Emicizumab prophylaxis in patients with acquired haemophilia A (GTH-AHA-EMI): an open-label, single-arm, multicentre, phase 2 study.

BACKGROUND: Acquired haemophilia A is caused by neutralising autoantibodies against coagulation factor VIII, leading to severe bleeding. Standard treatment involves immunosuppressive therapy, which is associated with adverse events and mortality in the frail population of patients with acquired haemophilia A. This study investigated whether emicizumab, a factor VIIIa mimetic antibody, protects patients with acquired haemophilia A from bleeding and allows deferral of immunosuppression during the first 12 weeks after diagnosis. METHODS: We report final results of an open-label, single-arm, phase 2 clinical trial. Adult patients with acquired haemophilia A from 16 haemophilia treatment centres in Germany and Austria were eligible if they had not previously received immunosuppression. Patients received emicizumab subcutaneously (6 and 3 mg/kg on days 1 and 2, 1·5 mg/kg weekly until week 12), but no immunosuppression. Follow-up was until week 24. The primary endpoint was the number of clinically relevant bleeds per patient-week until week 12. Emicizumab was considered effective if the mean bleeding rate was significantly below 0·15 bleeds per patient-week, the rate observed in a previous study of patients with acquired haemophilia A treated with bypassing agents and immunosuppression but no emicizumab. The study is registered with clinicaltrials.gov, NCT04188639 and is complete. FINDINGS: Of 49 patients screened from March 25, 2021, to June 10, 2022, 47 were enrolled (23 women, 24 men). Median age was 76 years (IQR 66-80), 46 (98%) of 47 patients were White, median factor VIII activity was 1·4 IU/dL (0·3-5·6), and median inhibitor concentration was 11·4 Bethesda units per mL (3·9-42·7). Mean breakthrough bleeding rate was 0·04 bleeds per patient-week (upper 97·5% CI 0·06). 33 (70%) of 47 patients had no bleeding events, seven patients (15%) had one bleed, six patients (13%) had two bleeds, and one patient (2%) had three bleeds. Adverse events of grade 3 or worse included COVID-19 (n=2), acute kidney injury (n=2), and stroke (n=1). Four of 47 patients died, including two deaths related to bleeding, one from COVID-19, and one from cardiac arrest (none were judged as related to emicizumab). INTERPRETATION: This study suggests that emicizumab prophylaxis prevents bleeding in patients with acquired haemophilia A and that immunosuppressive therapy can be deferred while patients are receiving this treatment. The low number of thromboembolic events, severe infections, and fatalities observed in this study are promising. FUNDING: This study was supported by funding from Hoffman-La Roche.

Predictive value of molecular matching tools for the development of donor specific HLA-antibodies in patients undergoing lung transplantation.

Molecular matching is a new approach for virtual histocompatibility testing in organ transplantation. The aim of our study was to analyze whether the risk for de novo donor-specific HLA antibodies (dnDSA) after lung transplantation (LTX) can be predicted by molecular matching algorithms (MMA) and their combination. In this retrospective study we included 183 patients undergoing LTX at our center from 2012-2020. We monitored dnDSA development for 1 year. Eplet mismatches (epMM) using HLAMatchmaker were calculated and highly immunogenic eplets based on their ElliPro scores were identified. PIRCHE-II scores were calculated using PIRCHE-II algorithm (5- and 11-loci). We compared epMM and PIRCHE-II scores between patients with and without dnDSA using t-test and used ROC-curves to determine optimal cut-off values to categorize patients into four groups. We used logistic regression with AIC to compare the predictive value of PIRCHE-II, epMM, and their combination. In total 28.4% of patients developed dnDSA (n = 52), 12.5% class I dnDSA (n = 23), 24.6% class II dnDSA (n = 45), and 8.7% both class II and II dnDSA (n = 16). Mean epMMs (p-value = 0.005), mean highly immunogenic epMMs (p-value = 0.003), and PIRCHE-II (11-loci) (p = 0.01) were higher in patients with compared to without class II dnDSA. Patients with highly immunogenic epMMs above 30.5 and PIRCHE-II 11-loci above 560.0 were more likely to develop dnDSA (31.1% vs. 14.8%, p-value = 0.03). The logistic regression model including the grouping variable showed the best predictive value. MMA can support clinicians to identify patients at higher or lower risk for developing class II dnDSA and might be helpful tools for immunological risk assessment in LTX patients.

The prevalence of sepsis-induced coagulopathy in patients with sepsis - a secondary analysis of two German multicenter randomized controlled trials.

BACKGROUND: Sepsis and septic shock are frequently accompanied by coagulopathy. Since the sepsis-induced coagulopathy (SIC) score was first described, subsequent studies from Asia revealed a SIC prevalence of 40-60%. In Europe, however, SIC prevalence in patients fulfilling sepsis criteria according to the third international consensus definition (SEPSIS-3) has not yet been evaluated. METHODS: The Critical Care Trials Group of the German Sepsis Competence Network (SepNet) conducted a secondary analysis of two randomized controlled trials. Only patients fulfilling sepsis criteria according SEPSIS-3 were included in this secondary analysis. In a two step approach, SIC prevalence was determined in 267 patients with sepsis but not septic shock (at the time of inclusion) from the "Effect of Hydrocortisone on Development of Shock Among Patients With Severe Sepsis" (HYPRESS) trial. Then, we estimated SIC prevalence in 1,018 patients from the "Effect of Sodium Selenite Administration and Procalcitonin-Guided Therapy on Mortality in Patients With Severe Sepsis or Septic Shock" (SISPCT) trial using a simplified SIC score based on the platelet-SIC-subscore (PSSC). Study aims were to assess (i) the prevalence of SIC in patients with SEPSIS-3, (ii) the association of SIC with 90-day mortality and morbidity, (iii) the time when patients become SIC positive during the course of sepsis, and (iv) the value of the PSSC for predicting SIC. RESULTS: In the HYPRESS trial, SIC prevalence was 22.1% (95% confidence interval [CI] 17.5-27.5%). The estimated SIC prevalence in the SISPCT trial was 24.2% (95% CI 21.6-26.9%). In the HYPRESS trial, SIC was associated with significantly higher 90-day mortality (13.9% vs. 26.8%, p = 0.027) and morbidity. Logistic regression analysis adjusted for age, sex, treatment arm, and (SIC-adapted) SOFA score confirmed the negative association of SIC with survival (p = 0.011). In the SISPCT trial, increased PSSCs were associated with higher 90-day mortality (PSSC 0: 34.4%, PSSC 1: 40.5%, PSSC 2: 53.3%; p < 0.001). In both trials, SIC was already present at sepsis diagnosis or occurred during the following 4 days. CONCLUSIONS: SIC is a clinically relevant complication of sepsis. Although it might be less frequent than previously reported, its occurrence is associated with higher morbidity and mortality and should be interpreted as an early warning sign.

Corticotropin-stimulated steroid profiles to predict shock development and mortality in sepsis: From the HYPRESS study.

RATIONALE: Steroid profiles in combination with a corticotropin stimulation test provide information about steroidogenesis and its functional reserves in critically ill patients. OBJECTIVES: We investigated whether steroid profiles before and after corticotropin stimulation can predict the risk of in-hospital death in sepsis. METHODS: An exploratory data analysis of a double blind, randomized trial in sepsis (HYPRESS [HYdrocortisone for PRevention of Septic Shock]) was performed. The trial included adult patients with sepsis who were not in shock and were randomly assigned to placebo or hydrocortisone treatment. Corticotropin tests were performed in patients prior to randomization and in healthy subjects. Cortisol and precursors of glucocorticoids (17-OH-progesterone, 11-desoxycortisol) and mineralocorticoids (11-desoxycorticosterone, corticosterone) were analyzed using the multi-analyte stable isotope dilution method (LC-MS/MS). Measurement results from healthy subjects were used to determine reference ranges, and those from placebo patients to predict in-hospital mortality. MEASUREMENTS AND MAIN RESULTS: Corticotropin tests from 180 patients and 20 volunteers were included. Compared to healthy subjects, patients with sepsis had elevated levels of 11-desoxycorticosterone and 11-desoxycortisol, consistent with activation of both glucocorticoid and mineralocorticoid pathways. After stimulation with corticotropin, the cortisol response was subnormal in 12% and the corticosterone response in 50% of sepsis patients. In placebo patients (n = 90), a corticotropin-stimulated cortisol-to-corticosterone ratio > 32.2 predicted in-hospital mortality (AUC 0.8 CI 0.70-0.88; sensitivity 83%; and specificity 78%). This ratio also predicted risk of shock development and 90-day mortality. CONCLUSIONS: In this exploratory analysis, we found that in sepsis mineralocorticoid steroidogenesis was more frequently impaired than glucocorticoid steroidogenesis. The corticotropin-stimulated cortisol-to-corticosterone ratio predicts the risk of in-hospital death. Trial registration Clinical trial registered with www. CLINICALTRIALS: gov Identifier: NCT00670254. Registered 1 May 2008, https://clinicaltrials.gov/ct2/show/NCT00670254 .

Ecological effects of selective oral decontamination on multidrug-resistance bacteria acquired in the intensive care unit: a case-control study over 5 years.

PURPOSE: This case-control study investigated the long-term evolution of multidrug-resistant bacteria (MDRB) over a 5-year period associated with the use of selective oropharyngeal decontamination (SOD) in the intensive care unit (ICU). In addition, effects on health care-associated infections and ICU mortality were analysed. METHODS: We investigated patients undergoing mechanical ventilation > 48 h in 11 adult ICUs located at 3 campuses of a university hospital. Administrative, clinical, and microbiological data which were routinely recorded electronically served as the basis. We analysed differences in the rates and incidence densities (ID, cases per 1000 patient-days) of MDRB associated with SOD use in all patients and stratified by patient origin (outpatient or inpatient). After propensity score matching, health-care infections and ICU mortality were compared. RESULTS: 5034 patients were eligible for the study. 1694 patients were not given SOD. There were no differences in the incidence density of MDRB when SOD was used, except for more vancomycin-resistant Enterococcus faecium (0.72/1000 days vs. 0.31/1000 days, p < 0.01), and fewer ESBL-producing Klebsiella pneumoniae (0.22/1000 days vs. 0.56/1000 days, p < 0.01). After propensity score matching, SOD was associated with lower incidence rates of ventilator-associated pneumonia and death in the ICU but not with ICU-acquired bacteremia or urinary tract infection. CONCLUSIONS: Comparisons of the ICU-acquired MDRB over a 5-year period revealed no differences in incidence density, except for lower rate of ESBL-producing Klebsiella pneumoniae and higher rate of vancomycin-resistant Enterococcus faecium with SOD. Incidence rates of ventilator-associated pneumonia and death in the ICU were lower in patients receiving SOD.

Emergency Use of Convalescent Plasma: Perception of the Regulatory Framework from a Clinical Perspective.

The pandemic spread of an infectious disease poses a plethora of challenges to society, clinicians, health care providers and regulating authorities. In order to mount a rapid response and to provide hope in a potentially catastrophic situation as the current COVID-19 pandemic, emergency plans, regulations and funding strategies have to be developed on regional, national and international levels. The speed needed to establish rapid response programs is challenged by the dynamics of the spread of the disease, the concurrent and competing development of different and potentially more effective treatment options, and not the least by regulatory uncertainty. Convalescent plasma, that is plasma collected from patients who have recovered from COVID-19 infections, has emerged as one of the first potential treatment options in the absence of drugs or vaccines with proven efficacy against SARS-CoV-2. The societal aspects of convalescent plasma and the public awareness gave an additional boost to the rapid employment of convalescent plasma donation platforms immediately after the SARS-CoV-2 outbreak. At the same time, uncertainty remains as to the efficacy of convalescent plasma. With evidence mostly limited to empirical reports, convalescent plasma has been used for decades for the prophylaxis and treatment of various infectious diseases. Clinical trials have addressed different infectious agents, stages of disease, target groups of patients and yielded sometimes inconclusive results. The aim of this short review is to delineate the regulatory background for the emergency use of convalescent plasma in the USA, in the European Union and in Germany, and the transition to the setting of clinical trials. In addition, we describe observations made in the process of collecting COVID-19 convalescent plasma (herein referred to as CCP), and formulate proposals to further improve the framework for rapid responses in future emergency situations.

[Update of the Surviving Sepsis Campaign guidelines 2021-What is new?] / Update der Surviving-Sepsis-Campaign-Leitlinie 2021 ­ Was ist neu?

The revised and redefined "International Guidelines for Management of Sepsis and Septic Shock 2021" of the Surviving Sepsis Campaign were published on 4 October 2021. As in the previous version from 2016, the focus of these international guidelines is on the diagnosis and acute treatment measures in sepsis. The topics long-term outcome and treatment targets for rehabilitation are extensively discussed and accompanied by specific recommendations. These recommendations and the underlying studies reflect the increasing awareness about the long-term consequences of severe diseases requiring intensive medical care. This article summarizes the updates in a clearly comprehensible form.

A novel approach to laboratory assessment and reporting of platelet von Willebrand factor.

The interaction of platelets with von Willebrand factor is essential for primary hemostasis. Concentration and activity of plasma von Willebrand factor are routine parameters in the assessment of hemostasis disorders. In addition to plasma von Willebrand factor, platelet von Willebrand factor, synthesized in megakaryocytes and stored in α-granules of circulating platelets, is known to contribute to primary hemostasis and the microenvironment of thrombus formation. The laboratory assessment of platelet von Willebrand factor however is cumbersome and not widely established as a routine parameter. We here propose a method for laboratory assessment and reporting of platelet von Willebrand factor potentially useful for laboratory routines in specialized laboratories. Our model allows to describe platelet von Willebrand factor as 1. the concentration of platelet von Willebrand factor in whole blood, 2. the amount of platelet von Willebrand factor in a sample with a defined concentration of 1000 platelets/nl, and 3. the concentration of platelet von Willebrand factor in one platelet. According to our results in healthy individuals, the proportion of platelet von Willebrand factor activity is estimated to be about 10% of total von Willebrand factor in human plasma under physiological circumstances. The concentration of platelet von Willebrand factor is estimated to be 0.4 IU/ml in a sample with a defined concentration of 1000 platelets/nl and to be about 42 IU/ml in one platelet (both expressed as VWF:Ag).

[SEPSIS-3.0-Is intensive care medicine ready for ICD-11?] / SEPSIS-3.0 ­ Ist die Intensivmedizin bereit für die ICD-11?

BACKGROUND: The 11th revision of the International Classification of Diseases (ICD-11) will come into effect in January 2022. Among other things, The Third International Consensus Definitions for Sepsis and Septic Shock (SEPSIS­3 definition) will be implemented in it. This defines sepsis as a "life-threatening organ dysfunction caused by a dysregulated host response to infection". The aim of the present secondary analysis of a survey on the topic of "sepsis-induced coagulopathy" was to evaluate whether the SEPSIS­3 definition, 4 years after its international introduction, has arrived in everyday clinical practice of intensive care units (ICU) run by anesthesiologists in Germany and thus the requirements for its use of the ICD-11 are given. METHODS: Between October 2019 and May 2020, we carried out a nationwide survey among German medical directors of ICUs. In a separate block of questions we asked about the definition of sepsis used in daily practice. In addition, we asked whether the quick-sequential (sepsis-related) organ failure assessment (qSOFA) score is used in screening for sepsis in the hospital to which to the participating ICU belongs. RESULTS: A total of 50 medical directors from anesthesiological ICUs took part in the survey. In total, the ICUs evaluated stated that they had around 14% of the high-care beds registered in Germany. The SEPSIS­3 definition is integrated into everyday clinical practice at 78.9% of the university hospitals and 84.0% of the participating teaching hospitals. In contrast, the qSOFA screening test is only used by 26.3% of the participating university hospitals, but at least 52% of the teaching hospitals and 80% of the other hospitals. CONCLUSION: The data show that both SEPSIS­3 and qSOFA have become part of everyday clinical practice in German hospitals. The cautious use of qSOFA at university hospitals with simultaneous broad acceptance of the SEPSIS­3 definition can be interpreted as an indication that the search for a suitable screening test for sepsis has not yet been completed.

[Practice of pharmaceutical thrombosis prophylaxis and anticoagulation in patients with sepsis and pre-existing anticoagulation or heparin-induced type II thrombocytopenia-Results of a nationwide survey in German intensive care units]. / Praxis der medikamentösen Thromboseprophylaxe und Antikoagulation bei Patienten mit Sepsis und vorbestehender Antikoagulation oder Heparin-induzierter Thrombozytopenie Typ II ­ Ergebnisse einer deutschlandweiten Umfrage auf Intensivstationen.

BACKGROUND: A pre-existing anticoagulation treatment and predisposing diseases for thromboembolic events represent common problems in patients with sepsis or septic shock; however, these conditions are not addressed in current national guidelines for sepsis and septic shock. One of the aims of this nationwide survey in Germany was therefore to determine how intensive care physicians deal with these problems. METHODS: From October 2019 to May 2020, we conducted a nationwide survey among German medical directors of intensive care units (ICU) addressing anticoagulation and drug-based prophylaxis of venous thromboembolism (VTE) in patients with sepsis and sepsis-induced coagulopathy. One focus was the procedure for patients with a pre-existing anticoagulation treatment or a previously known heparin-induced thrombocytopenia (HIT) type 2 (acute symptomatic vs. dating back years). RESULTS: In most of the participating ICUs pre-existing anticoagulation is largely continued with low molecular weight heparin preparations or unfractionated heparin. In patients with pre-existing HIT type 2 both acute symptomatic and dating back years, argatroban represents the drug of choice. There is a high degree of variability in the definition of the target values, usually being well above the range for pure VTE prophylaxis. CONCLUSION: Data on the continuation of anticoagulation beyond VTE prophylaxis with a subsequently increased risk of bleeding in patients with sepsis and septic shock is limited and treatment decisions are in many cases subject to individual consideration by the practitioner. The results of our survey imply the need for a systematic work-up of this topic in order to support daily practice in many ICUs with the required evidence.

[Anticoagulation in intensive care medicine]. / Antikoagulation in der Intensivmedizin.

Critically ill patients are at high risk of hemostasis disorders, which can be associated with both an increased risk of bleeding and an increased risk of thromboembolic events. In the case of acute vascular events, specific therapy with drug anticoagulation or platelet aggregation inhibition is essential. In patients with pre-existing conditions, the appropriate continuation of anticoagulation during intensive care treatment is important. Furthermore, in everyday clinical practice, prophylaxis of thromboembolism as well as the question of potential therapeutic options in the treatment of sepsis and infection-triggered disorders of blood coagulation are important. Specific questions arise with the use of extracorporeal devices such as renal replacement and circulatory assist systems. A number of new anticoagulation and anti-platelet drugs have become available in recent years. Laboratory monitoring of anticoagulation is central. In this overview, current aspects of these topics are presented.

[Tranexamic acid for bleeding prophylaxis in orthopedic surgery and trauma-standard or customized therapy?] / Tranexamsäure zur Blutungsprophylaxe bei Trauma und orthopädischen Eingriffen ­ Standard oder individualisierte Anwendung?

The use of tranexamic acid (TXA) is established in the treatment of bleeding, especially of bleeding due to hyperfibrinolysis. In recent years the prophylactic use of TXA in trauma and orthopedic surgery has increased leading to open questions regarding potentially associated risks and a possible classification as off label use. The available literature provides a sound basis for the recommendation that TXA can be used in these indications provided that an individual risk assessment is done in patients with increased risks for thromboembolic complications. Although the prophylactic use of TXA in orthopedic surgery and trauma is not explicitly listed in the product characteristics, it should not be regarded as an off label use.

[Treatment of sepsis-induced coagulopathy : Results of a Germany-wide survey in intensive care units]. / Therapie der sepsisinduzierten Koagulopathie : Ergebnisse einer deutschlandweiten Umfrage auf Intensivstationen.

BACKGROUND: In the context of sepsis and septic shock, coagulopathy often occurs due to the close relationship between coagulation and inflammation. Sepsis-induced coagulopathy (SIC) is the most severe and potentially fatal form. Anticoagulants used in prophylactic or therapeutic doses are discussed to potentially exert beneficial effects in patients with sepsis and/or SIC; however, due to the lack of evidence recent guidelines are limited to recommendations for drug prophylaxis of venous thromboembolism (VTE), while treatment of SIC has not been addressed. METHODS: In order to determine the status quo of VTE prophylaxis as well as treatment of SIC in German intensive care units (ICU), we conducted a Germany-wide online survey among heads of ICUs from October 2019 to May 2020. In April 2020, the survey was supplemented by an additional block of questions on VTE prophylaxis and SIC treatment in coronavirus disease 2019 (COVID-19) patients. RESULTS: A total of 67 senior doctors took part in the survey. The majority (n = 50; 74.6%) of the responses were from ICU under the direction of an anesthesiologist and/or a department of anesthesiology. Most of the participants worked either at a university hospital (n = 31; 47.8%) or an academic teaching hospital (n = 27; 40.3%). The survey results show a pronounced heterogeneity in clinical practice with respect to the prophylaxis of VTE as well as SIC treatment. In an exemplary case of pneumogenic sepsis, low molecular weight heparins (LMWH) were by far the most frequently mentioned group of medications (n = 51; 76.1% of the responding ITS). In the majority of cases (n = 43; 64.2%), anti-FXa activity is not monitored with the use of LMWH in prophylaxis doses. Unfractionated heparin (UFH) was listed as a strategy for VTE prophylaxis in 37.3% of the responses (n = 25). In an exemplary case of abdominal sepsis 54.5% of the participants (n = 36; multiple answers possible) stated the use of UFH or LMWH and UFH with dosage controlled by PTT is used on two participating ICUs. The anti-FXa activity under prophylactic anticoagulation with LMWH is monitored in 7 participating clinics (10.6%) in abdominal sepsis. Systematic screening for sepsis-associated coagulation disorders does not take place in most hospitals and patterns in the use of anticoagulants show significant variability between ICUs. In the case of COVID-19 patients, it is particularly noticeable that in three quarters of the participating ICUs the practice of drug-based VTE prophylaxis and SIC treatment does not differ from that of non-COVID-19 patients. CONCLUSION: The heterogeneity of answers collected in the survey suggests that a systematic approach to this topic via clinical trials is urgently needed to underline individualized patient care with the necessary evidence.

Comparison of Two Different Fibrinogen Concentrates in an in vitro Model of Dilutional Coagulopathy.

INTRODUCTION: Fibrinogen concentrates are widely used to restore clot stability in situations of bleeding. Fibrinogen preparations are produced using different production methods, resulting in different compounds. Thus, different preparations might have a distinct impact on blood coagulation. We tested the effect of fibrinogen concentrates Haemocomplettan® (CSL Behring, Marburg, Germany) and fibryga® (Octapharma GmbH, Langenfeld, Germany) on the impairments induced by 60% dilutional coagulopathy in vitro. MATERIALS AND METHODS: The influence of the fibrinogen concentrates fibryga® and Haemocomplettan® on colloid (gelatine, hydroxyethyl starch [HES], albumin)-induced or crystalloid (Ringer's acetate)-induced dilutional coagulopathy was analysed using rotational thromboelastometry (ROTEM®) and standard laboratory tests. The following experimental conditions were analysed in vitro: whole blood, 60% dilution (40% blood and 60% diluent) ± 50 or 100 mg/kg-1 fibryga® or Haemocomplettan®, respectively. RESULTS: Dilution with either diluent resulted in prolonged clotting time (CT) in an extrinsic activated test (CTEXTEM) and decreased maximum clot firmness (MCFFIBTEM) as expressed, e.g., by gelatine: (59.5 s [62/54.8] vs. 95 s [102.8/86.8]; p < 0.001 and 14 mm [16/10.5] vs. 3 mm [4-3]; p < 0.001). Substitution after 60% dilution with HES resulted in no difference between the preparations, except for shorter thrombin time with fibryga® (14 s [15/14] vs. 18 s [18.8/17]; p = 0.0093; low dose). CTEXTEM was higher with Haemocomplettan® in a gelatine-induced dilution (51 s [54.5/47.5] vs. 63 s [71/60.3]; p = 0.0202; low dose) whereas thrombin time was lower with fibryga® (19.5 s [20.8/19] vs. 27 s [29/25.3]; p = 0.0017). In dilution with albumin, differences in CTEXTEM (69 s [76.5/66] vs. 56 s [57/53.3]; p = 0.0114; low dose) and thrombin time (18 s [18/17] vs. 24.5 s [25.8/24]; p = 0.0202; low dose) were seen. In dilution with crystalloid solution, again differences in CTEXTEM (53.5 s [57.8/53] vs. 45 s [47/43]; p = 0.035; low dose) and thrombin time (17 s [17/16] vs. 23.5 s [24/23]; p = 0.0014; low dose) were seen. Fibrinogen levels were more increased by high-dose substitution of both preparations. CONCLUSION: Based on this data it can be stated that both fibryga® and Haemocomplettan® had the same performance in our in vitro model except for CTEXTEM and thrombin time.

Emicizumab in the Treatment of Acquired Haemophilia: A Case Report.

The prognosis of acquired haemophilia A (AHA) is severe and treatment options are limited. Emicizumab is a novel bispecific humanized monoclonal antibody in the treatment of inherited AHA with inhibitors. An 83-year-old AHA patient with congestive heart failure and a high risk for thromboembolic and cardiac events who had initially been treated successfully with steroids and substitution of recombinant B-domain-deleted porcine FVIII developed severe bleeding complications and a secondary increase in inhibitor titres after 4 weeks of treatment. Conventional therapeutic strategies failed, and the patient was subsequently treated with emicizumab on off-label and named patient use premises. After the application of emicizumab, the clinical conditions stabilized and no further substitution of coagulation factors was needed. The patient could be discharged and survived 36 days in a cardiac rehabilitation centre without indications for spontaneous bleeding or thromboembolic events. We suggest that the effects of emicizumab in acquired haemophilia should be evaluated in clinical trials.

Perioperative Management of a Patient with Severe Factor V Deficiency Presenting with Chronic Subdural Hematoma: A Clinical Report.

BACKGROUND: Severe factor V deficiency is an extremely rare coagulation disorder. Patients with factor V activity <5% usually become symptomatic in early childhood. CASE DESCRIPTION: We report the case of an 82-year-old woman with incidentally diagnosed severe factor V deficiency, who developed a symptomatic chronic subdural hematoma, requiring burr hole craniostomy. Successful management was achieved by a multidisciplinary approach. Preoperatively, factor V activity was increased from 2% to 50% by administration of 25 mL/kg body weight of fresh frozen plasma over 30 minutes under close cardiopulmonary monitoring in the intensive care unit. Straight afterward, the patient was transferred to the operating room where surgery was performed under general anesthesia. Burr hole craniostomy could be performed without perioperative complications. In the postoperative days, there was no relevant recurrence of the subdural hematoma in the follow-up computed tomography scans under frequent control of coagulation parameters. However, despite further transfusion of fresh frozen plasma, factor V activity did not increase >16%. The patient was discharged without any neurologic deficits. In a hemostaseologic follow-up 2 months after surgery, factor V activity <1% was confirmed with evidence of a factor V inhibitor in the modified Bethesda assay. Most likely, the patient suffered from an acquired form of factor V deficiency with preformed antibodies that had been boosted by the initial treatment with fresh frozen plasma. CONCLUSIONS: We conclude that in this rare bleeding disorder, intracranial surgery was successfully managed because of a thoroughly planned perioperative therapeutic strategy. However, if there is time prior to surgery, a full checkup of the bleeding disorder is advisable.