Hemophilia is a rare disorder that is complex to diagnose and to manage. These evidence-based guidelines offer practical recommendations on the diagnosis and general management of hemophilia, as well as the management of complications including musculoskeletal issues, inhibitors, and transfusion-transmitted infections. By compiling these guidelines, the World Federation of Hemophilia aims to assist healthcare providers seeking to initiate and/or maintain hemophilia care programs, encourage practice harmonization around the world and, where recommendations lack adequate evidence, stimulate appropriate studies.

/pdf/guidelines-for-the-management-of-hemophilia-1x6t2d999b.pdf

Guidelines for the management of hemophilia.

In Sweden, prophylactic treatment of boys with severe haemophilia has been practised since 1958 in an attempt to convert the disease from a severe to a milder form. The present study population consisted of 60 severe haemophiliacs (52 A, 8 B), aged 3-32 years. Treatment is started when the boys are 1-2 years of age, the regimens used being 24-40 IU F VIII kg-1 three times weekly in haemophilia-A cases (i.e. greater than 2000 IU kg-1 annually) and 25-40 IU F IX kg-1 twice weekly in haemophilia-B cases. The orthopaedic and radiological joint scores (maximum scores of 90 and 78, respectively) are evaluated as recommended by the World Federation of Haemophilia. Of those subjects aged 3-17 years, 29 out of 35 individuals had joint scores of zero. The oldest group had only minor joint defects. The VIII:C and IX:C concentrations had usually not fallen below 1% of normal. All 60 patients are able to lead normal lives. In conclusion, it appears to be possible to prevent haemophilic arthropathy by giving effective continuous prophylaxis from an early age, and preventing the VIII:C or IX:C concentration from falling below 1% of normal.

Twenty-five years' experience of prophylactic treatment in severe haemophilia A and B

The aims of severe perioperative bleeding management are three-fold. First, preoperative identification by anamesis and laboratory testing of those patients for whom the perioperative bleeding risk may be increased. Second, implementation of strategies for correcting preoperative anaemia and stabilisation of the macro- and microcirculations in order to optimise the patient’s tolerance to bleeding. Third, targeted procoagulant interventions to reduce the amount of bleeding, morbidity, mortality and costs. The purpose of these guidelines is to provide an overview of current knowledge on the subject with an assessment of the quality of the evidence in order to allow anaesthetists throughout Europe to integrate this knowledge into daily patient care wherever possible. The Guidelines Committee of the European Society of Anaesthesiology (ESA) formed a task force with members of scientific subcommittees and individual expert members of the ESA. Electronic databases were searched without language restrictions from the year 2000 until 2012. These searches produced 20 664 abstracts. Relevant systematic reviews with meta-analyses, randomised controlled trials, cohort studies, case-control studies and cross-sectional surveys were selected. At the suggestion of the ESA Guideline Committee, the Scottish Intercollegiate Guidelines Network (SIGN) grading system was initially used to assess the level of evidence and to grade recommendations. During the process of guideline development, the official position of the ESA changed to favour the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. This report includes general recommendations as well as specific recommendations in various fields of surgical interventions. The final draft guideline was posted on the ESA website for four weeks and the link was sent to all ESA members. Comments were collated and the guidelines amended as appropriate. When the final draft was complete, the Guidelines Committee and ESA Board ratified the guidelines.

https://epub.ub.uni-muenchen.de/24023/1/oa_24023.pdf

Management of severe perioperative bleeding Guidelines from the European Society of Anaesthesiology

von Willebrand disease (VWD) is a commonly encountered inherited bleeding disorder affecting both males and females, causing mucous membrane and skin bleeding symptoms, and bleeding with surgical or other haemostatic challenges. VWD may be disproportionately symptomatic in women of child-bearing age. It may also occur less frequently as an acquired disorder (acquired von Willebrand syndrome). VWD is caused by deficiency or dysfunction of von Willebrand factor (VWF), a plasma protein that mediates platelet haemostatic function and stabilizes blood coagulation factor VIII. The pathophysiology, classification, diagnosis and management of VWD are relatively complex, but understanding them is important for proper diagnosis and management of patients with VWD. These evidence-based guidelines for diagnosis and management of VWD from the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel (USA) review relevant publications, summarize current understanding of VWD pathophysiology and classification, and present consensus diagnostic and management recommendations based on analysis of the literature and expert opinion. They also suggest an approach for clinical and laboratory evaluation of individuals with bleeding symptoms, history of bleeding or conditions associated with increased bleeding risk. This document summarizes needs for further research in VWF, VWD and bleeding disorders, including clinical research to obtain more objective information about bleeding symptoms, advancements in diagnostic and therapeutic tools, and enhancement in the education and training of clinicians and scientists in bleeding and thrombotic disorders. The NHLBI Web site (http://www.nhlbi.nih.gov/guidelines/vwd) has a more detailed document, a synopsis of these recommendations, and patient education information.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2516.2007.01643.x

von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA).

The management of perioperative bleeding involves multiple assessments and strategies to ensure appropriate patient care. Initially, it is important to identify those patients with an increased risk of perioperative bleeding. Next, strategies should be employed to correct preoperative anaemia and to

/pdf/management-of-severe-perioperative-bleeding-guidelines-from-2wdggnur4g.pdf

Management of severe perioperative bleeding: guidelines from the European Society of Anaesthesiology: First update 2016.

Human parvovirus B19 can be transmitted by coagulation factor concentrates and is highly resistant to virucidal methods. To evaluate whether the additional removal of virus by chromatographic methods during the manufacture of high-purity concentrates reduces the risk of B19 transmission, we have prospectively evaluated the rate of anti-B19 seroconversion in two groups of susceptible (anti-B19 negative) hemophiliacs infused with high-purity, heated (pasteurized) or solvent-detergent-treated factor VIII concentrates. Both products infected a relatively high proportion of patients (nine of 20).

Human parvovirus B19 infection in hemophiliacs first infused with two high-purity, virally attenuated factor VIII concentrates.

Haemarthrosis triggers haemophilic arthropathy (HA) because bleeding starts synovitis immediately, damages cartilage and leads to loss of function and disability. The aim of our study was to investigate the capacity of ultrasonography (US) in detecting bleeding and joint damage in HA. The joints of 62 patients (pts) with haemophilia A or haemophilia B were consecutively evaluated and scored (score ranging from 0 to 21) for effusion (E), bone remodelling (BR), cartilage damage (CD), synovial hypertrophy (SH), haemosiderin (H), osteophytes (O), haemarthrosis (Hae), erosion (Er) and fibrotic septa (FS) with US. X-rays [Pettersson Score (PXS)] were performed in 61 patients and clinical evaluation [World Federation Haemophiliac orthopaedic score (WFHO)] was performed in all patients. A total of 20 healthy subjects and 20 patients affected by Rheumatoid Arthritis (RA) were used as controls. Power Doppler US (PDUS) was performed in all patients on the knee, ankle and elbow joints. A total of 83 joints were studied (50 knees; 12 elbows and 21 ankles). US showed effusion in 57 joint, bone remodelling in 62, cartilage damage in 64, synovial hypertrophy in 45, haemosiderin in 39, osteophytes in 30, haemarthrosis in 24, erosion in 5 and fibrotic septa in 3. The X-rays score showed remodelling in 47 joints, narrowing joint space in 44, displacement/angulation in 39, osteoporosis in 42, subchondral irregularity in 44, subchondral cyst formation in 37, osteophytes in 36 and erosions in 25. The US score in healthy subjects was always ≤ 5 (range 0 to 4). In haemophiliacs, 34 of 83 joints showed US score ≤ 5, and 49 US score > 5. Joints with US score ≤ 5 had a low PXS (SRCC = 0.375, P 5 showed a high PXS (SRCC = 0.440, P < 0.01). A significant correlation between US score and PXS for bone remodelling [Spearman's rho Correlation Coefficient (SRCC) = 0.429, P < 0.01] and for osteophytes (SRCC = 0.308, P < 0.05) was found. The correlation between the US score and number of bleedings in 83 joints was very significant (SRCC = 0.375, P < 0.01). A total of 24 bleeding joints were identified and verified with aspiration of haematic fluid. US may detect bone and cartilage alterations and synovitis. Indeed, PDUS identified bleeding also in asymptomatic joints and was able to show different entity of haemarthrosis. US may be a feasible and reliable tool to evaluate joint modifications in HA.

Ultrasound detects joint damage and bleeding in haemophilic arthropathy: a proposal of a score.

A group of 27 first infused haemophiliacs was studied for association between heat-treated clotting factor concentrates and transmission of human parvovirus B19. The prevalence rate of B19 antibody, detected by the Immunoelectroosmophoresis (IEOP) reaction, was 55.5% in this group of first infused subjects, significantly higher than the 29.3% of the control group of 58 healthy blood donors but lower than the 93.3% of antibody positive subjects in a group of 30 haemophiliacs multitreated with unheated products. Five of 17 B19 antibody negative patients produced human parvovirus IgM, detectable by radioimmunoassay, after the first treatment with heated concentrates; two of them developed viraemia 6 and 10 days, respectively, after the first infusion dose. These results lead to the conclusion that human parvovirus is transmissible by blood derivatives even when they have been exposed to steam- or dry-heat treatment.

Human parvovirus infection in haemophiliacs first infused with treated clotting factor concentrates.

Single-dose kinetics of 4 Factor VIII concentrates (Kryobulin, Hemofil T, Koate, cryoprecipitate) were studied in 41 patients with haemophilia-A. Model-independent methods were adopted for calculating the kinetic parameters (area under the curve, clearance, area under the moment curve, mean residence time, volume of distribution at steady-state). No substantial difference was observed in the kinetic characteristics of the 4 Factor VIII concentrates. A considerable interindividual variability of the calculated kinetic parameters was demonstrated for all concentrates. Our findings support the need to individualize Factor VIII dosage.

Kinetic evaluation of four Factor VIII concentrates by model-independent methods.

BACKGROUND AND OBJECTIVES: Recombinant factor VIIa (rFVIIa) has been widely used in the treatment of bleedings occurring in hemophiliacs with inhibitors. Very few reports exist on the use of rFVIIa in patients with inherited FVII deficiency. Pharmacokinetic studies on rFVIIa have been performed exclusively in hemophiliacs, patients with cirrhosis or volunteers pretreated with acenocoumarol. The aim of this study was to evaluate the kinetics of rFVIIa in patients naturally deficient of FVII. DESIGN AND METHODS: A single dose kinetic study with rFVIIa was performed in 5 patients affected by severe congenital deficiency of factor VII in order to evaluate the true kinetic parameters of rFVIIa without the interference of FVII. Two dosages, 15 and 30 microg/kg, were used in a crossover schedule. FVII:C and FVIIa concentration/time curves were analyzed by a model-independent method. Antithrombin (AT), prothombin fragment 1+2 (F1+2) and tissue factor pathway inhibitor (TFPI) were assayed. RESULTS: No differences emerged between the dosages with respect to dose-independent parameters [total body clearance (CL), volume of distribution area (VdArea), mean residence time (MRT)]. No significant changes of AT, TFPI, and F1+2 were observed. Comparing the results with those of other studies performed in adult hemophiliacs, in patients affected by cirrhosis or in volunteers on oral anticoagulant therapy (OAT), CL and VdArea of rFVIIa were definitely higher and in vivo recovery was lower. INTERPRETATION AND CONCLUSIONS: These findings suggest that the kinetics of rFVIIa are not dose-dependent. In the absence of FVII, the changes of VdArea and CL may be in agreement with a mechanism of competition between FVII and rFVIIa for tissue factor binding.

Massimo Morfini

Papers

Human parvovirus B19 infection in hemophiliacs first infused with two high-purity, virally attenuated factor VIII concentrates.

Ultrasound detects joint damage and bleeding in haemophilic arthropathy: a proposal of a score.

Human parvovirus infection in haemophiliacs first infused with treated clotting factor concentrates.

Kinetic evaluation of four Factor VIII concentrates by model-independent methods.

Pharmacokinetic evaluation of recombinant, activated factor VII in patients with inherited factor VII deficiency.