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Platelets, the small, anucleate blood cells that originate from megakaryocytes in the bone marrow, are typically associated with coagulation. However, it is now apparent that platelets are more multifaceted than originally thought, with their function extending beyond their traditional role in hemostasis to acting as important mediators of brain function. In this review, we outline the broad repertoire of platelet function in the central nervous system, focusing on the similarities between platelets and neurons. We also summarize the role that platelets play in the pathophysiology of various neurological diseases, with a particular focus on neuroinflammation and neurodegeneration. Finally, we highlight the exciting prospect of harnessing the unique features of the platelet proteome and extracellular vesicles, which are rich in neurotrophic, antioxidative, and antiinflammatory factors, for the development of novel neuroprotective and neuroregenerative interventions to treat various neurodegenerative and traumatic pathologies.
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Plaquetas , Encéfalo , Plaquetas/fisiología , Encéfalo/fisiología , Hemostasis/fisiologíaRESUMEN
BACKGROUND: The burgeoning field of regenerative medicine has significantly advanced with recent findings on biotherapies using human platelet lysates (HPLs), derived from clinical-grade platelet concentrates (PCs), for treating brain disorders. These developments have opened new translational research avenues to explore the neuroprotective effects of platelet-extracellular vesicles (PEVs). Their potential in managing neurodegenerative conditions like traumatic brain injury (TBI) and Parkinson's disease (PD) warrants further exploration. We aimed here to characterize the composition of a PEV preparation isolated from platelet concentrate (PC) supernatant, and determine its neuroprotective potential and neurorestorative effects in cellular and animal models of TBI and PD. METHODS: We isolated PEVs from the supernatant of clinical-grade PC collected from healthy blood donors utilizing high-speed centrifugation. PEVs were characterized by biophysical, biochemical, microscopic, and LC-MS/MS proteomics methods to unveil biological functions. Their functionality was assessed in vitro using SH-SY5Y neuronal cells, LUHMES dopaminergic neurons, and BV-2 microglial cells, and in vivo by intranasal administration in a controlled cortical impact (CCI)-TBI model using 8-weeks-old male C57/BL6 mice, and in a PD model induced by MPTP in 5-month-old male C57/BL6 mice. RESULTS: PEVs varied in size from 50 to 350 nm, predominantly around 200 nm, with concentrations ranging between 1010 and 1011/mL. They expressed specific platelet membrane markers, exhibited a lipid bilayer by cryo-electron microscopy and, importantly, showed low expression of pro-coagulant phosphatidylserine. LC-MS/MS indicated a rich composition of trophic factors, including neurotrophins, anti-inflammatory agents, neurotransmitters, and antioxidants, unveiling their multifaceted biological functions. PEVs aided in the restoration of neuronal functions in SH-SY5Y cells and demonstrated remarkable neuroprotective capabilities against erastin-induced ferroptosis in dopaminergic neurons. In microglial cells, they promoted anti-inflammatory responses, particularly under inflammatory conditions. In vivo, intranasally delivered PEVs showed strong anti-inflammatory effects in a TBI mouse model and conserved tyrosine hydroxylase expression of dopaminergic neurons of the substantia nigra in a PD model, leading to improved motor function. CONCLUSIONS: The potential of PEV-based therapies in neuroprotection opens new therapeutic avenues for neurodegenerative disorders. The study advocates for clinical trials to establish the efficacy of PEV-based biotherapies in neuroregenerative medicine.
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Plaquetas , Lesiones Traumáticas del Encéfalo , Vesículas Extracelulares , Ratones Endogámicos C57BL , Fármacos Neuroprotectores , Enfermedad de Parkinson , Vesículas Extracelulares/metabolismo , Animales , Humanos , Lesiones Traumáticas del Encéfalo/metabolismo , Ratones , Plaquetas/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/administración & dosificación , Masculino , Enfermedad de Parkinson/terapia , Administración Intranasal , Modelos Animales de EnfermedadRESUMEN
Industrial plasma fractionation, a complex and highly regulated technology, remains largely inaccessible to many low- and middle-income countries (LMICs). This, combined with the limited availability and high cost of plasma-derived medicinal products (PDMPs), creates deficiency of access to adequate treatment for patients in resource-limited countries, and leads to their suffering. Meanwhile, an increasing number of LMICs produce surplus plasma, as a by-product of red blood cell preparation from whole blood, that is discarded because of the lack of suitability for fractionation. This article reviews pragmatic technological options for processing plasma collected from LMICs into therapies and supports a realistic stepwise approach aligned with recent World Health Organization guidance and initiatives launched by the Working Party for Global Blood Safety of the International Society of Blood Transfusion. When industrial options based on contract or toll plasma fractionation programme and, even more, domestic fractionation facilities require larger volumes of quality plasma than is produced, alternative methods should be considered. In-bag minipool or small-scale production procedures implementable in blood establishments or national service centres are the only realistic options available to gradually reduce plasma wastage, provide safer treatments for patients currently treated with non-pathogen-reduced blood products and concurrently improve Good Manufacturing Practice (GMP) levels with minimum capital investment. As a next step, when the available volume of quality-assured plasma reaches the necessary thresholds, LMICs could consider engaging with an established fractionator in a fractionation agreement or a contract in support of a domestic fractionation facility to improve the domestic PDMP supply and patients' treatment.
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Proteínas Sanguíneas , Países en Desarrollo , Humanos , Proteínas Sanguíneas/uso terapéutico , Transfusión Sanguínea , Plasma , Seguridad de la SangreRESUMEN
The Asia-Pacific Plasma Leaders' Network (APPLN) plays a crucial role in addressing the regional shortage of plasma-derived medicinal products (PDMPs), particularly in low- and middle-income countries (LMICs). It provides a platform for experts to share their expertise and drive multi-stakeholder collaborations. While several PDMPs are acknowledged by the World Health Organization (WHO) as life-saving therapeutics on the Model List of Essential Medicine for treating various chronic and acute life-threatening diseases, there are still many inadequacies in the availability and affordability of PDMPs. These challenges arise from insufficient domestic supplies of plasma suitable for fractionation, as well as a lack of technical and financial capabilities to implement contract or domestic plasma fractionation programmes. At two separate dialogue forums organized by the APPLN in 2023, experts discussed the unmet needs of PDMPs for individuals living with haemophilia and immunodeficiencies in the region. They also highlighted the limited access to early diagnosis and patient-centred care in several LMICs. To address these issues, there is an urgent need to increase the availability of high-quality domestic plasma for fractionation. Adopting a stepwise approach to utilize unused recovered plasma and establishing contract fractionation programmes could be viable strategies to potentially enhance PDMP availability in LMICs. However, achieving this goal requires improving existing domestic infrastructures for blood collection, implementing adequate policy reforms and fostering competent local leadership. Ultimately, there is no 'one-size-fits-all' strategy for securing safe plasma proteins for all patients in need. Collaborative efforts are essential for achieving progressive self-sufficiency in PDMPs.
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The development of intravenous IgG (IVIG) formulations in the 1970s enabled expanded use for treating primary antibody deficiency syndromes and autoimmune conditions. Recent advancements include the use of IVIG in secondary immune deficiencies related to hematologic malignancies and stem cell transplantation, along with the newly emerging prophylactic applications following chimeric antigen receptor T-cell (CAR-T) therapies. Novel therapeutic areas such as bispecific antibodies (BsAbs) for lymphoma and myeloma have increased the use of IgG, given the associated risks of infections. Today, the concept of a rational personalized clinical use of IgG in the context of evolving clinical indications in high-income countries (HIC) is emerging, as unmet challenges in line with managing shortages due to increasing demands globally. The current work aims to review and link the indications for IgG to their characteristics and formulations, their dose, route and frequency of administrations and duration of therapy to meet the needs of individual patients. It will also explore the means to rationalize and monitor IgG use in HIC in the time of shortage, while explaining pragmatic strategies to improve supply and use in low- and middle-income countries (LMIC).
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Convalescent plasma (CP) recurs as a frontline treatment in epidemics because it is available as soon as there are survivors. The COVID-19 pandemic represented the first large-scale opportunity to shed light on the mechanisms of action, safety, and efficacy of CP using modern evidence-based medicine approaches. Studies ranging from observational case series to randomized controlled trials (RCTs) have reported highly variable efficacy results for COVID-19 CP (CCP), resulting in uncertainty. We analyzed variables associated with efficacy, such as clinical settings, disease severity, CCP SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) antibody levels and function, dose, timing of administration (variously defined as time from onset of symptoms, molecular diagnosis, diagnosis of pneumonia, or hospitalization, or by serostatus), outcomes (defined as hospitalization, requirement for ventilation, clinical improvement, or mortality), CCP provenance and time for collection, and criteria for efficacy. The conflicting trial results, along with both recent WHO guidelines discouraging CCP usage and the recent expansion of the FDA emergency use authorization (EUA) to include outpatient use of CCP, create confusion for both clinicians and patients about the appropriate use of CCP. A review of 30 available RCTs demonstrated that signals of efficacy (including reductions in mortality) were more likely if the CCP neutralizing titer was >160 and the time to randomization was less than 9 days. The emergence of the Omicron variant also reminds us of the benefits of polyclonal antibody therapies, especially as a bridge to the development and availability of more specific therapies.
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COVID-19 , COVID-19/terapia , Humanos , Inmunización Pasiva , Estudios Observacionales como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Sueroterapia para COVID-19RESUMEN
Platelets are small anucleated blood cells primarily known for their vital hemostatic role. Allogeneic platelet concentrates (PCs) collected from healthy donors are an essential cellular product transfused by hospitals to control or prevent bleeding in patients affected by thrombocytopenia or platelet dysfunctions. Platelets fulfill additional essential functions in innate and adaptive immunity and inflammation, as well as in wound-healing and tissue-repair mechanisms. Platelets contain mitochondria, lysosomes, dense granules, and alpha-granules, which collectively are a remarkable reservoir of multiple trophic factors, enzymes, and signaling molecules. In addition, platelets are prone to release in the blood circulation a unique set of extracellular vesicles (p-EVs), which carry a rich biomolecular cargo influential in cell-cell communications. The exceptional functional roles played by platelets and p-EVs explain the recent interest in exploring the use of allogeneic PCs as source material to develop new biotherapies that could address needs in cell therapy, regenerative medicine, and targeted drug delivery. Pooled human platelet lysates (HPLs) can be produced from allogeneic PCs that have reached their expiration date and are no longer suitable for transfusion but remain valuable source materials for other applications. These HPLs can substitute for fetal bovine serum as a clinical grade xeno-free supplement of growth media used in the in vitro expansion of human cells for transplantation purposes. The use of expired allogeneic platelet concentrates has opened the way for small-pool or large-pool allogeneic HPLs and HPL-derived p-EVs as biotherapy for ocular surface disorders, wound care and, potentially, neurodegenerative diseases, osteoarthritis, and others. Additionally, allogeneic platelets are now seen as a readily available source of cells and EVs that can be exploited for targeted drug delivery vehicles. This article aims to offer an in-depth update on emerging translational applications of allogeneic platelet biotherapies while also highlighting their advantages and limitations as a clinical modality in regenerative medicine and cell therapies.
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Vesículas Extracelulares , Trasplante de Células Madre Hematopoyéticas , Humanos , Medicina Regenerativa , Plaquetas , Tratamiento Basado en Trasplante de Células y TejidosRESUMEN
BACKGROUND AND OBJECTIVES: Serum eye drops (SEDs) are used to treat ocular surface disease (OSD) and to promote ocular surface renewal. However, their use and production are not standardized, and several new forms of human eye drops have been developed. MATERIALS AND METHODS: The International Society for Blood Transfusion Working Party (ISBT WP) for Cellular Therapies held a workshop to review the current types of eye drops of human origin (EDHO) status and provide guidance. RESULTS: The ISBT WP for Cellular Therapies introduced the new terminology 'EDHO' to emphasize that these products are analogous to 'medical products of human origin'. This concept encompasses their source (serum, platelet lysate, and cord blood) and the increasingly diverse spectrum of clinical usage in ophthalmology and the need for traceability. The workshop identified the wide variability in EDHO manufacturing, lack of harmonized quality and production standards, distribution issues, reimbursement schemes and regulations. EDHO use and efficacy is established for the treatment of OSD, especially for those refractory to conventional treatments. CONCLUSION: Production and distribution of single-donor donations are cumbersome and complex. The workshop participants agreed that allogeneic EDHO have advantages over autologous EDHO although more data on clinical efficacy and safety are needed. Allogeneic EDHOs enable more efficient production and, when pooled, can provide enhanced standardization for clinical consistency, provided optimal margin of virus safety is ensured. Newer products, including platelet-lysate- and cord-blood-derived EDHO, show promise and benefits over SED, but their safety and efficacy are yet to be fully established. This workshop highlighted the need for harmonization of EDHO standards and guidelines.
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Síndromes de Ojo Seco , Donantes de Tejidos , Humanos , Soluciones Oftálmicas/uso terapéutico , Resultado del Tratamiento , Suero , Síndromes de Ojo Seco/tratamiento farmacológicoRESUMEN
Classically, patients with solid and hematologic malignancies have been treated with a combination of chemotherapy with or without a holistic targeted strategy using approved conventional therapy. While the evidence-based use of Immunomodulatory drugs and Immune checkpoint inhibitors (ICIs), including those targeting the PD-1, PD-L1 and CTLA-4, have reshaped the treatment paradigm for many malignant tumors and significantly stretched the life expectancy of patients, as for any interventional therapy, the rise in ICI applications, was associated with the observation of more immune-related hematological adverse events. Many of these patients require transfusion support during their treatment in line with precision transfusion. It has been presumed that transfusion-related immunomodulation (TRIM) and the microbiome can pose immunosuppressive effects on the recipients. Looking to the past and beyond and translating available data into practice in the evolving role of pharmaceutical therapy to ICI-receiving patients, we performed a narrative review of the literature on the immune-related hematological adverse events of ICIs, immunosuppressive mechanisms linked to blood product transfusions, as well as the detrimental impact of transfusions and its related microbiome on the sustained efficacy of ICIs and the patients' survival outcomes. Recent reports are pointing to the negative impact of transfusion on ICI response. Studies have concluded that packed RBC [PRBC] transfusions lead to an inferior progression-free and overall survival in patients with advanced cancer receiving ICIs, even after adjustments for other prognostic variables. The attenuation of the effectiveness of immunotherapy likely results from the immunosuppressive effects of PRBC transfusions. It is, therefore, wise to look retrospectively and prospectively at the impact of transfusion on ICI effects and adopt, in the interim, a restrictive transfusion strategy, if applicable, for those patients.
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Neoplasias Hematológicas , Neoplasias , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Estudios Retrospectivos , Neoplasias/tratamiento farmacológico , Neoplasias Hematológicas/tratamiento farmacológico , Transfusión SanguíneaRESUMEN
Platelet extracellular vesicles (PEVs) are an emerging delivery vehi for anticancer drugs due to their ability to target and remain in the tumor microenvironment. However, there is still a lack of understanding regarding yields, safety, drug loading efficiencies, and efficacy of PEVs. In this study, various methods were compared to generate PEVs from clinical-grade platelets, and their properties were examined as vehicles for doxorubicin (DOX). Sonication and extrusion produced the most PEVs, with means of 496 and 493 PEVs per platelet (PLT), respectively, compared to 145 and 33 by freeze/thaw and incubation, respectively. The PEVs were loaded with DOX through incubation and purified by chromatography. The size and concentration of the PEVs and PEV-DOX were analyzed using dynamic light scattering and nanoparticle tracking analysis. The results showed that the population sizes and concentrations of PEVs and PEV-DOX were in the ranges of 120-150 nm and 1.2-6.2 × 1011 particles/mL for all preparations. The loading of DOX determined using fluorospectrometry was found to be 2.1 × 106, 1.7 × 106, and 0.9 × 106 molecules/EV using freeze/thaw, extrusion, and sonication, respectively. The internalization of PEVs was determined to occur through clathrin-mediated endocytosis. PEV-DOX were more efficiently taken up by MDA-MB-231 breast cancer cells compared to MCF7/ADR breast cancer cells and NIH/3T3 cells. DOX-PEVs showed higher anticancer activity against MDA-MB-231 cells than against MCF7/ADR or NIH/3T3 cells and better than acommercial liposomal DOX formulation. In conclusion, this study demonstrates that PEVs generated by PLTs using extrusion, freeze/thaw, or sonication can efficiently load DOX and kill breast cancer cells, providing a promising strategy for further evaluation in preclinical animal models. The study findings suggest that sonication and extrusion are the most efficient methods to generate PEVs and that PEVs loaded with DOX exhibit significant anticancer activity against MDA-MB-231 breast cancer cells.
What is the context?â Current synthetic drug delivery systems can have limitations and side effects.â Platelet extracellular vesicles (PEVs) are a natural and potentially safer alternative for delivering cancer drugs to tumors.â However, there is still a lack of understanding about how to produce PEVs and how effective they are in delivering drugs.What is new?â We compared different methods for producing PEVs from clinical-grade platelets and found that sonication and extrusion were the most effective methods.â The PEVs were loaded with a cancer drug called doxorubicin (DOX) and tested their ability to kill breast cancer cells.What is the impact?â PEVs loaded with DOX were effective at killing cancer cells, especially MDA-MB-231 breast cancer cells.â This study demonstrates that PEVs are a promising strategy for delivering cancer drugs to tumors and that sonication and extrusion are the most efficient methods for producing PEVs.â The results suggest that further evaluation of PEVs in preclinical animal models is warranted to determine their potential as a cancer drug delivery system.Abbreviations: ADP: adenosine diphosphate; bFGF: basic fibroblast growth factor; BSA: bovine serum albumin; CD41: platelet glycoprotein IIb; CD62P: P-selectin; CFDASE: 5-(and-6)-carboxyfluorescein diacetate: succinimidyl ester; CPLT: cryopreserved platelet; CPZ: chlorpromazine hydrochloride; CTC: circulating tumor cell; DMSO: dimethyl sulfoxide; DDS: drug delivery system; DOX: doxorubicin; EPR: enhanced permeability and retention; EV: extracellular vesicle; FBS: fetal bovine serum; GMP: good manufacturing practice; GF: growth factor; HER2: human epidermal growth factor receptor 2; HGF: hepatocyte growth factor; Lipo-DOX: liposomal doxorubicin; MDR: multi-drug resistance; MMP-2: matrix metalloproteinase-2; MP: microparticle; MSC: mesenchymal stromal cell; NP: nanoparticle; NTA: nanoparticle tracking analysis; PAR-1: protease activated receptor-1; PAS: platelet additive solution; PBS: phosphate-buffered saline; PC: platelet concentrate; PEG: polyethylene glycol; PEV: platelet-derived extracellular vesicle; DOX-PEV: doxorubicin-loaded platelet-derived extracellular vesicle-encapsulated; PFA: paraformaldehyde; PF4: platelet factor 4; P-gp: P-glycoprotein; PLT: platelet; PS: phosphatidylserine; SDS-PAGE: sodium dodecylsulfate polyacrylamide gel electrophoresis; SEM: scanning electron microscopy; TCIPA: tumor cell-induced PLT aggregation; TDDS: targeted drug delivery system; TEG: thromboelastography; TF: tissue factor; TF-EV: extracellular vesicle expressing tissue factor; TME: tumor microenvironment; TNBC: triple-negative breast cancer; TXA2: thromboxane-A2; VEGF: vascular endothelial growth factor; WHO: World Health Organization.
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Antineoplásicos , Vesículas Extracelulares , Nanopartículas , Ratones , Animales , Plaquetas , Antineoplásicos/farmacología , Doxorrubicina/farmacologíaRESUMEN
Impaired wound healing is a significant complication of diabetes. Platelet-derived extracellular vesicles (pEVs), rich in growth factors and cytokines, show promise as a powerful biotherapy to modulate cellular proliferation, angiogenesis, immunomodulation, and inflammation. For practical home-based wound therapy, however, pEVs should be incorporated into wound bandages with careful attention to delivery strategies. In this work, a gelatin-alginate hydrogel (GelAlg) loaded with reduced graphene oxide (rGO) was fabricated, and its potential as a diabetic wound dressing was investigated. The GelAlg@rGO-pEV gel exhibited excellent mechanical stability and biocompatibility in vitro, with promising macrophage polarization and reactive oxygen species (ROS)-scavenging capability. In vitro cell migration experiments were complemented by in vivo investigations using a streptozotocin-induced diabetic rat wound model. When exposed to near-infrared light at 2 W cm- 2, the GelAlg@rGO-pEV hydrogel effectively decreased the expression of inflammatory biomarkers, regulated immune response, promoted angiogenesis, and enhanced diabetic wound healing. Interestingly, the GelAlg@rGO-pEV hydrogel also increased the expression of heat shock proteins involved in cellular protective pathways. These findings suggest that the engineered GelAlg@rGO-pEV hydrogel has the potential to serve as a wound dressing that can modulate immune responses, inflammation, angiogenesis, and follicle regeneration in diabetic wounds, potentially leading to accelerated healing of chronic wounds.
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Plaquetas , Complicaciones de la Diabetes , Vesículas Extracelulares , Cicatrización de Heridas , Plaquetas/química , Vesículas Extracelulares/química , Oxidación-Reducción , Complicaciones de la Diabetes/tratamiento farmacológico , Humanos , Animales , Ratones , Ratas , Línea Celular , Ratas Wistar , Supervivencia Celular , Especies Reactivas de Oxígeno/metabolismo , Hidrogeles/químicaRESUMEN
Neurodegenerative disorders of the central nervous system (CNS) and brain traumatic insults are characterized by complex overlapping pathophysiological alterations encompassing neuroinflammation, alterations of synaptic functions, oxidative stress, and progressive neurodegeneration that eventually lead to irreversible motor and cognitive dysfunctions. A single pharmacological approach is unlikely to provide a complementary set of molecular therapeutic actions suitable to resolve these complex pathologies. Recent preclinical data are providing evidence-based scientific rationales to support biotherapies based on administering neurotrophic factors and extracellular vesicles present in the lysates of human platelets collected from healthy donors to the brain. Here, we present the most recent findings on the composition of the platelet proteome that can activate complementary signaling pathways in vivo to trigger neuroprotection, synapse protection, anti-inflammation, antioxidation, and neurorestoration. We also report experimental data where the administration of human platelet lysates (HPL) was safe and resulted in beneficial neuroprotective effects in established rodent models of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, traumatic brain injury, and stroke. Platelet-based biotherapies, prepared from collected platelet concentrates (PC), are emerging as a novel pragmatic and accessible translational therapeutic strategy for treating neurological diseases. Based on this assumption, we further elaborated on various clinical, manufacturing, and regulatory issues that need to be addressed to ensure the ethical supply, quality, and safety of HPL preparations for treating neurodegenerative and traumatic pathologies of the CNS. HPL made from PC may become a unique approach for scientifically based treatments of neurological disorders readily accessible in low-, middle-, and high-income countries.
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Enfermedades Neurodegenerativas , Fármacos Neuroprotectores , Enfermedad de Parkinson , Encéfalo/metabolismo , Humanos , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/metabolismo , Neuroprotección , Fármacos Neuroprotectores/metabolismo , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Parkinson/metabolismoRESUMEN
BACKGROUND AND OBJECTIVES: Actions are needed to improve access to safe plasma-derived medicinal products (PDMPs) in low- and middle-income countries (LMICs). MATERIALS AND METHODS: The International Society of Blood Transfusion (ISBT) Working Party for Global Blood Safety organized an on-line workshop during 21-23 September 2021 to advance access to safe plasma proteins in resource-constrained countries, consistent with recent World Health Organization (WHO) guidance documents. RESULTS: The meeting drew attention to the considerable unmet needs for access to essential PDMPs in LMICs, in particular coagulation factors and immunoglobulins, and stepwise actions to address these deficits. First, improved access to safe plasma protein therapies requires blood component separation with prevention of wastage of recovered plasma. Quality and safety of collected blood and plasma must be assured so that plasma in excess of transfusion needs can be processed into safe plasma proteins. Second, local production of safe plasma proteins can be implemented using available technologies to locally obtain pathogen-reduced plasma and prepare pathogen-reduced cryoprecipitate and immunoglobulins from small plasma pools. Third, when a sufficient, stable volume of quality-assured plasma is available (approximately 50,000 L/year), contract or toll fractionation by a foreign plasma fractionator can expand the supply of PDMPs. Fourth, when the national infrastructure supports high-technology industrial production and stable volumes of quality plasma reach at least 200,000 L/year, technology transfer for domestic fractionation can be considered. CONCLUSION: Action is needed including commitments of the organizations that made the workshop possible (WHO, ISBT, World Federation of Haemophilia [WFH], Plasma Protein Therapeutics Association [PPTA], International Plasma Fractionation Association [IPFA], International Patient Organization of Primary Immunodeficiencies [IPOPI] and International Federation of Blood Donor Organizations [FIODS]).
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Factores de Coagulación Sanguínea , Proteínas Sanguíneas , Transfusión de Componentes Sanguíneos , Transfusión Sanguínea , Humanos , Plasma/químicaRESUMEN
BACKGROUND AND OBJECTIVES: The coronavirus disease 2019 (COVID-19) pandemic has impacted blood systems worldwide. Challenges included maintaining blood supplies and initiating the collection and use of COVID-19 convalescent plasma (CCP). Sharing information on the challenges can help improve blood collection and utilization. MATERIALS AND METHODS: A survey questionnaire was distributed to International Society of Blood Transfusion members in 95 countries. We recorded respondents' demographic information, impacts on the blood supply, CCP collection and use, transfusion demands and operational challenges. RESULTS: Eighty-two responses from 42 countries, including 24 low- and middle-income countries, were analysed. Participants worked in national (26.8%) and regional (26.8%) blood establishments and hospital-based (42.7%) institutions. CCP collection and transfusion were reported by 63% and 36.6% of respondents, respectively. Decreases in blood donations occurred in 70.6% of collecting facilities. Despite safety measures and recruitment strategies, donor fear and refusal of institutions to host blood drives were major contributing factors. Almost half of respondents working at transfusion medicine services were from large hospitals with over 10,000 red cell transfusions per year, and 76.8% of those hospitals experienced blood shortages. Practices varied in accepting donors for blood or CCP donations after a history of COVID-19 infection, CCP transfusion, or vaccination. Operational challenges included loss of staff, increased workloads and delays in reagent supplies. Almost half of the institutions modified their disaster plans during the pandemic. CONCLUSION: The challenges faced by blood systems during the COVID-19 pandemic highlight the need for guidance, harmonization, and strengthening of the preparedness and the capacity of blood systems against future infectious threats.
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COVID-19 , Pandemias , Bancos de Sangre , Donantes de Sangre , Transfusión Sanguínea , COVID-19/epidemiología , COVID-19/terapia , Humanos , Inmunización Pasiva , Encuestas y Cuestionarios , Sueroterapia para COVID-19RESUMEN
Traumatic brain injury (TBI) leads to major brain anatomopathological damages underlined by neuroinflammation, oxidative stress and progressive neurodegeneration, ultimately leading to motor and cognitive deterioration. The multiple pathological events resulting from TBI can be addressed not by a single therapeutic approach, but rather by a synergistic biotherapy capable of activating a complementary set of signalling pathways and providing synergistic neuroprotective, anti-inflammatory, antioxidative, and neurorestorative activities. Human platelet lysate might fulfil these requirements as it is composed of a plethora of biomolecules readily accessible as a TBI biotherapy. In the present study, we tested the therapeutic potential of human platelet lysate using in vitro and in vivo models of TBI. We first prepared and characterized platelet lysate from clinical-grade human platelet concentrates. Platelets were pelletized, lysed by three freeze-thaw cycles, and centrifuged. The supernatant was purified by 56°C 30 min heat treatment and spun to obtain the heat-treated platelet pellet lysate that was characterized by ELISA and proteomic analyses. Two mouse models were used to investigate platelet lysate neuroprotective potential. The injury was induced by an in-house manual controlled scratching of the animals' cortex or by controlled cortical impact injury. The platelet lysate treatment was performed by topical application of 60 µl in the lesioned area, followed by daily 60 µl intranasal administration from Day 1 to 6 post-injury. Platelet lysate proteomics identified over 1000 proteins including growth factors, neurotrophins, and antioxidants. ELISA detected several neurotrophic and angiogenic factors at â¼1-50 ng/ml levels. We demonstrate, using two mouse models of TBI, that topical application and intranasal platelet lysate consistently improved mouse motor function in the beam and rotarod tests, mitigated cortical neuroinflammation, and oxidative stress in the injury area, as revealed by downregulation of pro-inflammatory genes and the reduction in reactive oxygen species levels. Moreover, platelet lysate treatment reduced the loss of cortical synaptic proteins. Unbiased proteomic analyses revealed that heat-treated platelet pellet lysate reversed several pathways promoted by both controlled cortical impact and cortical brain scratch and related to transport, postsynaptic density, mitochondria or lipid metabolism. The present data strongly support, for the first time, that human platelet lysate is a reliable and effective therapeutic source of neurorestorative factors. Therefore, brain administration of platelet lysate is a therapeutical strategy that deserves serious and urgent consideration for universal brain trauma treatment.
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Terapia Biológica/métodos , Plaquetas/metabolismo , Lesiones Traumáticas del Encéfalo/metabolismo , Lesiones Traumáticas del Encéfalo/terapia , Administración Intranasal , Animales , Lesiones Traumáticas del Encéfalo/patología , Línea Celular Tumoral , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
There is concrete evidence that outdated allogeneic platelet concentrates not used for transfusion are valuable sources of functional trophic factors, including growth factors, cytokines, chemokines, anti-inflammatory and antioxidant molecules. Such outdated platelet concentrates can be used to produce human platelet lysates (HPL), a proven potent growth supplement for the propagation of therapeutic human cells, including mesenchymal stromal cells. On-going preclinical studies demonstrate the interest in such "outdated" allogeneic platelet lysates for treating corneal diseases and neurological disorders of the central nervous system, potentially opening vital therapeutic perspectives.
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Plaquetas/metabolismo , Técnicas de Cultivo de Célula/métodos , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Medicina Regenerativa/métodos , Diferenciación Celular , HumanosRESUMEN
Autoimmune rheumatic disorders (ARD) represent a wide spectrum of disorders that affect in priority the joints, bones, muscles, and connective tissues. Examples of ARD include rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, polymyositis, systemic sclerosis, antiphospholipid syndrome and mixed connective tissue disease. Patients with ARD often require transfusion of red cell concentrates (RCC) or other blood-derived components. The presence of an autoimmune background, often complicated by the use of immunosuppressive medications, renders these patients quite vulnerable. Exposing them to RCC, when indicated, can trigger transfusion-related immunomodulation that can be aggravated by the role played by the donor microbiome, and the complement activation and the immune dysregulation induced by iron, leading to an amplification of the immune problems. Furthermore, patients are challenged by the transfused extracellular vesicles which could have a potentially negative role, particularly in patients with antiphospholipid syndrome. Despite the very vigorous screening, transfusion transmissible infections can still represent a risk to these patients, particularly in cytomegalovirus seronegative patients or when dormant pathogens are activated in the immunosuppressed transfusion recipient. The ARD population is also more at risk for transfusion-related reactions. One, therefore, has to consider a restrictive transfusion strategy if possible and, if needed, resort to the numerous blood bank procedures to reduce the immunogenicity of blood products or use safer, more targeted, industrial plasma-derived products subjected to purification and pathogen reduction technologies.
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Síndrome Antifosfolípido , Artritis Reumatoide , Enfermedades Autoinmunes , Carcinoma de Células Renales , Neoplasias Renales , Humanos , Enfermedades Autoinmunes/tratamiento farmacológico , Transfusión Sanguínea/métodosRESUMEN
The COVID-19 pandemic caused by the SARS-CoV-2 virus has significantly disrupted and burdened the diagnostic workup and delivery of care, including transfusion, to cancer patients across the globe. Furthermore, cancer patients suffering from solid tumors or hematologic malignancies were more prone to the infection and had higher morbidity and mortality than the rest of the population. Major signaling pathways have been identified at the intersection of SARS-CoV-2 and cancer cells, often leading to tumor progression or alteration of the tumor response to therapy. The reactivation of oncogenic viruses has also been alluded to in the context and following COVID-19. Paradoxically, certain tumors responded better following the profound infection-induced immune modulation. Unveiling the mechanisms of the virus-tumor cell interactions will lead to a better understanding of the pathophysiology of both cancer progression and virus propagation. It would be challenging to monitor, through the different cancer registries, retrospectively, the response of patients who have been previously exposed to the virus in contrast to those who have not contracted the infection.
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COVID-19 , Neoplasias , Humanos , Neoplasias/terapia , Pandemias , Estudios Retrospectivos , SARS-CoV-2RESUMEN
Platelets are at the crossroads between thrombosis and inflammation. When activated, platelets can shed bioactive extracellular vesicles [pEVs] that share the hemostatic potential of their parent cells and act as bioactive shuttles of their granular contents. In a viral infection, platelets are activated, and pEVs are generated with occasional virion integration. Both platelets and pEVs are engaged in a bidirectional interaction with neutrophils and other cells of the immune system and the hemostatic pathways. Severe COVID-19 infection is characterized by a stormy thromboinflammatory response with platelets and their EVs at the center stage of this reaction. This review sheds light on the interactions of platelets, pEVS and SARS-CoV-2 infection and prognostic and potential therapeutic role of pEVs. The review also describes the role of pEVs in the rare adenovirus-based COVID-19 vaccine-induced thrombosis thrombocytopenia.
Asunto(s)
COVID-19 , Vesículas Extracelulares , Hemostáticos , Trombosis , Plaquetas/metabolismo , Vacunas contra la COVID-19 , Vesículas Extracelulares/metabolismo , Hemostáticos/metabolismo , Humanos , SARS-CoV-2RESUMEN
Corneal endothelial cells (CECs) slowly decrease in number with increasing age, which is a clinical issue as these cells have very limited regenerative ability. Therapeutic platelet biomaterials are increasingly used in regenerative medicine and cell therapy because of their safety, cost-effective manufacture, and global availability from collected platelet concentrates (PCs). Platelet extracellular vesicles (PEVs) are a complex mixture of potent bioactive vesicles rich in molecules believed to be instrumental in tissue repair and regeneration. In this study we investigated the feasibility of using a PEVs preparation as an innovative regenerative biotherapy for corneal endothelial dysfunction. The PEVs were isolated from clinical-grade human PC supernatants by 20,000 × g ultracentrifugation and resuspension. PEVs exhibited a regular, fairly rounded shape, with an average size of <200 nm and were present at a concentration of approximately 1011 /mL. PEVs expressed cluster of differentiation 41 (CD41) and CD61, characteristic platelets membrane markers, and CD9 and CD63. ELISA and LC-MS/MS proteomic analyses revealed that the PEVs contained mixtures of growth factors and multiple other trophic factors, as well as proteins related to extracellular exosomes with functional activities associated with cell cadherin and adherens pathways. CECs treated with PEVs showed increased viability, an enhanced wound-healing rate, stronger proliferation markers, and an improved adhesion rate. PEVs did not exert cellular toxicity as evidenced by the maintenance of cellular morphology and preservation of corneal endothelial proteins. These findings clearly support further investigations of PEV biomaterials in animal models for translation as a new CEC regeneration biotherapy.