Blood advances最新文献

Von Willebrand factor (VWF) is a key coagulation protein, tethering platelets to sites of injury through binding sites for platelet GPIbα and for exposed subendothelial collagen. VWF synthesis occurs in endothelial cells and megakaryocytes, a complex process involving the VWF propeptide, dimerization and multimerization, and glycosylation. Von Willebrand disease (VWD) results from defects or dysfunction in VWF and includes both quantitative and qualitative issues with the VWF protein. VWF is cleaved by ADAMTS13 and ultimately cleared from circulation. While it is clear that VWF plays an important role in clot formation, it may also be important in a number of other areas including angiogenesis. Our knowledge of VWF has come a long way in the 100 years since the first publication by Erik von Willebrand in 1926 thanks to a large number of researchers in the VWF biology field.

Abstract: Outside of pregnancy, placental growth factor (PlGF), is produced by erythroid cells in typically undetectable levels. In pregnancy, PlGF is strongly expressed by the trophoblast layer covering the placental villi. PlGF levels rise progressively due to placental growth, peak at 28 to 30 weeks gestation, and then slowly decline toward term. Low PlGF has emerged as a powerful diagnostic test for preterm preeclampsia. However, its interpretation in context of sickle cell disease (SCD) is potentially confounded by upregulation of cellular PlGF expression in nonpregnant individuals with SCD, and higher third trimester circulating PlGF levels documented in healthy Black compared with White individuals. Primary objectives were to determine the distribution of PlGF at midtrimester in pregnant individuals with SCD compared with unaffected Black controls and to explore the diagnostic accuracy of PlGF in the context of suspected preeclampsia in pregnancies of individuals with SCD. Secondary objective was to examine the relationship between low PlGF and placental disease in pregnancies of individuals with SCD. Pregnant individuals with SCD at Mount Sinai Hospital in Canada (January 2017 to September 2021) with at least 1 PlGF measurement 20+0 to 35+6 weeks gestation, and pregnant Black controls without SCD with suspected preeclampsia or growth restriction, were included in this retrospective study. Maternal and neonatal outcomes were extracted from medical records. For early-onset, but not late-onset, preeclampsia, a PlGF cutoff of <100 pg/mL demonstrated 100% sensitivity and specificity at 20 to 24 weeks gestation. This study is, to our knowledge, the first to demonstrate the utility of PlGF in predicting early-onset preeclampsia in pregnancies of individuals with SCD, allowing clinicians to anticipate and mitigate adverse pregnancy outcomes.

Plasma cell dyscrasias (PCD) are a group of hematological disorders associated with immune dysfunction from underlying disease and/or treatment. With continued circulation of SARS-CoV-2, optimizing and maintaining durable protection in this vulnerable population through vaccination remains important. A prospective cohort study was conducted between August 2021 and January 2023 across 12 sites in Canada to evaluate humoral immunity to COVID-19 vaccination in participants with hematological malignancies. Participants were monitored longitudinally, and finger-prick dried blood spot (DBS) cards were obtained at specific intervals based on vaccination. Serum antibodies against SARS-CoV-2 proteins after the 3rd, 4th and 5th dose were measured by high-throughput ELISA. Differences in anti-spike seropositivity by vaccine dose number and clinical risk factors were analyzed by logistic regression. A total of 262 unique participants with 983 samples were included for analysis, among which 66% were diagnosed with PCD. Analysis of the predicted probability of immunity showed consistently higher proportions of PCD participants with vaccine (anti-S) immunity compared to those with infection-derived (anti-N) immunity throughout the study. While vaccine responses appeared to wane 6 months after dose 3 and, to a lesser extent, dose 4, subsequent doses cumulatively increased anti-S immunity. Seropositivity decreased with anti-CD38 therapy and older age, although receipt of additional vaccine doses significantly improved anti-S immunity. Overall, this study demonstrated that the third and subsequent COVID-19 vaccine doses could safely improve humoral immunity in PCD participants. While anti-CD38 therapy and age reduced seropositivity, antibody responses could still be enhanced with vaccine doses beyond the primary three-dose series.

Abstract: Although obesity is an established modifiable risk factor for multiple myeloma (MM), the influence of obesity on survival among Black patients, among whom obesity and MM are more common, is less clear. We evaluated the association of body mass index (BMI) with progression free survival and overall survival among 834 histologically confirmed patients with newly diagnosed MM (NDMM) enrolled in the Integrative Molecular And Genetic Epidemiology study between 2009 and 2020. We estimated the association of BMI with the risk for progressed disease and all-cause and MM-specific mortality using hazard ratios (HR) and corresponding 95% confidence intervals (CI), calculated from multivariable Cox proportional hazard models adjusted for prognostic factors. When compared with NDMM patients with a normal BMI at diagnosis (18.5-24.9 kg/m2) positive associations with all-cause mortality were observed at the extremes with a 52% and 147% increased risk for death in patients with underweight (BMI, <18.5 kg/m2, HR, 1.52; 95% CI 0.48-4.84) and those with obesity (BMI, ≥30.0 kg/m2, HR, 2.47; 95% CI, 1.26-4.85), respectively. Patients with severe obesity (BMI, ≥35kg/m2) had the highest risk when compared with those with a normal BMI (HR, 3.14; 95% CI, 1.50-6.55), particularly among White (HR, 3.22; 95% CI, 1.30-7.94) and female (HR, 4.17; 95% CI, 1.20-14.47) patients with NDMM; however, the differences by race and sex were not statistically significant (Pinteraction ≥.60). Severe obesity was also associated with an 83% elevated risk for progressed disease among patients with NDMM (HR, 1.83; 95% CI, 1.04-3.24). These findings were similar for MM-specific mortality and highlight weight management as a potential strategy to improve the prognosis of all patients with NDMM.

Abstract: Antiangiogenic agents, including vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs), represent an important class of treatments for a range of solid tumors. However, concerns have arisen over potential associations between antiangiogenic agents and thromboembolic events. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) that compared a frequently used VEGFR TKI, cabozantinib, with placebo or usual care. The primary outcome was the risk of any thromboembolism. Secondary outcomes included the risk of venous thromboembolism (VTE), risk of arterial thromboembolism (ATE) and progression-free survival. 14 RCTs were included with a combined total of 4204 patients, of whom 212 (5%) developed thromboembolism. Cabozantinib was associated with a significantly increased risk of any thromboembolism (risk ratio [RR], 2.41; 95% confidence interval [CI], 1.72-3.39) driven by VTE (RR, 3.21; 95% CI, 1.86-5.55) but not ATE (RR, 1.31; 95% CI, 0.76-2.26). To account for between-group differences in time on treatment, progression-free survival-adjusted analyses were conducted, with cabozantinib remaining associated with a significantly increased risk of any thromboembolism (RR, 1.47; 95% CI, 1.02-2.12) and VTE (RR, 1.92; 95% CI, 1.08-3.43) but not ATE (RR, 0.76; 95% CI, 0.41-1.40). In a retrospective single health care system cohort study of 295 patients treated with cabozantinib, a thromboembolism rate of 180 per 1000 patient-years on treatment was observed, with most events occurring in the first 3 months after initiation. Together these data demonstrate that cabozantinib is associated with a significantly increased risk of VTE in patients with cancer.

Abstract: Synchronous systemic and de novo secondary central nervous system (CNS) large B-cell lymphoma (LBCL) is an aggressive clinical entity with a historically poor prognosis. Given the rarity of this presentation, prospective studies are limited, and treatment paradigms and outcomes are extrapolated from small, heterogenous retrospective studies. We performed a retrospective study with extended follow-up for 63 consecutive patients with previously untreated synchronous systemic and de novo secondary CNS LBCLs presenting to 2 institutions over 21 years. Most patients had diffuse LBCL (73%) and were treated with an average of 6 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, Oncovin [vincristine], and prednisone) intercalated with high-dose IV methotrexate (R-CHOP-M). The overall response rate was 84% (75% complete). With a median follow-up of 8.1 years, the median progression-free survival (PFS) was 1.2 years, and the 6-year PFS rate was 37%. The median overall survival (OS) was 7.9 years, and the 6-year OS rate was 52%. Normal lactate dehydrogenase (LDH), low International Prognostic Index (IPI) score, and brain parenchymal-only CNS disease were associated with improved PFS, whereas normal LDH and parenchymal disease were associated with OS. The 25% of patients who underwent consolidation with high-dose chemotherapy (HDC) and autologous stem cell transplant (ASCT) had superior PFS and OS than patients who did not receive a transplant, with particular benefit in those with IPI score of ≥3. This study demonstrates that a proportion of patients presenting with secondary CNS involvement are cured with upfront chemoimmunotherapy with or without HDC/ASCT and helps identify prognostically favorable subgroups, which can guide counseling of patients with this rare, high-risk clinical presentation.