Current Opinion in Hematology最新文献

Purpose of review: Platelets are essential effector cells in the immune continuum. Understanding platelet roles during infectious diseases is paramount to understanding pathological and protective immune responses. In this review, we compiled recent data about platelets in immune response to infectious diseases.

Recent findings: Platelets recognize and respond to pathogens, including viruses, bacteria and parasites, contributing to the assembly of the immune response. Platelet activation and platelet-leukocyte aggregates formation have been observed in naturally infected humans and in experimental models of diseases. In this review we discuss recent findings on the mechanisms and outcomes of platelet activation and platelet-leukocyte interaction in infectious diseases and response to vaccine. Pathogens may modulate platelet response to escape immune surveillance, but platelets still contribute to host defense. We compiled evidence of platelet mediated-pathological responses, but also their contributions to pathogen clearance. We focused on the participation of platelets in pathophysiological and protective responses in infectious diseases of global impact such as COVID-19, HIV-1, viral hemorrhagic fevers, bacterial sepsis and parasite infections.

Summary: Platelets contribute to protective and pathological responses by regulating innate and adaptive immunity through activation, hyperaggregability and directly interacting with pathogens. Even though many mechanisms underlying platelet roles in infectious disease have been revealed, much remains to be investigated.

Purpose of review: This review examines the enzymatic regulation of coagulation and fibrinolysis, focusing on key players such as thrombin, plasmin, and ADAMTS13. We highlight how dysregulation of these enzymes contributes to thrombotic and hemorrhagic disorders and review emerging diagnostic biomarkers and therapeutic strategies.

Recent findings: Recent studies demonstrate the prognostic utility of biomarkers such as thrombin-antithrombin (TAT) and plasmin-α2-antiplasmin (PAP) complexes across critical illnesses including trauma, sepsis, and stroke. Advances in plasmin and thrombin generation assays, enzyme-specific assays, and enzyme-modulating therapies (e.g., factor XI inhibitors and recombinant ADAMTS13) are reshaping approaches to hemostatic balance.

Summary: Understanding hemostatic enzymatic regulation offers new avenues for risk stratification, diagnosis, and treatment of coagulation disorders. Although significant progress has been made, challenges remain in translating laboratory findings to clinical practice, necessitating further large-scale validation. Precision-guided enzymatic therapies hold promise for improving outcomes in acute care settings.

Purpose of review: In this review, we will describe murine models developed to examine human platelet function.

Recent findings: Platelets are critical cells necessary to regulate hemostasis after vessel injury. However, excessive platelet activation can lead to thrombotic complications. Preclinical/translational models are critical in developing therapeutics against platelet activation and to understand mechanistically how platelets function. Researchers have relied on murine models to study platelet function in vivo due to ease of establishing genetic knockouts as well as their lower cost and high throughput nature compared to larger animal models. However, while murine platelets are similar to human based on transcriptomic and proteomic analysis, there are significant differences between the two species, which limits their translation to the human system. To overcome these hurdles, investigators have targeted human platelet genes into the murine genome to express human receptors in mouse platelets. In addition, transfusion models of human platelets into mice have provided valuable insight into human platelet function.

Summary: Murine models are a value tool to examine platelet function in hemostasis and thrombosis. Continued focus on developing mouse models where platelets resemble those circulating in humans will offer valuable insight into important pathways, which may be targeted in the future.

Purpose of review: Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia. The long-term prognosis for APL is generally more favorable than for other types of acute leukemia due to the use of differentiation therapies. However, early hemorrhagic death remains a significant clinical challenge in APL patients.

Recent findings: Real-world studies reveal that the rate of early hemorrhagic death remains high (10-30%) in APL patients in the era of differentiation therapy. APL patients have systemic hemostatic changes including activation of coagulation followed by consumption of coagulation factors, hyperfibrinolysis, and severe thrombocytopenia. Our study found that tissue factor contributes to a bleeding phenotype in mouse models of APL. In-vitro studies suggest that there may be direct or indirect interaction between APL cells and brain endothelial cells.

Summary: Predictors of hemorrhagic death in APL are only partially understood. The associations between bleeding and hyperfibrinolysis or thrombocytopenia in APL need to be determined. The interaction between APL cells and brain endothelial cells need to be determined in vivo .

Purpose of review: Increasing evidence has shown that immune and thrombotic pathways cooperate to ensure efficient immune and hemostatic functions. Due to their involvement in various cardiovascular and inflammatory conditions, this interplay has gained significant interest, leading to many important discoveries. However, difference between mice and humans have limited the translatability of some of these findings. One key receptor involved in immuno-thrombosis but lacking in mice is the Fc gamma receptor IIA (FcγRIIA).

Recent findings: Innovative in-vitro and in-vivo models for anti-PF4 immune disorders have greatly impacted our understanding of the role of FcγRIIA in these disorders and has revealed novel therapeutic strategies with great translational potential. Epideminological studies have hinted at a role for FcγRIIA in cardiovascular diseases; however, conclusive mechanistic studies are currently lacking.

Summary: Humanized transgenic FcγRIIA mice have greatly advanced our understanding of the role of FcγRIIA in anti-PF4 immune disorders, immune thrombocytopenia and lupus; however, they have only rarely been used in models of thrombo-inflammation. To improve translation from bench to bedside, inclusion of FcγRIIA transgenic mouse models is encouraged.

Purpose of review: Mesenchymal stromal cells (MSCs) are widely utilized in preclinical and clinical studies, with over 1500 clinical trials, including applications in Covid-19 treatment. This review consolidates recent advances in understanding MSC biology, mechanisms of action, and clinical utility.

Recent findings: This review discusses recent progress made in understanding MSC biology, including immunomodulatory mechanisms mediated by microRNAs and long noncoding RNAs. Clinically, MSC therapies have shown promise in treating conditions like Covid-19-associated ARDS and several MSC therapeutic products have been approved. Single-cell analyses have shed light on MSC heterogeneity, revealing tissue-specific and conserved subpopulations influenced by the extracellular matrix. The FDA's updated recommendations on potency assays emphasize a holistic approach to quality control, reinforcing the need for a universal reference standard to improve reproducibility and clinical outcomes. In addition, to better understand their limited success in randomized clinical trials, we highlight the importance of a universal reference standard for MSC potency.

Summary: MSCs offer significant therapeutic potential, but addressing challenges in heterogeneity and potency standardization is essential. Advances in understanding their immune properties and clinical applications provide opportunities to refine and expand their use in regenerative medicine.

Purpose of review: Blood cancers are one of the most common cancers worldwide. These diseases stem from defects in blood components having cytogenetic aberrations and genetic mutations. There have been vast improvements in terms of treatment options and survival outcomes. Nevertheless, due to the clonal nature and heterogeneity of the diseases, the number of cases reported exhibit a rising pattern due to chemoresistance and disease relapse thus posing a healthcare burden. Therefore, the need for more specific forms of targeted therapies is ever-present.

Recent findings: CRISPR has emerged as a key player and is the epitome of gene editing technology in this post genomic era. In line with the current trend, numerous studies in blood cancer research have extensively utilized CRISPR-based applications to understand the functional genomics of hematologic malignancies and identify potential therapeutic targets for development of novel therapeutic applications.

Summary: The importance of comprehending the utilities of state-of-the-art technologies such as CRISPR for studying hematologic malignancies has never been more apparent and timelier. Therefore, this review attempts to scrutinize the versatility of CRISPR applications which range from functional genomics to immunotherapeutic applications.

Purpose of review: The development and widespread use of genetic testing for diagnosis of red blood cell (RBC) membrane disorders and other hereditary hemolytic anemias (HHA) have expanded our understanding of these diseases and revealed additional complexities. We describe here such complexities and make suggestions regarding genotypic/phenotypic evaluation with the goal of early diagnosis of patients with HHA before inappropriate treatment or complications occur.

Recent findings: Widespread use of clinical genetic diagnosis in patients, for more than a decade now, has revealed the heterogeneity of RBC membranopathies, even when caused by different variants in the same gene, and sometimes due to the same genetic variant, likely because of genetic modifiers or mutations in other genes encoding for RBC membrane proteins, enzymes, or globins. Many under-recognized diseases are now more easily diagnosed.

Summary: Despite complexities in the genetic evaluation of RBC membranopathies, the future holds great promise for timely and accurate diagnosis. Correlation and documentation of genotypic and phenotypic data from affected individuals and family members will allow for improved detection and interpretation of genetic results. The use of such testing in newborns and children with HHA can optimize treatment decisions and explore possibilities for novel targeted or genetic therapies.

Purpose of review: The incidence of mental health conditions within hematopoietic stem cell transplant (HSCT) patients is high and has profound impacts on quality of life after transplant. Mental health is an underexplored and underutilized outcome in this patient population.

Recent findings: Standard mental health interventions in this patient population have shown limited results. Multiple factors including acuity of systemic illness, proinflammatory states, heterogeneous patient populations, and use of specific therapeutics could impact results. This presents the opportunity to identify new areas of improvement, such as focusing on leukocyte recovery, exogenous steroid use, and cytokine response to inform new bedside interventions.

Summary: Overall, interventions incorporating the biological mechanisms of mental health are underutilized in the HSCT patient population and offer a novel approach to improving morbidity, mortality and quality of life.