Platelets are critical for haemostasis, thrombosis, and inflammatory responses, but the events that lead to mature platelet production remain incompletely understood. The bone marrow has been ...proposed to be a major site of platelet production, although there is indirect evidence that the lungs might also contribute to platelet biogenesis. Here, by directly imaging the lung microcirculation in mice, we show that a large number of megakaryocytes circulate through the lungs, where they dynamically release platelets. Megakaryocytes that release platelets in the lungs originate from extrapulmonary sites such as the bone marrow; we observed large megakaryocytes migrating out of the bone marrow space. The contribution of the lungs to platelet biogenesis is substantial, accounting for approximately 50% of total platelet production or 10 million platelets per hour. Furthermore, we identified populations of mature and immature megakaryocytes along with haematopoietic progenitors in the extravascular spaces of the lungs. Under conditions of thrombocytopenia and relative stem cell deficiency in the bone marrow, these progenitors can migrate out of the lungs, repopulate the bone marrow, completely reconstitute blood platelet counts, and contribute to multiple haematopoietic lineages. These results identify the lungs as a primary site of terminal platelet production and an organ with considerable haematopoietic potential.
Despite great advances in understanding the mechanisms underlying blood production, lineage specification at the level of multipotent progenitors (MPPs) remains poorly understood. Here, we show that ...MPP2 and MPP3 are distinct myeloid-biased MPP subsets that work together with lymphoid-primed MPP4 cells to control blood production. We find that all MPPs are produced in parallel by hematopoietic stem cells (HSCs), but with different kinetics and at variable levels depending on hematopoietic demands. We also show that the normally rare myeloid-biased MPPs are transiently overproduced by HSCs in regenerating conditions, hence supporting myeloid amplification to rebuild the hematopoietic system. This shift is accompanied by a reduction in self-renewal activity in regenerating HSCs and reprogramming of MPP4 fate toward the myeloid lineage. Our results support a dynamic model of blood development in which HSCs convey lineage specification through independent production of distinct lineage-biased MPP subsets that, in turn, support lineage expansion and differentiation.
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•Blood production is mediated by functionally distinct lineage-biased MPPs•MPP subsets are independently produced by HSCs•Myeloid-biased MPPs serve as a potent source of myeloid amplification•Regeneration occurs at the expense of HSC engraftment and self-renewal activity
Pietras et al. show that HSCs produce functionally distinct lineage-biased MPPs that work together to adapt blood production to hematopoietic demands. Two rare subsets of myeloid-biased MPPs are important for maintaining blood homeostasis at steady state and serve as a potent source of myeloid amplification in regenerative conditions.
We developed a technology (capturing activated neuronal ensembles CANE) to label, manipulate, and transsynaptically trace neural circuits that are transiently activated in behavioral contexts with ...high efficiency and temporal precision. CANE consists of a knockin mouse and engineered viruses designed to specifically infect activated neurons. Using CANE, we selectively labeled neurons that were activated by either fearful or aggressive social encounters in a hypothalamic subnucleus previously known as a locus for aggression, and discovered that social-fear and aggression neurons are intermixed but largely distinct. Optogenetic stimulation of CANE-captured social-fear neurons (SFNs) is sufficient to evoke fear-like behaviors in normal social contexts, whereas silencing SFNs resulted in reduced social avoidance. CANE-based mapping of axonal projections and presynaptic inputs to SFNs further revealed a highly distributed and recurrent neural network. CANE is a broadly applicable technology for dissecting causality and connectivity of spatially intermingled but functionally distinct ensembles.
•CANE is a new technology for capturing activated (Fos+) neuronal ensembles•CANE tags Fos+ neurons with high specificity, temporal precision, and efficiency•Hypothalamic neurons eliciting social-fear behaviors are identified using CANE•CANE-based mapping reveals a highly distributed and recurrent social-fear circuit
Sakurai et al. developed a new technology (CANE) to capture and manipulate recently activated (Fos+) neurons in the mouse brain. CANE is applied to delineate the causal functions and connectivity of hypothalamic neurons activated by a social-fear experience.
Participants with hemophilia A received B-domain–deleted factor VIII gene therapy delivered in an AAV5 vector. A decrease in annualized bleeding rates was maintained for 2 years despite declining ...factor VIII levels.
Patients with severe hemophilia A were treated with an adenoviral construct containing coagulation factor VIII cDNA and followed for 1 to 3 years. Median factor VIII activity at 49 to 52 weeks was 24 ...IU per deciliter, and annualized bleeding rates decreased after treatment. Elevations in alanine aminotransferase were the most common toxic effect and were mainly controlled with glucocorticoids.
Adeno-associated virus (AAV)-mediated gene therapy may provide durable protection from bleeding events and reduce treatment burden for people with hemophilia A (HA). However, pre-existing immunity ...against AAV may limit transduction efficiency and hence treatment success. Global data on the prevalence of AAV serotypes are limited. In this global, prospective, noninterventional study, we determined the prevalence of pre-existing immunity against AAV2, AAV5, AAV6, AAV8, and AAVrh10 among people ≥12 years of age with HA and residual FVIII levels ≤2 IU/dL. Antibodies against each serotype were detected using validated, electrochemiluminescent-based enzyme-linked immunosorbent assays. To evaluate changes in antibody titers over time, 20% of participants were retested at 3 and 6 months. In total, 546 participants with HA were enrolled at 19 sites in 9 countries. Mean (standard deviation) age at enrollment was 36.0 (14.87) years, including 12.5% younger than 18 years, and 20.0% 50 years of age and older. On day 1, global seroprevalence was 58.5% for AAV2, 34.8% for AAV5, 48.7% for AAV6, 45.6% for AAV8, and 46.0% for AAVrh10. Considerable geographic variability was observed in the prevalence of pre-existing antibodies against each serotype, but AAV5 consistently had the lowest seroprevalence across the countries studied. AAV5 seropositivity rates were 51.8% in South Africa (
= 56), 46.2% in Russia (
= 91), 40% in Italy (
= 20), 37.2% in France (
= 86), 26.8% in the United States (
= 71), 26.9% in Brazil (
= 26), 28.1% in Germany (
= 89), 29.8% in Japan (
= 84), and 5.9% in the United Kingdom (
= 17). For all serotypes, seropositivity tended to increase with age. Serostatus and antibody titer were generally stable over the 6-month sampling period. As clinical trials of AAV-mediated gene therapies progress, data on the natural prevalence of antibodies against various AAV serotypes may become increasingly important.
Venous thromboembolism (VTE) is a common complication among patients with cancer. Patients with cancer and VTE are at a markedly increased risk for morbidity and mortality.
These evidence-based ...guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in their decisions about the prevention and treatment of VTE in patients with cancer.
ASH formed a multidisciplinary guideline panel balanced to minimize potential bias from conflicts of interest. The guideline development process was supported by updated or new systematic evidence reviews. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to assess evidence and make recommendations.
Recommendations address mechanical and pharmacological prophylaxis in hospitalized medical patients with cancer, those undergoing a surgical procedure, and ambulatory patients receiving cancer chemotherapy. The recommendations also address the use of anticoagulation for the initial, short-term, and long-term treatment of VTE in patients with cancer.
Strong recommendations include not using thromboprophylaxis in ambulatory patients receiving cancer chemotherapy at low risk of VTE and to use low-molecular-weight heparin (LMWH) for initial treatment of VTE in patients with cancer. Conditional recommendations include using thromboprophylaxis in hospitalized medical patients with cancer, LMWH or fondaparinux for surgical patients with cancer, LMWH or direct oral anticoagulants (DOAC) in ambulatory patients with cancer receiving systemic therapy at high risk of VTE and LMWH or DOAC for initial treatment of VTE, DOAC for the short-term treatment of VTE, and LMWH or DOAC for the long-term treatment of VTE in patients with cancer.
Platelets have a wide range of functions including critical roles in hemostasis, thrombosis, and immunity. We hypothesized that during acute inflammation, such as in life-threatening sepsis, there ...are fundamental changes in the sites of platelet production and phenotypes of resultant platelets. Here, we showed during sepsis that the spleen was a major site of megakaryopoiesis and platelet production. Sepsis provoked an adrenergic-dependent mobilization of megakaryocyte-erythrocyte progenitors (MEPs) from the bone marrow to the spleen, where IL-3 induced their differentiation into megakaryocytes (MKs). In the spleen, immune-skewed MKs produced a CD40 ligandhi platelet population with potent immunomodulatory functions. Transfusions of post-sepsis platelets enriched from splenic production enhanced immune responses and reduced overall mortality in sepsis-challenged animals. These findings identify a spleen-derived protective platelet population that may be broadly immunomodulatory in acute inflammatory states such as sepsis.
BACKGROUND
Posttransfusion purpura (PTP) is a rare condition characterized by severe thrombocytopenia following receipt of blood products. Most reported PTP cases involve alloantibodies directed ...against human platelet antigen (HPA)‐1a. We present a case of PTP‐mediated severe thrombocytopenia associated with alloantibodies directed against HPA‐4a in the setting of combination checkpoint inhibitor therapy.
CASE REPORT
A 62‐year‐old woman with rectal melanoma that progressed on combination checkpoint inhibitors (ipilimumab and nivolumab) was admitted for abdominoperineal resection. She received multiple blood products during surgery, and between the sixth and eighth days post‐surgery her platelet (PLT) count decreased from 126 × 109/L to a nadir of 1 × 109/L. She received intravenous immunoglobulin (IVIG), steroids, and romiplostim with eventual recovery of her PLT count to 50 × 109/L 20 days after surgery. She tested positive for anti‐HPA‐4a and was shown not to express HPA‐4a, confirming a diagnosis of PTP.
CONCLUSION
Alloantibodies strongly reactive to HPA‐4a were detected in this patient who received multiple blood products during abdominoperineal resection surgery. Her thrombocytopenia improved with prompt administration of IVIG, steroids, and romiplostim. PTP must always be considered in patients with acute severe thrombocytopenia after receipt of blood products, and treatment should not be delayed while awaiting laboratory confirmation. To our knowledge, this is the second reported case of PTP with antibodies against HPA‐4a.
Cases of de novo immune thrombocytopenia (ITP), including a fatality, following SARS-CoV-2 vaccination in previously healthy recipients led to studying its impact in preexisting ITP. In this study, 4 ...data sources were analyzed: the Vaccine Adverse Events Reporting System (VAERS) for cases of de novo ITP; a 10-center retrospective study of adults with preexisting ITP receiving SARS-CoV-2 vaccination; and surveys distributed by the Platelet Disorder Support Association (PDSA) and the United Kingdom (UK) ITP Support Association. Seventy-seven de novo ITP cases were identified in VAERS, presenting with median platelet count of 3 1-9 ×109/L approximately 1 week postvaccination. Of 28 patients with available data, 26 responded to treatment with corticosteroids and/or intravenous immunoglobulin (IVIG), and/or platelet transfusions. Among 117 patients with preexisting ITP who received a SARS-CoV-2 vaccine, 19 experienced an ITP exacerbation (any of: ≥50% decline in platelet count, nadir platelet count <30 × 109/L with >20% decrease from baseline, and/or use of rescue therapy) following the first dose and 14 of 70 after a second dose. Splenectomized persons and those who received 5 or more prior lines of therapy were at highest risk of ITP exacerbation. Fifteen patients received and responded to rescue treatment. In surveys of both 57 PDSA and 43 UK patients with ITP, prior splenectomy was associated with worsened thrombocytopenia. ITP may worsen in preexisting ITP or be identified de novo post–SARS-CoV2 vaccination; both situations responded well to treatment. Proactive monitoring of patients with known ITP, especially those postsplenectomy and with more refractory disease, is indicated.
•SARS-CoV-2 vaccines are generally safe in patients with preexisting ITP but thrombocytopenia exacerbation may occur and requires monitoring.•Splenectomy and past use of 5 or more therapies predict higher risk of worsening thrombocytopenia in ITP patients post-SARS-CoV-2 vaccine.
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