving on-demand therapy was 32.9 hours (mean, 31.5 hr). In adults, the median half-lives of functional C1-INH plasma levels after on-demand therapy were 39.1 hours (mean, 47.8 hr) and 30.9 hours (mean 33.3 hr) for patients on IRT. The median times to achieve maximum plasma activity after administration were 0.6 hour for children, 1.0 hour for adults receiving on-demand treatment, and 0.5 hour for adults on IRT. CONCLUSIONS: pC1-INH concentrate has a long median terminal elimination half-life and rapidly reaches maximum plasma concentrations. This rapid onset of clinical efficacy is essential in patients suffering from HAE.

Multimerization of peptide mimotopes for blocking of factor VIII neutralizing antibodies.

About 30 % of patients with severe hemophilia A develop neutralizing antibodies (inhibitors) to coagulation factor VIII (FVIII) upon treatment with exogenous factor preparations. Two peptides, C6 (NPVENMMDRDSQ) and H10 (QSPWQTWFTRAL), that mimic putative inhibitor epitopes (mimotopes), were previously selected by phage display screening of plasma samples from patients with inhibitors. Synthetic peptide mimotopes inhibited IgG binding to FVIII (IC(50): 30-50 microM). This effect was increased by an equimolar combination of both mimotopes. Mimotopes were fused to the C-terminal multimerization domain of the C4bp alpha-chain and expressed as multimers in 293T cells. Multimerized mimotopes showed improved binding to anti-FVIII IgG and prolonged in vitro half-life relative to synthetic peptides. The two mimotopes were combined in heteromultimers by co-transfection of 293T cells with respective vectors, resulting in bi-specific molecules that almost completely blocked polyclonal antibody binding to FVIII (IC(50): 2-3 microM). This strategy is capable of functionally improving synthetic peptides by multimerization and could provide a basis for novel therapeutic approaches for patients with hemophilia A and inhibitors.

C1-inhibitor concentrate for individual replacement therapy in patients with severe hereditary angioedema refractory to danazol prophylaxis.

BACKGROUND: Hereditary angioedema (HAE) caused by functional deficiency of C1-inhibitor (C1-INH) is a rare disease that manifests with recurrent spontaneous nonallergic edema of the subcutaneous tissues and mucous membranes. In cases of laryngeal edema that are not treated immediately, HAE is associated with high mortality rates. Attenuated androgens (e.g., danazol) are usually administered for prophylaxis, but associated side effects may limit their use. This study investigated the efficacy, safety, and quality of life (QoL) associated with a pasteurized plasma-derived C1-inhibitor (pC1-INH) concentrate for individual replacement therapy (IRT) in patients with severe HAE suffering from frequent attacks who were intolerant or not responding to danazol. STUDY DESIGN AND METHODS: Twenty-two patients with severe HAE and danazol incompatibility or insufficient efficacy of danazol were recruited. Intraindividual comparisons of efficacy, safety, and QoL with pC1-INH concentrate IRT versus danazol treatment were made using retrospective and prospective patient data. Pharmacokinetic data were collected for 15 of the 22 patients. RESULTS: In patients receiving pC1-INH regularly, the median number of attacks per year decreased significantly compared to danazol prophylaxis (p < 0.001), and the 24 laryngeal edema episodes per year ceased. Superior efficacy of pC1-INH was found for all QoL variables (e.g., general condition, social activities). No transmission of human immunodeficiency virus or hepatitis A, B, or C was observed. CONCLUSION: In patients with severe HAE who experience severe side effects and/or lack of efficacy of danazol prophylaxis, very early substitution with pC1-INH can completely abolish the incidence of potentially fatal laryngeal edema and can reduce the incidence of acute attacks.

The role of VWF for the success of immune tolerance induction.

One of the primary and most serious treatment-related complications in haemophilia A is the formation of anti-factor VIM (FVIII) antibodies, which significantly impacts patient care. For these patients, immunomodulatory therapy becomes important to induce immunological tolerance to FVIII. Immune tolerance induction (ITI) is an efficient therapeutic approach to eliminating inhibitors. Several ITI protocols are currently in use, including the Malmö-, Bonn- and van-Creveld-protocol. Successful utilisation of these protocols enables regular FVIII treatment (in the case of surgery and bleeding), prophylactic treatment (to prevent haemophilic arthropathy and life-threatening bleeding), improvement in quality of life and cost savings. Success rates with ITI may vary depending on patient variables and factors related to the therapeutic regimen, including concentrate purity and von Willebrand factor (VWF) content. Both in vitro and in vivo studies support the clinical observation that the VWF content may have an important role in the success rate of ITI. Over the past 25 years extensive experience has been gained in ITI using the VWF/FVIII product HaemateP/Humate-P. Overall success rates of around 80% have been observed using the Bonn-protocol with plasma-derived VWF/FVIII, whereas the success rates with high-purity or recombinant FVIII products were much lower at 3 German haemophilia centres. Further research is required to better understand the impact of different variables on ITI including the role of VWF, and this is being investigated in several ongoing studies. Meanwhile, current guidelines recommend the use of VWF-FVIII concentrates for ITI where first-line therapy with high-purity FVIII concentrates has failed.

Humoral immune responsiveness to a defined epitope on factor VIII before and after B cell ablation with rituximab.

In hemophilia A, up to 30% of patients develop neutralizing antibodies (inhibitors) to factor VIII (FVIII). Treatment of an inhibitor patient with anti-CD20 (rituximab) provided an opportunity to study the humoral immune response to the well defined and constantly administered antigen, FVIII, before therapy and after B cell repopulation. Levels of CD20(+) B cells, inhibitor titers as well as antibody titers to selected antigens and FVIII-specific IgG subclasses were monitored. Inhibitors were absent for 420 days after B cell depletion, whereas antibody titers to other monitored antigens remained constant. No changes of FVIII specific IgG subclass distribution were observed. In order to characterize specific epitopes phage displayed random peptide libraries were screened with plasma before treatment and after recurrence of inhibitors. A peptide corresponding to a dominant amino acid motif selected by phage display bound FVIII-specific IgG1 before and after anti-CD20 treatment and partially restored FVIII activity in vitro. This peptide mimics a conformational epitope in the A2 domain of factor VIII, which is still recognized after inhibitor relapse despite complete B cell depletion and long-term absence of inhibitors. Mapping of specific epitopes on a defined antigen gives further information on mechanisms underlying B cell repopulation after rituximab therapy.