Blood

Tissue factor, coagulation factor XII, platelets, and neutrophils are implicated as important players in the pathophysiology of (experimental) venous thrombosis (VT). Their role became evident in mouse models where surgical handlings were required to provoke VT. Combined inhibition of natural anticoagulants antithrombin ( Serpinc1 ) and protein C ( Proc ) using small interfering (si) RNA without additional triggers also results in a venous thrombotic phenotype in mice, most notably with vessel occlusion in large veins of the head...

Primary immunodeficiencies affecting the function of neutrophils and other phagocytic leukocytes are notable for an increased susceptibility to bacterial and fungal infections as a result of impaired leukocyte recruitment, ingestion, and/ or killing of microbes. The underlying molecular defects can also impact other innate immune responses to infectious and inflammatory stimuli, leading to inflammatory and autoimmune complications that are not always directly related to infection. This review will provide an update on congenital disorders affecting neutrophil function where a combination of host defense and inflammatory complications are prominent, including NADPH oxidase defects in chronic granulomatous disease and β2 integrin defects in leukocyte adhesion deficiency...

Neutrophils represent the first line of cellular defense against invading microorganism by rapidly moving across the blood endothelial cell barrier and exerting effector cell functions. The neutrophil recruitment cascade to inflamed tissues involves elements of neutrophil rolling, firm adhesion and crawling onto the endothelial cell surface before extravasating by breaching the endothelial cell barrier. Neutrophil interactions with endothelial cell s occur via various adhesive modules and is a critical event to determine the mode of neutrophil transmigration, either at the endothelial cell junction ('paracellular') or directly through the EC body ('transcellular')...

Neutrophils are an absolutely essential part of the innate immune system, playing an essential role in the control of infectious diseases but more recently are also being viewed as important players in tissue repair. Neutrophils are able to counteract an infection through phagocytosis and/or the release of neutrophil extracellular traps (NETs). By contrast, neutrophils help repair damaged tissues limiting NET production but still phagocytosing debris. However, when inflammation is recurrent, or the inciting agent persists, neutrophils through a frustrated inability to resolve the problem can release NETs to exacerbate tissue damage during inappropriate inflammation...

No abstract text is available yet for this article.

TThe microbiota has emerged as an important regulator of the host immunity by the induction, functional modulation or suppression of local and systemic immune responses. In return, the host immune system restricts translocation and fine-tunes the composition and distribution of the microbiota to maintain a beneficial symbiosis. This paradigm applies to neutrophils, a critical component of the innate immunity, allowing their production and function to be influenced by microbial components and metabolites derived from the microbiota, and engaging them in the process of microbiota containment and regulation...

The niche that supports hematopoietic stem and progenitor cells (HSPC) in the bone marrow is a highly dynamic structure. It maintains core properties of HSPC in the steady state, and modulates their proliferation and differentiation in response to changing physiological demands or pathological insults. The dynamic and environment-sensing properties of the niche are shared by the innate immune system. Thus, it is not surprising that innate immune cells, including macrophages and neutrophils, are now recognized as important regulators of the hematopoietic niche, and ultimately of the stem cells from which they derive...

Reactive and clonal neutrophil expansion has been associated with thrombosis, suggesting that neutrophils play a role in this process. However, while there is no doubt that activated monocytes trigger coagulation in a tissue factor-dependent manner, it remains uncertain whether stimulated neutrophils can also directly activate coagulation. After more than a decade of debate, it is now largely accepted that normal human neutrophils do not synthetize tissue factor, the initiator of the extrinsic pathway of coagulation...

Neutrophils act as the body's first line of defense against infection and respond to diverse inflammatory cues, including cancer. Neutrophils display plasticity with the ability to adapt their function in different inflammatory contexts. In the tumor microenvironment, neutrophils have varied functions and have been classified using different terms including N1/N2 neutrophil, tumor-associated neutrophil (TAN), and polymorphonuclear-myeloid derived suppressor cell (PMN-MDSC). These populations of neutrophils are primarily defined by their functional phenotype as few specific cell surface markers have been identified...

This phase Ib dose-escalation study evaluated isatuximab plus pomalidomide/dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM). Patients who had received ≥2 prior MM therapies, including lenalidomide and a proteasome inhibitor (PI), were enrolled and received isatuximab at 5, 10, or 20 mg/kg (weekly [QW] for 4 weeks, followed by every 2 weeks [Q2W]), pomalidomide 4 mg (Days 1-21), and dexamethasone 40 mg (QW) in 28-day cycles until progression/intolerable toxicity. The primary objective was to determine the safety and recommended dose of isatuximab with this combination...

This single-arm, open-label, phase 1b study evaluated the maximum tolerated dose (MTD) of venetoclax when given with obinutuzumab and its safety and tolerability in patients with relapsed/refractory (R/R) or previously untreated (1L) chronic lymphocytic leukemia. Venetoclax dose initially was escalated (100-400 mg) in a 3+3 design to define the MTD combined with standard-dose obinutuzumab. Patients received venetoclax (Schedule A) or obinutuzumab (Schedule B) first to compare safety and determine dose/schedule for expansion...

No abstract text is available yet for this article.

Molecular causes of many inherited platelet disorders have been unraveled. Next generation sequencing facilitates diagnosis in 30-50% of patients. However, interpretation of genetic variants is challenging and requires careful evaluation in the context of the patient's phenotype. Before detailed testing is initiated, the treating physician and the patient should be aware why testing is performed and should agree on the consequences it may have, especially before testing for variants in genes associated with an increased risk for hematologic malignancies...

Chronic transfusion therapy (CTT) prevents stroke in selected patients with sickle cell anemia (SCA). We have shown that CTT mitigates signatures of cerebral metabolic stress, reflected by elevated oxygen extraction fraction (OEF), which likely drives stroke risk reduction. The region of highest OEF falls within the border zone, where cerebral blood flow (CBF) nadirs, and OEF in this region was reduced after CTT. The neuroprotective efficacy of hydroxyurea (HU) remains unclear. To test our hypothesis that patients receiving HU therapy have lower cerebral metabolic stress compared to patients not receiving disease-modifying therapy, we prospectively obtained brain MRIs with voxel-wise measurements of CBF and OEF in 84 participants with SCA who were grouped by therapy: no disease-modifying therapy, HU, or CTT...

Current guidelines advocate to limit red-cell transfusion during surgery, but the feasibility and safety of such strategy remains unclear as the majority of evidence is based on postoperative stable patients. We assessed the effects of a protocol aiming to restrict red-cell transfusion throughout hospitalization for vascular surgery. Fifty-eight patients scheduled for lower limb-bypass or open abdominal aortic aneurysm repair were randomized upon hemoglobin drop below 9.7g/dL to a low-trigger (hemoglobin<8...

Novel strategies, such as chemosensitization with targeted agents, that build on the success of standard immunochemotherapy show promise for the treatment of non-Hodgkin lymphoma (NHL). Here, we report a phase 1b study investigating dose escalation of the BCL2 inhibitor, venetoclax, in combination with rituximab or obinutuzumab and cyclophosphamide, doxorubicin, vincristine, and prednisone (R-/G-CHOP) chemotherapy in B-cell NHL. Objectives included safety assessment and determination of a recommended phase 2 dose (RP2D)...

Ibrutinib, a once-daily oral inhibitor of Bruton's tyrosine kinase, has greatly improved outcomes for patients with chronic lymphocytic leukemia (CLL). The phase 3 RESONATE™, which compared single-agent ibrutinib to ofatumumab in high-risk, relapsed patients with CLL, provided support for approval of ibrutinib in the US and Europe. We describe long-term follow-up of patients treated in RESONATE, where continued superiority of progression-free survival (PFS) (hazard ratio [HR] 0.133; 95% CI, 0.099-0.178) was observed...

The establishment of efficient and stable splicing patterns in terminally differentiated cells is critical to maintenance of specific functions throughout the lifespan of an organism. The human (h)α-globin gene contains three exons separated by two short introns. Naturally occurring α-thalassemia mutations that trigger aberrant splicing have revealed the presence of cryptic splice sites within the hα-globin gene transcript. How cognate (functional) splice sites are selectively utilized in lieu of these cryptic sites has remained unexplored...

Liquid biopsies have been considered the holy grail towards achieving effective cancer management, with blood tests offering a minimally invasive, safe, and sensitive alternative or complementary approach for tissue biopsies. Currently, blood-based liquid biopsy measurements focus on evaluation of biomarker types, including circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), extracellular vesicles (EVs; exosomes, oncosomes), and tumor-educated platelets (TEPs). Despite the potential of individual techniques, each has its own advantages and disadvantages...

The phase 3 CLARION study compared carfilzomib-melphalan-prednisone (KMP) with bortezomib-melphalan-prednisone (VMP) in transplant-ineligible newly-diagnosed multiple myeloma (NDMM) patients. Patients were randomized 1:1 to KMP or VMP for nine 42-day cycles (C). Patients received carfilzomib on days (D) 1, 2, 8, 9, 22, 23, 29, 30 (20 mg/m2: C1D1, C1D2; 36 mg/m2 thereafter) or bortezomib on D1, 4, 8, 11, 22, 25, 29, 32 (1.3 mg/m2; D4, 11, 25, 32 omitted for C5-9). Melphalan (9 mg/m2) and prednisone (60 mg/m2) were administered on D1-4...