Emicizumab for acquired hemophilia A: Report of two cases and dosing strategies.

Acquired hemophilia A (AHA) is a rare autoimmune bleeding disorder caused by autoantibodies against FVIII. Severe AHA is life-threatening. Currently, licensed hemostatic agents for the treatment of severe AHA have short half-lives and require intravenous administration, leading to a need for hospitalization, higher costs, and negative effects on quality of life. We present two cases of severe AHA with high inhibitor titers where emicizumab was safely and effectively used with intensive immunosuppression. These reports suggest in vivo efficacy even in high inhibitor environments. The optimal dosing regimen (accelerated vs. standard loading, maintenance frequency) is unknown and we discuss the current approaches.

Clinical Utility of Neutrophil to Lymphocyte Ratio in Sickle Cell Disease With Vaso-Occlusive Crisis.

BACKGROUND AND OBJECTIVES: The neutrophil-to-lymphocyte ratio represents a universally accessible value that correlates with inflammation and prognosis in several disease states; however, the role of this biomarker in sickle cell disease remains poorly explored. Hence, the objective of the present study was to determine its potential clinical utility in patients with sickle cell disease. PATIENTS: Herein, we retrospectively reviewed 143 patients with sickle cell disease who presented to the emergency department with fever and painful vaso-occlusive crisis. RESULTS: The examined cohort had a prevalence of 11% confirmed bacterial infection, with approximately two-thirds reporting the use of hydroxyurea. The neutrophil-to-lymphocyte ratio was lowest in the vaso-occlusive crisis-only group when compared with all other groups; this ratio was the highest in those with a confirmed bacterial infection. Patients with confirmed bacterial infection experienced the longest mean length of in-hospital stay, approximately 2 weeks, whereas patients with viral infections and vaso-occlusive crisis had the shortest stay (4-5 days). An elevated neutrophil-to-lymphocyte ratio on presentation correlated with confirmed bacterial infection (area under the curve 0.76); maximum specificity (76%) and sensitivity (69%) for confirmed bacterial infection were achieved using a neutrophil-to-lymphocyte ratio threshold ≥4.6. However, the neutrophil-to-lymphocyte ratio did not predict acute chest syndrome in this patient cohort. CONCLUSION: The neutrophil-to-lymphocyte ratio is a promising biomarker in sickle cell disease with diagnostic and prognostic utility.

Coagulopathy following Crotaliπae snakebites in northeast Florida.

Effects of Crotalinae envenomation vary by geographical areas and research into coagulopathy and effects of antivenom are needed to optimize management. This was a single-center retrospective review with testing on presentation and 4 h after; antivenom administration was noted and data analyzed overall and comparing envenomations. One hundred and nineteen snakebites evaluated with 59 identified as Crotalinae and half receiving antivenom. PT/aPTT was elevated in 20% of water moccasin/copperhead and 21% of rattlesnake bites. DIC-like syndrome occurred in 8% water moccasin/copperhead and 6% rattlesnake bites. Antivenom did not seem to correct PT or aPTT at 4 h follow-up in most cases. Thrombotic microangiopathy was not seen. Coagulopathy was prevalent affecting one in five patients in this cohort and does seem to persist at short interval follow-up, even in those receiving antivenom. We support guidelines recommending clinical monitoring and serial coagulation profiles in such cases. Blood Coagul Fibrinolysis 30:000 - 000 Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

Procalcitonin as a diagnostic marker for infection in sickle cell disease.

BACKGROUND: Patients with sickle cell disease (SCD) are at increased risks of infection. Fever often occurs with vaso-occlusive crisis (VOC), posing a diagnostic challenge in SCD. Procalcitonin (PCT) is an infectious biomarker validated in the general population but with limited data on use in SCD. METHODS: We performed a retrospective single-center study (n = 145) with primary objective of assessing ability of PCT to differentiate infection from VOC in SCD presenting with fever. Subgroups included confirmed bacterial infection (CBI), suspected bacterial infection, viral infection, and VOC. A secondary objective examined the association of PCT with acute chest syndrome. Clinical characteristics and data were collected and analyzed to assess the diagnostic performance of PCT and associated variables. RESULTS: Of the cohort, 16% had CBI and 8% had viral infection. PCT was able to discriminate CBI from viral infection [AUC = 0.89 (95%CI, 0.78-0.99)] and VOC [AUC = 0.87 (95%CI, 0.78-0.97)]. PCT had an association with ACS but poor diagnostic performance [AUC = 0.69 (95% CI, 0.54-0.84)]. CONCLUSION: PCT has utility in distinguishing confirmed bacterial infection from VOC or viral infection and is a promising biomarker when investigating fever in SCD.

Sinonasal renal cell-like adenocarcinoma arising in von Hippel Lindau (VHL) syndrome.

Sinonasal renal cell-like adenocarcinoma (SNRCLA) is a rare and relatively novel diagnosis. Hereditary and somatic genomic signatures are not well defined in this disease. We report the case of a 35-year-old African-American male with von Hippel Lindau (VHL) syndrome who developed SNRCLA. He underwent surgical resection followed by adjuvant radiation and has no recurrence one year from diagnosis. A review of the literature yielded two similar cases in the setting of VHL. In our case with associated VHL syndrome, next generation sequencing detected MST1R mutation, a possible driver. SNRCLA is an emerging tumor associated with VHL syndrome and it is hoped that future studies shed light on the underlying biology of this unique tumor.

Novel splicing (c.6529-1G>T) and missense (c.1667G>A) mutations causing factor V deficiency.

Congenital factor V deficiency (FVD) is a rare bleeding disorder. In this study, we investigated the genetic basis in an African American patient with factor V activity 3%. Custom sequence capture and targeted next-generation (NGS) sequencing of the F5 gene were undertaken followed by PCR and Sanger sequencing. Two novel variants were identified. In silico analyses correlated clinically with the patient's factor V activity and hemorrhagic tendency. A review of the literature regarding these genomic alterations is presented. We described two novel mutations causing moderate FVD. The first, Chr1:g.169483698C>A with cDNA change (F5):c.6529-1G>T, occurred in a conserved nucleotide at the canonical acceptor splice site of intron 24. The second, Chr1:g.169515775C>T with cDNA change (F5):c.1667G>A, was a missense variant of exon 11, affecting a highly conserved amino acid in the A2 domain. Further research into the mechanisms of F5 mutations leading to FVD and residual factor V expression are needed.

Timely Delivery of Discharge Medications to Patients' Bedsides: A Patient-centered Quality Improvement Project.

INTRODUCTION: Patients who are unable to fill prescriptions after discharge are at risk of hospital readmission. Ensuring that patients have prescriptions in hand at the time of discharge is a critical component of a safe and effective discharge process. Using a "Meds to Beds" program, we aimed to increase the percentage of patients discharged from Holtz Children's Hospital with medications in hand from 49% to 80%, reduce turnaround time (TAT) from electronic prescription signature to bedside delivery from 4.9 hours (±2.6 hours) to 2 hours, and increase caregiver satisfaction. METHODS: We formed a multidisciplinary team and implemented 4 patient-centered interventions through iterative plan-do-study-act cycles. Statistical process control charts were used to understand the impact of the interventions over 10 months. Hospital length of stay and discharges before 2:00 pm were used as balancing measures. We measured caregiver satisfaction using a telephone survey administered by pediatric residents within 7 days after discharge. RESULTS: The mean percentage of patients discharged with medications in hand increased to 76%. TAT decreased to 3.5 hours (±1.8 hours). Length of stay did not significantly increase, whereas the percentage of patients discharged before 2:00 pm did. Caregivers of patients who had prescriptions delivered to their bedside reported high levels of satisfaction. CONCLUSIONS: Using a "Meds to Beds" program, we increased the percentage of patients discharged with medications in hand, decreased TAT with reduced variability, and achieved high levels of caregiver satisfaction. Importantly, there was a shift in the culture of the institution toward improved medication access for patients.

Anti-PF4/heparin antibodies are increased in hospitalized patients with bacterial sepsis.

Heparin-induced thrombocytopenia (HIT) is caused by antibodies targeting platelet factor 4 (PF4)/heparin complexes. The immune response leading to HIT remains perplexing with many paradoxes. Unlike other drug induced reactions, anti-PF4/heparin antibody generation does not follow the classic immunologic response. Research in murine models suggests that that there is close interplay among infection, PF4 and the immune system. We hypothesized there would be a relatively higher prevalence of anti-PF4/heparin antibodies in patients hospitalized for sepsis. We retrospectively examined anti-PF4/heparin antibody testing in 200 such patients. This included patients who had sepsis with bacteremia (n = 57), sepsis with fungemia (n = 7) and sepsis without bacteremia or fungemia (n = 136). For comparison, data from 50 patients without sepsis during the same time period was used. Results confirmed that patients hospitalized with sepsis have higher anti-PF4/heparin antibody levels. The groups of patients having sepsis with bacteremia, and sepsis without bacteremia, had significantly higher OD than the control group without sepsis (p < 0.05). There was no significant difference between Gram negative and Gram positive bacteremia and antibody levels. This suggests that bacterial cell wall components of both classes have similar antigenicity. Interestingly, patients who had sepsis with fungemia had much lower antibody levels compared to those with sepsis and bacteremia, and sepsis without bacteremia or fungemia. Despite the small sample size for fungemia, this difference trended strongly towards statistical significance (p = 0.05). It would be interesting to investigate this further in a larger study or using in vitro studies. In summary, there is an increased prevalence of anti-PF4/heparin antibodies in patients hospitalized with bacterial but not fungal sepsis. These results indicate that bacterial infection has a role to play in preimmunization leading to anti-PF4/heparin antibody generation.

Temporality of heparin-induced antibodies: a retrospective study in outpatients undergoing hemodialysis on unfractionated heparin.

BACKGROUND: Heparin-induced antibodies (HIA) are responsible for causing heparin-induced thrombocytopenia and thrombosis. Research has shown that the temporality of heparin-induced antibodies does not follow the classic immunologic response. The immunobiology of HIA generation remains unclear with varying in vitro and in vivo data. Outpatients undergoing hemodialysis (HD) are exposed to heparin chronically. The HIA immune response can therefore be investigated in vivo in this population. METHODS: We examined the time between the start of HD using unfractionated heparin and HIA levels in 212 outpatients during a 6-year period. Antibodies were detected on enzyme-linked immunosorbent assay. HIA levels were analyzed to determine significance of the trend over time. HIA subgroups were also analyzed for correlation with subsequent thrombotic events and platelet count during follow up. RESULTS: Overall, the HIA response in HD was found to peak early with waning antibody response despite continued exposure to heparin. The peak prevalence of a strong immune response (optical density > 1.000) was early and short lived, while weaker immune response (optical density 0.400-1.000) persisted for the first 6 months then declined. The mean follow-up time per patient was 2.3 ± 1.4 years. Despite circulating HIA, including high titers, no patients developed HIT in this sample. There was no association between HIA and thrombocytopenia. There was increased incidence of thrombosis in patients with strong HIA compared to other groups, but this did not achieve statistical significance. CONCLUSIONS: The data suggest a significant temporal pattern of HIA in outpatients undergoing HD using unfractionated heparin. Positive HIA was not found to be significantly associated with thrombocytopenia or thrombosis risk in these patients. However, while not achieving statistical significance, subsequent thrombotic events occurred most frequently in the strong positive HIA group (optical density > 1.000). Further research into HIA and risk of thrombosis in this population is needed.

Acute glomerulonephritis secondary to Streptococcus anginosus.

Streptococcus anginosus is a clinically important pathogen that is emerging globally but remains poorly investigated. Here, we report the first case of acute glomerulonephritis resulting from infection with S. anginosus Glomerulonephritis is typically caused by S. pyogenes and reports secondary to other strains including S. zooepidemicus and S. constellatus exist. Infection with S. anginosus in this patient was associated with acute nephritis (haematuria, oedema and hypertension), nephrotic syndrome and progressive azotemia. There was activation of the complement system. The presence of low C1q and elevated anti-C1q binding complexes points to a potential pathogenic role. Testing for streptococcal antigens was strongly positive. Emerging nephritogenic strains of S. anginosus present a significant health concern for both developed and developing countries.