The transcription factor Foxm1 is essential for the quiescence and maintenance of hematopoietic stem cells.

Foxm1 is known as a typical proliferation-associated transcription factor. Here we found that Foxm1 was essential for maintenance of the quiescence and self-renewal capacity of hematopoietic stem cells (HSCs) in vivo in mice. Reducing expression of FOXM1 also decreased the quiescence of human CD34(+) HSCs and progenitor cells, and its downregulation was associated with a subset of myelodysplastic syndrome (MDS). Mechanistically, Foxm1 directly bound to the promoter region of the gene encoding the receptor Nurr1 (Nr4a2; called 'Nurr1' here), inducing transcription, while forced expression of Nurr1 reversed the loss of quiescence observed in Foxm1-deficient cells in vivo. Thus, our studies reveal a previously unrecognized role for Foxm1 as a critical regulator of the quiescence and self-renewal of HSCs mediated at least in part by control of Nurr1 expression.

Differentiation of Prior SARS-CoV-2 Infection and Postacute Sequelae by Standard Clinical Laboratory Measurements in the RECOVER Cohort.

BACKGROUND: There are currently no validated clinical biomarkers of postacute sequelae of SARS-CoV-2 infection (PASC). OBJECTIVE: To investigate clinical laboratory markers of SARS-CoV-2 and PASC. DESIGN: Propensity score-weighted linear regression models were fitted to evaluate differences in mean laboratory measures by prior infection and PASC index (≥12 vs. 0). (ClinicalTrials.gov: NCT05172024). SETTING: 83 enrolling sites. PARTICIPANTS: RECOVER-Adult cohort participants with or without SARS-CoV-2 infection with a study visit and laboratory measures 6 months after the index date (or at enrollment if >6 months after the index date). Participants were excluded if the 6-month visit occurred within 30 days of reinfection. MEASUREMENTS: Participants completed questionnaires and standard clinical laboratory tests. RESULTS: Among 10 094 participants, 8746 had prior SARS-CoV-2 infection, 1348 were uninfected, 1880 had a PASC index of 12 or higher, and 3351 had a PASC index of zero. After propensity score adjustment, participants with prior infection had a lower mean platelet count (265.9 × 109 cells/L [95% CI, 264.5 to 267.4 × 109 cells/L]) than participants without known prior infection (275.2 × 109 cells/L [CI, 268.5 to 282.0 × 109 cells/L]), as well as higher mean hemoglobin A1c (HbA1c) level (5.58% [CI, 5.56% to 5.60%] vs. 5.46% [CI, 5.40% to 5.51%]) and urinary albumin-creatinine ratio (81.9 mg/g [CI, 67.5 to 96.2 mg/g] vs. 43.0 mg/g [CI, 25.4 to 60.6 mg/g]), although differences were of modest clinical significance. The difference in HbA1c levels was attenuated after participants with preexisting diabetes were excluded. Among participants with prior infection, no meaningful differences in mean laboratory values were found between those with a PASC index of 12 or higher and those with a PASC index of zero. LIMITATION: Whether differences in laboratory markers represent consequences of or risk factors for SARS-CoV-2 infection could not be determined. CONCLUSION: Overall, no evidence was found that any of the 25 routine clinical laboratory values assessed in this study could serve as a clinically useful biomarker of PASC. PRIMARY FUNDING SOURCE: National Institutes of Health.

Structural racism is a mediator of disparities in acute myeloid leukemia outcomes.

Non-Hispanic Black (NHB) and Hispanic patients with acute myeloid leukemia (AML) have higher mortality rates than non-Hispanic White (NHW) patients despite more favorable genetics and younger age. A discrete survival analysis was performed on 822 adult patients with AML from 6 urban cancer centers and revealed inferior survival among NHB (hazard ratio [HR] = 1.59; 95% confidence interval [CI]: 1.15, 2.22) and Hispanic (HR = 1.25; 95% CI: 0.88, 1.79) patients compared with NHW patients. A multilevel analysis of disparities was then conducted to investigate the contribution of neighborhood measures of structural racism on racial/ethnic differences in survival. Census tract disadvantage and affluence scores were individually calculated. Mediation analysis of hazard of leukemia death between groups was examined across 6 composite variables: structural racism (census tract disadvantage, affluence, and segregation), tumor biology (European Leukemia Network risk and secondary leukemia), health care access (insurance and clinical trial enrollment), comorbidities, treatment patterns (induction intensity and transplant utilization), and intensive care unit (ICU) admission during induction chemotherapy. Strikingly, census tract measures accounted for nearly all of the NHB-NHW and Hispanic-NHW disparity in leukemia death. Treatment patterns, including induction intensity and allogeneic transplant, and treatment complications, as assessed by ICU admission during induction chemotherapy, were additional mediators of survival disparities in AML. This is the first study to formally test mediators for observed disparities in AML survival and highlights the need to investigate the mechanisms by which structural racism interacts with known prognostic and treatment factors to influence leukemia outcomes.

Effect of Thromboprophylaxis on Clinical Outcomes After COVID-19 Hospitalization.

BACKGROUND: Patients hospitalized with COVID-19 have an increased incidence of thromboembolism. The role of extended thromboprophylaxis after hospital discharge is unclear. OBJECTIVE: To determine whether anticoagulation is superior to placebo in reducing death and thromboembolic complications among patients discharged after COVID-19 hospitalization. DESIGN: Prospective, randomized, double-blind, placebo-controlled clinical trial. (ClinicalTrials.gov: NCT04650087). SETTING: Done during 2021 to 2022 among 127 U.S. hospitals. PARTICIPANTS: Adults aged 18 years or older hospitalized with COVID-19 for 48 hours or more and ready for discharge, excluding those with a requirement for, or contraindication to, anticoagulation. INTERVENTION: 2.5 mg of apixaban versus placebo twice daily for 30 days. MEASUREMENTS: The primary efficacy end point was a 30-day composite of death, arterial thromboembolism, and venous thromboembolism. The primary safety end points were 30-day major bleeding and clinically relevant nonmajor bleeding. RESULTS: Enrollment was terminated early, after 1217 participants were randomly assigned, because of a lower than anticipated event rate and a declining rate of COVID-19 hospitalizations. Median age was 54 years, 50.4% were women, 26.5% were Black, and 16.7% were Hispanic; 30.7% had a World Health Organization severity score of 5 or greater, and 11.0% had an International Medical Prevention Registry on Venous Thromboembolism risk prediction score of greater than 4. Incidence of the primary end point was 2.13% (95% CI, 1.14 to 3.62) in the apixaban group and 2.31% (CI, 1.27 to 3.84) in the placebo group. Major bleeding occurred in 2 (0.4%) and 1 (0.2%) and clinically relevant nonmajor bleeding occurred in 3 (0.6%) and 6 (1.1%) apixaban-treated and placebo-treated participants, respectively. By day 30, thirty-six (3.0%) participants were lost to follow-up, and 8.5% of apixaban and 11.9% of placebo participants permanently discontinued the study drug treatment. LIMITATIONS: The introduction of SARS-CoV-2 vaccines decreased the risk for hospitalization and death. Study enrollment spanned the peaks of the Delta and Omicron variants in the United States, which influenced illness severity. CONCLUSION: The incidence of death or thromboembolism was low in this cohort of patients discharged after hospitalization with COVID-19. Because of early enrollment termination, the results were imprecise and the study was inconclusive. PRIMARY FUNDING SOURCE: National Institutes of Health.

Acute hepatic porphyrias: Recommendations for diagnosis and management with real-world examples.

Acute hepatic porphyria (AHP) is a group of four rare inherited diseases, each resulting from a deficiency in a distinct enzyme in the heme biosynthetic pathway. Characterized by acute neurovisceral symptoms that may mimic other medical and psychiatric conditions, lack of recognition of the disease often leads to a delay in diagnosis and initiation of effective treatment. Biochemical testing for pathway intermediates that accumulate when the disease is active forms the basis for screening and establishing a diagnosis. Subsequent genetic analysis identifies the pathogenic variant, supporting screening of family members and genetic counseling. Management of AHP involves avoidance of known exogenous and hormonal triggers, symptomatic treatment, and prevention of recurrent attacks. Here we describe six case studies from our own real-world experience to highlight current recommendations and challenges associated with the diagnosis and long-term management of the disease.

A multi-institutional comparison of mitoxantrone, etoposide, and cytarabine vs high-dose cytarabine and mitoxantrone therapy for patients with relapsed or refractory acute myeloid leukemia.

Relapsed or refractory acute myeloid leukemia (R/R AML) has a poor prognosis and is best treated with salvage chemotherapy as a bridge to allogeneic stem cell transplant (alloSCT). However, the optimal salvage therapy remains unknown. Here we compared two salvage regimens; mitoxantrone, etoposide, and cytarabine (MEC) and mitoxantrone and high-dose Ara-C (Ara-C couplets). We analyzed 155 patients treated at three academic institutions between 1998 and 2017; 87 patients received MEC and 68 received Ara-C couplets. The primary endpoint was overall response (OR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of hospitalization, hematologic and nonhematologic toxicities, and success in proceeding to alloSCT. Baseline characteristics of the cohorts were well matched, though patients receiving Ara-C couplets had more co-morbidities (48.5% vs 33%; P = .07). OR was achieved in 43.7% of MEC and 54.4% of Ara-C couplets patients (P = .10). Ara-C couplets patients also trended towards a longer OS and PFS, more frequently proceeded to alloSCT (31% vs 54.4%; P = .003), and experienced less febrile neutropenia (94% vs 72%; P < .001) and grade 3/4 gastrointestinal toxicities (17.2% vs 2.94%; P = .005). No significant differences in other toxicities or median duration of hospitalization were noted. This is the first multi-institutional study directly comparing these regimens in a racially diverse population of R/R AML patients. Although these regimens have equivalent efficacy in terms of achieving OR, Ara-C couplets use is associated with significant reductions in toxicities, suggesting it should be used more frequently in these patients.

Porphyric Neuropathy: Pathophysiology, Diagnosis, and Updated Management.

PURPOSE OF REVIEW: To review the peripheral neurological complications of the acute hepatic porphyrias, as well as the latest advances in their pathophysiology and management. RECENT FINDINGS: The diagnosis of porphyric neuropathy remains challenging as varying neuropathic patterns are encountered depending on disease stage, including a non-length-dependent distribution pattern. The major pathophysiologic mechanism is δ-aminolevulinic acid (ALA)-induced neurotoxicity. The less restrictive blood-nerve barrier in the autonomic ganglia and myenteric plexus may explain the frequency of dysautonomic manifestations. Recently, a prophylactic small interfering RNA (siRNA)-based therapy that reduces hepatic ALA Synthase-1 mRNA was approved for patients with recurrent neuro-visceral attacks. Neurologists should appreciate the varying patterns of porphyric neuropathy. As with most toxin-induced axonopathies, long-term outcomes depend on early diagnosis and treatment. While the short-term clinical and biochemical benefits of siRNA-based therapy are known, its long-term effects on motor recovery, chronic pain, and dysautonomic manifestations are yet to be determined.

Myelodysplastic syndrome and acute myeloid leukemia after receipt of granulocyte colony-stimulating factors in older patients with non-Hodgkin lymphoma.

BACKGROUND: Granulocyte colony-stimulating factors (G-CSFs), which are used for the prevention of complications from chemotherapy-related neutropenia, are linked to the risk of developing second primary myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The objective of this study was to examine the correlation between using a specific G-CSF agent and the risk of MDS/AML among older patients with non-Hodgkin lymphoma (NHL). METHODS: This was a retrospective cohort study of adults aged >65 years who were diagnosed with first primary NHL between 2001 and 2011. With data from the Surveillance, Epidemiology, and End Results-Medicare-linked database, adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for the risk of MDS/AML associated with the receipt of G-CSF(filgrastim and pegfilgrastim) in Cox proportional-hazards models, which were stratified according to treatment accounting for confounding by indication. RESULTS: Among 18,245 patients with NHL patients who had a median follow-up of 3.5 years, 56% received chemotherapy and/or immunotherapy, and G-CSF was most commonly used in those who received rituximab plus multiple chemotherapy regimens (77%). Subsequent MDS/AML diagnoses were identified in 666 patients (3.7%). A modest increased risk of MDS/AML was observed with the receipt of G-CSF (HR, 1.28; 95% CI, 1.01-1.62) and a trend was observed with increasing doses (Ptrend < .01). When specific agents were analyzed, an increased risk of MDS/AML was consistently observed with filgrastim (≥10 doses: HR, 1.67; 95% CI, 1.25-2.23), but not with pegfilgrastim (≥10 + doses: HR, 1.11; 95% CI, 0.84-1.45). CONCLUSIONS: A higher of MDS/AML was observed in patients with NHL risk among those who received G-CSF that was specific to the use of filgrastim (≥10 doses), but not pegfilgrastim. Neutropenia prophylaxis is an essential component of highly effective NHL treatment regimens. The differential risk related to the types of G-CSF agents used warrants further study given their increasing use and newly available, US Food and Drug Administration-approved, biosimilar products.

A novel drug interaction between busulfan and blinatumomab.

Busulfan is an alkylating agent used in pre-transplant conditioning for patients undergoing hematopoietic stem cell transplantation. Several factors contribute to variations in busulfan drug disposition including bioavailability, age, liver function, genetic polymorphisms, and concurrent administration of other drugs. Busulfan is metabolized by hepatic oxidation via the cytochrome P450 3A4 system as well as through conjugation with glutathione. Interactions with drugs such as phenytoin, itraconazole, and metronidazole have been reported to alter busulfan clearance and result in sub- or supra-therapeutic concentrations. We report a case of a clinically significant drug interaction between intravenous busulfan and the bifunctional T-cell engager, blinatumomab, observed through busulfan therapeutic drug monitoring. We found that busulfan clearance was reduced resulting in a higher area under the concentration-time curve when it was administered 48 h after blinatumomab. Repeat busulfan pharmacokinetic testing two weeks later demonstrated increased clearance of the drug and a 31% higher dose recommendation. Similar to other protein therapeutics, cytokine elevations during blinatumomab treatment can lead to cytochrome 3A4 suppression. We hypothesize that the increased busulfan levels observed could be related to a cytokine-mediated CYP3A4 suppression. This represents a unique pharmacologic consideration in hematopoietic stem cell transplantation which would impact several drugs that undergo CYP3A4 metabolism, including calcineurin inhibitors, cyclophosphamide, sirolimus, and triazole antifungals. Additionally, this mechanism of CYP3A4 suppression may be relevant in treatments and disease states where cytokine levels are elevated such as haploidentical stem cell transplantation, graft-versus-host disease, and use of chimeric antigen receptor T-cell therapy.

Haploidentical Peripheral Blood Stem Cell Transplantation Demonstrates Stable Engraftment in Adults with Sickle Cell Disease.

We report on the screening and development of haploidentical hematopoietic stem cell transplantation (HSCT) for adult patients with clinically aggressive sickle cell disease (SCD) at our institution. Of 50 adult SCD patients referred for HSCT between January 2014 and March 2017, 20% were denied by insurance. Of 41 patients initially screened, 10% lacked an available haploidentical donor, 29% had elevated donor-specific antibodies (DSAs), and 34% declined to proceed to HSCT. All 10 patients who were transplanted received peripheral blood stem cells. The initial 2 were conditioned with alemtuzumab/total body irradiation (TBI) 3 Gy followed by post-transplant cyclophosphamide and failed to engraft. The next 8 patients received the regimen developed at Johns Hopkins University with TBI 3 Gy. Granulocyte colony-stimulating factor was administered from day +12 in those with HbS < 30%. All 8 patients engrafted with a median time to neutrophil >.5 × 109/L of 22 days (range, 18 to 23). One patient subsequently lost the graft, and 7 (87.5%) maintained >95% donor cell chimerism at 1-year post-HSCT. Two patients developed acute graft-versus-host disease (GVHD) of at least grade II. One had chronic GVHD and died >1 year after HSCT of unknown causes. With a median follow-up of 16 months (range, 11 to 29), 7 patients (87.5%) are alive. Our findings suggest that limited insurance coverage, high rate of DSAs, and patient declining HSCT may limit the availability of haploidentical HSCT in adult SCD patients. The modified Hopkins regimen used here demonstrates high engraftment and low morbidity rates and should be tested in larger, multicenter, prospective clinical trials.

Nonmyeloablative Stem Cell Transplantation with Alemtuzumab/Low-Dose Irradiation to Cure and Improve the Quality of Life of Adults with Sickle Cell Disease.

Allogeneic hematopoietic stem cell transplantation (HSCT) is rarely performed in adult patients with sickle cell disease (SCD). We utilized the chemotherapy-free, alemtuzumab/total body irradiation 300 cGy regimen with sirolimus as post-transplantation immunosuppression in 13 high-risk SCD adult patients between November 2011 and June 2014. Patients received matched related donor (MRD) granulocyte colony-stimulating factor-mobilized peripheral blood stem cells, including 2 cases that were ABO incompatible. Quality-of-life (QoL) measurements were performed at different time points after HSCT. All 13 patients initially engrafted. A stable mixed donor/recipient chimerism was maintained in 12 patients (92%), whereas 1 patient not compliant with sirolimus experienced secondary graft failure. With a median follow-up of 22 months (range, 12 to 44 months) there was no mortality, no acute or chronic graft-versus-host disease (GVHD), and no grades 3 or 4 extramedullary toxicities. At 1 year after transplantation, patients with stable donor chimerism have normalized hemoglobin concentrations and improved cardiopulmonary and QoL parameters including bodily pain, general health, and vitality. In 4 patients, sirolimus was stopped without rejection or SCD-related complications. These results underscore the successful use of a chemotherapy-free regimen in MRD HSCT for high-risk adult SCD patients and demonstrates a high cure rate, absence of GVHD or mortality, and improvement in QoL including the applicability of this regimen in ABO mismatched cases (NCT number 01499888).

A treatment algorithm to identify therapeutic approaches for leg ulcers in patients with sickle cell disease.

Sickle cell leg ulcers (SCLUs) are a common complication of sickle cell disease (SCD). Patients who develop ulcers appear to have a more severe haemolysis-associated vasculopathy than individuals who do not develop them, and manifest other complications such as priapism and pulmonary hypertension. SCLUs are slow to heal and often recur, affecting both the emotional and physical well-being of patients. Here we summarise what is known about the pathophysiology of SCLUs, describe available treatment options and propose a treatment algorithm.

Differential effects of epigenetic modifiers on the expansion and maintenance of human cord blood stem/progenitor cells.

Epigenetic therapies, including DNA methyltransferase and histone deacetylase (HDAC) inhibitors, are increasingly being considered to treat hematological malignancies, but their effects on normal hematopoietic stem cells (HSCs) remain largely unexplored. We compared the effects of several HDAC inhibitors, including valproic acid (VPA) and trichostatin A (TSA), alone or in combination with 5-aza-2'-deoxycytidine (5azaD) on the expansion of HSCs. VPA induced the highest expansion of CD34+CD90+ cells and progenitor cells compared with other HDAC inhibitors or the sequential addition of 5azaD/TSA in culture. Xenotransplantation studies demonstrated that VPA prevents HSC loss, whereas 5azaD/TSA treatment leads to a net expansion of HSCs that retain serial transplantation ability. 5azaD/TSA-mediated HSC expansion was associated with increased histone acetylation and transient DNA demethylation, which corresponded with higher gene transcript levels. However, some genes with increased transcript levels lacked changes in methylation. Importantly, a global microarray analysis revealed a set of differentially expressed genes in 5azaD/TSA- and VPA-expanded CD34+ cells that might be involved in the expansion and maintenance of transplantable HSCs, respectively. In summary, our data indicate that treatment of HSCs with different chromatin-modifying agents results in either the expansion or maintenance of HSCs, an observation of potential therapeutic importance.

Combination of linear accelerator-based intensity-modulated total marrow irradiation and myeloablative fludarabine/busulfan: a phase I study.

Here we examined the addition of intensity-modulated total marrow irradiation (TMI) delivered using a linear accelerator to a myeloablative chemotherapy conditioning regimen before allogeneic hematopoietic stem cell transplantation (HSCT). In this phase I study, we enrolled 14 patients with high-risk hematologic malignancies who received escalating doses of TMI at 3 Gy (n = 3), 6 Gy (n = 3), 9 Gy (n = 6), and 12 Gy (n = 2) in combination with intravenous (i.v.) fludarabine 160 mg/m(2) and targeted busulfan (area under the curve, 4800 µM*minute). Peripheral blood mobilized stem cells were obtained from HLA-matched related (n = 9) or unrelated (n = 4) or 1 antigen-mismatched unrelated (n = 1) donors. All patients rapidly engrafted and recovered their immune cells. Overall, Bearman extrahematologic toxicity were limited to grades 1 or 2, with oral mucositis grade 1 in 64% and grade 2 in 36% of the patients. With a median follow-up of 1126 days (range, 362 to 1469) for living patients, the overall survival was 50% and relapse-free survival was 43%. Of 7 deaths, 3 were due to relapse and 4 to transplantation-related complications. We conclude that 9 Gy TMI can be combined with myeloablative chemotherapy in the design of new preparative regimens for HSCT. This study was registered at clinicaltrials.gov as NCT00988013.

Comparison of thrombotic and clinical outcomes in SARS-CoV-2-pneumonia versus other viral pneumonia in an urban academic medical center.

BACKGROUND: Infection with viral pneumonia (PNA) is known to offset the coagulation cascade. Recent studies assessing novel SARS-CoV-2 infection observed a high frequency of systemic thrombotic events resulting in ambiguity if severity of infection or specific viral strain drive thrombosis and worsen clinical outcomes. Furthermore, limited data exists addressing SARS-CoV-2 in underrepresented patient populations. OBJECTIVES: Assess clinical outcomes events and death in patients diagnosed with SARS-CoV-2 pneumonia compared to patients with other types of viral pneumonia. METHODS: Retrospective cohort study evaluated electronic medical records in adult patients admitted to University of Illinois Hospital and Health Sciences System (UIHHSS) with primary diagnosis of SARS-CoV-2 PNA or other viral (H1N1 or H3N2) PNA between 10/01/2017 and 09/01/2020. Primary composite outcome was the following event incidence rates: death, ICU admission, infection, thrombotic complications, mechanical ventilation, renal replacement therapy, and major bleeding. RESULTS: Of 257 patient records, 199 and 58 patients had SARS-CoV-2 PNA and other viral PNA, respectively. There was no difference in primary composite outcome. Thrombotic events (n = 6, 3%) occurred solely in SARS-CoV-2 PNA patients in the ICU. A significantly higher incidence of renal replacement therapy (8.5% vs 0%, p=0.016) and mortality (15.6% vs 3.4%, p=0.048) occurred in the SARS-CoV-2 PNA group. Multivariable logistic regression analysis revealed age, presence of SARS-CoV-2, and ICU admission, aOR 1.07, 11.37, and 41.95 respectively, was significantly associated with mortality risk during hospitalization; race and ethnicity were not. CONCLUSION: Low overall incidence of thrombotic events occurred only in the SARS-CoV-2 PNA group. SARS-CoV-2 PNA may lead to higher incidence of clinical events than those observed in H3N2/H1N1 viral pneumonia, and that race/ethnicity does not drive mortality outcomes.

Therapeutic trials for long COVID-19: A call to action from the interventions taskforce of the RECOVER initiative.

Although most individuals recover from acute SARS-CoV-2 infection, a significant number continue to suffer from Post-Acute Sequelae of SARS-CoV-2 (PASC), including the unexplained symptoms that are frequently referred to as long COVID, which could last for weeks, months, or even years after the acute phase of illness. The National Institutes of Health is currently funding large multi-center research programs as part of its Researching COVID to Enhance Recover (RECOVER) initiative to understand why some individuals do not recover fully from COVID-19. Several ongoing pathobiology studies have provided clues to potential mechanisms contributing to this condition. These include persistence of SARS-CoV-2 antigen and/or genetic material, immune dysregulation, reactivation of other latent viral infections, microvascular dysfunction, and gut dysbiosis, among others. Although our understanding of the causes of long COVID remains incomplete, these early pathophysiologic studies suggest biological pathways that could be targeted in therapeutic trials that aim to ameliorate symptoms. Repurposed medicines and novel therapeutics deserve formal testing in clinical trial settings prior to adoption. While we endorse clinical trials, especially those that prioritize inclusion of the diverse populations most affected by COVID-19 and long COVID, we discourage off-label experimentation in uncontrolled and/or unsupervised settings. Here, we review ongoing, planned, and potential future therapeutic interventions for long COVID based on the current understanding of the pathobiological processes underlying this condition. We focus on clinical, pharmacological, and feasibility data, with the goal of informing future interventional research studies.

Effect of P2Y12 Inhibitors on Organ Support-Free Survival in Critically Ill Patients Hospitalized for COVID-19: A Randomized Clinical Trial.

Importance: Platelet activation is a potential therapeutic target in patients with COVID-19. Objective: To evaluate the effect of P2Y12 inhibition among critically ill patients hospitalized for COVID-19. Design, Setting, and Participants: This international, open-label, adaptive platform, 1:1 randomized clinical trial included critically ill (requiring intensive care-level support) patients hospitalized with COVID-19. Patients were enrolled between February 26, 2021, through June 22, 2022. Enrollment was discontinued on June 22, 2022, by the trial leadership in coordination with the study sponsor given a marked slowing of the enrollment rate of critically ill patients. Intervention: Participants were randomly assigned to receive a P2Y12 inhibitor or no P2Y12 inhibitor (usual care) for 14 days or until hospital discharge, whichever was sooner. Ticagrelor was the preferred P2Y12 inhibitor. Main Outcomes and Measures: The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death and, for participants who survived to hospital discharge, the number of days free of cardiovascular or respiratory organ support up to day 21 of the index hospitalization. The primary safety outcome was major bleeding, as defined by the International Society on Thrombosis and Hemostasis. Results: At the time of trial termination, 949 participants (median [IQR] age, 56 [46-65] years; 603 male [63.5%]) had been randomly assigned, 479 to the P2Y12 inhibitor group and 470 to usual care. In the P2Y12 inhibitor group, ticagrelor was used in 372 participants (78.8%) and clopidogrel in 100 participants (21.2%). The estimated adjusted odds ratio (AOR) for the effect of P2Y12 inhibitor on organ support-free days was 1.07 (95% credible interval, 0.85-1.33). The posterior probability of superiority (defined as an OR > 1.0) was 72.9%. Overall, 354 participants (74.5%) in the P2Y12 inhibitor group and 339 participants (72.4%) in the usual care group survived to hospital discharge (median AOR, 1.15; 95% credible interval, 0.84-1.55; posterior probability of superiority, 80.8%). Major bleeding occurred in 13 participants (2.7%) in the P2Y12 inhibitor group and 13 (2.8%) in the usual care group. The estimated mortality rate at 90 days for the P2Y12 inhibitor group was 25.5% and for the usual care group was 27.0% (adjusted hazard ratio, 0.96; 95% CI, 0.76-1.23; P = .77). Conclusions and Relevance: In this randomized clinical trial of critically ill participants hospitalized for COVID-19, treatment with a P2Y12 inhibitor did not improve the number of days alive and free of cardiovascular or respiratory organ support. The use of the P2Y12 inhibitor did not increase major bleeding compared with usual care. These data do not support routine use of a P2Y12 inhibitor in critically ill patients hospitalized for COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04505774.

Control of intracellular heme levels: heme transporters and heme oxygenases.

Heme serves as a co-factor in proteins involved in fundamental biological processes including oxidative metabolism, oxygen storage and transport, signal transduction and drug metabolism. In addition, heme is important for systemic iron homeostasis in mammals. Heme has important regulatory roles in cell biology, yet excessive levels of intracellular heme are toxic; thus, mechanisms have evolved to control the acquisition, synthesis, catabolism and expulsion of cellular heme. Recently, a number of transporters of heme and heme synthesis intermediates have been described. Here we review aspects of heme metabolism and discuss our current understanding of heme transporters, with emphasis on the function of the cell-surface heme exporter, FLVCR. Knockdown of Flvcr in mice leads to both defective erythropoiesis and disturbed systemic iron homeostasis, underscoring the critical role of heme transporters in mammalian physiology. This article is part of a Special Issue entitled: 11th European Symposium on Calcium.