Hepatocellular carcinoma (HCC) is a major complication of chronic hepatitis C virus (HCV) infection. Among haemophilic (H) men, HCV is the leading cause of liver disease. Direct-acting antiviral agents (DAA) reduce HCV viral load, but impact on HCC is unknown.This was a retrospective study of adult H and nonhaemophilic (NH) male discharges, with and without HCC, identified by ICD-10 codes in the National Inpatient Sample (NIS) database, 2016-2018, with DAA availability. Analyses included discharge-level weights to reflect national estimates. Categorical variables were assessed by Rao-Scott chi-square and continuous variables by weighted simple linear regression. HCC correlates were determined by weighted multivariable logistic regression.Among 7,674,969 adult male discharges, 3730 H (.04%) were identified in 2016-2018, of whom 10.06% had HCV and 1.07% had HCC, significantly higher than NH (1.22% and .27%, respectively) all P < .001. Annual HCC rates were similar during the 3-year period (2016-2018) in H and NH. Among H, HCC is associated with older age and higher rates of HCV, HBV, NASH, end-stage liver disease, and Charlson comorbidity (CCI), each P < .001. Among HCC, H were younger and more likely HIV+, each P < .001, but less likely alcoholic (P = .018) or hyperlipidaemic (P = .008) compared to NH. In multivariable regression, risk factors for HCC among H included NASH (OR 21.6), HCV (OR 3.96), CCI (OR1.54), all P < .001, while HIV and hyperlipidaemia were protective.From 2016 to 2018, HCC rates did not change significantly in haemophilia discharges. NASH, HCV, and CCI are significant risks for HCC in haemophilia during the DAA-era.
Abstract The immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide yield high response rates in patients with multiple myeloma, but the use of IMiDs in multiple myeloma is associated with neutropenia and increased risk for venous thromboembolism (VTE) by mechanisms that are unknown. We show that IMiDs down-regulate PU.1, a key transcription factor involved in granulocyte differentiation in vitro and in patients treated with lenalidomide. Loss of PU.1 results in transient maturation arrest with medullary accumulation of immature myeloid precursors and subsequent neutropenia. Accumulation of promyelocytes leads to high levels of the platelet aggregation agonist, cathepsin G stored in the azurophilic granules of promyelocytes. High levels of cathepsin G subsequently may increase the risk of VTE. To our knowledge, this is the first report investigating the underlying mechanism of IMiD-induced neutropenia and increased risk of VTE in multiple myeloma.
Recurrent joint bleeds are a major cause of morbidity in severe hemophilia. Prophylaxis with efmoroctocog alfa (a recombinant factor VIII Fc fusion protein, [rFVIIIFc]) has demonstrated benefits beyond bleed control, including joint health maintenance.To assess long-term efficacy and safety of rFVIIIFc prophylaxis in severe hemophilia A in phase 3 pivotal (A-LONG/Kids A-LONG) and extension (ASPIRE) studies.Longitudinal analysis included pooled data from A-LONG/Kids A-LONG and ASPIRE. Subgroup analyses investigated outcomes in modified Hemophilia Joint Health Score or Hemophilia Joint Health Score and target joints in subjects with 4 to 5 years follow-up on individualized prophylaxis (IP), and those with the highest annualized bleeding rate (ABR) quartile during Year 1 of IP.Overall, rFVIIIFc consumption remained stable and low ABRs were maintained, with a median treatment duration of 4.2/3.4 years in subjects from A-LONG/Kids A-LONG, respectively. Median overall ABR also remained low (1.0-2.0) in subjects on IP for 4 to 5 years. Sustained improvements in modified Hemophilia Joint Health Score or Hemophilia Joint Health Score were demonstrated over a median follow-up of 3.7 years. In subjects from A-LONG/Kids A-LONG, 99.6% (n = 234)/100% (n = 9) of evaluable baseline target joints were resolved, with no recurrence in 95%/100% of target joints. In IP subjects within the highest ABR quartile in Year 1, continued improvements were observed over a median follow-up of 4.3 years in ABR and joint health, without increased factor consumption. No inhibitors or treatment-related serious adverse events were reported.Previously treated subjects of all ages receiving long-term prophylaxis with rFVIIIFc had sustained clinical benefits, including improved joint health and low ABR.
Bleeding and bruising are common symptoms for which children are referred to a pediatric hematologist. Although bleeding scores have been validated to quantify bleeding risk in adults, there are no similar definitive data in children. The aim was to describe presenting bleeding symptoms in children and evaluate if these bleeding symptoms were predictive of von Willebrand disease (VWD) or low von Willebrand factor (VWF).We performed a retrospective chart review of consecutive pediatric patients referred for perceived bleeding symptoms to the coagulation clinic at The Children's Hospital of Pittsburgh of UPMC. All underwent a uniform bleeding symptom inventory and hemostatic testing. Single and multiple variable logistic regression models were created to predict either VWD, low VWF, or nonspecific defective platelet aggregation, using the predictor variables of family bleeding history, mucocutaneous bleeding, cutaneous bleeding, and surgical bleeding, based on The International Society on Thrombosis and Hemostasis (ISTH) bleeding definitions.Of 298 pediatric patients evaluated, 8% had VWD (VWF:RCo and VWF:Ag ≤ 30 IU/dl) and 34% had low VWF (VWF:RCo and VWF:Ag 30-50 IU/dl). Further, 16% had a nonspecific platelet aggregation disorder, 41% had normal hemostatic testing, and 1% had factor VIII or IX deficiency. In single and multiple variable logistic regression analysis, neither a personal or family bleeding history at presentation, nor the presence of two or more bleeding symptoms were predictive of VWD, low VWF, or nonspecific defective platelet aggregation.These findings suggest that qualitative assessment of bleeding symptoms alone is not useful in children.
von Willebrand factor (VWF) is a multimeric glycoprotein that mediates platelet adhesion and is decreased in von Willebrand disease (VWD). 1-8 deamino-d-arginine vasopressin (DDAVP), the most common treatment for VWD, is limited by tachyphylaxis and inconvenience, and in 20% of the patients, unresponsiveness. Recombinant human interleukin-11 (rhIL-11), a gp-130 signalling cytokine with haematopoietic and anti-inflammatory activity, increases VWF antigen and its activity in heterozygous VWF(+/-) mice and dogs. To determine the biological efficacy and safety of rhIL-11 in non-bleeding human subjects with mild VWD, we conducted a phase II prospective open-label trial of rhIL-11 at 10, 25 and 50 mug kg(-1) subcutaneously (s.c.), given daily for 7 days in nine subjects with mild VWD. VWF and factor VIII (FVIII) levels increased gradually and progressively after s.c. rhIL-11, which was sustained through 7 days of dosing to 1.5- to 3-fold over baseline. Following intravenous DDAVP, 0.3 mug kg(-1), on day 7 there was a further boost in VWF and FVIII levels, suggesting that the mechanism of rhIL-11 differs from that of DDAVP. Platelet VWF mRNA expression measured by quantitative PCR increased from two- to eightfold over baseline, suggesting that the mechanism of rhIL-11 effect may be upregulation of VWF mRNA. VWF and FVIII levels returned to baseline by day 14. rhIL-11 was well tolerated with less than grade-1 hypertension, hypokalaemia and fluid retention. Recombinant IL-11 increases VWF levels in humans with mild VWD, justifying future clinical trials to determine its potential in preventing or reducing bleeding in this patient population.
