[Treatment of haemophilia in Austria]. / Hämophilie-Behandlung in Österreich.

This guideline is intended to provide practical guidance for the diagnosis and treatment of haemophilia in Austria. Few randomized controlled interventional trials are available addressing the treatment of haemophilia, therefore recommendations are usually based on low level of evidence and represent expert consensus.This guideline is based on the WFH guideline, published in 2020, and adapted according to the national circumstances and experience.It includes recommendations and suggestions for diagnosis and follow-up visits and pharmacological therapies for treatment and prophylaxis. Further topics comprise special aspects in children and adults with severe haemophilia, outcome measurement, and management of trauma, special bleedings and interventions, including dental procedures, inhibitors, management of haemophilia carriers, and psychosocial aspects.

Long-Term Comparison of Two- and Three-Dimensional Computed Tomography Analyses of Cranial Bone Defects in Severe Parietal Thinning.

Parietal thinning was detected in a 72-year-old with recurrent headaches. Quantification of bone loss was performed applying two- and three-dimensional methods using computerized tomographies. Two-dimensional methods provided accurate measurements using single-line analyses of bone thicknesses (2.13 to 1.65 and 1.86 mm on the left and 4.44 to 3.08 and 4.20 mm on the right side), single-point analyses of bone intensities (693 to 375 and 403 on the left and 513 to 393 and 411 Houndsfield Units on the right side) and particle-size analyses of low density areas (16 to 22 and 12 on the left and 18 to 23 and 14 on the right side). Deteriorations between days 0 and 220 followed by bone stability on day 275 were paralleled using the changed volumes of bone defects to 1200 and finally 1133 mm3 on the left side and to 331 and finally 331 mm3 on the right side. Interfolding as measurement of the bones' shape provided changes to -1.23 and -1.72 mm on the left and to -1.42 and -1.30 mm on the right side. These techniques suggest a stabilizing effect of corticosteroids between days 220 and 275. Reconstruction of computerized tomographies appears justified to allow for quantification of bone loss during long-term follow-up.

Progress in Hemostasis (Part 1): Improved Management of Inherited Platelet Disorders: Reality or Illusion?

Platelets are key drivers of hemostasis. Low platelet counts, dysfunction in platelet adhesion, and aggregation lead to increased bleeding tendency. Inherited platelet disorders (IPDs) form a highly heterogeneous group of rare diseases with variable bleeding tendency. IPDs may be associated with other signs and symptoms often referred to as "syndromic." The underlying genetic defect may prone patients to develop hematopoietic diseases such as leukemia. Over the last decade, accumulating knowledge in genetics has led to the detection of many "new" platelet disorders. However, still many patients with a well-described platelet dysfunction remain undetected until severe bleeding occurs.

State-of-the-Art Targeted High-Throughput Sequencing for Detecting Inherited Platelet Disorders.

Inherited platelet disorders (IPDs) are a heterogeneous group of rare entities caused by molecular divergence in genes relevant for platelet formation and function. A rational diagnostic approach is necessary to counsel and treat patients with IPDs. With the introduction of high-throughput sequencing at the beginning of this millennium, a more accurate diagnosis of IPDs has become available. We discuss advantages and limitations of genetic testing, technical issues, and ethical aspects. Additionally, we provide information on the clinical significance of different classes of variants and how they are correctly reported.

Treatment of Inherited Platelet Disorders: Current Status and Future Options.

Inherited platelet disorders (IPDs) comprise a heterogeneous group of entities that manifest with variable bleeding tendencies. For successful treatment, the underlying platelet disorder, bleeding severity and location, age, and sex must be considered in the broader clinical context. Previous information from the AWMF S2K guideline #086-004 (www.awmf.org) is evaluated for validity and supplemented by information of new available and future treatment options and clinical scenarios that need specific measures. Special attention is given to the treatment of menorrhagia and risk management during pregnancy in women with IPDs. Established treatment options of IPDs include local hemostatic treatment, tranexamic acid, desmopressin, platelet concentrates, and recombinant activated factor VII. Hematopoietic stem cell therapy is a curative approach for selected patients. We also provide an outlook on promising new therapies. These include autologous hematopoietic stem cell gene therapy, artificial platelets and nanoparticles, and various other procoagulant treatments that are currently tested in clinical trials in the context of hemophilia.

Loss or Dilution-A New Diagnostic Method to Assess the Impact of Dilution on Standard Laboratory Parameters.

Intraoperative fluid therapy is regularly used in patients undergoing cardiac surgery procedures with cardiopulmonary bypass (CPB). Although fluid administration has several advantages, it unavoidably leads to hemodilution. The hemodilution may further influence the interpretation of concentration-based laboratory parameters like hemoglobin (Hgb), platelet count (PLT) or prothrombin time (PT). These all parameters are commonly used to guide blood product substitution. To assess the impact of dilution on these values, we performed a prospective observational study in 174 patients undergoing elective cardiac surgery. We calculated the total blood volume according to Nadler's formula, and fluid therapy was correlated with a newly developed dilution coefficient formula at the end of CPB. Intravenously applied fluids were measured from the beginning of the anesthesia (baseline, T0) and 15 min after the end of protamine infusion (end of CPB, T1). The amount of the administered volume (crystalloids or colloids) was calculated according to the percentage of the intravascular fluid effect, and intraoperative diuresis was further subtracted. The median blood volume increased by 148% in all patients at T1 compared to the calculated total blood volume at T0. This led to a dilution-dependent decrease of 38% in all three parameters (Hgb 24%, corrCoeff = 0.53; PLT 41%, corrCoeff = 0.68; PT 44%, corrCoeff = 0.54). The dilution-correlated decrease was significant for all parameters (p < 0.001), and the effect was independent from the duration of CPB. We conclude that the presented calculation-based approach could provide important information regarding actual laboratory parameters and may help in the guidance of the blood product substitution and potential transfusion thresholds. Further research on the impact of dilution and related decision-making for blood product substitution, including its impact on morbidity and mortality, is warranted.

Clinical Trials in Chronic Arthritic Diseases with Underestimated Impact of Placebo Effects on Study Size Calculation.

Whether and to which extent placebo treatment in double-blinded randomized controlled clinical trials is effective in chronic arthritic diseases has not been studied before. Therefore, a systematic literature search was undertaken to detect eligible trials. Demographic data of the placebo groups as well as concomitant and previous disease outcomes were collected. Analyses of significant bivariate correlations and linear regression between clinical endpoints and characteristics of the placebo groups were performed. A total of 152 double-blinded randomized controlled studies, including 21,616 participants in the placebo groups, was analyzed. The results of bivariate correlations and linear regressions revealed significant positive associations between responses in the placebo groups and the following factors: (i) naïvety of previous treatment and (ii) early stage of disease. In addition to the clinical relevance, the results support the importance of the placebo effect on study size calculations, and will allow an optimized calculation of patients' numbers for early placebo-controlled trials conducted in patients with chronic arthritic diseases.

Low Bone Mineral Density in Hemophiliacs.

OBJECTIVE: To review the current knowledge on bone health in patients with hemophilia A and the underlying pathogenetic mechanisms. DATA SOURCES: Original research articles, meta-analyses, and scientific reviews. DATA SYNTHESIS: Already in childhood, patients with hemophilia A are prone to low bone mineral density, leading to osteopenia and/or osteoporosis. Initially associated with the life style of hemophilia, today we are faced with accumulating evidence that coagulation factor VIII is involved directly or indirectly in bone physiology. CONCLUSION: Understanding the role of factor VIII and the mechanisms of decreased bone mineral density in hemophilia A is critically important, especially as non-factor replacement therapies are available, and treatment decisions potentially impact bone health.

Optimization of the Alizarin Red S Assay by Enhancing Mineralization of Osteoblasts.

The alizarin red S assay is considered the gold standard for quantification of osteoblast mineralization and is thus widely used among scientists. However, there are several restrictions to this method, e.g., moderate sensitivity makes it difficult to uncover slight but significant effects of potentially clinically relevant substances. Therefore, an adaptation of the staining method is appropriate and might be obtained by increasing the mineralization ability of osteoblasts. In this study, cell culture experiments with human (SaOs-2) and murine (MC3T3-E1) osteoblasts were performed under the addition of increasing concentrations of calcium chloride (1, 2.5, 5, and 10 mM) or calcitonin (1, 2.5, 5, and 10 nM). After three or four weeks, the mineralization matrix was stained with alizarin red S and the concentration was quantified photometrically. Only calcium chloride was able to significantly increase mineralization, and therefore enhanced the sensitivity of the alizarin red S staining in a dose-dependent manner in both osteoblastic cell lines as well as independent of the cell culture well surface area. This cost- and time-efficient optimization enables a more sensitive analysis of potentially clinically relevant substances in future bone research.

Administration of fibrinogen concentrate combined with prothrombin complex maintains hemostasis in children undergoing congenital heart repair (a long-term propensity score-matched study).

BACKGROUND: Bleeding is a common problem in children with congenital heart disease undergoing major cardiac surgery requiring cardiopulmonary bypass (CPB). Little is known about optimal management with blood products. OBJECTIVE: To investigate clinical outcome and hemostatic effects of fibrinogen concentrate (FC) in combination with prothrombin complex concentrate (PCC) versus standard treatment with fresh frozen plasma (FFP) in children undergoing cardiac surgery. METHODS: For this single-institution cohort study, data on 525 children were analyzed. Propensity score matching in 210 children was applied to reduce the impact of various baseline characteristics. RESULTS: Three children treated with FC/PCC developed surgical site bleeding requiring surgical revision. One child developed central venous line-related thrombosis. Blood loss through chest tube drainage was independent of FC/PCC. Coagulation abnormalities were not present in any of these children. Time to extubation and ICU stay did not differ. In the FC/PCC group, children received (median, Q1, Q3) 52 mg/kg (32, 83) FC and 28IU/kg (13, 44) PCC. Fibrinogen concentration was comparable at baseline. On admission to the ICU, fibrinogen was higher in children receiving FC/PCC, namely, 232 mg/dL (196, 280), than in children receiving FFP (186 mg/dL, 149, 224; P < .001). On discharge from the ICU, values did not differ ((FC/PCC 416 mg/dL (288, 501)), non-FC/PCC 418 mg/dL (272, 585; P = 1.000)). CONCLUSION: FC/PCC was well tolerated and permitted hemostasis to be maintained, even in the very young. We were not able to detect a signal for inferiority of this treatment. We conclude that FC/PCC can safely replace FFP.

Cardiac output and cerebral blood flow during carotid surgery in regional versus general anesthesia: A prospective randomized controlled study.

OBJECTIVE: Carotid endarterectomy (CEA) is a preventive procedure aimed at decreasing the subsequent risk of fatal or disabling stroke in patients with significant carotid stenosis. It is well-known that carotid surgery under ultrasound-guided regional anesthesia (US-RA) causes a significant increase in blood pressure, heart rate and stress hormone levels owing to increased sympathetic activity. However, little is known about the effects on cardiac output (CO), cardiac index (CI), and cerebral blood flow (CBF) under US-RA as compared with general anesthesia (GA). METHODS: Patients scheduled for CEA were randomized prospectively to receive US-RA (n = 37) or GA (n = 41). The primary end point was the change in CI after induction of anesthesia and the change from baseline over time at four different times during the entire procedure in the respective randomized US-RA and GA groups. In addition to systolic blood pressure and heart rate, we also recorded peak systolic velocity, end-diastolic velocity, and minimum diastolic velocity as seen from transcranial Doppler ultrasound examination, as well as regional cerebral oxygenation (rSO2) as seen from near-infrared refracted spectroscopy to evaluate cerebral blood flow. RESULTS: In the US-RA group, the CI increased after induction of anesthesia (3.7 ± 0.8 L/min/m2) and remained constant until the end of the procedure. In the GA group CI was significantly lower (2.4 ± 0.6 L/min/m2; P < .001). After induction of anesthesia, the rSO2 remained constant in the GA group on both the ipsilateral (63 ± 9 rSO2) and the contralateral (65 ± 7 rSO2) sides; in contrast, it significantly increased in the US-RA group (ipsilateral 72 ± 8 rSO2; P < .001; contralateral 72 ± 6 rSO2; P < .001). The transcranial Doppler ultrasound parameters (peak systolic velocity, end-diastolic velocity, and minimum diastolic velocity) did not differ between the US-RA and the GA group. The clinical outcome was similarly favorable for both groups. CONCLUSIONS: CI was maintained near baseline values throughout the procedure during US-RA, whereas a significant decrease in CI values was observed during CEA under GA. Near-infrared refracted spectroscopy values, reflecting blood flow in small vessels, were higher in US-RA patients than in those with GA. These differences did not influence clinical outcome.

Pain management in hemophilia: expert recommendations.

INTRODUCTION: As a typical consequence of bleeding into muscles and joints, patients with severe hemophilia suffer from acute and chronic pain. In spite of its high prevalence, pain in this patient group is not always sufficiently considered or treated in an effective manner. AIM: The recommendations presented in this paper address possible improvements in pain management in hemophilia patients and particularities that have to be taken into account in this patient group. METHOD: The manifold aspects of pain management in hemophilia patients were discussed within the framework of an expert meeting. Based on the available literature and the experts' clinical experience, the participants developed a set of recommendations presented in this paper. RESULTS: Pain management in patients with hemophilia is often insufficient, a fact that not only influences the patients' quality of life but also implies the risk of difficult to manage chronic pain. Both the prevalent polypharmacy (due to comorbidities) as well as the underlying disease itself present special challenges to pain therapy in this patient group. The present review and recommendations are intended to support medical professionals in recognising the risks of pain chronicity, applying basic principles of multimodal pain therapy, including the options of psychological intervention and modalities of physical medicine in therapy concepts, and reaching a comprehensive understanding of the range of analgesic options available.

Practical Guidance of the GTH Haemophilia Board on the Use of Emicizumab in Patients with Haemophilia A.

Emicizumab has been approved for bleeding prophylaxis in patients with haemophilia A (PWHAs) with or without inhibitors. Because of substantial differences between factor VIII (FVIII) and Emicizumab, the 'Ständige Kommission Hämophilie' of the German, Austrian, Swiss Society for Thrombosis and Haemostasis Research (GTH) established a practical guidance for the use of Emicizumab in PWHAs. A systematic literature research was conducted in PubMed. Based on this and on personal experience, this practical guidance has been developed. Each single statement has been discussed among members of the 'Ständige Kommission Hämophilie' and revised accordingly. The final set of recommendations has been approved by all authors analogous to the Delphi method. This practical guidance is provided for physicians treating PWHAs with regard to general aspects, patient education, bleeding treatment, surgery, use of Emicizumab in previously untreated patients (PUPs), patients with newly diagnosed inhibitors and elderly patients. Patients should be treated in expert centres and adequate laboratory tests to monitor Emicizumab levels, FVIII replacement and inhibitors should be available. Early experience of immune tolerance induction protocols integrating Emicizumab is reviewed, and the limited experience in PUPs and very young children is described. So far, no thromboembolic complications have been reported with the concomitant use of FVIII or recombinant activated FVII for bleeding treatment or surgery. Activated prothrombin complex concentrate doses of >100 U/kg for >24 hours should be avoided whenever possible because of the high risk of thrombosis and/or thrombotic microangiopathy. In conclusion, this study is designed to support haemophilia physicians using Emicizumab in physicians treating hemophilia and using (PWHAs). With further post-marketing experience and trials, regular updates are necessary.

Perinatal Management of Haemophilia.

The aim of this review is to provide practical guidance for the treatment of carriers of haemophilia and newborns presenting with haemophilia. Both mother and newborn have an increased risk for clinically relevant bleeding. An experienced team should manage genetic counselling, prenatal diagnosis, pregnancy, delivery and the newborn presenting with haemophilia. Published and regularly updated guidelines must guide this team. Vaginal and caesarean deliveries before labour entail a comparable bleeding risk. Haemophilia carriers should receive factor concentrate (FC) at the time of delivery if their factor level is below normal. Evidence remains insufficient to recommend systemic desmopressin and tranexamic acid for the prevention of peripartum haemorrhage. Primary prophylaxis with FC for all newborns with severe haemophilia is not justified. The pattern of bleeding seen in the affected newborns is essentially different from that seen in older children. Estimated frequency of intracranial haemorrhage (ICH) is 2 to 3%. Cranial ultrasound is a good screening method for ICH in newborns. Many neonatal bleeds are iatrogenic in origin. The most prominent concerns regarding neonatal factor replacement are the risk for inhibitor development, followed by local bleeding and issues related to poor vascular access. The preference for plasma-derived FC and recombinant FC differs widely between centres and countries. Replacement therapy should be monitored since newborns may require higher doses of FC. Emicizumab, licensed for all age groups since 2019, should not be used in newborns with severe haemophilia A and acute bleeding, although "non-factor" agents are expected to revolutionise haemophilia therapy.

Paroxysmal Nocturnal Hemoglobinuria: An Underestimated Cause of Pediatric Thromboembolism.

Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic disease caused by complement-mediated hemolysis. Clinical symptoms include intravascular hemolysis, nocturnal hemoglobinuria, thromboses, cytopenia, fatigue, abdominal pain, and a strong tendency toward bone marrow failure. It is a rare disease, especially in children, with high mortality rates without appropriate treatment. We here present the case of a 17-year-old girl with unprovoked muscle vein thrombosis. Flow cytometric analysis showed deficiency of glycosyl-phosphatidylinositol-anchored membrane proteins on all three hematopoietic cell lines and confirmed the diagnosis of PNH. Treatment with the monoclonal antibody eculizumab achieved long-term remission. As flow cytometry is normally not part of the routine diagnostics for pediatric thrombosis, awareness is crucial and PNH is important to consider in all children with thrombosis at atypical sites and abnormalities in blood counts with regard to hemolysis and cytopenia.

Child Abuse or Bleeding Disorder-An Interdisciplinary Approach.

Children with an unexplained bleeding tendency are frequently referred to a haemostaseologist for further evaluation. Careful standardized history taking and clinical evaluation should allow for distinguishing bleeds after minor injury and trauma which are very common in all children. However, in two groups of children bleeding symptoms may be more significant than expected: those with an underlying coagulation disorder and those who have been subjected to physical child abuse. The coexistence of child abuse and a bleeding disorder must always be considered. An extended coagulation diagnostic is required if the morphology of bleedings is not clearly suspicious for child abuse and in the absence of typical concomitant injuries, e.g., bone fractures. An interdisciplinary approach involving a forensic pathologist and a paediatric haemostaseologist for assessment of bleeding symptoms, the explanation of the clinical findings, and the critical evaluation of laboratory results are essential in such cases. This review is focussed on symptoms in accidental and nonaccidental injuries in children assisting haemostaseologists in decision making in cases of child protection issues.

Epidemiology and Treatment of Patients with Haemophilia in Austria-Update from the Austrian Haemophilia Registry.

The Austrian Haemophilia Registry collects epidemiological data on patients with haemophilia, on treatment modalities and potential side effects. The Registry covers more than 85% of the assumed total number of haemophilia patients in Austria. This report summarizes data on 753 patients: 84.3% (635) have haemophilia A and 15.7% (118) have haemophilia B. Patients' median age is 34 years (range: 1-93 years). Of the total cohort, 39.0% (294) patients have severe haemophilia, 11.3% (85) moderate haemophilia, and 49.4% (372) mild haemophilia. Of the patients with severe haemophilia, 38.4% (113) have been infected with hepatitis C virus (HCV) and 12.6% (37) are human immunodeficiency virus (HIV) positive. Overall, 10.6% (67) of patients with haemophilia A and 1.7% (2) of those with haemophilia B have had an inhibitor in their history. Among patients with severe haemophilia, 68.4% (201) receive prophylaxis and 28.6% (84) receive on-demand therapy. There are 65.0% (191) patients with severe haemophilia who are treated with recombinant products. In conclusion, most patients with severe haemophilia receive prophylactic treatment. HCV and HIV infections are still important issues in the Austrian haemophilia population.

Shiga toxin 2a binds antithrombin and heparin, but does not directly activate platelets.

Escherichia coli-induced hemolytic uremic syndrome (eHUS) is a life-threatening complication of infection with Shiga toxin (Stx), in particular Stx2a-producing Escherichia coli. Enhanced coagulation activation with formation of microthrombi seems to be a key event in development of eHUS. Platelet activation has been postulated as a possible, but controversially debated mechanism. The present study investigated the effect of Stx2a on plasmatic coagulation and platelets. Binding studies were initially performed with ELISA and co-immunoprecipitation and supported by quartz crystal microbalance with dissipation monitoring (QCM-D). Antithrombin (AT) activity was measured using the automated BCS XP® system. ROTEM® was used for functional coagulation testing. Platelet binding and activation was studied with FACS and light-transmission aggregometry. We found binding of Stx2a to AT, an important inhibitor of blood coagulation, but only a mild albeit significant reduction of AT activity against FXa in the presence of Stx2a. QCM-D analysis also showed binding of Stx2a to heparin and an impaired binding of AT to Stx2a-bound heparin. ROTEM® using Stx2a-treated platelet-poor plasma revealed a significant, but only moderate shortening of clotting time. Neither binding nor activation of platelets by Stx2a could be demonstrated. In summary, data of this study suggest that Stx2a binds to AT, but does not induce major effects on plasmatic coagulation. In addition, no interaction with platelets occurred. The well-known non-beneficial administration of heparin in eHUS patients could be explained by the interaction of Stx2a with heparin.