Cerebral Intraparenchymal Hemorrhage due to Implantation of Electrodes for Deep Brain Stimulation: Insights from a Large Single-Center Retrospective Cross-Sectional Analysis.

Cerebral intraparenchymal hemorrhage due to electrode implantation (CIPHEI) is a rare but serious complication of deep brain stimulation (DBS) surgery. This study retrospectively investigated a large single-center cohort of DBS implantations to calculate the frequency of CIPHEI and identify patient- and procedure-related risk factors for CIPHEI and their potential interactions. We analyzed all DBS implantations between January 2013 and December 2021 in a generalized linear model for binomial responses using bias reduction to account for sparse sampling of CIPHEIs. As potential risk factors, we considered age, gender, history of arterial hypertension, level of invasivity, types of micro/macroelectrodes, and implanted DBS electrodes. If available, postoperative coagulation and platelet function were exploratorily assessed in CIPHEI patients. We identified 17 CIPHEI cases across 839 electrode implantations in 435 included procedures in 418 patients (3.9%). Exploration and cross-validation analyses revealed that the three-way interaction of older age (above 60 years), high invasivity (i.e., use of combined micro/macroelectrodes), and implantation of directional DBS electrodes accounted for 82.4% of the CIPHEI cases. Acquired platelet dysfunction was present only in one CIPHEI case. The findings at our center suggested implantation of directional DBS electrodes as a new potential risk factor, while known risks of older age and high invasivity were confirmed. However, CIPHEI risk is not driven by the three factors alone but by their combined presence. The contributions of the three factors to CIPHEI are hence not independent, suggesting that potentially modifiable procedural risks should be carefully evaluated when planning DBS surgery in patients at risk.

The effect of recombinant versus plasma-derived von Willebrand factor on prolonged PFA closure times in ECMO patients with acquired von Willebrand syndrome - an observational study.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is applied in patients with respiratory or cardiopulmonary failure, but bleeding is a frequent complication contributing to the high mortality rates in this patient collective. A major factor predisposing patients to bleeding events is an acquired von Willebrand syndrome (aVWS). So far, specific treatment options for this phenomenon are lacking. In hereditary von Willebrand disease (VWD), treatment with recombinant or plasma-derived von Willebrand factor (rVWF or pVWF) is common practice. Closure time measured by the Platelet Function Analyser-200 (PFA-200) is an established assay to detect defects in primary hemostasis and the method is useful to monitor the effect of hemostatic therapy. The aim of this study was to assess the effect of recombinant (rVWF) vs. plasma-derived von Willebrand factor (pVWF) on closure times measured by PFA in blood obtained from ECMO patients with aVWS. METHODS: Blood was sampled from thirteen patients receiving extracorporeal membrane oxygenation and three patients with hereditary VWD. Diagnosis of aVWS was made by conventional coagulation parameters and by multimeric structure analysis. PFA analysis of blood spiked with rVWF or pVWF was performed. RESULTS: Thirteen patients receiving ECMO were recruited. Ten patients survived and three patients suffered major bleeding complications. PFA closure times in ECMO patients with aVWS spiked with rVWF were significantly shorter at all concentrations than with pVWF (e.g., rVWF vs. pVWF: 1 U/ml: 150.4 ± 21.7 s vs. 263.8 ± 11.7 s; 4 U/ml: 97.8 ± 9.8 s vs. 195.8 ± 15.4 s, p<0.001). PFA closure times were also significantly shorter in three patients with hereditary VWD treated with rVWF compared to pVWF (e.g., 1 U/ml rVWF vs. pVWF: 73.7±1.33 s vs. 231.3±43.4 s, p<0.01) CONCLUSION: In summary, this study shows that rVWF compared to pVWF more effectively reduced PFA closures times in blood samples of ECMO patients with aVWS. Higher doses of VWF are needed to normalize PFA closure time in blood samples of patients with ECMO-induced aVWS compared to hereditary VWD. These data support the use of PFA-200 to monitor hemostatic effects in a future clinical trial involving ECMO patients with aVWS.

Residual anti-Xa activity in plasma of patients presenting for electively planned neuraxial regional anesthesia.

OBJECTIVE: To determine the incidence of increased anti-Xa activity within plasma levels 24 hours after administration of therapeutic dose low-molecular-weight heparin in patients presenting for elective neuraxial anesthesia. BACKGROUND: Guidelines for neuroaxial regional anesthesia for patients with antithrombotic drugs recommend time intervals for waiting. There is scientific evidence to suggest that the recommended interval of 24 hours may be insufficient in patients treated with therapeutic dose low-molecular-weight heparin. METHODS: Retrospective cohort analysis of 74 patients who received therapeutic dose low-molecular-weight heparin before planned neuraxial anesthesia between April 1, 2015 and April 1, 2020 at Freiburg University Hospital. Primary endpoint was the occurrence of elevated plasma anti-Xa levels in prophylactic range or higher (>0.2 IU/mL) 24 hours after the last application of the therapeutic dose. RESULTS: 24 hours after the last dose of therapeutic low-molecular-weight heparin, 18.0% of patients had elevated anti-Xa activity levels >0.2 IU/mL. A weak correlation between the time since the last administration of low-molecular-weight heparin and plasma anti-Xa levels could be found. No other risk factors were seen. CONCLUSIONS: Relevant residual anticoagulant activity, as measured by plasma anti-Xa levels within a prophylactic range, is measurable 24 hours after the last administration of therapeutic dose low-molecular-weight heparin. TRIAL REGISTRATION NUMBER: German Clinical Trials Register DRKS00022099.

Laboratory Findings, Medical Imaging, and Clinical Outcome in Children with Cerebral Sinus Venous Thrombosis.

INTRODUCTION: Cerebral sinus venous thrombosis (CSVT) is a rare disease, especially in children. Therefore, thrombophilia markers, risk factors, treatment strategy, and MRI, as well as clinical outcome need further investigation to support future diagnostic and therapeutic guidelines for children. METHODS: We retrospectively identified all children with CSVT treated in our center between January 1, 2000, and December 31, 2015. Risk factors and laboratory findings were investigated. Furthermore, outcome and treatment satisfaction were evaluated using magnetic resonance imaging (MRI) analyses and a modified questionnaire. RESULTS: All 43 patients, who agreed to participate, were treated with therapeutic levels of heparin; 86% of children had an increased risk for thromboembolic events upon onset of CSVT (acute disease: 58.1%, perinatal risk factors: 9.3%, medical intervention/immobility: 14%, chronic disease: 16.3%). Thrombophilia markers showed positive results (e.g., reduced values for protein C/S, factor-V-Leiden mutation) in 58% of children at the time of CSVT diagnosis but dropping to 20.9% over the course of the disease. Forty-two of 43 patients received MRI follow-ups and the outcome showed complete recanalization in 69% of the patients and partial recanalization in 31%. At the onset of CSVT, 88% of patients reported restrictions in everyday life due to CSVT; at follow-up this percentage declined to 18%. Satisfaction with the outcome among parents/patients according to the questionnaire was high with 1.7 (German school grades from 1 to 6). CONCLUSIONS: All 42 children with MRI follow-up demonstrated complete or partial recanalization under anticoagulation. This positive result underlines the need for future studies on anticoagulation to optimize therapy regimens of pediatric CSVT.

Novel Likely Pathogenic Variant in the A3 Domain of von Willebrand Factor Leading to a Collagen-Binding Defect.

Von Willebrand disease (VWD) is the most prevalent congenital bleeding disorder. Diagnosis and classification of VWD is complex due to its heterogeneity regarding clinical manifestations and molecular genetic analysis. Genetic investigations became an inherent part of diagnosis and help distinguish different types/subtypes of VWD. Although many variants have been listed being causative for VWD, the genetic etiology remains undefined in a lot of patients. We report about two siblings with severely reduced values for von Willebrand factor collagen-binding activity (VWF:CB). Genetic analysis using panel sequencing identified a heterozygous non-synonymous single nucleotide variant in exon 30. At the protein level, the alteration (p.Ser1731Leu) is located in the A3 collagen-binding domain. The amino acid position is already known to be important for collagen binding because p.Ser1731Thr has been reported to affect the VWF:CB.

Reference Intervals in Coagulation Analysis.

Blood coagulation analysis is characterized by the application of a variety of materials, reagents, and analyzers for the determination of the same parameter, or analyte, by different laboratories worldwide. Accordingly, the application of common reference intervals, that, by definition, would represent a "range of values (of a certain analyte) that is deemed normal for a physiological measurement in healthy persons," is difficult to implement without harmonization of procedures. In fact, assay-specific reference intervals are usually established to allow for the discrimination of normal and abnormal values during evaluation of patient results. While such assay-specific reference intervals are often determined by assay manufacturers and subsequently adopted by customer laboratories, verification of transferred values is still mandatory to confirm applicability on site. The same is true for reference intervals that have been adopted from other laboratories, published information, or determined by indirect data mining approaches. In case transferable reference intervals are not available for a specific assay, a direct recruiting approach may or needs to be applied. In comparison to transferred reference interval verification, however, the direct recruiting approach requires a significantly higher number of well-defined samples to be collected and analyzed. In the present review, we aim to give an overview on the above-mentioned aspects and procedures, also with respect to relevant standards, regulations, guidelines, but also challenges for both, assay manufacturers and coagulation laboratories.

Emicizumab in children: bleeding episodes and outcome before and after transition to Emicizumab.

PURPOSE: Real-world data and study data regarding therapy with Emicizumab in pediatric cohorts with haemophilia A is scarce. Especially, data on previously untreated pediatric patients (PUPs) and minimally treated patients (MTPs) are missing. METHODS: Thirteen pediatric patients with haemophilia A and treatment with Emicizumab were retrospectively evaluated for Annual Bleeding Rates (ABR) pre-and post-Emicizumab treatment. Safety data and data on management of minor surgery as well as laboratory results were collected. Additionally, we describe the clinical features of two PUPs and one MTP that are included in our cohort. RESULTS: Median age at initiation of Emicizumab was 5.3 (range: 0.26-17.5) years, three patients were younger than one year at initiation of treatment with Emicizumab. Median follow-up time on Emicizumab was 23.8 (range: 0.7-40) months. Total ABR (p = 0.009) as well as spontaneous (p = 0.018), traumatic (p = 0.018), and joint (p = 0.027) ABR reduced significantly post-Emicizumab transition. Safety profile was favourable as only one local site reaction occurred; no cessation of treatment was necessary. Surgery was successfully performed in three patients receiving rFVlla pre- and post-surgery. Emicizumab trough levels showed a median of 43.2 µg/ml (range: 23.9-56.8) after three doses of 3 mg/kg and 51.9 µg/ml (range: 30.4-75) at first follow-up with 1.5 mg/kg. CONCLUSION: Emicizumab is safe and efficient in pediatric patients with and without inhibitors. More data on larger multicenter cohorts and especially on PUPs/MTPs are still needed.

Acquired von Willebrand Syndrome and Desmopressin Resistance During Venovenous Extracorporeal Membrane Oxygenation in Patients With COVID-19: A Prospective Observational Study.

OBJECTIVES: Although COVID-19 is associated with high von Willebrand factor (vWF) parameters promoting thrombosis, venovenous extracorporeal membrane oxygenation (vvECMO) is associated with the development of acquired von Willebrand syndrome (AVWS) promoting bleeding. This study was designed to assess both the incidence and severity of AVWS in COVID-19 patients undergoing vvECMO, and the benefit of comprehensive vWF analyses. DESIGN: Prospective observational study. SETTING: ICU at a tertiary-care center. PATIENTS: Twenty-seven consecutive COVID-19 patients with acute respiratory distress syndrome (ARDS) requiring vvECMO. MEASUREMENTS AND MAIN RESULTS: Comprehensive vWF analyses (including sodium dodecyl-sulfate polyacrylamide gel electrophoresis) were performed before, during, and after vvECMO. In a subgroup of 12 patients with AVWS, effectiveness of treatment with desmopressin was assessed. The patients' mean age was 53 years (range, 23-73), 70% were male, and all had various comorbidities. Following markedly elevated vwf antigen (vWF: Ag; mean, 546% ( sd , 282]), vWF collagen binding capacity (mean, 469% [ sd , 271]), vWF activity (vWF:A; mean, 383% [ sd , 132]), and factor VIII activity (mean, 302% [ sd , 106]), and only borderline decreases in high-molecular-weight (HMW) vWF multimers before vvECMO, all of these variables decreased and HMW vWF multimers became undetectable within hours following initiation of vvECMO. All variables fully recovered within 3-38 hours after discontinuation of vvECMO. During vvECMO, decreases in the vWF:A/vWF:Ag ratio correlated with absent HMW vWF multimers. Desmopressin did not affect vWF parameters. CONCLUSIONS: In patients with COVID-19-associated ARDS, AVWS developed soon after initiation of vvECMO. The vWF:A/vWF:Ag ratio was a suitable screening test for AVWS. As desmopressin was ineffective, bleeding during vvECMO-associated AVWS should preferably be treated with concentrates containing vWF.

Type 2B von Willebrand Disease: Early Manifestation as Neonatal Thrombocytopenia.

Here, we report about a preterm female newborn with a prolonged course of severe thrombocytopenia and hematomas. The family history was positive for von Willebrand disease type 2B (VWD 2B). Diagnosis of VWD 2B was identified analyzing von Willebrand factor (VWF) parameters (VWF:antigen, VWF:activity, VWF multimer analyses) and performing light transmission aggregometry (with half concentration of ristocetin). In addition, the diagnosis was confirmed by molecular genetic analysis: identification of a disease-causing missense mutation (Val1316Met) in the VWF gene associated with a severe course of VWD 2B, which had been previously reported. Treatment with a VWF-containing plasma concentrate was initiated. Because the combination of prematurity and very low platelet count is often associated with intracranial bleeding, at the beginning platelet concentrates were transfused. Fortunately, the patient did not develop serious bleeding episodes. Interestingly, the patient had a mutation in the VWF gene, which had been described to be associated with aggravation of thrombocytopenia especially in stressful situations. Therefore, we replaced venous blood withdrawals by capillary blood samplings when possible and, consequently, we observed an increase of the platelet count after this change in management. At the age of 2 months, the patient was discharged after stabilization of the platelet count without any bleeding signs and without a need of long-term medication.

A case of septic arthritis caused by a Mycoplasma salivarium strain resistant towards Ciprofloxacin and Clarithromycin in a patient with chronic lymphatic leukemia.

Mycoplasma salivarium is a rare agent of septic arthritis in immunocompromised patients. We report a case of septic arthritis due to Mycoplasma salivarium in a patient with B-cell chronic lymphocytic leukemia who underwent chemotherapy with rituximab and bendamustin. Therapy of arthritis due to Mycoplasma salivarium is difficult because there are almost no susceptibility data available. The present case illustrates that antimicrobial susceptibility of Mycoplasma strains is not necessarily predictable and that antibiotic therapy should therefore be guided by in vitro susceptibility testing.