9–36) for patients ≤18, and 11 (0.8–61) for adult patients. Less agreement was observed concerning estimated effective dose for secondary prophylaxis in adults: median 2000 IU every other day The majority (63%) of experts expected that a single minor joint bleed could cause irreversible damage, and would accept up to three minor joint bleeds or one trauma related joint bleed annually on prophylaxis. Expert judgement elicitation allowed structured capturing of quantitative selleck kinase inhibitor expert estimates. It generated novel data to be used

in computer modelling, clinical care, and trial design. “
“Summary.  In an ongoing health-technology assessment of haemophilia treatment in Sweden, performed by the governmental agency Dental and Pharmaceutical Benefits Agency (TLV; tandva˚rds-och lākemedelsförma˚nsverket), the Swedish Council on Health Technology Assessment (SBU; statens beredning för medicinsk utvārdering) was called upon to evaluate treatment of haemophilia A and B and von selleck chemicals Willebrand’s disease (VWD) with clotting factor concentrates. To evaluate the following questions: What are the short-term and long-term effects of different treatment strategies? What methods are available to treat haemophilia patients that have developed inhibitors against factor concentrates? Based on the questions addressed by the project, a systematic database search was conducted in PubMed, NHSEED, Cochrane Library, EMBASE

and other relevant databases. The literature search covered all studies in the field published from 1985 up to the spring of 2010. In most instances, the scientific evidence is insufficient for the questions raised in the review. Concentrates of coagulation factors have good haemostatic effects

on acute bleeding and surgical intervention in haemophilia A and B and VWD, but conclusions cannot be drawn about possible differences in the effects of different dosing strategies for acute bleeding and surgery. Prophylaxis initiated at a young age can prevent future joint damage in persons with RG7420 price haemophilia. The available treatment options for inhibitors have been insufficiently assessed. The economic consequences of various treatment regimens have been insufficiently analysed. Introduction of national and international registries is important. “
“Sweden has been a pioneer in the treatment of haemophilia, with the first concentrate available in the 1950s. Treatment has improved over the years to its current state-of-the art. The aim of the current study was to evaluate the long-term outcome of haemophilia in terms of incidence, morbidity and mortality. Patients diagnosed with haemophilia A or B registered at the national haemophilia centres and/or the Patient Registry and born before 2009 and alive in 1968 were enrolled and linked to the Cause of Death-, Migration- and Medical Birth registries. Five age- and sex-matched controls were selected for each patient. A total of 1431 patients with haemophilia A or B were compared with 7150 controls.

Preprocessing of the microarray data was done using robust multiarray analysis. Probe-set intensities

were transformed to logarithmic scale, and a cutoff of 5 was applied. Probe sets were considered to be differentially expressed if they showed click here a fold change equal to or greater than 2. This study was supported through the Israeli National Strategic Center For Gene Therapy located in the Goldyne Savad Institute of Gene Therapy at Hadassah University Hospital. In an effort to determine the effect of CCR5 on liver inflammation, we generated the two strains, Mdr2: CCR5 and the Mdr2:CCR1 DKOs. The rational to generate the Mdr2:CCR1 DKO was a result of the fact that it shares some of the ligands of CCR5 (e.g., RANTES and MIP-1α) and therefore would indicate whether the effects we observed were CCR5 specific. Analysis of liver sections revealed that there is a significant difference in inflammation between the Mdr2-KO mouse, the Mdr2:CCR5 DKO, and the Mdr2:CCR1 DKO. Whereas Mdr2-KO and Mdr2:CCR1 DKO mice exhibit massive

infiltration of immune NVP-BGJ398 ic50 cells to the liver, Mdr2:CCR5 DKO mice display significantly reduced inflammation (Fig. 1A). Immunohistochemical (IHC) staining of liver sections revealed a robust accumulation of F4/80+ macrophages and neutrophils in damaged livers of Mdr2-KO and Mdr2:CCR1-DKO mice, but not in Mdr2:CCR5-DKO mice (Fig. 1B,C and Supporting Fig. 1A,B). Overall, Mdr2:CCR5-DKO mice exhibit a significantly less-damaged liver. Hepatocyte damage was evaluated by measurement of serum ALT and AST. Liver enzyme levels of 1- to 6-month-old mice were measured to assess liver damage. High levels of ALT and AST were detected in the serum of Mdr2-KO, Mdr2:CCR5, and Mdr2:CCR1 DKO mice, compared to WT controls, implying that

hepatocyte Oxymatrine damage in all three mouse strains was significant, but, in the absence of CCR5, was not accompanied by inflammation (Fig. 1D). In an effort to understand the molecular, and possibly cellular, mechanism of HCC in Mdr2-KO mice, we performed, in a previous investigation, a gene expression profiling study. This investigation revealed a marked elevation of the inflammatory chemokine, RANTES, a ligand of both CCR1 and CCR5, in the liver of Mdr2-KO FVB.129 mice.[16] Using real-time PCR and ELISA assay, we confirmed that RANTES expression is indeed up-regulated in livers of Mdr2-KO C57Bl6 mice, compared to control C57Bl6 WT mice (Fig. 2A,B). The elevated levels in the liver of RANTES where found in all three strains, compared to WT mice (Fig. 2B). Surprisingly, we found that the levels of RANTES were increased significantly only in the blood of Mdr2:CCR5 DKO, compared to Mdr2-KO, and Mdr2:CCR1 DKO (Fig. 2C).

METHODS: Advanced liver fibrosis was induced in C57Bl/6 mice by repeated injections of thioacetamide (TAA). Novel anti-LOXL2 therapeutic antibody (AB0023mAB,

30mg/kg) or control antibody (M64, 30mg/kg) was administered i. p. twice a week (n=10-16 per group) during fibrosis progression (delayed treatment, from week 6 to 12 of TAA) or during fibrosis reversal (recovery, 1 to 12 weeks after TAA). Collagen cross-linking was assessed ex vivo using a step-wise collagen extraction/fractionation method. RESULTS: Immunohistochemical Selleckchem Crizotinib analysis revealed that LOXL2 was virtually absent from healthy liver, but was strongly induced in TAA-induced fibrotic liver, with predominant localization within fibrotic septa. Delayed anti-LOXL2 treatment of pre-established, JAK inhibitor advanced liver fibrosis (week 6 through 12 of TAA) inhibited fibrotic matrix stabilization, with a 30% reduction in the highly cross-linked collagen fraction. Histological signs of bridging fibrosis improved, with a 25% decrease in net collagen deposition in LOXL2-treated group as assessed biochemically via hydroxyproline (p = 0.025). When LOXL2 was inhibited during fibrosis recovery, profound

acceleration of remodeling of fibrotic septa was observed, with thinning and splitting of collagen fibrils histologically, and a 36% decrease in hepatic collagen levels (p = 0.021) peaking at the early recovery time-point (4 weeks). In contrast, no significant effect on collagen cross-linking, fibrosis progression, or reversal was detected

using histological or biochemical methods in control antibody -treated mice. CONCLUSIONS: 1) Antibody-mediated LOXL2 inhibition effectively suppressed collagen cross-linking during experimental liver fibrosis progression in vivo. 2) LOXL2 inhibition rapidly and potently accelerated hepatic fibrosis resolution in the recovery model from TAAinjury. 3) Feasibility of antibody targeting of LOXL2 to prevent and reverse liver cirrhosis should be evaluated in future clinical trials. Disclosures: Derek Marshall – Employment: Gilead Sciences Vivian Barry – Employment: Hydroxychloroquine Gilead Sciences, Inc.; Stock Shareholder: Gilead Sciences, Inc. Victoria Smith – Employment: Gilead Sciences Inc Satyajit Karnik – Employment: Gilead Sciences Nezam H. Afdhal – Consulting: Merck, Vertex, Idenix, GlaxoSmithKline, Springbank, Gilead, Pharmasett, Abbott; Grant/Research Support: Merck, Vertex, Idenix, GlaxoSmithKline, Springbank, Gilead, Pharmasett, Abbott Yury Popov – Consulting: Gilead Sciences, Inc, Ymir Genomics; Grant/Research Support: Gilead Sciences, Inc The following people have nothing to disclose: Naoki Ikenaga, Shuhei Yoshida, Susan B.

Fibrosis 4 (FIB4) scoring system based on routine laboratory tests is widely used to estimate the amount of liver fibrosis in NAFLD and help identify patients that would require further evaluation with a liver biopsy. Liver stiffness measurement (LSM) using vibration controlled transient elastography by Fibroscan is a novel non-invasive tool and currently available in the United States for assessment of liver fibrosis in patients with FK866 clinical trial chronic liver disease. Aim: The aim of the current study is to determine the diagnostic accuracy

of FIB4 and LSM for prediction of clinically significant fibrosis in patients with NAFLD and also examine the relationship between FIB4 score and LSM.

Methods: Patients with biopsy proven NAFLD (duration between liver biopsy and Fibroscan <1 year) or NASH related cirrhosis were identified from an IRB approved prospective database of patients undergoing Fibroscan. Clinically significant fibrosis was defined as presence of clinically obvious cirrhosis or METAVIR Fibrosis stage of ≥ 2. Results: A total of 94 patients met study inclusion criteria from a total of 217 NAFLD learn more patients that underwent Fibroscan. The mean age of the study cohort was 54 ± 10 years (60% woman; 94% Caucasian) with a BMI of 31 ± 12 kg/m2. The mean ALT was 49 ± 36 U/L. Clinically significant fibrosis was present in 70% (n=66)

of the study cohort. The diagnostic accuracy of LSM for clinically significant fibrosis was good (AUROC=0.81) while the diagnostic accuracy of FIB4 score was poor (AUROC=0.63) (Figure 1). The optimal LSM cut-off value for a diagnosis of clinically significant fibrosis was 10.3 Pembrolizumab order kPa with a sensitivity of 80% and specificity of 75%. The correlation between LSM and FIB score was weak but significant (r=0.35, p-val=0.001). Conclusion: LSM as measured by Fibroscan could be a useful tool for prediction of clinically significant fibrosis and appears to be superior to currently used FIB4 score. AUROC curves for LSM and FIB4 for clinically significant fibrosis in NAFLD Disclosures: Naga P. Chalasani – Consulting: Salix, Abbvie, Lilly, Boerhinger-Ingelham, Aege-rion; Grant/Research Support: Intercept, Lilly, Gilead, Cumberland, Galectin The following people have nothing to disclose: Raj Vuppalanchi, Samer Gaw-rieh, Regina Weber Nonalcoholic fatty liver disease (NAFLD), the most common cause of chronic liver disease in Western countries, may progress to cirrhosis, liver failure, and complicated hepatocellular carcinoma.

109 Aminotransferases improved more with metformin than with vitamin E or diet alone. However, there was only a modest improvement in hepatic steatosis

and inflammation in the subset of 17 patients undergoing paired liver biopsies with metformin treatment. In a 48-week open-label study in 26 patients, metformin improved NASH activity in only 30% of patients, although interpretation of the study was confounded by a significant weight loss in the responders (19% lost more than 10 kilograms).110 Haukeland et al.112 reported a similar lack of efficacy in a larger (n=48) randomized control trial (RCT) of metformin vs. placebo with a similar dietary and exercise intervention in both groups. Other studies also failed to show major benefit AP24534 for metformin on hepatic insulin sensitivity,

aminotransferases111-116 or liver histology.111, 113, 116 A recent meta-analysis4 concluded that 6-12 months of metformin plus lifestyle intervention did not improve aminotransferases or liver histology, compared with lifestyle intervention alone, independently of metformin dose or the presence of diabetes. Recommendation 19. Metformin has no significant effect on liver histology and is not recommended as a specific treatment for liver disease in adults with NASH. (Strength – 1, Evidence – A) Several studies investigated the effect of pioglitazone and rosiglitazone on aminotransferases and liver histology in adults with NASH. In an early uncontrolled open-label study117 17-AAG cell line in 22 subjects with biopsy-proven NASH, rosiglitazone improved aminotransferases

and hepatic steatosis, ballooning and inflammation scores, but not fibrosis. But in a subsequent RCT, Ratziu et al.118 observed that rosiglitazone improved aminotransferases and hepatic steatosis, but not necroinflammation or fibrosis and its two-year open-label extension phase also showed similar results.119 Belfort et al.120 conducted a RCT of pioglitazone (45 mg/day) in patients with NASH who had impaired glucose tolerance or T2DM. Although Cell Penetrating Peptide there was a significant weight gain (2.5 ± 0.5 kg) with pioglitazone, it significantly improved aminotransferases, steatosis, ballooning, and inflammation. The NAS improved with pioglitazone in 73% compared to 24% of placebo-treated patients (P<0.001) and there was a trend towards improvement in fibrosis among patients randomized to pioglitazone (P=0.08). Aithal et al.121 performed a RCT of lifestyle intervention with either pioglitazone 30 mg/day or placebo for 12 months in a total of 74 patients with NASH. While steatosis did not improve significantly compared to placebo, hepatocellular injury and fibrosis improved significantly.

pylori would likely result in the development of more resistant strains of Mycobacterium tuberculosis. It has already been illustrated that its efficacy

may be reduced somewhat by past rifampicin treatment [47]. Finally, serious myelotoxicity and ocular adverse events have been reported with this treatment [48,49]. Sequential therapy has been proposed as an alternative to standard triple therapy MK2206 for the eradication of H. pylori [50]. The primary goal of this regimen is to overcome clarithromycin resistance. Hypothetically, during the first 5 days of therapy, amoxicillin would weaken the bacterial cell wall, which prevents the formation of the channels that block clarithromycin from entering the bacterium and hence cause resistance to the antibiotic. Then, in the second phase of therapy, clarithromycin and a nitroimidazole are added for a further 5 days. Proton-pump inhibitor is continued throughout treatment. A meta-analysis demonstrated that eradication rates with sequential therapy are 93.4%

compared with 76.9% for standard triple therapy [19]. Another meta-analysis concluded that the number needed to treat (NNT) for sequential therapy to achieve eradication that would not have otherwise been achieved with standard triple therapy was 8 [51]. All of the studies in this meta-analysis were on Italian patients. Several studies in the last 12–18 months, however, have focussed on the efficacy of sequential therapy in other populations. In a Korean cohort, the eradication rate of sequential BAY 80-6946 nmr therapy was 91.8% by ITT [52]. In treatment naive patients in Turkey, ITT eradication rates were 82.1% in a trial which used sequential isothipendyl therapy with tetracycline [53]. Other forms of sequential therapy have also been trialed including a 14-day version, which substituted levofloxacin for clarithromycin. This also appears to be a viable option based on ITT eradication rates of over 80% in trials in Spain and Turkey [22,54]. Concomitant therapy has also been proposed. It is intended to reduce the complexity associated with sequential therapy by having the patient take all three antibiotics for the entire ten-day duration of therapy. When compared

to standard triple therapy in a meta-analysis, concomitant therapy had an ITT eradication rate of 89.7%, superior to standard triple therapy with a pooled odds ratio of 2.86 [55]. It must be noted that although it is designed to overcome clarithromycin resistance, clarithromycin is central to both sequential and concomitant therapy and would still be at the mercy of changes in patterns of clarithromycin resistance which are probably primarily contingent on the rates of prescription of clarithromycin in the community for non-gastrointestinal infections [56,57]. In addition, there exists a body of opinion that clarithromycin and metronidazole ought not be used together for H. pylori eradication as those who fail to have eradication will subsequently have at least single and often double resistance [58].

05). When compared to the RAT and RAP, only the results of endoscopy, which is statistically significant (P < 0.05) which was RAT better than RAP. Conclusion: The use of a combination of teprenone, ranitidine, and antacids provided improved clinical, endoscopy, histopathology, inflammatory cells better than the combination of ranitidine, antacids and placebo in chronic gastritis. Key Word(s): 1. chronic gastritis; 2. teprenone; 3. endoscopic; 4. histopathology; Presenting Author:

IMAM SUPRIANTO Additional Authors: MG-132 manufacturer SUYATA., SYADRA BARDIMAN, FUAD BAKRY Corresponding Author: IMAM SUPRIANTO Affiliations: Moehammad Hoesin hospital Objective: Chronic gastritis is a localized or diffuse chronic inflammation of the lining of the stomach, histopathologically characterized by infiltration of lymphocytes and plasma cells in the mucosa. The imbalance between aggressive and defensive factors leads to this condition. Teprenone is a systemic CHIR-99021 manufacturer cytoprotective agent used to repair gastric mucosal

lesions by increasing the synthesis, secretion, and mucus viscosity, increasing the gastric phospholipids, prostaglandin E2, prostacyclin and heat shock protein. The purpose of this study was to determine the effectiveness of teprenone as an adjunct in the treatment of chronic gastritis Methods: This study was a double blind randomized clinical trial in the form of add on, which conducted at the outpatient clinic of Gastroenterology and Hepatology, Department of Internal Medicine Moehammad Hoesin Hospital Palembang, from June 2011 until February 2012. Patients were divided into 2 groups: the group given ranitidine, antacids, placebo (RAP) and the group given ranitidine, antacids, teprenone (RAT) for 4 weeks. Effectiveness assessed by clinical improvement, endoscopy, histopathology, inflammatory cells and Helicobacter Pylori. Data were analyzed using SPSS version 17 with the X2 and T test. Results: Of

the 40 patients who participated in this study, 12 men and 28 women, there were statistically significant differences in the RAT groups in the improvement of clinical symptoms, endoscopy, histopathology, ADP ribosylation factor inflammatory cells and Helicobacter Pylori (P < 0.05). While in the RAP group, there was no significant difference in improvement of endoscopy, histopathology, inflammatory cells and Helicobacter Pylori (P > 0.05). When compared to the RAT and RAP, only the results of endoscopy, which is statistically significant (P < 0.05) which was RAT better than RAP. Conclusion: The use of a combination of teprenone, ranitidine, and antacids provided improved clinical, endoscopy, histopathology, inflammatory cells better than the combination of ranitidine, antacids and placebo in chronic gastritis. Key Word(s): 1. chronic gastritis; 2. teprenone; 3. endoscopic; 4.

942; 95% confidence interval [CI], 0.893–0.994) and cholesterol (OR, 0.981; 95%CI, 0.969–0.992) levels, older age (OR, 1.043; 95%CI, 1.002–1.085), Lapatinib in vivo high ferritin (OR, 1.003; 95%CI, 1.001–1.005), and necroinflammation (OR, 2.235; 95%CI, 1.014–4.929) were independently associated with severe fibrosis (F3–F4) by multivariate logistic analysis. Seventy patients (41%) achieved SVR. By multivariate analysis, hepatic steatosis (OR, 0.971; 95%CI, 0.944–0.999), lower cholesterol (OR, 1.009; 95% CI, 1.000–1.018), and 25(OH)D levels (OR, 1.039; 95%CI, 1.002–1.077) were independently associated with no SVR. Conclusion: G1 CHC patients had low 25(OH)D serum

levels, possibly because of reduced CYP27A1 expression. Low vitamin D is linked to severe fibrosis and low SVR on interferon (IFN)-based therapy. (HEPATOLOGY 2010.) T the activated hormonal form of vitamin D, 1-25-dihydroxyvitamin D, is essential for calcium and bone homeostasis.1, 2 Vitamin D 25 and 1α-hydroxylation occurs in the liver and in the kidney, respectively, involving different isoforms of cytochrome P450 (CYP), namely CYP2R1, CYP27A1, and others in the liver, and CYP27B1 in the kidney.3 Vitamin D deficiency is associated with many common and serious pathological Anti-infection Compound Library conditions, including cancer, autoimmune disease, cardiovascular disease, insulin resistance (IR), and diabetes.1, 4, 5 There is also an association between vitamin D status and both cholestatic and noncholestatic

chronic liver diseases.6–10 In patients with noncholestatic chronic hepatitis and cirrhosis, some studies8–10 have reported normal serum levels of 25-hydroxyvitamin D (25[OH]D), the liver-hydroxylated form of vitamin D and the best estimate of overall vitamin D status.1, 2 Conversely, other studies have found low serum 25(OH)D levels in patients with chronic hepatitis and cirrhosis of different origins.11–13 Low 25(OH)D levels have been Fossariinae related to poor liver function because of the association between vitamin D status and

hepatic function indexes11 or the stage of cirrhosis.11, 14, 15 In keeping with these studies, several reports describe reduced bone mineral density in patients with chronic liver disease8, 9, 13, 15, 17, 18 and cirrhosis.9, 10, 12, 13, 19 Recently, Targher et al.18 observed lower 25(OH)D serum levels in patients with biopsy-proven nonalcoholic fatty liver disease, identifying an independent association between the histological characteristics of nonalcoholic fatty liver disease and low 25(OH)D levels. Experimental evidence also suggested the potential ability of vitamin D, through interaction with its nuclear receptor (vitamin D receptor), to interfere with inflammatory response and fibrogenesis.4 The aim of our study was to evaluate serum levels of 25(OH)D in a cohort of patients with biopsy-proven genotype 1 (G1) chronic hepatitis C (CHC), and to investigate the potential relationships between 25(OH)D, the histological features of disease, and the response to antiviral therapy.

“
“The “Guideline on the Use of New Anticancer Drugs for the Treatment of Hepatocellular Carcinoma” was prepared by the Study Group on New Liver Cancer Therapies established

by the “Research Project on Emergency Measures to Overcome Hepatitis” under the auspices of the Health and Labour Sciences Research Grant. The Guideline brings together data collected by the Study Group on the use and incidence of adverse events in 264 patients with advanced hepatocellular carcinoma (HCC) treated using sorafenib and in 535 patients with advanced HCC treated using miriplatin at 16 participating institutions up until 22 December 2010, as well as referring to the published studies, academic presentations, and reports from the private sector. The aim of this Guideline is to facilitate understanding and current thinking regarding the Palbociclib nmr proper usage of new anticancer drugs towards actual use in therapy. In terms of the format, the Guideline presents “clinical questions” on issues pertaining to medical care, makes “recommendations” on diagnosis and treatment in response to each of

Ferroptosis inhibitor these clinical questions, and provides a rationale for these recommendations in the form of “scientific statements”. “
“Background and Aims:  There is growing evidence that genetic mutations/variants increase susceptibility to the development and progression of chronic pancreatitis (CP). Several mutations have been identified that have a direct and indirect role in events leading to CP. Mutations in the serine protease inhibitor, Kazal type-1 (SPINK-1) gene have been reported to lower the threshold for pancreatitis in the presence of other genetic or environmental factors. The prevalence and impact of SPINK-1 mutations on the clinical course and outcomes of CP remains unclear. This study was conducted to assess the prevalence

of the SPINK-1/N34S variant in patients with CP, and to understand the impact of the SPINK-1 mutation on the natural history of CP. Methods:  A retrospective-prospective analysis of 239 patients with CP was performed. A detailed history, including duration of symptoms, type of pain (intermittent flares or chronic continuous pain), number of flares requiring hospital admission, alcohol and smoking history, and family find more history was obtained. The baseline morphological stage of CP was categorized by Cambridge classification. Clinical outcome variables included frequency and severity of pain episodes, presence of exocrine failure (defined by presence of steatorrhea and/or fecal elastase < 200 ug/g), and diabetes. The genetic tests included the cationic trypsinogen gene-1 mutation, cystic fibrosis gene mutations (Genzyme assay), and the SPINK-1/N34S mutation. Results:  Of the 239 patients with CP, 13 (5.4%) were positive for the SPINK-1/N34S mutation. There were 35 (14.6%) patients with idiopathic pancreatitis (IP) in this cohort.

The past few years have reflected a second landmark in the development of therapeutic agents, and many new products are now being introduced into the market for patients with or without inhibitor. This article discusses progress with the development of a range of modern haemostasis products, and includes descriptions of new bypassing agents, biosimilar substances and materials for the treatment of rare bleeding disorders. Essential considerations for the current treatment

of haemophilia patients include the requirement for frequent intravenous injections and the development of inhibitors. Although longer acting FVIII or FIX products offer a very promising Crizotinib clinical trial improvement for regular prophylactic treatment, physical and mental burdens remain especially in paediatric and old patient groups. Furthermore, the risk of inhibitor development remains a serious problem. Existing bypassing agents such as rFVIIa and APCC do not always provide adequate haemostasis, and clinical management is more challenging in patients with high-responding inhibitors who fail ITI. In this context, therefore, more potent and longer acting bypassing agents are being investigated. Recently, two novel bypassing agents have been developed in Japan; an intrinsic bypassing agent, hBS23, which is a humanized bispecific antibody to FIXa and FX mimicking FVIIIa, and a plasma-derived buy RG7420 extrinsic bypassing agent (MC710) comprising a mixture of FVIIa

and FX. Clinical trials using these agents are ongoing or recently completed. The principle of the bispecific antibody is based on the hypothesis that FVIII co-factor function is enhanced by interactions between FIXa and FX. The humanized IgG antibody, designated hBS23, targets both proteins, and effectively acts as FVIIIa in the blood clotting cascade by spatially arranging the two target molecules, in correct contact with each other, to facilitate FXIa-catalyzed conversion of FX to its activated form FXa. [1]. Kinetic studies of FXa generation by FIXa in the presence of phospholipid indicated that hBS23 increased the kcat/Km by 2 × 104 -fold equivalent to 7.3% FVIIIa. Conventionally, native FVIII is activated

by thrombin PD184352 (CI-1040) generated in the initial coagulation process triggered by extrinsic TF/FVIIa. In contrast, the bispecific antibody mimics FVIIIa and is not dependent on thrombin activation. In consequence, the haemostatic effectiveness of the antibody is rapid and does not need stabilization by VWF. Furthermore, the reaction is not affected by APC/PS or by the presence of FVIII inhibitors. Initial studies demonstrated that the antibody shortened the APTT of haemophilia A plasma with inhibitor to within normal range and an intravenous dose of 0.3 mg kg−1 exerted haemostatic activity preventing the progression of bleeding symptoms in a non-human primate model of acquired haemophilia A to the same extent as recombinant porcine FVIII maintained at a plasma level of ≥1 U dL−1.