Complications to acute bacterial rhinosinusitis in children - a prospective study; bacterial cultures, virus detection, allergy sensitization and immunoglobulins.

BACKGROUND: Prospective studies of complications due to acute rhinosinusitis are lacking, bacterial cultures are hard to obtain and the role of airborne allergies, viruses and immunoglobulin levels are unclear. The aim was to investigate the role of bacteria, viruses, allergy and immunoglobulins in children hospitalized due to rhinosinusitis. METHODOLOGY: A prospective cohort study in Stockholm, Sweden, of children up to 18 years of age, hospitalized due to acute bacterial rhinosinusitis, from April 1st, 2017 to April 1st, 2020. RESULTS: Of 55 children included, 51% had a positive viral nasopharyngeal PCR and 29% had a positive allergy sensitization test. A higher percentage of middle meatus cultures were positive for bacterial growth compared to nasopharyngeal and displayed a wider array of bacteria. Dominating bacteria were S. milleri in surgical (7/12 cases), S. pyogenes in middle meatus (13/52 cases), and S. pyogenes and H. influenza in nasopharyngeal cultures (8/50 cases respectively). Nasal cultures were negative in 50% of surgical cases. An association was found between S. pyogenes and peak CRP; H. influenzae and peak CRP; S. pneumoniae and peak CRP; and possibly between M. catarrhalis and days of IV antibiotics. Further, an association between influenza A/B and S. pyogenes; a positive viral PCR and lower grade of complication and peak CRP; and a possible association between influenza virus and lower grade of complication. Allergy sensitization was possibly associated with a higher number of days with IV antibiotics. No immunoglobulin deficiencies were found. CONCLUSIONS: There seem to be differences in the patterns of bacterial growth in nasopharyngeal, middle meatus and surgical cultures in children with complications to acute bacterial rhinosinusitis. Presence of certain viruses and sensitization to airborne allergies seem to play a role in complications to acute bacterial rhinosinusitis in children.

Antibodies to calnexin and mutated calreticulin are common in human sera.

PURPOSE OF THE STUDY: Calreticulin is an endoplasmic reticulum chaperone protein, which is involved in protein folding and in peptide loading of major histocompatibility complex class I molecules together with its homolog calnexin. Mutated calreticulin is associated with a group of hemopoietic disorders, especially myeloproliferative neoplasms. Currently only the cellular immune response to mutated calreticulin has been described, although preliminary findings have indicated that antibodies to mutated calreticulin are not specific for myeloproliferative disorders. These findings have prompted us to characterize the humoral immune response to mutated calreticulin and its chaperone homologue calnexin. PATIENTS AND METHODS: We analyzed sera from myeloproliferative neoplasm patients, healthy donors and relapsing-remitting multiple sclerosis patients for the occurrence of autoantibodies to wild type and mutated calreticulin forms and to calnexin by enzyme-linked immunosorbent assay. RESULTS: Antibodies to mutated calreticulin and calnexin were present at similar levels in serum samples of myeloproliferative neoplasm and multiple sclerosis patients as well as healthy donors. Moreover, a high correlation between antibodies to mutated calreticulin and calnexin was seen for all patient and control groups. Epitope binding studies indicated that cross-reactive antibodies bound to a three-dimensional epitope encompassing a short linear sequence in the C-terminal of mutated calreticulin and calnexin. CONCLUSION: Collectively, these findings indicate that calreticulin mutations may be common and not necessarily lead to onset of myeloproliferative neoplasm, possibly due to elimination of cells with mutations. This, in turn, may suggest that additional molecular changes may be required for development of myeloproliferative neoplasm.

A novel desmoplakin mutation causes dilated cardiomyopathy with palmoplantar keratoderma as an early clinical sign.

BACKGROUND: PPKs represent a heterogeneous group of disorders with hyperkeratosis of palmar and/or plantar skin. PPK, hair shaft abnormalities, cardiomyopathy and arrhythmias can be caused by mutations in desmosomal genes, e.g. desmoplakin (DSP). PPK should trigger genetic testing to reveal mutations with possible related cardiac disease. OBJECTIVES: To report a large multigenerational family with a novel DSP mutation associated with early-onset PPK and adult-onset cardiomyopathy and arrhythmias. METHODS: A custom-designed in-house panel of 35 PPK related genes was used to screen mutations in the index patient with focal PPK. The identified DSP mutation was verified by Sanger sequencing. DNA samples from 20 members of the large multigenerational family were sequenced for the DSP mutation. Medical records were reviewed. Clinical dermatological evaluation was performed, including light microscopy of hair samples. Cardiac evaluation included clinical examination, echocardiography, cardiac magnetic resonance imaging (CMR), electrocardiogram (ECG), Holter monitoring and laboratory tests. RESULTS: We identified a novel autosomal dominant truncating DSP c.2493delA p.(Glu831Aspfs*33) mutation associated with dilated cardiomyopathy (DCM) with arrhythmia susceptibility and focal PPK as an early cutaneous sign. The mutation was found in nine affected family members, but not in any unaffected members. Onset of dermatological findings preceded cardiac symptoms which were variable and occurred at adult age. CONCLUSIONS: We report a novel truncating DSP mutation causing focal PPK with varying severity and left ventricular dilatation and ventricular extrasystoles. This finding emphasizes the importance of genetic diagnosis in patients with PPK for clinical counselling and management of cardiomyopathies and arrhythmias.

Induction of remission in female rheumatoid arthritis patients is associated with stabilization of myocardial abnormalities: a prospective cardiac magnetic resonance follow-up study.

Objectives: To study whether female patients with active rheumatoid arthritis (RA) have myocardial abnormalities and whether progression of myocardial involvement can be attenuated by disease-modifying anti-rheumatic drugs (DMARDs).Method: Cardiac magnetic resonance (cMR; 1.5 or 3.0 T), including late gadolinium enhancement (LGE), T1 relaxation time, and ventricular functions, was performed in 30 patients with untreated active early RA starting first DMARDs, and 28 patients with chronic RA with inadequate response to conventional synthetic DMARDs starting biological DMARDs. cMR was repeated in RA patients 1 year later. cMR was conducted once in 22 fibromyalgia (FM) subjects and in 35 healthy volunteers serving as controls. All subjects were non-smoking females without coronary heart disease, heart failure, or diabetes.Results: Compared with controls, 58 RA patients had slightly lower ventricular function, although in the normal range, and longer T1 time at baseline. None of the FM subjects had LGE, but it was frequent in RA (67%). During the 1 year DMARD treatment, Disease Activity Score based on 28-joint count-C-reactive protein declined, ventricular functions tended to improve, but the number of patients with LGE remained unchanged. However, the number of LGE-positive heart segments either decreased or stayed the same in 91% of RA patients. In early RA patients, achieving tight remission was associated with LGE stabilization, after adjustment for age, metabolic syndrome, baseline inflammatory activity, and leisure-time physical activity.Conclusion: Treatment targeted to tight remission in early stages of RA seems to be important to prevent not only joint damage but also myocardial abnormalities.

Sinonasal outcome test-22 and peak nasal inspiratory flow - valuable tools in obstructive sleep apnoea.

BACKGROUND: Sinonasal complaints contribute to low adherence to continuous positive airway pressure (CPAP) treatment. We aimed to investigate sinonasal health in obstructive sleep apnoea (OSA) patients, using the sinonasal outcome test-22 (SNOT-22), and to analyse whether SNOT-22 is affected by CPAP adherence. We also aimed to investigate whether peak nasal inspiratory flow (PNIF) was able to predict adherence to CPAP. METHODS: The study population comprised 197 OSA patients (60 females) initiating CPAP treatment. The SNOT-22, PNIF and the Epworth Sleepiness Scale were assessed at baseline and follow-up. One-night polygraphy, the Hospital Anxiety and Depression Scale, peak expiratory flow and health-related issues were assessed at baseline. At follow-up, the patients were categorised into adherent (more than 4 hours/night) and non-adherent (less than 4 hours/night) to CPAP treatment. RESULTS: The average time for following up CPAP treatment was (mean plus or minus SD) 24.0 plus or minus 23.9 days and it did not differ significantly between the groups. The SNOT-22 score was elevated among all OSA patients, 36.1 plus or minus 19.4. There was a larger improvement in the SNOT-22 score at follow-up among adherent CPAP users compared with non-adherent users (-10.4 plus or minus 13.9 vs. -3.2 plus or minus 15.4). A PNIF value of less than 100 litres/min increased the risk of non-adherence to CPAP with an adjusted odds ratio (OR) of 2.40 ((95% CI 1.16-5.00)). CONCLUSIONS: The SNOT-22 was elevated in patients with OSA, indicating a considerable sinonasal disease burden. The SNOT-22 improved with good CPAP adherence. A low PNIF value was able to predict poor CPAP adherence. Both the SNOT-22 and PNIF can be valuable tools in the evaluation of OSA patients and in the management of CPAP treatment.

Clinical management of 52 consecutive retro-rectal tumours treated at a tertiary referral centre.

AIM: The aim of this single-institution study was to analyse the diagnostic methods, preoperative work-up and outcomes of 52 retro-rectal tumours. METHOD: All patients treated for retro-rectal tumours from 2012 to 2017 were included. RESULTS: Out of 52 patients, 40 (77%) were women. The median age of patients at the time of surgery was 43 (19-76) years, and 30 (58%) were asymptomatic at the time of diagnosis. All tumours were visible on magnetic resonance imaging (MRI) prior to surgery. The sensitivity and specificity for predicting malignancy on preoperative imaging for retro-rectal tumours were 25% and 98%, respectively. Forty-four procedures (85%) were performed using the perineal approach. The median hospital stay was 3 (1-18) days. There was no 30-day postoperative mortality. Eleven (21%) patients developed postoperative complications, mostly surgical site infections. Twenty-nine tumours (56%) were benign tailgut cysts. Four (8%) tumours were malignant and were considered to be removed with a tumour-free resection margin. Local recurrent disease was detected on MRI in 14 (27%) patients at a median of 1.05 (range 0.78-1.77) years after primary surgery. Only the multi-lobular shape of the tumour was found to be an independent risk factor for recurrence (P = 0.030). CONCLUSION: A preoperative MRI is mandatory in order to plan the surgical strategy for retro-rectal tumours. Symptomatic, solid, large tumours should be removed because of the risk of malignancy. Minor cystic lesions with thin walls as well as asymptomatic recurrences of benign tumours are suitable to be followed conservatively.

Oncological outcomes before and after the extralevator abdominoperineal excision era in rectal cancer patients treated with abdominoperineal excision in a single centre, high volume unit.

AIM: The extralevator abdominoperineal excision (ELAPE) has been expected to reduce the risk of positive circumferential resection margins (CRMs) and local recurrence in locally advanced distal rectal cancer. The aim was to determine whether there is any difference in local recurrence rates between patients who were operated on for distal rectal cancer before and after the introduction of ELAPE in our unit. PATIENTS AND METHODS: In all, 206 patients with distal rectal cancer without distant metastases (T1-4N0-2M0) were treated with curative intent. The patients were divided into two cohorts operated in 2000-2007 (A) and 2008-2014 (B). The ELAPE procedure was introduced in 2008. Since then, it has been used in cases of T4 and T3 tumours with threatened margins. In T1-T3 tumours without threatened margins a conventional abdominal perineal excision has been performed. RESULTS: There was no significant difference in overall survival or cancer-specific survival between the two time periods. The local recurrence rate was 15.5% in group A and 6.7% in group B (P = 0.048), although there was no significant difference in the cumulative local recurrence rate. Intra-operative tumour perforation occurred significantly more often during the earlier period when ELAPE was not in use: group A 15/71 (21.1%) vs group B 11/135 (8.1%), P = 0.01. CRM was positive more often in group A (16.4%) vs group B (7.4%), P = 0.054. CONCLUSION: The local recurrence rate, intra-operative tumour perforation and positive CRM rate were significantly lower during the later period when more extensive surgery (ELAPE) was performed for locally advanced T3-T4 rectal cancer with threatened margins.

Age-adjusted D-dimer cut-off leads to more efficient diagnosis of venous thromboembolism in the emergency department: a comparison of four assays.

Essentials Age-adjusted D-dimer cut-offs decrease the false positives in the elderly. Four D-dimer assays were compared in venous thromboembolism outpatients in an emergency ward. Age-adjusted cut-off resulted in improved specificity with maintained sensitivity for all assays. There was a substantial decrease in false positive results, especially in the older population. SUMMARY: Background The study compares different D-dimer assays and age-adjusted cut-offs in outpatients with suspected venous thromboembolism (VTE). The plasma concentration of this sensitive biomarker is increased by activated coagulation, but also by several conditions that are linked to an increased risk of VTE. One such condition is old age, which poses a common clinical problem where many prefer not to analyze D-dimer in elderly patients. Age-adjusted cut-offs have been validated for both deep venous thrombosis (DVT) and pulmonary embolism, aiming to increase specificity without notably decreasing sensitivity. Objectives We evaluated four common D-dimer assays in parallel, with and without applying age-adjusted cut offs for VTE. Patients/methods The prospective single-center study was conducted in 940 outpatients attending the emergency department with clinically suspected pulmonary embolism or DVT. Four automated D-dimer assays were compared (Siemens INNOVANCE® , Roche Tina-quant, Medirox MRX and STA® -Liatest® D-Di PLUS). Results All assays performed with areas under the ROC curve (AUC) > 0.9 and maintained their sensitivities after implementation of age-adjusted cut-offs. Specificities increased by 6-7% and number needed to test decreased by < 0.3. The rate of false positive results decreased by 6% overall and by 10-20% for patients ≥ 70. Conclusions Age-adjusted cut-offs resulted in maintained high sensitivity and a modest improvement in specificity and number needed to test for all evaluated D-dimer assays. There was a significant reduction in false positive results, which reflects avoidable unnecessary imaging without any compromise of clinical safety. This suggests a potential to benefit the management of VTE in elderly patients, both clinically and economically.

The Largest Electron Differential Energy Flux Observed at Mars by the Mars Express Spacecraft, 2004-2016.

The goal of this paper is to understand the processes by which solar wind electrons are energized in the Martian magnetosphere and how this compares to processes at Venus and Earth. Each is unique in the source of its magnetic field topology and how this influences electron energization. To achieve this goal, 24 million spectra spanning 13 years have been examined using the electron spectrometer from the Mars Express spacecraft between about 12,000 km and about 250 km altitude, and from all latitudes and local times. The top 10 largest differential energy flux at energies above the differential energy flux peak have been found: seven spectra from the magnetosheath near noon, three from the dark tail (the largest two from the middle and ionospheric edge of the magnetosheath). Spectral comparisons show a decade range in the peak of the electron distributions; however, all distributions show a similar energy maximum dictated by solar wind/planet interaction. Similarly derived, the largest Venus spectrum occurred near the magnetosheath bow shock and had the same shape as the most intense Mars inner magnetosheath spectrum. The Mars and Venus dayside spectra compared to the Mars nightside spectrum that included an enhanced optical signal attributed to discrete "auroral" precipitation show a similar shape. These spectra are also compared to a selected auroral zone electron spectra from the Earth. The Mars and Venus results suggest that there is no more energy needed to generate electrons forming the nightside precipitation than is gained during the solar wind/planet interaction.

The calreticulin (CALR) exon 9 mutations are promising targets for cancer immune therapy.

The calreticulin (CALR) exon 9 mutations are found in ∼30% of patients with essential thrombocythemia and primary myelofibrosis. Recently, we reported spontaneous immune responses against the CALR mutations. Here, we describe that CALR-mutant (CALRmut)-specific T cells are able to specifically recognize CALRmut cells. First, we established a T-cell culture specific for a CALRmut epitope. These specific T cells were able to recognize several epitopes in the CALRmut C terminus. Next, we established a CALRmut-specific CD4+ T-cell clone by limiting dilution. These CD4+ T cells recognized autologous CALRmut monocytes and hematopoietic stem cells, and T-cell recognition of target cells was dependent on the presence of CALR. Furthermore, we showed that the CALRmut response was human leukocyte antigen (HLA)-DR restricted. Finally, we demonstrated that the CALRmut-specific CD4+ T cells, despite their phenotype, were cytotoxic to autologous CALRmut cells, and that the cytotoxicity was mediated by degranulation of the T cells. In conclusion, the CALR exon 9 mutations are targets for specific T cells and thus are promising targets for cancer immune therapy such as peptide vaccination in patients harboring CALR exon 9 mutations.

Mortality caused by intracranial bleeding in non-severe hemophilia A patients.

Essentials Data on bleeding-related causes of death in non-severe hemophilia A (HA) patients are scarce. Such data may provide new insights into areas of care that can be improved. Non-severe HA patients have an increased risk of dying from intracranial bleeding. This demonstrates the need for specialized care for non-severe HA patients. SUMMARY: Background Non-severe hemophilia (factor VIII concentration [FVIII:C] of 2-40 IU dL-1 ) is characterized by a milder bleeding phenotype than severe hemophilia A. However, some patients with non-severe hemophilia A suffer from severe bleeding complications that may result in death. Data on bleeding-related causes of death, such as fatal intracranial bleeding, in non-severe patients are scarce. Such data may provide new insights into areas of care that can be improved. Aims To describe mortality rates, risk factors and comorbidities associated with fatal intracranial bleeding in non-severe hemophilia A patients. Methods We analyzed data from the INSIGHT study, an international cohort study of all non-severe hemophilia A patients treated with FVIII concentrates during the observation period between 1980 and 2010 in 34 participating centers across Europe and Australia. Clinical data and vital status were collected from 2709 patients. We report the standardized mortality rate for patients who suffered from fatal intracranial bleeding, using a general European male population as a control population. Results Twelve per cent of the 148 deceased patients in our cohort of 2709 patients died from intracranial bleeding. The mortality rate between 1996 and 2010 for all ages was 3.5-fold higher than that in the general population (95% confidence interval [CI] 2.0-5.8). Patients who died from intracranial bleeding mostly presented with mild hemophilia without clear comorbidities. Conclusion Non-severe hemophilia A patients have an increased risk of dying from intracranial bleeding in comparison with the general population. This demonstrates the need for specialized care for non-severe hemophilia A patients.

The association between health utility and joint status among people with severe haemophilia A: findings from the KAPPA register.

INTRODUCTION: People with severe haemophilia A have reportedly impaired health related quality of life (utility) mainly due to recurrent bleeding, arthropathy and treatment burden. AIM: To estimate utilities and evaluate their potential correlates - most importantly the joint status - among people with severe haemophilia A. METHODS: In this cross-sectional study, eligible participants had severe haemophilia A, were aged ≥15, negative for factor VIII inhibitor and included in the KAPPA register of Denmark, Norway and Sweden. Data on demographics, treatment history, haemophilia joint health score, and EQ-5D utility were obtained from the register. We used box plots to present utilities and joint status and ordinary least squares regression to evaluate correlates of utilities. Participants were consecutively enrolled in the KAPPA register between April 2013 and June 2016. RESULTS: Overall, 173 participants with median age of 34 (interquartile range: 25-45) were included. Twelve (6.9%) participants were on episodic treatment while 161 (93.1%) were treated using prophylaxis. Concomitant diseases and positive inhibitor history were reported for 73 (43.2%) and 21 (12.1%) participants, respectively. The highest median utility (1.0) was observed among those aged <29 on prophylaxis and those aged 30-44 who had started prophylaxis by age 3. In the multi-variable regression, joint scores of 16-25 (Coef. -0.18, 95% CI: -0.30, -0.06), 26-35 (Coef. -0.21, 95% CI: -0.36, -0.06) and >35 (Coef. -0.37, 95% CI: -0.52, -0.23) were associated with lower utilities. CONCLUSION: Moderate to severe joint manifestations are associated with reduced utilities among persons with severe haemophilia A.

Comparative burden of arthropathy in mild haemophilia: a register-based study in Sweden.

INTRODUCTION: Mild haemophilia is a congenital bleeding disorder affecting males. The burden of arthropathy in mild haemophilia has not been comprehensively described. AIM: The aim of this study was to compare the incidence, age at diagnosis and surgery for arthropathy and related hospitalizations between people with mild haemophilia and the general population in Sweden. METHODS: This was a register-based cohort study. Eligible participants were those with mild haemophilia born between 1941 and 2008 and a randomly selected, birthdate and sex-matched comparison group from the general population. Follow-up was from birth (or earliest 1984) until death, emigration or end of the study in 2008. Data on arthropathy were obtained from a national patient register. Negative binomial and competing risk regression and Kaplan-Meier estimate curves were used in the analysis. RESULTS: Overall, 315 people with haemophilia and 1529 people in the comparison group were included. Participants with haemophilia born between 1984 and 2008 had a ninefold (95% CI: 3.3-27.2) and 16-fold (95% CI: 6.7-36.5) increased incidence of arthropathy-related hospital admission and arthropathy diagnosis respectively. None in this cohort underwent surgery. Among participants with haemophilia born prior to 1984, the rates of arthropathy diagnosis and surgery of the index joints (knee, elbow, ankle) were increased twofold (95% CI: 1.0-3.2) and fivefold (95% CI: 1.7-17.8) respectively. CONCLUSION: Our data suggested a higher burden of arthropathy among individuals with mild haemophilia compared to the general population. Further research should investigate the need for targeted joint screening programmes among individuals with mild haemophilia.

The Results of Pancreatic Resections and Long-Term Survival for Pancreatic Ductal Adenocarcinoma: A Single-Institution Experience.

OBJECTIVES: Since the early 1990s, low long-term survival rates following pancreatic surgery for pancreatic ductal adenocarcinoma have challenged us to improve treatment. In this series, we aim to show improved survival from pancreatic ductal adenocarcinoma during the era of centralized pancreatic surgery. METHODS: Analysis of all pancreatic resections performed at Helsinki University Hospital and survival of pancreatic ductal adenocarcinoma patients during 2000-2013 were included. Post-operative complications such as fistulas, reoperations, and mortality rates were recorded. Patient and tumor characteristics were compared with survival data. RESULTS: Of the 853 patients undergoing pancreatic surgery, 581 (68%) were pancreaticoduodenectomies, 195 (21%) distal resections, 28 (3%) total pancreatectomies, and 49 (6%) other procedures. Mortality after pancreaticoduodenectomy was 2.1%. The clinically relevant B/C fistula rate was 7% after pancreaticoduodenectomy and 13% after distal resection, and the re-operation rate was 5%. The 5- and 10-year survival rates for pancreatic ductal adenocarcinoma were 22% and 14%; for T1-2, N0 and R0 tumors, the corresponding survival rates were 49% and 31%. Carbohydrate antigen 19-9 >75 kU/L, carcinoembryonic antigen >5 µg/L, N1, lymph-node ratio >20%, R1, and lack of adjuvant therapy were independent risk factors for decreased survival. CONCLUSION: After centralization of pancreatic surgery in southern Finland, we have managed to enable pancreatic ductal adenocarcinoma patients to survive markedly longer than in the early 1990s. Based on a 1.7-million population in our clinic, mortality rates are equal to those of other high-volume centers and long-term survival rates for pancreatic ductal adenocarcinoma have now risen to some of the highest reported.

European retrospective study of real-life haemophilia treatment.

INTRODUCTION: Haemophilia treatment varies significantly between individuals, countries and regions and details of bleed rates, factor consumption and injection frequency are often not available. AIM: To provide an overview of the FVIII/FIX treatment practice and outcome for patients with haemophilia A (HA) or haemophilia B (HB) across Europe. METHODS: Non-interventional, 12-month retrospective study where anonymized data were retrieved from haemophilia centres/registers in Belgium, France, Germany, Italy, Spain, Sweden and the United Kingdom. Male patients (all ages) receiving coagulation factor treatment 24 months prior to the study, with basal FVIII/FIX levels ≤5 IU dL-1 , without inhibitors, were included. Data were summarized descriptively. RESULTS: In total, 1346 patients with HA and 312 with HB were included in the analysis; 75% and 57% had severe disease (FVIII/FIX < 1 IU dL-1 ) respectively. Prophylaxis was most common for severe haemophilia, especially for children, whereas on-demand treatment was more common for moderate haemophilia in most countries. The mean (SD) prescribed prophylactic treatment ranged from 67.9 (30.4) to 108.4 (78.1) (HA) and 32.3 (10.2) to 97.7 (32.1) (HB) IU kg-1 per week, across countries. Most patients on prophylaxis were treated ≥3 times/week (HA) or two times/week (HB). The median annual bleeding rate (ABR) for patients on prophylaxis ranged from 1.0 to 4.0 for severe HA, and from 1.0 to 6.0 for severe HB, while those with moderate haemophilia generally had slightly higher ABRs. Median ABRs for on-demand-treated severe HA ranged from 4.5 to 18.0, and for HB, 1.5 to 14.0. CONCLUSION: Treatment practice varied greatly between centres and countries and patients treated on-demand and prophylactically both experienced bleeds, emphasizing the need for further optimization of care.

Variation in baseline factor VIII concentration in a retrospective cohort of mild/moderate hemophilia A patients carrying identical F8 mutations.

Essentials Factor VIII levels vary in mild and moderate hemophilia A (MHA) patients with the same mutation. We aimed to estimate the variation and determinants of factor VIII levels among MHA patients. Age and genotype explain 59% of the observed inter-individual variation in factor VIII levels. Intra-individual variation accounted for 45% of the variation in the three largest mutation groups. SUMMARY: Background The bleeding phenotype in patients with mild/moderate hemophilia A (MHA) is inversely associated with the residual plasma concentration of factor VIII (FVIII:C). Within a group of patients with the same F8 missense mutation, baseline FVIII:C may vary, because, in healthy individuals, von Willebrand factor (VWF) levels, ABO blood group and age are also known to influence baseline FVIII:C. Our understanding of the pathophysiologic process of the causative genetic event leading to reduced baseline FVIII:C in MHA patients is still limited. Objectives To estimate the variation and determinants of baseline FVIII:C among MHA patients with the same F8 missense mutation. Methods Three hundred and forty-six patients carrying mutations that were present in at least 10 patients in the cohort were selected from the INSIGHT and the RISE studies, which are cohort studies including data of 3534 MHA patients from Europe, Canada, and Australia. Baseline FVIII:C was measured with a one-stage clotting assay. We used Levene's test, univariate and multivariate linear regression, and mixed-model analyses. Results For 59% of patients, the observed variation in baseline FVIII:C was explained by age and genotype. Compared to FVIII:C in patients with Arg612Cys, FVIII:C was significantly different in patients with eight other F8 missense mutations. Intra-individual variation explained 45% of the observed variance in baseline FVIII:C among patients with the same mutation. Conclusion Our results indicate that baseline FVIII:C levels are not exclusively determined by F8 genotype in MHA patients. Insights into other factors may provide potential novel targets for the treatment of MHA.

A prospective diagnostic accuracy study evaluating rotational thromboelastometry and thromboelastography in 100 patients with von Willebrand disease.

INTRODUCTION: Rotational thromboelastometry (ROTEM® ) and thromboelastography (TEG® ) are increasingly used in the perioperative and emergency assessment of bleeding tendencies. The diagnostic value of ROTEM and TEG for von Willebrand disease (VWD) remains to be established. AIM: To investigate whether ROTEM and TEG can discriminate patients with VWD from healthy controls. METHODS: Rotational thromboelastometry and TEG whole blood coagulation profiles were compared between VWD patients (n = 100) and healthy controls (n = 89). Measures of diagnostic accuracy were calculated, including sensitivity, specificity and receiver operating characteristic (ROC) curve. RESULTS: Prolonged TEG R-time had a positive and negative predictive value (PPV, NPV) of 0.84 and 0.68 respectively. TEG clotting index (CI) had a PPV of 1.00 and an NPV of 0.60. Both R-time and CI had a high specificity and accurately discriminated VWD patients from healthy controls, with an ROC area under the curve of 0.85 and 0.99 respectively. In multivariate analysis, low FVIII levels, but not von Willebrand factor (VWF) antigen or activity, determined hypocoagulable TEG R (R2 = 0.35) and CI levels (R2 = 0.51). The ROTEM coagulation profiles of VWD patients did not differ from healthy controls. CONCLUSIONS: Thromboelastography R and CI accurately discriminated VWD patients from healthy controls, partly through the detection of low FVIII levels. The test's performance may be improved through adjustment of the test thresholds to a local reference population. Both intrinsic pathway-activated (INTEM) and tissue factor pathway-activated (EXTEM) ROTEM were of limited diagnostic value in VWD.

Long-term liver-related morbidity and mortality related to chronic hepatitis C virus infection in Swedish patients with inherited bleeding disorders.

INTRODUCTION: Hepatitis C virus (HCV) infection is common in patients with inherited bleeding disorders treated with clotting factor concentrates prior to the introduction of viral inactivation of these products. The long-term consequences of hepatitis C infection in Swedish patients are not fully understood. AIM: To examine the impact of HCV infection on liver-related morbidity and mortality in Swedish patients with inherited bleeding disorders. METHODS: We retrospectively collected data on 183 patients with inherited bleeding disorders infected with HCV who attended the Coagulation Unit at Karolinska University Hospital, Sweden. Data regarding end-stage liver disease (ESLD), defined as presence of ascites, encephalopathy, variceal bleeding, hepatocellular carcinoma or liver-related death, were collected from the patient records and the national registers. RESULTS: The median follow-up time was 35.9 years (IQR 29.0-41.2). A total of 41% had achieved sustained virological response (SVR) after treatment. In total, 14.2% developed ESLD at the median age of 52.6 years (IQR 46.5-64.7). Nineteen (35.8%) of all deaths were due to liver-related causes. Co-infection with human immunodeficiency virus (HIV), older age at time of infection and severe form of bleeding disorder was associated with higher risk of developing ESLD, while SVR was a strong protective factor. CONCLUSIONS: This study demonstrated that liver-related morbidity and mortality was significant in patients with bleeding disorders and HCV infection in Sweden. Patients with HCV-infection should be candidates for treatment with the new highly effective antiviral drugs, since SVR proved to be a strong protective factor.