Acute pulmonary injury in hematology patients supported with pathogen-reduced and conventional platelet components.

ABSTRACT: Patients treated with antineoplastic therapy often develop thrombocytopenia requiring platelet transfusion, which has potential to exacerbate pulmonary injury. This study tested the hypothesis that amotosalen-UVA pathogen-reduced platelet components (PRPCs) do not potentiate pulmonary dysfunction compared with conventional platelet components (CPCs). A prospective, multicenter, open-label, sequential cohort study evaluated the incidence of treatment-emergent assisted mechanical ventilation initiated for pulmonary dysfunction (TEAMV-PD). The first cohort received CPC. After the CPC cohort, each site enrolled a second cohort transfused with PRPC. Other outcomes included clinically significant pulmonary adverse events (CSPAE) and the incidence of treatment-emergent acute respiratory distress syndrome (TEARDS) diagnosed by blinded expert adjudication. The incidence of TEAMV-PD in all patients (1068 PRPC and 1223 CPC) was less for PRPC (1.7 %) than CPC (3.1%) with a treatment difference of -1.5% (95% confidence interval [CI], -2.7 to -0.2). In patients requiring ≥2 PCs, the incidence of TEAMV-PD was reduced for PRPC recipients compared with CPC recipients (treatment difference, -2.4%; 95% CI, -4.2 to -0.6). CSPAE increased with increasing PC exposure but were not significantly different between the cohorts. For patients receiving ≥2 platelet transfusions, TEARDS occurred in 1.3% PRPC and 2.6% CPC recipients (P = .086). Bayesian analysis demonstrated PRPC may be superior in reducing TEAMV-PD and TEARDS for platelet transfusion recipients compared with CPC recipients, with 99.2% and 88.8% probability, respectively. In this study, PRPC compared with CPC demonstrated high probability of reduced severe pulmonary injury requiring assisted mechanical ventilation in patients with hematology disorders dependent on platelet transfusion. This trial was registered at www.ClinicalTrials.gov as #NCT02549222.

Treatment practices and response in kaposiform hemangioendothelioma: A multicenter cohort study.

BACKGROUND AND OBJECTIVES: Kaposiform hemangioendothelioma (KHE) and tufted angioma (TA) are rare vascular tumors in children historically associated with significant morbidity and mortality. This study was conducted to determine first-line therapy in the absence of available prospective clinical trials. METHODS: Patients from 17 institutions diagnosed with KHE/TA between 2005 and 2020 with more than 6 months of follow-up were included. Response rates to sirolimus and vincristine were compared at 3 and 6 months. Durability of response and response to other treatment modalities were also evaluated. RESULTS: Of 159 unique KHE/TA subjects, Kasabach-Merritt phenomenon (KMP) was present in 64 (40.3%), and only two patients were deceased (1.3%). Over 60% (n = 96) demonstrated treatment response at 3 months, and more than 70% (n = 114) by 6 months (no significant difference across groups). The vincristine group had higher radiologic response at 3 months compared to sirolimus (72.7% vs. 20%, p = .03), but there were no differences between these groups at 6 months. There were no differences in rates of recurrent or progressive disease between vincristine and sirolimus. CONCLUSIONS: In this large, multicenter cohort of 159 patients with KHE/TA, rates of KMP were consistent with historical literature, but the mortality rate (1.3%) was much lower. Overall treatment response rates were high (>70%), and there was no significant difference in treatment response or durability of disease comparing sirolimus to vincristine. Our results support individualized treatment decision plans depending on clinical scenario and patient/physician preferences. Response criteria and response rates reported here will be useful for guiding future treatment protocols for vascular tumors.

Gene Therapy with Etranacogene Dezaparvovec for Hemophilia B.

BACKGROUND: Moderate-to-severe hemophilia B is treated with lifelong, continuous coagulation factor IX replacement to prevent bleeding. Gene therapy for hemophilia B aims to establish sustained factor IX activity, thereby protecting against bleeding without burdensome factor IX replacement. METHODS: In this open-label, phase 3 study, after a lead-in period (≥6 months) of factor IX prophylaxis, we administered one infusion of adeno-associated virus 5 (AAV5) vector expressing the Padua factor IX variant (etranacogene dezaparvovec; 2×1013 genome copies per kilogram of body weight) to 54 men with hemophilia B (factor IX activity ≤2% of the normal value) regardless of preexisting AAV5 neutralizing antibodies. The primary end point was the annualized bleeding rate, evaluated in a noninferiority analysis comparing the rate during months 7 through 18 after etranacogene dezaparvovec treatment with the rate during the lead-in period. Noninferiority of etranacogene dezaparvovec was defined as an upper limit of the two-sided 95% Wald confidence interval of the annualized bleeding rate ratio that was less than the noninferiority margin of 1.8. Superiority, additional efficacy measures, and safety were also assessed. RESULTS: The annualized bleeding rate decreased from 4.19 (95% confidence interval [CI], 3.22 to 5.45) during the lead-in period to 1.51 (95% CI, 0.81 to 2.82) during months 7 through 18 after treatment, for a rate ratio of 0.36 (95% Wald CI, 0.20 to 0.64; P<0.001), demonstrating noninferiority and superiority of etranacogene dezaparvovec as compared with factor IX prophylaxis. Factor IX activity had increased from baseline by a least-squares mean of 36.2 percentage points (95% CI, 31.4 to 41.0) at 6 months and 34.3 percentage points (95% CI, 29.5 to 39.1) at 18 months after treatment, and usage of factor IX concentrate decreased by a mean of 248,825 IU per year per participant in the post-treatment period (P<0.001 for all three comparisons). Benefits and safety were observed in participants with predose AAV5 neutralizing antibody titers of less than 700. No treatment-related serious adverse events occurred. CONCLUSIONS: Etranacogene dezaparvovec gene therapy was superior to prophylactic factor IX with respect to the annualized bleeding rate, and it had a favorable safety profile. (Funded by uniQure and CSL Behring; HOPE-B ClinicalTrials.gov number, NCT03569891.).

Comparative risk of pulmonary adverse events with transfusion of pathogen reduced and conventional platelet components.

BACKGROUND: Platelet transfusion carries risk of transfusion-transmitted infection (TTI). Pathogen reduction of platelet components (PRPC) is designed to reduce TTI. Pulmonary adverse events (AEs), including transfusion-related acute lung injury and acute respiratory distress syndrome (ARDS) occur with platelet transfusion. STUDY DESIGN: An open label, sequential cohort study of transfusion-dependent hematology-oncology patients was conducted to compare pulmonary safety of PRPC with conventional PC (CPC). The primary outcome was the incidence of treatment-emergent assisted mechanical ventilation (TEAMV) by non-inferiority. Secondary outcomes included: time to TEAMV, ARDS, pulmonary AEs, peri-transfusion AE, hemorrhagic AE, transfusion reactions (TRs), PC and red blood cell (RBC) use, and mortality. RESULTS: By modified intent-to-treat (mITT), 1068 patients received 5277 PRPC and 1223 patients received 5487 CPC. The cohorts had similar demographics, primary disease, and primary therapy. PRPC were non-inferior to CPC for TEAMV (treatment difference -1.7%, 95% CI: (-3.3% to -0.1%); odds ratio = 0.53, 95% CI: (0.30, 0.94). The cumulative incidence of TEAMV for PRPC (2.9%) was significantly less than CPC (4.6%, p = .039). The incidence of ARDS was less, but not significantly different, for PRPC (1.0% vs. 1.8%, p = .151; odds ratio = 0.57, 95% CI: (0.27, 1.18). AE, pulmonary AE, and mortality were not different between cohorts. TRs were similar for PRPC and CPC (8.3% vs. 9.7%, p = .256); and allergic TR were significantly less with PRPC (p = .006). PC and RBC use were not increased with PRPC. DISCUSSION: PRPC demonstrated reduced TEAMV with no excess treatment-related pulmonary morbidity.

Case Series of Thrombosis With Thrombocytopenia Syndrome After COVID-19 Vaccination-United States, December 2020 to August 2021.

BACKGROUND: Thrombosis with thrombocytopenia syndrome (TTS) is a potentially life-threatening condition associated with adenoviral-vectored COVID-19 vaccination. It presents similarly to spontaneous heparin-induced thrombocytopenia. Twelve cases of cerebral venous sinus thrombosis after vaccination with the Ad26.COV2.S COVID-19 vaccine (Janssen/Johnson & Johnson) have previously been described. OBJECTIVE: To describe surveillance data and reporting rates of all reported TTS cases after COVID-19 vaccination in the United States. DESIGN: Case series. SETTING: United States. PATIENTS: Case patients receiving a COVID-19 vaccine from 14 December 2020 through 31 August 2021 with thrombocytopenia and thrombosis (excluding isolated ischemic stroke or myocardial infarction) reported to the Vaccine Adverse Event Reporting System. If thrombosis was only in an extremity vein or pulmonary embolism, a positive enzyme-linked immunosorbent assay for antiplatelet factor 4 antibodies or functional heparin-induced thrombocytopenia platelet test result was required. MEASUREMENTS: Reporting rates (cases per million vaccine doses) and descriptive epidemiology. RESULTS: A total of 57 TTS cases were confirmed after vaccination with Ad26.COV2.S (n = 54) or a messenger RNA (mRNA)-based COVID-19 vaccine (n = 3). Reporting rates for TTS were 3.83 per million vaccine doses (Ad26.COV2.S) and 0.00855 per million vaccine doses (mRNA-based COVID-19 vaccines). The median age of patients with TTS after Ad26.COV2.S vaccination was 44.5 years (range, 18 to 70 years), and 69% of patients were women. Of the TTS cases after mRNA-based COVID-19 vaccination, 2 occurred in men older than 50 years and 1 in a woman aged 50 to 59 years. All cases after Ad26.COV2.S vaccination involved hospitalization, including 36 (67%) with intensive care unit admission. Outcomes of hospitalizations after Ad26.COV2.S vaccination included death (15%), discharge to postacute care (17%), and discharge home (68%). LIMITATIONS: Underreporting and incomplete case follow-up. CONCLUSION: Thrombosis with thrombocytopenia syndrome is a rare but serious adverse event associated with Ad26.COV2.S vaccination. The different demographic characteristics of the 3 cases reported after mRNA-based COVID-19 vaccines and the much lower reporting rate suggest that these cases represent a background rate. PRIMARY FUNDING SOURCE: Centers for Disease Control and Prevention.

US Case Reports of Cerebral Venous Sinus Thrombosis With Thrombocytopenia After Ad26.COV2.S Vaccination, March 2 to April 21, 2021.

Importance: Cerebral venous sinus thrombosis (CVST) with thrombocytopenia, a rare and serious condition, has been described in Europe following receipt of the ChAdOx1 nCoV-19 vaccine (Oxford/AstraZeneca), which uses a chimpanzee adenoviral vector. A mechanism similar to autoimmune heparin-induced thrombocytopenia (HIT) has been proposed. In the US, the Ad26.COV2.S COVID-19 vaccine (Janssen/Johnson & Johnson), which uses a human adenoviral vector, received Emergency Use Authorization (EUA) on February 27, 2021. By April 12, 2021, approximately 7 million Ad26.COV2.S vaccine doses had been given in the US, and 6 cases of CVST with thrombocytopenia had been identified among the recipients, resulting in a temporary national pause in vaccination with this product on April 13, 2021. Objective: To describe reports of CVST with thrombocytopenia following Ad26.COV2.S vaccine receipt. Design, Setting, and Participants: Case series of 12 US patients with CVST and thrombocytopenia following use of Ad26.COV2.S vaccine under EUA reported to the Vaccine Adverse Event Reporting System (VAERS) from March 2 to April 21, 2021 (with follow-up reported through April 21, 2021). Exposures: Receipt of Ad26.COV2.S vaccine. Main Outcomes and Measures: Clinical course, imaging, laboratory tests, and outcomes after CVST diagnosis obtained from VAERS reports, medical record review, and discussion with clinicians. Results: Patients' ages ranged from 18 to younger than 60 years; all were White women, reported from 11 states. Seven patients had at least 1 CVST risk factor, including obesity (n = 6), hypothyroidism (n = 1), and oral contraceptive use (n = 1); none had documented prior heparin exposure. Time from Ad26.COV2.S vaccination to symptom onset ranged from 6 to 15 days. Eleven patients initially presented with headache; 1 patient initially presented with back pain and later developed headache. Of the 12 patients with CVST, 7 also had intracerebral hemorrhage; 8 had non-CVST thromboses. After diagnosis of CVST, 6 patients initially received heparin treatment. Platelet nadir ranged from 9 ×103/µL to 127 ×103/µL. All 11 patients tested for the heparin-platelet factor 4 HIT antibody by enzyme-linked immunosorbent assay (ELISA) screening had positive results. All patients were hospitalized (10 in an intensive care unit [ICU]). As of April 21, 2021, outcomes were death (n = 3), continued ICU care (n = 3), continued non-ICU hospitalization (n = 2), and discharged home (n = 4). Conclusions and Relevance: The initial 12 US cases of CVST with thrombocytopenia after Ad26.COV2.S vaccination represent serious events. This case series may inform clinical guidance as Ad26.COV2.S vaccination resumes in the US as well as investigations into the potential relationship between Ad26.COV2.S vaccine and CVST with thrombocytopenia.

Dilutional coagulopathy in pediatric scoliosis surgery: A single center report.

BACKGROUND: Children undergoing posterior spinal fusion experience high blood loss often necessitating transfusion. An appropriately activated coagulation system provides hemostasis during surgery, but pathologic dysregulation can cause progressive bleeding and increased transfusions. Despite receiving antifibrinolytics for clot stabilization, many patients still require transfusions. AIMS: We sought to examine the association of dilutional coagulopathy with blood loss and blood transfusion in posterior spinal fusion for pediatric scoliosis patients. METHODS: A retrospective, single institution study of children undergoing posterior spinal fusion >6 levels with a standardized, prospective anesthetic protocol utilizing antifibrinolytics. Blood loss was evaluated using a hematocrit-based calculation. To evaluate transfusions, a normalized Blood Product Transfusion calculation was developed. Factors associated with blood loss and blood transfusions were determined by univariate analysis and multivariate regression modeling with multicollinearity and mediation analysis. RESULTS: Patients received 73.7 mL/kg (standard deviation ±30.8) of fluid poor in coagulation factors. Estimated blood loss was 42.6 mL/kg (standard deviation ±18.0). There was a significant association between estimated blood loss and total fluids delivered (Spearman's rho = 0.51, 95% confidence interval 0.33-0.65, P < 0.001). Factors significantly associated with normalized Blood Product Transfusion in this cohort included age, weight, scoliosis type, levels fused, total osteotomies, pelvic fixation, total fluid, maximum prothrombin time, and minimum fibrinogen. Regression modeling showed the best combination of variables for modeling normalized Blood Product Transfusion included patient weight, number of levels fused, total fluid administered, and maximum prothrombin time. CONCLUSION: Blood product transfusion remains a frustrating problem in pediatric scoliosis. Identifying and controlling dilutional coagulopathy in these patients may reduce blood loss and the need for blood transfusion.

Post-tonsillectomy hemorrhagic outcomes in children with bleeding disorders at a single institution.

OBJECTIVE: To report on the post-tonsillectomy bleeding outcomes and factors associated with hemorrhage among children with pre- or post-operatively diagnosed bleeding disorders treated with an institutional protocol. METHODS: Retrospective cohort study of patients with hematologic disorders who underwent tonsillectomy between 2003 and 2016 and were treated with perioperative desmopressin or factor replacement and/or aminocaproic acid. Postoperative outcomes were compared to controls matched for age, sex, and indication for surgery. Analysis of factors associated with hemorrhage was performed in patients with bleeding disorders using Mann-Whitney U or chi-squared tests. RESULTS: 45 patients with hematologic disorders met inclusion criteria. Platelet dysfunction, including von Willebrand Disease (vWD), was the most common diagnosis (77.8%). Most patients had a preoperative diagnosis of a bleeding disorder and received perioperative hematologic medications (86.7%). Compared to matched controls, patients with hematologic disorders experienced more postoperative bleeding (15.5%; 12 bleeds, 7 patients vs. 1.7%; 1 bleed, 1 patient, p = 0.05) and had longer postoperative stays (1.3 days vs. 0.4 days, p < 0.001). Among the patients with hematologic disorders, patients who experienced a postoperative bleed were significantly more likely to have a factor deficiency (e.g. Hemophilia over vWD) and have a postoperative diagnosis (compared to preoperative diagnosis) for which they did not receive perioperative hematologic medication. Of patients with a postoperative bleed, all those diagnosed postoperatively required at least one surgical intervention to control bleeding compared to 33% of patients with a preoperative diagnosis. A history of post-surgical bleeding, male sex, age at surgery, and pharyngitis as surgical indication were not associated with higher hemorrhage rates in this group. CONCLUSIONS: This study suggests a clinically important magnitude of increased bleeding risk in patients with hematologic disease. This risk appears to decrease with the use of an institutional protocol consisting of desmopressin or factor replacement and an antifibrinolytic agent extending through postoperative day 10.

The Intrinsic Pathway of Coagulation as a Target for Antithrombotic Therapy.

Plasma coagulation in the activated partial thromboplastin time assay is initiated by sequential activation of coagulation factors XII, XI, and IX. While this series of proteolytic reactions is not an accurate model for hemostasis in vivo, there is mounting evidence that factor XI and factor XII contribute to thrombosis, and that inhibiting them can produce an antithrombotic effect with a small effect on hemostasis. This article discusses the contributions of components of the intrinsic pathway to thrombosis in animal models and humans, and results of early clinical trials of drugs targeting factors IX, XI, and XII.