Pulmonary hypertension is a highly prevalent complication of sickle cell disease and is a strong risk factor for early mortality. However, the pathophysiologic mechanisms leading to pulmonary vasculopathy remain unclear. Transgenic mice provide opportunities for mechanistic studies of vascular pathophysiology in an animal model. By microcardiac catheterization, all mice expressing exclusively human sickle hemoglobin had pulmonary hypertension, profound pulmonary and systemic endothelial dysfunction, and vascular instability characterized by diminished responses to authentic nitric oxide (NO), NO donors, and endothelium-dependent vasodilators and enhanced responses to vasoconstrictors. However, endothelium-independent vasodilation in sickle mice was normal. Mechanisms of vasculopathy in sickle mice involve global dysregulation of the NO axis: impaired constitutive nitric oxide synthase activity (NOS) with loss of endothelial NOS (eNOS) dimerization, increased NO scavenging by plasma hemoglobin and superoxide, increased arginase activity, and depleted intravascular nitrite reserves. Light microscopy and computed tomography revealed no plexogenic arterial remodeling or thrombi/ emboli. Transplanting sickle marrow into wild-type mice conferred the same phenotype, and similar pathobiology was observed in a nonsickle mouse model of acute alloimmune hemolysis. Although the time course is shorter than typical pulmonary hypertension in human sickle cell disease, these results demonstrate that hemolytic anemia is sufficient to produce endothelial dysfunction and global dysregulation of NO. IntroductionPulmonary hypertension is a highly prevalent complication of sickle cell disease that is associated with early mortality. [1][2][3][4] The putative mechanisms responsible for pulmonary hypertension are the focus of intense current research and remain incompletely defined. 5 One mechanism proposed is that hemolytic anemia and decompartmentalization of erythrocyte hemoglobin and arginase into plasma leads to nitric oxide (NO) scavenging and arginine degradation, limiting the bioavailability of NO. 3,[6][7][8][9][10] This process would ultimately lead to acute changes in pulmonary vascular endothelial and vasomotor function and chronic pathologic intimal and smooth muscle hyperplasia. Alternatively, chronic lung disease caused by recurrent pulmonary infarction, pneumonia, acute chest syndrome, and thromboembolism could lead to chronic hypoxemia, pulmonary fibrosis, thrombotic vascular obliteration, and secondary pulmonary hypertension. [11][12][13][14][15] Pulmonary hypertension could also arise from chronic hypoxia or chronic nocturnal hypoxia. [16][17][18] Additional factors contributing to pulmonary hypertension include right-heart failure secondary to a chronic high cardiac output as compensation for chronic anemia and left ventricular diastolic dysfunction secondary to cardiac tissue microinfarction and/or iron overload. [19][20][21][22] In short, is exposure to hemoglobin S (HbS) erythrocytes sufficient to cause pulmonar...

Female sex, black race, and fear of hospitals are three major factors negatively associated with prior history of blood donation. Fear of hospitals affects blood donation patterns across race and sex groups. Future study is needed to determine whether recruitment of blood donors may be more efficient if focused toward women, minorities, and donors' fears of healthcare facilities or hospitals.

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).

Despite increased rejection rates, graft and patient survivals indicate that desensitization of positive crossmatch patients is a reasonable alternative for a sensitized patient who could potentially wait 10 or more years for a suitable cadaveric kidney.

Pulmonary hypertension is a highly prevalent complication of sickle cell disease and is a strong risk factor for early mortality. However, the pathophysiological mechanisms by which sickle hemoglobin leads to pulmonary vasculopathy remain unclear. Transgenic mice provide opportunities for mechanistic studies of vascular pathophysiology in an animal model of severe sickle cell disease. Using micro-cardiac catheterization we found that all mice expressing exclusively human sickle hemoglobin develop pulmonary hypertension. Recognizing that the NO pathways can have complex abnormalities in other conditions of pulmonary hypertension, the NO axis in sickle mice was assessed by multiple methods. From a mechanistic standpoint the mice exhibit profound pulmonary and systemic endothelial dysfunction and vascular instability characterized by diminished responses to authentic nitric oxide (NO), NO donors and endothelium-dependent pulmonary vasodilators, and enhanced responses to vaso-constrictors. However, endothelium-independent vasodilation in the sickle mice was normal. Mechanisms of vasculopathy in sickle mice involve global dysregulation of the NO-axis: impaired constitutive nitric oxide synthase activity with loss of eNOS coupling (dimerization), increased NO scavenging by plasma hemoglobin and superoxide, increased arginase activity, and depleted intravascular nitrite reserves. Consistent with a functional rather than structural defect, light microscopy and computed tomography of the lungs revealed no plexogenic arterial remodeling, thrombi/emboli, or inflammation. Transplanting sickle marrow into wild-type mice conferred the same phenotype. Similar pathobiology was observed in a non-sickle mouse model of acute alloimmune hemolysis, supporting a major role of hemolysis as a mechanism for this dysregulation of NO and vasculopathy. In this study, alloimmune hemolytic mice were chosen for comparison in order to generalize beyond hemoglobinopathies. Future analogous studies with thalassemic mice may be useful to model pulmonary hypertension in human thalassemia intermedia. In conclusion, this animal model extends the evidence for global impairment in NO responsiveness and NO production in sickle cell disease, and suggests that hemolytic anemia is associated with endothelial dysfunction and pulmonary hypertension.

Both platelet concentrates (PC) derived from whole blood or single donor platelets (SDP) obtained from a single donor by apheresis are indicated to treat acute hemorrhage secondary to thrombocytopenia or to provide prophylaxis from hemorrhage in patients with bone marrow aplasia. Currently platelet transfusion therapy is limited by several concerns, including the consequences of alloimmunization in chronically transfused patients and septic reactions caused by bacterial contamination. There is debate about which platelet product should be used; many transfusion services favor the primary use of PC, whereas others favor SDP. This review will discuss five areas that should be considered when considering the use of SDP or PC: (1) the impact on infectious complications, (2) transfusion reaction rate, (3) leukodepletion, (4) reduction of transfusion frequency in patients with bone marrow suppression and, (5) the treatment and prevention of alloimmunization. The authors believe that SDP offers major advantages over PC for most of these issues, particularly when improved patient care is given primary emphasis.

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 × 10/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.

Background Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX). Methods In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung–Knapp–Sidik–Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. Results A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. Conclusions Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care.