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Research describing patient experience and outcomes with extended half-life recombinant factor VIII (EHL rFVIII) outside of clinical trials is limited. Real-world rFVIII consumption studies, when people with hemophilia A (PWHA) switch from standard half-life (SHL) to EHL rFVIII, may help payers and clinicians make more informed treatment choices.To conduct a retrospective, observational, U.S.-based analysis to describe clinical and demographic profiles of PWHA who switched to prophylactic rurioctocog alfa pegol.Data were obtained from PWHA treated by 38 prescribers across 21 states using specialty pharmacy database case report forms, electronic medical records, and direct communication with providers, PWHA, or their guardians. Assessments included disease severity, pain severity, number and location of target joints, prior HA therapy, reasons for switching, treatment duration, dosing frequency, adherence, and annualized bleeding rates (ABRs) before and after switching to rurioctocog alfa pegol from SHL or another EHL rFVIII.Data were collected from 56 PWHA. The mean age was 26 years (range = 5-88); median age was 24 years (interquartile range = 14-34); 20% were aged12 years; and 89% (50/56) had severe HA. All PWHA had ≥ 12 months of rFVIII treatment before switching to rurioctocog alfa pegol. The population had a mean 1.8 target joints. Baseline subjective pain assessment was mild to moderate for 68% (38/56) of respondents. Before receiving rurioctocog alfa pegol, most PWHA received antihemophilic factor (recombinant) for prophylaxis (73%, 41/56) or breakthrough bleeding (59%, 33/56). Mean dosing frequency for prior prophylaxis was 2.8 per week for SHL rFVIII and 1.8 per week for EHL rFVIII, and 2.2 per week for all PWHA after switching to rurioctocog alfa pegol prophylaxis. The median time on rurioctocog alfa pegol prophylaxis was 12.0 months versus 80.8 months on previous SHL rFVIII and 13.5 months on previous EHL rFVIII. Mean ABRs on prior prophylaxis were 5.9 for SHL rFVIII (n = 35) and 4.7 for EHL rFVIII (n = 3). After switching to rurioctocog alfa pegol, the overall mean ABR reduced by 71% (5.8 to 1.7,Switching from either an SHL or EHL rFVIII to rurioctocog alfa pegol is associated with fewer bleeding episodes owing to more effective prophylaxis and improved adherence. Those who switched from an SHL rFVIII reported reduced factor consumption with rurioctocog alfa pegol. This long-acting factor is an important additional option for the care of PWHA.This study was funded by Shire Development LLC, a Takeda company, Lexington, MA. Trio Health was involved in study design and acquisition, analysis, and interpretation of data and was funded by Shire Development LLC, a Takeda company. Aledort serves on the data and safety monitoring boards of Baxalta U.S. Inc., a Takeda company, and Octapharma; is chair of the scientific advisory board of Kedrion; and receives consultancy fees and honoraria from Baxalta U.S. Inc., a Takeda company. Milligan is an employee of Trio Health and reports research support from AbbVie, Gilead, Merck, Sanofi, and ViiV, unrelated to this study. Watt is an employee of Shire International GmbH, a Takeda company, and owns stock in the company. Booth was an employee of Baxalta U.S. Inc., a Takeda company, at the time of this study and owns stock in the company. Data from this study were presented at the AMCP Managed Care and Specialty Pharmacy Annual Meeting; April 23-28, 2018; Boston, MA; SETH (2018) Sociedad Espanola de Trombosis y Hemostasia-XXXIV Congreso Nacional; October 11-13, 2018; Grenada, Espana; and Blood 2018 Annual Scientific Meeting; October 21-24, 2018; Brisbane, Australia.

Patients affected by hemophilia A often require frequent prophylactic and therapeutic self-infusion. For those who develop inhibitors, treatment options are limited and mortality is increased. Emicizumab, a bispecific antibody to Factors IXa and X that carries out the function of Factor VIII (FVIII), represents a novel therapeutic approach. Areas covered: We review the clinical trials and key laboratory assay research for emicizumab. Emicizumab reduced the annualized bleeding rate by 87% compared to placebo in patients with inhibitors. For patients without inhibitors, emicizumab reduced the annualized bleeding rate 96-97% compared to no prophylaxis and 68% compared to prior FVIII prophylaxis. Three patients developed a thrombotic microangiopathy (TMA) and two patients had thrombotic events while on emicizumab in combination with activated prothrombin complex concentration (aPCC) alone or concurrent with activated recombinant factor FVII (rFVIIa). Expert opinion: Emicizumab represents a much-needed alternative approach to managing Factor VIII deficiency, especially for those with inhibitors or limited ability to self-infuse. For patients with inhibitors, thrombotic complications including TMA, not seen with other bypassing agents, raises concern about the use of emicizumab in combination with aPCC and how patients who have breakthrough bleeding can be safely managed.

Sickle cell disease (SCD) is a genetic disease caused by mutations in the beta globin gene, and inflammation plays a key role in driving many aspects of disease pathology. Early immune activation is believed to be associated with hemodynamic stresses and thrombus formation as cells traffic through blood vessels. We applied an extracorporeal perfusion system to model these effects ex vivo, and combined this with a phosphor-CyTOF workflow to comprehensively evaluate single-cell signatures of early activation across all major circulating immune subsets. These approaches showed immune activation following passage through the perfusion chamber, most notably in monocytes, which exhibited platelet aggregation and significantly elevated expression of multiple phospho-proteins. Overall, these studies outline a robust and broadly applicable workflow to leverage phospho-CyTOF to characterize immune activation in response to ex vivo or in vivo perturbations and may facilitate identification of novel therapeutic targets in SCD and other inflammatory diseases.

Congenital thrombotic thrombocytopenia purpura (cTTP) is a very rare disorder worldwide. Standard treatment of recognized cases has been to administer fresh frozen plasma as the source of ADAMTS13, to replenish the absent ADAMTS13 enzyme. An alternative source, a plasma-derived factor VIII concentrate used for hemophilia A, and found to contain this enzyme, was reported to be effective in 1 patient in the United States. We now report details on a US cohort of 8 cTTP patients who have been successfully treated for varying periods with a marketed antihemophilic factor concentrate Koate-DVI. This biological product has been used successfully on demand in varying doses to treat acute exacerbations, as well as prophylactically (3 to 6 U ADAMTS13 every 3 to 21 d). Self-infused at home, in lieu of fresh frozen plasma therapy in the hospital setting, this product has effectively prevented episodes of thrombocytopenia, microangiopathic hemolytic anemia, and the concomitant organ damage in these patients. This specific virus inactivated product can be used to prevent further manifestations of this congenital enzyme deficiency.

The establishment of dedicated comprehensive treatment centres more than a half century ago transformed the management of haemophilia in the United States. Formerly, a disease associated with crippling disability and premature death, today, persons with haemophilia who are treated appropriately from infancy and do not develop inhibitors can expect a normal life expectancy and relatively few bleeding episodes. The evolution of the comprehensive haemophilia care, while chastened by the viral epidemics of the 1980s, has been marked by ongoing advances, including prophylaxis, immune tolerance induction, new drugs and gene therapy research. Current challenges include sustaining the comprehensive care model despite decreased funding and expanding the delivery and affordability of comprehensive haemophilia care.

The fifth Åland Island meeting on von Willebrand disease (VWD) was held on the Åland Islands, Finland, from 22 to 24 September 2016 – 90 years after the first case of VWD was diagnosed in a patient from the Åland Islands in 1926. This meeting brought together experts in the field of VWD to share knowledge and expertise on current trends and challenges in VWD. Topics included the storage and release of von Willebrand factor (VWF), epidemiology and diagnostics in VWD, treatment of VWD, angiogenesis, and VWF inhibitors.

Deaths Associated with Emicizumab Since the approval of emicizumab for patients with hemophilia A, a few deaths have been reported without sufficient detail to assess their relationship with the an...

Thrombopoietin receptor agonists increase platelet counts and reduce bleeding risk in patients with immune thrombocytopenia (ITP). Studies have reported that these agents may represent a risk factor for thromboembolic events, especially in the elderly, who are at increased risk for such complications relative to younger patients. In this retrospective analysis, efficacy and safety data for romiplostim in patients with ITP aged ≥65 years versus those aged65 years are described. Data from 3 studies (N = 159; 24.5% ≥ 65 years of age) were analyzed for efficacy. Data from 13 studies (N = 1037; 28.4% ≥ 65 years of age) were analyzed for adverse events (AEs). Relative risk (RR) ratios with 95% CIs were calculated for duration-adjusted incidences of AEs for romiplostim versus placebo/standard of care (SOC) in patients ≥ 65 and65 years. Slightly higher platelet response rates were seen among romiplostim-treated patients ≥ 65 versus65 years. In the safety analyses, 65 (6.3%) received placebo/SOC, 69 (6.7%) received placebo/SOC and then romiplostim, and 903 (87.1%) received romiplostim only. Duration-adjusted AE rates were similar for romiplostim versus placebo/SOC in older and younger patients. The risks for grade ≥ 3 bleeding (RR 1.92; 95% CI, 0.47-7.95) and thromboembolic events (RR 3.85; 95% CI, 0.53-27.96) were numerically but not significantly higher for romiplostim versus placebo/SOC in patients ≥ 65 years. Romiplostim is effective and, with the exception of nonsignificant trends showing increased risks of grade ≥ 3 bleeding and thromboembolic events (a trend observed in other studies), generally well tolerated in older patients with ITP.

Hemophilia A is a congenital, recessive, X-linked bleeding disorder that is managed with infusions of plasma-derived or recombinant factor (F) VIII. The primary considerations in FVIII replacement therapy today are the: 1) immunogenicity of FVIII concentrates, 2) role of longer-acting FVIII products, 3) prophylactic use of FVIII in children and adults with severe hemophilia A, and 4) affordability and availability of FVIII products. Improving patient outcomes by increasing the use of FVIII prophylaxis, preventing or eliminating FVIII inhibitors, and expanding access to FVIII concentrates in developing countries are the major challenges confronting clinicians who care for patients with hemophilia A.

There are no studies demonstrating that prothrombin complex concentrates (PCC) improves outcome compared FFP in patients with warfarin-associated intracranial hemorrhage. A prospective, observational study was conducted of patients who received PCC (Bebulin VH), FFP, or PCC + FFP. All groups received vitamin K 10 mg IV. INR reversal (

Most studies on immune tolerance induction (ITI) therapy in haemophilia A patients are focused on primary ITI in children. Here we report on the ITI outcome in a large retrospective cohort, including adults and patients with rescue ITI, treated with a pdFVIII/VWF concentrate. Retrospective data from haemophilic patients (FVIII< 2%) with inhibitors from 22 centres in Spain, Italy and Germany, who underwent primary or rescue ITI with pdFVIII/VWF concentrate, were collected. Complete success (CS), partial success (PS) and failure were defined based on the criteria of the consensus recommendations of the 2006 International ITI Workshop. A total of 41 cases of primary ITI (32 children and 9 adults) and 19 cases of rescue ITI (17 children and 2 adults) were evaluated. Success (CS+PS) rate of 87% was achieved in primary ITI and 74% in the higher risk profile of rescue ITI. Eight of nine (85%) patients with poorest prognosis (three or more of the known risk factors of poor response to ITI) achieved success (CS+PS). CS of 100% was observed in eight primary ITI patients with titre at start of ITI ≤2.5 BU and inhibitor peak ≤25 BU. The favourable response rates in primary and rescue ITI in children and in adult patients, even in the presence of poor prognostic factors, should be encouraged for broadening the indication of immune tolerance therapy in haemophilia A patients with inhibitors.

Fibrinogen plays a key role in the coagulation process, and therefore maintaining adequate quantities of fibrinogen is an essential step in achieving satisfactory hemostasis in patients with acquired hypofibrinogenemia. Potential options for treating acquired hypofibrinogenemia in patients with uncontrolled bleeding include the use of cryoprecipitate or fibrinogen replacement therapy. This review provides a brief overview of the hemostatic process and the methods for assessing coagulopathy and discusses the efficacy and safety of cryoprecipitate and fibrinogen concentrate in restoring fibrinogen levels, achieving hemostasis and reducing transfusion requirements in different patient populations requiring rapid hemostasis. Other issues relevant to the clinical use of these agents in restoring hemostasis, including variations in product composition, preparation time and cost, are also examined.

Early brain injury (EBI) following aneurysmal subarachnoid hemorrhage (SAH) is an important predictor of poor functional outcome, yet the underlying mechanism is not well understood. Animal studies suggest that platelet activation and inflammation with subsequent microthrombosis and ischemia may be a mechanism of EBI. A prospective, hypothesis-driven study of spontaneous, SAH patients and controls was conducted. Platelet activation [thromboelastography maximum amplitude (MA)] and inflammation [C-reactive protein (CRP)] were measured serially over time during the first 72 h following SAH onset. Platelet activation and inflammatory markers were compared between controls and SAH patients with mild [Hunt–Hess (HH) 1–3] versus severe (HH 4–5) EBI. The association of these biomarkers with 3-month functional outcomes was evaluated. We enrolled 127 patients (106 SAH; 21 controls). Platelet activation and CRP increased incrementally with worse EBI/HH grade, and both increased over 72 h (all P

Summary There is lack of evidence-based recommendations or clear-cut consensus regarding the clinical and economic utility of regular prophylaxis started in adulthood, with the aim of keeping the clinical situation from getting worse by prevention of further bleeds contributing to increasing musculo-skeletal or other morbidity in haemophilia. Such a prophylaxis program has been shown in relatively small cohorts to be effective in reducing bleeding occurrence, with a variable effect on the joint status, but with significantly higher factor consumption and consequently higher costs than on-demand therapy. There has been no attempt to identify subsets of patients who may benefit from “tertiary” prophylaxis more than others, for example, due to their bleeding phenotype and/or requirements for product issued on-demand or to identify the dosage that provides the optimal balance of clinical benefit and cost effectiveness. This article reviews the published literature on prophylaxis started beyond the age of 18 years, the barriers to the uptake of prophylaxis programs particularly in adults and highlights areas in need of further research.

The very high cost of haemophilia care, including the increase in use of factor prophylaxis in both children and adults requires that funders of clotting factor concentrates require objective measures of health, such as joint status and quality of life (QOL). Many clinical trials, especially those for licensing of new products, are including QOL instruments in their protocols to evaluate the patients' perspective of wellbeing before and during therapy. This article gives a perspective on QOL the importance of QOL measurement in the field of haemophilia and its impact on patient outcome.

The development of peripheral artery disease (PAD), a marker for systemic atherosclerosis and ischemic risk, is an increasingly important concern in the aging hemophilia population. A growing body of data suggests that an absence or deficiency of factor VIII or factor IX may not protect against atherogenesis, implying that the prevalence of PAD in men with hemophilia (MWH) may be higher than previously believed. This article describes special considerations in PAD screening, risk-factor modification, and management in older MWH.

SummaryIt was the objective of this study to determine whether reduced cleavage of von Willebrand factor (VWF) multimers following aortic valve replacement (AVR) is a consequence of reduced shear stress or postoperative changes in VWF cleavage protease (ADAMTS-13) activity. Aortic stenosis (AS) may be complicated by acquired von Willebrand disease. Aortic valve replacement (AVR) corrects the associated haematologic abnormalities. We enrolled 114 patients with severe AS scheduled for either balloon aortic valvuloplasty (BAV; n=64) or AVR (n=50). Haematologic assessments of VWF levels and activity and ADAMTS-13 were performed before and 24 hours after valve intervention. The VWF:RCo to VWF:Ag ratio, a surrogate for large VWF multimer activity, increased by 37% (p < 0.0001) after AVR and by 10% (p = 0.0002) after BAV. ADAMTS-13 activity significantly decreased after AVR (579 ± 127 to 468 ± 135 ng/ml; p

Summary. Background: Inhibitors are a serious complication for patients with severe hemophilia A. Immune tolerance induction (ITI) is the primary method for eradicating these inhibitors. The role of type of concentrate and in particular the use of von Willebrand factor-containing, plasma-derived factor VIII (VWF/pd-FVIII) concentrate in primary or rescue ITI remains unclear. Objectives: To report retrospective collection of data on the use of a single VWF/pd-FVIII concentrate in primary and rescue ITI. Methods: Retrospective chart review of hemophilia A inhibitor patients at 11 US institutions who received VWF/pd-FVIII concentrate in primary or rescue ITI. Results: Primary ITI was carried out in eight inhibitor patients with a 75% complete and partial success. Secondary ITI was carried out in 25 inhibitor patients, with 52% attaining complete or partial success. Conclusions: This report represents the largest group of primarily pediatric, high-titer inhibitor patients treated with a single VWF/pd-FVIII concentrate. It adds retrospective data to the use of VWF-containing plasma-derived factor VIII concentrate in primary and rescue ITI, particularly in those patients with characteristics of poor response to ITI.

Sexual dysfunction is common in ageing men and may be exacerbated by the special medical issues and psychological problems associated with haemophilia. Sexual healthcare for men with haemophilia (MWH) requires a background understanding of common patterns of sexual function and dysfunction in the ageing male, expectable sexual complications of haemophilia and related comorbidities, and of sexually related psychological issues. Healthcare providers who treat MWH must be able to elicit a sexual history sufficient to differentiate problems involving a loss of sexual desire from ejaculatory difficulties and erectile dysfunction (ED). Other necessary skills include evaluating patients with ED for treatable causes, distinguishing organic from psychogenic ED, using phosphodieterase-5 inhibitors as first-line treatment for ED, and referring to specialized sexual urology and mental health professionals when appropriate.

Summary. At the present time, the most significant complication of hemophilia therapy is the development of neutralizing antibodies (inhibitors) to factor (F) VIII, which adds greatly to the difficulty and expense of preventing and treating bleeding episodes. Both patient-related and therapy-related variables contribute to the development of inhibitors. The multifactorial nature of inhibitor development and the relatively small numbers of patients that participate in clinical trials make it difficult to accurately assess the risk of inhibitor development. Adding to that challenge is the lack of a uniform standard of design for conducting clinical trials to evaluate the safety of FVIII products. This hinders the comparison of products and is an obstacle to the meta-analysis necessary to make statistically valid assessments of inhibitor risk. This article reviews similarities and differences in clinical trial guidelines of European and US regulatory agencies and discusses the need for their harmonization to facilitate the assessment of FVIII products.

Background: Prophylactic treatment with factor products has demonstrated superior outcomes and care compared to on-demand treatment in hemophilia patients, including patients with pre-existing joint diseases. However, 40% to 50% of severe or moderate hemophilia A and B patients are still treated on-demand in the US. Recombinant factor VIII and IX Fc fusion proteins (rFVIIIFc and rFIXFc) were the first extended half-life (EHL) products approved in the US (in 2014) with the promise of optimizing prophylactic regimens by achieving low bleeding rates and improving joint health with fewer injections overall. Objective: This is the first real-world study to assess the impact of EHL rFVIIIFc and rFIXFc on overall prophylaxis rates, particularly to understand how patients have transitioned from on-demand treatment. Methods: A retrospective analysis was conducted on aggregate, de-identified United States Specialty Pharmacy Provider (SPP) records from Jan 2014 to June 2018 (data pull on June 14th, 2018). Adult hemophilia patients (age 18 and above) were included for an analysis of treatment regimens prior to and after switching to EHL rFVIIIFc and rFIXFc (on-demand or prophylaxis). The results were descriptively compared to those who switch to the other EHL PEGylated rFVIII and rFIX albumin Fusion Protein (rFIX-FP) and conventional factors. Results: A total of 304 hemophilia A patients who switched to rFVIIIFc and 133 hemophilia B patients who switched to rFIXFc were included in this study. For the hemophilia A and B patients, the median age was 31 and 32 years and median weight was 82 and 79 kg. The proportion of patients who switched from on-demand treatment with conventional factors to prophylaxis treatment with EHL rFVIIIFc and rFIXFc among all patients who switched to these products increased over time since the FDA approval (3 time points: 2014-2015, 2016-2017, and 2018: rFVIIIFc: 13%, 20%, and 21%; rFIXFc: 25%, 29%, and 57%). Such proportions were higher compared to those who switched from on-demand with conventional factors to prophylaxis with the other EHLs (2016-2017, 2018: PEGylated rFVIII: 16%, 18%; rFIX-FP: 18%, 13%, see comparison in the Figure) and with conventional factors (2014-2015, 2016-2017, and 2018: conventional rFVIII: 10%, 7%, and 9%; conventional rFIX: sample size was too small and not suitable for analysis). Discussion: rFVIIIFc and rFIXFc have transformed the paradigm of hemophilia care by shifting on demand patients to prophylaxis significantly faster than conventional factors and any other EHLs to date. This shift is significant as it is helping more hemophilia patients achieve optimal protection through low bleeding rates and improved joint health over the long-term. Figure. Figure. Disclosures Jain: Bioverativ: Employment. Li:Bioverativ: Employment. Krishnan:Bioverativ: Employment. Hagberg:Bioverativ: Employment. Su:Bioverativ: Employment.

Summary. Background: Romiplostim is a peptibody protein that raises platelet counts during long-term treatment of patients with chronic immune thrombocytopenia (ITP). Clinical outcomes related to increased platelet counts include a reduced risk of bleeding and a potential risk of thrombosis. Objective: To evaluate bleeding and thrombotic events occurring in chronic ITP patients during two phase 3, randomized, placebo-controlled, 24-week studies of romiplostim and during subsequent treatment in an open-label extension study. Patients/Methods: In the phase 3 trials, 125 patients were randomized to romiplostim or placebo; romiplostim dose was adjusted to maintain platelet counts of 50–200 × 109 L−1. Patients who completed the phase 3 trials could enroll in the extension study in which all patients received romiplostim. Results: In the phase 3 trials, a significantly greater percentage of patients treated with placebo (34%) had bleeding adverse events of moderate or greater severity than did patients treated with romiplostim (15%, P = 0.018). In the extension study, the incidence of bleeding adverse events of moderate or greater severity decreased from 23% of patients in the first 24 weeks to 12% after 24–48 weeks, remaining ≤ 6% thereafter. The exposure-adjusted incidence of thrombotic events was 0.1 per 100 patient-weeks in the phase 3 studies, and 0.08 per 100 patient-weeks in the extension study where patients received romiplostim for up to 144 additional weeks. Conclusions: The incidence and severity of bleeding was decreased in chronic ITP patients treated with romiplostim compared with placebo, and the incidence of thrombotic events was not different between the two groups.

Hepatitis C virus (HCV) is a blood-borne infection readily transmitted by transfusion. Persons with hemophilia were at very high risk of acquiring HCV, but the chronology and correlates of HCV incidence in the US hemophilia population remain unknown. The authors used multiple data sources and new statistical methods to reconstruct HCV incidence in White males with hemophilia A from 1940 through 1990. HCV incidence was approximately 1%/year until 1950 but 2-3%/year by 1955. With mild hemophilia, HCV incidence increased in the 1960s, reaching a plateau of approximately 8%/year from 1969 to 1980. With moderate and severe hemophilia, HCV incidence increased steeply to peaks of 11.7%/year in 1970 and 17.2%/year in 1968, respectively. Overall, HCV incidence declined after 1970, steeply after 1984, to nearly zero by 1990. With improving and increasing use of plasma derivatives, the size of the hemophilia population increased 86% during these 50 years. Study results imply that these life-saving treatments also carried an increasing risk of HCV, particularly before clotting factor concentrates were licensed in the 1970s. They also suggest that multiple synergistic interventions since 1970, particularly donor deferral, screening for hepatitis B and human immunodeficiency virus, and viral inactivation of clotting factor concentrates, were needed to reduce transfusion of HCV prior to its discovery.

Before the mid-1980s, haemophilia often was unknowingly treated with contaminated plasma products, resulting in high rates of human immunodeficiency virus (HIV-1), hepatitis C virus (HCV) and hepatitis B virus (HBV) infections. To estimate the impact of these infections, a new cohort was established. All HCV-seropositive patients, age 13-88 years, at 52 comprehensive haemophilia treatment centres were eligible. Cross-sectional data collected during April 2001 to January 2004 (median June 2002) were analysed. Plasma HIV-1 and HCV RNA were quantified by polymerase chain reaction. Highly active antiretroviral therapy (HAART) was defined as use of at least three recommended medications. Among 2069 participants, 620 (30%) had HIV-1. Of 1955 with known HBV status, 814 (42%) had resolved HBV and 90 (4.6%) were HBV carriers. Although 80% of the HIV-1-positive participants had > or = 200 CD4+ cells microL(-1), only 59% were on HAART. HIV-1 RNA was undetectable in 23% of those not taking antiretroviral medications. Most (72%) participants had received no anti-HCV therapy. HCV RNA was detected less frequently (59%) among participants treated with standard interferon plus ribavirin (P = 0.0001) and more frequently among HIV-1-positive than HIV-1-negative participants (85% vs. 70%, P < 0.0001). HIV-1-positive participants were more likely to have pancytopenia and subclinical hepatic abnormalities, as well as persistent jaundice, hepatomegaly, splenomegaly and ascites. HAART recipients did not differ from HIV-negative participants in the prevalence of ascites. The clinical abnormalities were more prevalent with older age but were not confounded by HBV status or self-reported alcohol consumption. Eleven participants presented with or previously had hepatocellular carcinoma or non-Hodgkin lymphoma. Although prospective analysis is needed, our data reveal the scale of hepatic and haematological disease that is likely to manifest in the adult haemophilic population during the coming years unless most of them are successfully treated for HIV-1, HCV or both.

In the 20th century, haemophilia evolved from a life-threatening, crippling disease to one for which the prognosis is excellent and many patients lead normal, productive lives. Although dramatic achievements in the treatment of haemophilia have occurred, the current therapies have significant drawbacks. Among these is the relatively high incidence of inhibitor development, the requirement for frequent intravenous infusions to prevent bleeding complications, the lack of effective treatment for established joint disease, and the high cost of treatment. The future goal of haemophilia treatment first and foremost is curing this genetic condition via gene therapy. As this goal is likely many years away, improvements in the current factor products in order to reduce the development of inhibitors and to reduce the frequency of therapy are more immediately achievable goals. Finally, improving the treatment of bleeding complications, particularly in inhibitor patients, and developing novel adjunctive therapies for the management of joint disease are also important goals for the near future. This review will discuss in detail the cu-rrent and future goals of haemophilia therapy.

Many issues affect hemophilia care providers when managing bleeding episodes in individuals with hemophilia. A diverse group of hemophilia providers from the United States met at two workshops to discuss the issues influencing treatment choices in the current millennium and to learn about current advances in treatment of hemophilia. This paper provides a summary of the discussions at these workshops. Despite the progress made in the management of patients with hemophilia, the workshop highlighted the fact that there were still many unanswered questions. Pediatr Blood Cancer 2005;45:611–615. © 2005 Wiley-Liss, Inc.

Summary. Liver biopsy plays a pivotal role in the management of patients with a variety of liver diseases, including chronic hepatitis C virus. The major risk of the procedure is the potential for significant haemorrhagic complications. Although the data are limited, the procedure does not appear to pose excessive risk to the patient with inherited disorders of coagulation, provided that adequate haemostasis can be achieved prior to the liver biopsy. This requires close coordination of care between the hepatologist and the haematologist. Indications for liver biopsy should be the same in patients with haemophilia as in other populations.

Immune thrombocytopenia purpura (ITP) is characterized by destruction of circulating platelets and the presence of antiplatelet antibodies. Many of the current immunomodulatory therapies act by reducing platelet destruction and usually do not have a lasting effect. This prospective, exploratory study characterized patients with ITP by identifying their demographic and comorbid clinical factors, use of treatments, serologic markers of autoimmunity, and possible relationships between platelet counts, concentrations of endogenous thrombopoietin (eTPO), and the presence of circulating anti-TPO antibodies. Data including medical history and laboratory evaluations were collected at a single patient visit on 205 patients (19 children, 186 adults). Reported histories revealed a 5% rate of thrombotic/ischemic events. Autoimmune markers including direct antiglobulin test and antinuclear antibodies were found more frequently than in the normal population; antiplatelet antibody testing was not done. eTPO concentrations were comparable to concentrations found in healthy volunteers. Our study confirmed that no significant inverse correlation occurred between circulating concentrations of eTPO and platelet counts in patients with ITP (Spearman r = -0.15). Two of the 205 patients tested (1%) had neutralizing activity of recombinant human TPO in a biological assay; however, this activity was confirmed to be anti-TPO antibody in only 1 patient.

The impact on the cost of care for haemophilia patients with inhibitors is not well defined. To quantify the effect on health care expenditures associated with inhibitors to factor VIII (FVIII) or FIX, we conducted a retrospective cohort study examining product use and outcomes in adult and paediatric haemophilia patients with and without inhibitors. Twelve patients with inhibitors to FVIII or FIX (cases) identified in the haemophilia surveillance system (HSS) at two centres were matched on age, severity of haemophilia, and treatment centre to haemophilia patients without inhibitors. Patients with HIV or significant liver disease were excluded from the study. All eligible non-inhibitor control patients were selected for inclusion in the study, resulting in a total of 28 controls. We then tracked product usage and hospitalizations from programme entry until 1998 or loss to follow-up, producing a total database of 184 person-years of experience. A descriptive matched analysis was conducted to examine annual differences in the cost of product used and hospitalizations. We found that the median cost for factor products among haemophilia patients with inhibitors was $55,853/year, $2,760 less than comparable haemophilia patients without inhibitors. The median number of hospitalizations per year was 1.0 for both inhibitor and non-inhibitor patients and the median number of days hospitalized was virtually the same. Although these findings do not appear to support the belief that there is a substantial increase in the cost of care for haemophilia patients with inhibitors, it does document that a few outlier patients can drive the cost of treatment for this disease. As the largest component of the cost of care is that of factor concentrate, it becomes imperative in the current health care environment to better define the true costs and benefits of treatments designed to eradicate or manage inhibitors. A careful cost accounting of immune tolerance induction (ITI) and other therapeutic strategies, taking into account successes and failures and duration and intensity of therapy, should help to better define the costs and benefits of such approaches. Methods to identify high cost inhibitor patients should be developed so that these strategies may be targeted to appropriate candidates.

Achieving adequate hemostasis in patients with hemophilia and high-titer inhibitor antibodies remains a challenge despite the development of plasma-derived and recombinant therapies to bypass the inhibitory effect. A group of hemophilia treaters met to examine the factors that influence physician choices among the very costly and cumbersome available therapies. Specific knowledge deficits in need of prospective research were identified with respect to the rational treatment of inhibitor patients.

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