Trial Of Pathogen-reduced Cryoprecipitate vs. Cryoprecipitated AHF to Lower Operative Transfusions (TOP-CLOT): study protocol for a single center, prospective, cluster randomized trial.

BACKGROUND: Intraoperative hemorrhage in cardiac surgery increases risk of morbidity and mortality. Low pre-operative and perioperative levels of fibrinogen, a key clotting factor, are associated with severity of hemorrhage and increased transfusion of blood components. The ability to supplement fibrinogen during hemorrhagic resuscitation is delayed 45-60 min because cryoprecipitated antihemophilic factor (cryo AHF) is stored frozen, due to a short post-thaw shelf life. Pathogen Reduced Cryoprecipitated Fibrinogen Complex (INTERCEPT Fibrinogen Complex, IFC) can be kept thawed, at room temperature, for up to 5 days, making it possible to be immediately available for hemorrhaging patients. This trial will investigate if earlier correction of acquired hypofibrinogenemia with IFC in hemorrhaging cardiac surgery patients reduces the total number of perioperatively transfused allogeneic blood products (red blood cells, plasma, and platelets) as compared to cryo AHF. METHODS: This is a single center, prospective, cluster randomized trial with an adaptive design. Acquired hypofibrinogenemia will be assessed by rotational thromboelastometry (ROTEM) and the threshold for cryo AHF/IFC transfusion defined as FIBTEM A10 ≤ 10 mm in bleeding patients. IFC/cryo AHF will be randomized by 1-month blocks. Cardiac surgery patients will be enrolled in the study if they have an eligible procedure and at least one dose of a cryo AHF/IFC product (approximately 2 g fibrinogen) is transfused. Data from the electronic health record, including the blood bank and lab information systems, will be prospectively collected from the health system's data warehouse. DISCUSSION: This trial aims to provide evidence of the clinical efficacy of utilizing readily available thawed IFC during acute bleeding in the cardiac surgery setting compared to traditional cryo AHF. TRIAL REGISTRATION: ClinicalTrials.gov NCT05711524. Feb 3, 2023.

Insights into highly engraftable hematopoietic cells from 27-year cryopreserved umbilical cord blood.

Umbilical cord blood transplantation is a life-saving treatment for malignant and non-malignant hematologic disorders. It remains unclear how long cryopreserved units remain functional, and the length of cryopreservation is often used as a criterion to exclude older units. We demonstrate that long-term cryopreserved cord blood retains similar numbers of hematopoietic stem and progenitor cells compared with fresh and recently cryopreserved cord blood units. Long-term cryopreserved units contain highly functional cells, yielding robust engraftment in mouse transplantation models. We also leverage differences between units to examine gene programs associated with better engraftment. Transcriptomic analyses reveal that gene programs associated with lineage determination and oxidative stress are enriched in high engrafting cord blood, revealing potential molecular markers to be used as potency markers for cord blood unit selection regardless of length of cryopreservation. In summary, cord blood units cryopreserved for extended periods retain engrafting potential and can potentially be used for patient treatment.

Epstein-Barr virus-associated risk factors for post-transplant lymphoproliferative disease in pediatric liver transplant recipients.

BACKGROUND: Post-transplant lymphoproliferative disorder (PTLD) are the most common de novo malignancies after liver transplantation (LT) in children. The aim of our study was to assess the role of pre-LT EBV status and post-LT EBV viral load as risk factors for developing PTLD in a cohort of pediatric LT recipients. METHODS: Data of all children who underwent LT between January 2002 and December 2019 were collected. Two cohorts were built EBV pre-LT primary infected cohort and EBV post-LT primary infected cohort. Moreover, using the maximal EBV viral load, a ROC curve was constructed to find a cutoff point for the diagnosis of PTLD. RESULTS: Among the 251 patients included in the study, fifteen PTLD episodes in 14 LT recipients were detected (2 plasmacytic hyperplasia, 10 polymorphic PTLD, 2 monomorphic PTLD, and 1 Classical-Hodgkin's lymphoma). Patients of the EBV post-LT primary infected cohort were 17.1 times more likely to develop a PTLD than patients of the EBV pre-LT primary infected cohort (2.2-133.5). The EBV viral load value to predict PTLD was set at 211 000 UI/mL (93.3% sensitivity and 77.1% specificity; AUC 93.8%; IC 0.89-0.98). In EBV post-LT primary infected cohort, patients with a viral load above 211 000 were 30 times more likely to develop PTLD than patients with a viral load below this value (OR 29.8; 3.7-241.1; p < 0.001). CONCLUSIONS: The combination of pretransplant EBV serological status with EBV post-transplant viral load could be a powerful tool to stratify the risk of PTLD in pediatric LT patients.

Congenital infection of SARS-CoV-2 in live-born neonates: a population-based descriptive study.

OBJECTIVE: To evaluate the evidence of mother-to-child transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: This is a descriptive, multicentre, observational study in nine tertiary care hospitals throughout Spain. The study population was women with coronavirus disease 2019 during pregnancy. Mother-to-child transmission was defined as positive real-time RT-PCR of SARS-CoV-2 in amniotic fluid, cord blood, placenta or neonatal nasopharyngeal swabs taken immediately after birth. RESULTS: We included 43 women with singleton pregnancies and one with a twin pregnancy, as a result we obtained 45 samples of placenta, amniotic fluid and umbilical cord blood. The median gestational age at diagnosis was 34.7 weeks (range 14-41.3 weeks). The median interval between positive RT-PCR and delivery was 21.5 days (range 0-141 days). Fourteen women (31.8%, 95% CI 18.6%-47.6%) were positive at the time of delivery. There was one singleton pregnancy with SARS-CoV-2 RT-PCR positive in the placenta, amniotic fluid and umbilical cord blood (2.2%, 95% CI 0.1%-11.8%). Nasopharyngeal aspiration was performed on 38 neonates at birth, all of which were negative (0%, 95% CI 0%-9.3%). In 11 neonates the nasopharyngeal aspiration was repeated at 24-48 hours, and one returned positive (9.1%, 95% CI 0.2%-41.3%). CONCLUSIONS: The presence of SARS-CoV-2 in placenta, amniotic fluid and cord blood shows that mother-to-child transmission is possible but uncommon.

Kaposi sarcoma in a child after hematopoietic stem cell transplantation: Should pre-transplant HHV-8 screening be considered in recipients from high prevalence areas?

Kaposi sarcoma (KS) is an angioproliferative disease associated with human herpesvirus 8 (HHV-8). We report the case of a 10-year-old male from a high HHV-8 prevalence area, diagnosed with severe aplastic anemia who underwent an upfront hematopoietic stem cell transplantation (HSCT). Five months after transplant, the patient was diagnosed with KS with skin, mucosae, lymph nodes and lung involvement. After withdrawal of immunosuppression the patient achieved complete remission without requiring further treatments. KS may occur after HSCT in patients from high HHV-8 prevalence areas. Considering that, we propose that screening of HHV-8 by antibody testing could be considered in HSCT donors/recipients from these areas.

Ten years of TRALI mitigation: measuring our progress.

BACKGROUND: Transfusion-related acute lung injury (TRALI) is a leading cause of transfusion-associated mortality for which multiple mitigation strategies have been implemented over the past decade. However, product-specific TRALI rates have not been reported longitudinally and may help refine additional mitigation strategies. STUDY DESIGN AND METHODS: This retrospective multicenter study included analysis of TRALI rates from 2007 through 2017. Numerators included definite or probable TRALI reports from five blood centers serving nine states in the United States. Denominators were components distributed from participating centers. Rates were calculated as per 100,000 components distributed (p < 0.05 significant). RESULTS: One hundred four TRALI cases were reported from 10,012,707 components distributed (TRALI rate of 1.04 per 100,000 components). The TRALI rate was 2.25 for female versus 1.08 for male donated components (p < .001). The TRALI rate declined from 2.88 in 2007 to 0.60 in 2017. From 2007 to 2013, there was a significantly higher TRALI rate associated with female versus male plasma (33.85 vs. 1.59; p < 0.001) and RBCs (1.97 vs. 1.15; p = 0.03). From 2014 through 2017, after implementation of mitigation strategies, a significantly higher TRALI rate only from female-donated plateletpheresis continued to be observed (2.98 vs. 0.75; p = 0.04). CONCLUSION: Although the TRALI rates have substantially decreased secondary to multiple strategies over the past decade, a residual risk remains, particularly with female-donated plateletpheresis products. Additional tools that may further mitigate TRALI incidence include the use of buffy coat pooled platelets suspended in male donor plasma or platelet additive solution due to the lower amounts of residual plasma.

Leptomeningeal Carcinomatosis as the Initial Manifestation of Metastatic Disease diagnosed in Postmortem Examination: A Case Series.

Leptomeningeal carcinomatosis (LMC) refers to the infiltration of malignant cells in the pia-arachnoids. LMC is undiagnosed until autopsy in about 20% of cases. A nonspecific neurologic symptomatology makes diagnosis challenging; especially in the scenario of unknown malignancy. Diagnosis is made by the identification of malignant cells in CSF; though studies have shown that serial examination may be required for acceptable accuracy. We report 3 cases with distinct neurological presentations, negative cerebrospinal fluid (CSF) examinations and neurological imaging. A 52 year old woman with history of breast cancer on remission, a 2 year old male with left ear rhabdomyosarcoma status post resection, and a 59 year old woman with communicating hydrocephalus of unknown etiology. LMC was diagnosed at autopsy and confirmed by immunohistochemistry. LMC is a complication requiring a high level of clinical suspicion. Postmortem examination is an invaluable tool to confirm LMC as part of the multidisciplinary approach aiming towards the improvement of clinical diagnosis.

How do we manage blood donors and recipients after a positive Zika screening result?

Zika virus (ZIKV) is a mosquito-borne flavivirus that is the focus of an ongoing pandemic. ZIKV is notable for its severe neurologic sequelae in babies born to infected mothers. High rates of subclinical infection, as evidenced by the finding of ZIKV RNA in asymptomatic donors, raise concerns of risk to the blood supply. To date, a total of four suspected cases of transfusion-transmitted ZIKV have been reported (all in Brazil), none of which were associated with clinical infection in the transfusion recipients. In 2016, the US Food and Drug Administration issued a guidance mandating national blood donor screening for ZIKV in the United States. Five days after implementation of donor screening at our facility, we encountered a ZIKV-positive donor. We provide a practical approach to donor, recipient, and blood product management in the setting of a positive donor ZIKV result. Such has been informed by the challenges we faced in the workup of a ZIKV-reactive donation and recipient lookback.

Zika Virus and the Blood Supply: What Do We Know?

Zika virus (ZIKV), a mosquito-borne Flavivirus and emerging infectious disease, is the focus of an international public health emergency after its rapid spread through the Americas and the Caribbean. Although most ZIKV infections are subclinical or characterized by mild febrile illness, ZIKV has been implicated in severe complications, most notably microcephaly in babies born to incident infected mothers during pregnancy. As yet, the extent to which ZIKV is transfusion transmissible remains undefined. Nonetheless, a high prevalence of asymptomatic infection during outbreaks, the demonstration of ZIKV in blood donors, and 4 possible cases of transfusion-transmitted ZIKV in Brazil have raised concern for risk to the blood supply. Consequently, a proactive response is underway by blood collection agencies, regulatory bodies, national funding agencies, and industry alike. Mitigation strategies differ between endemic and nonendemic areas. In the continental United States, the American Association of Blood Banks and Food and Drug Administration guidelines recommend travel-based deferral for those returning from affected areas, and nucleic acid testing is being initiated under an investigational new drug application in Puerto Rico and selected areas of the United States. Options are less clear for countries where autochthonous vector-borne transmission is active. The burden of Zika falls in low-resource countries where high cost and technical barriers associated with testing and pathogen reduction pose barriers to implementation. Additional strategies include maintaining selective inventory for high-risk recipients (eg, pregnant women). We review the available data as of July 2016 on ZIKV in relation to the blood supply including risk, mitigation strategies, and barriers to implementation in addition to the research that is needed to address current uncertainty.

Patterns of HER2 Gene Amplification and Response to Anti-HER2 Therapies.

A chromosomal region that includes the gene encoding HER2, a receptor tyrosine kinase (RTK), is amplified in 20% of breast cancers. Although these tumors tend to respond to drugs directed against HER2, they frequently become resistant and resume their malignant progression. Gene amplification in double minutes (DMs), which are extrachromosomal entities whose number can be dynamically regulated, has been suggested to facilitate the acquisition of resistance to therapies targeting RTKs. Here we show that ~30% of HER2-positive tumors show amplification in DMs. However, these tumors respond to trastuzumab in a similar fashion than those with amplification of the HER2 gene within chromosomes. Furthermore, in different models of resistance to anti-HER2 therapies, the number of DMs containing HER2 is maintained, even when the acquisition of resistance is concomitant with loss of HER2 protein expression. Thus, both clinical and preclinical data show that, despite expectations, loss of HER2 protein expression due to loss of DMs containing HER2 is not a likely mechanism of resistance to anti-HER2 therapies.

Chorioangioma: an uncommon cause of hydramnios and consequent preterm labor in second trimester of pregnancy.

Placental chorioangiomas are relatively common benign placental tumors occurring with an incidence of approximately 1% of histologically studied placentas. However, they show clinical manifestations in very rare pregnancies usually at a median gestational age of 28 weeks. Our report presents an interesting and rare case of severe hydramnios with consequent preterm labor and delivery in the second trimester leading to neonatal death due to placental chorioangioma. An earlier diagnosis could have led to closer monitoring and prevention of the development of severe hydramnios with resultant preterm labor.