Microvascular Thrombosis Research Articles

Advancing Stroke Safety and Efficacy through Early Tirofiban Administration after Intravenous Thrombolysis: The multicenter, randomized, placebo-controlled, double-blind ASSET IT trial protocol.

Intravenous thrombolysis (IVT) is the cornerstone treatment for the acute ischemic stroke (AIS) within 4.5 hours after onset. Current guidelines recommend administering antiplatelet medications 24 hours after IVT. However, vascular re-occlusion is a common occurrence after IVT. Tirofiban, a platelet glycoprotein IIb/IIIa antagonist, can help deter macrovascular re-occlusion, prevent microvascular thrombosis, and enhance cerebral blood flow. This trial aims to assess whether early administration of tirofiban can improve clinical outcomes in patients with AIS who received IVT. The Advancing Stroke Safety and Efficacy through Early Tirofiban Administration after Intravenous Thrombolysis (ASSET IT) Trial is an investigator-initiated, randomized, placebo-controlled, double-blind, multi-center study. Up to 832 eligible patients will be consecutively randomized in a 1:1 ratio to receive either intravenous tirofiban or placebo over a period of 2 years across 38 stroke centers in China. The primary endpoint is excellent functional status at day 90, defined as a modified Rankin Score of 0-1. Primary safety endpoints include symptomatic intracerebral hemorrhage at 24 hours and mortality at 90 days.

Towards realistic blood cell biomechanics in microvascular thrombosis simulations

Abstract The paper is devoted to a three-dimensional mesoscale hemodynamic model for simulations of microvascular blood flows at cellular resolution. The focus is on creating a more accurate biomechanical model of red blood cells for further use in models of hemostasis and thrombosis. The presented model effectively and accurately reproduces peculiarities of blood flow under realistic hydrodynamic conditions in arterioles, venules, and capillaries, including the Fahraeus–Lindquist effect and subsequent platelet margination. In addition, shear-dependent platelet aggregation can also be captured using the proposed approach.

Detection of Thrombosis Using Soluble C-Type Lectin-like Receptor-2 with D-Dimer Level and Platelet Count

Introduction: Soluble C-type lectin-like receptor -2 (sCLEC-2) has been recognized as a marker of platelet activation, and attention has been drawn to formulas combining sCLEC-2 levels with platelet count and D-dimer levels. Methods: In this study, sCLEC-2 levels, as well as sCLEC-2/platelet count (sCLEC-2/PLT), sCLEC-2 × D-dimer (sCLEC-2xDD), and sCLEc-2xDD/PLT formulas were used to detect thrombotic diseases, including microvascular thrombosis (MVT), arterial thromboembolism (ATE), and venous thromboembolism (VTE), with the aim of evaluating the ability of the three parameters combined in these formulas to diagnose thrombotic diseases. Results: The plasma sCLEC-2 levels were significantly higher in patients with infectious or thrombotic diseases than in those with neither thrombosis nor infection; however, there was no significant difference among patients with infection, ATE, VTE, and MVT; the correlations among sCLEC-2, platelet count, and D-dimer level were poor. The sCLEC-2/PLT ratio was the highest in patients with MVT, and the sCLEC-2 × D-dimer value was higher in patients with MVT and VTE than in those with neither thrombosis nor infection. Although receiver operating characteristic (ROC) analysis shows the differential diagnosis of thrombotic diseases from non-thrombosis without infection, the sCLEC-2 × D-dimer/platelet count was useful for differential diagnosis among MVT and infection or non-thrombotic diseases. Conclusions: sCLEC-2 is useful for the diagnosis of thrombosis, and the formulas of sCLEC-2 with platelet count or D-dimer are useful for the diagnosis of thrombosis using ROC analyses for the thrombosis group vs. the non-thrombosis group without infection.

Thrombotic Microangiopathy in the Postpartum Period (Literature Review, Clinical Case Report)

Introduction. Thrombotic microangiopathy (TMA) is a heterogeneous group of diseases that, in the presence of endothelial damage, can lead to microvascular thrombosis, secondary platelet consumption, mechanical hemolysis and ischemic end-organs damage. Such triad of symptoms as acute kidney injury (AKI), microangiopathic hemolysis and thrombocytopenia may also accompany some pregnancy-specific conditions (severe preeclampsia/HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count), acute fatty liver disease of pregnancy (AFLP), and conditions not related to pregnancy, but triggered by it (catastrophic antiphospholipid syndrome (CAPS), lupus flare. The aim of the study. To review the current literature devoted to the problem of thrombotic microangiopathy, to demonstrate on a clinical case a step-by-step differentiated approach to the diagnosis of the type of thrombotic microangiopathy causing acute kidney injury in the postpartum period, and to describe modern methods of treatment of these diseases. Results. The classical types of TMA are thrombotic thrombocytopenic purpura (TTP) and typical hemolytic uremic syndrome (HUS), also known as enterohemorrhagic Shiga toxin-producing Escherichia coli (STEC)-associated HUS (STEC-HUS). Pathophysiologically, all forms of TMA involve complement-mediated endothelial cell damage, which mainly affects the capillary zone of the kidney. Pregnancy can trigger atypical HUS (aHUS) or TTP. The article describes the clinical case of a 37-year-old woman who developed AKI following a complicated delivery. A turn-based differential diagnosis of aHUS was performed. Unwarranted discontinuation of the targeted therapy with Eculisumab led to the development of chronic renal failure Conclusions. Thrombotics microangiopathy are the life-threatening conditions rarely seen in pregnancy making its early recognition difficult. As thrombotics microangiopathy require urgent treatment, plasmapheresis should be started as soon as they are suspected, followed by targeted therapy (Eculisumab, Rituximab) after the confirmation of the diagnosis. This may contribute to reducing maternal morbidity and mortality rates.

Comparison of the Efficacy and Safety of Low Molecular Weight Heparins and Fondaparinux in Patients With COVID-19: A Systematic Review and Meta-Analysis.

Individuals diagnosed with COVID-19 are at a higher risk of arterial and venous thrombosis, mostly pulmonary microvascular thrombosis, which may significantly impair treatment and result in morbidity. This is a systematic review and meta-analysis of research papers that aimto evaluate the risk of bleeding and thrombosis among patientstreated with low molecular weight heparin or fondaparinux (LMWH/F). Additionally, we measured the overall death events. This study was conducted in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. A search was conducted in the Clinicaltrials.gov, PubMed, Scopus, and Web of Science databases to identify observational cohort studies and randomized-controlled clinical trials (RCTs) that compared LMWH/F in proven COVID-19 patients. A total of 220 people from two studies were included. Patients who were treated with fondaparinux had a lower risk of developing venous thromboembolism (VTE) (odds ratio (OR) 0.39; 95% confidence interval (CI) (0.14, 1.096); p = 0.168); pulmonary embolism (OR 0.169, 95% CI (0.021, 1.356), p = 0.094); and deep vein thrombosis compared to patients who received LMWH therapy. The data show a lower mortality rate in the LMWH groups (OR 1.135, 95% CI (0.463, 2.785), p = 0.781) and a lower frequency of bleeding (OR 1.657, 95% CI (0.456, 5.908), p = 0.436). Both drugs have shown anti-thrombotic properties in COVID-19 patients. Fondaparinux was somewhat more effective in reducing thrombosis episodes. This research demonstrates the safe use of LMWH for VTE prophylaxis in hospitalized COVID-19 patients based on bleeding and mortality outcomes.

Von Willebrand Factor Antigen, Biomarkers of Inflammation, and Microvascular Flap Thrombosis in Reconstructive Surgery.

Background: Microvascular flap surgery has become a routine option for defect correction. The role of von Willebrand factor antigen (VWF:Ag) in the pathophysiology of flap complications is not fully understood. We aim to investigate the predictive value of VWF:Ag for microvascular flap complications and explore the relationship between chronic inflammation and VWF:Ag. Methods: This prospective cohort study included 88 adult patients undergoing elective microvascular flap surgery. Preoperative blood draws were collected on the day of surgery before initiation of crystalloids. The plasma concentration of VWF:Ag as well as albumin, neutrophil-to-lymphocyte ratio (NLR), interleukin-6, and fibrinogen were determined. Results: The overall complication rate was 27.3%, and true flap loss occurred in 11.4%. VWF:Ag levels were higher in true flap loss when compared to patients without complications (217.94 IU/dL [137.27-298.45] vs. 114.14 [95.67-132.71], p = 0.001). Regression analysis revealed the association between VWF:Ag and true flap loss at the cutoff of 163.73 IU/dL (OR 70.22 [10.74-485.28], p = 0.043). Increased VWF:Ag concentrations were linked to increases in plasma fibrinogen (p < 0.001), C-reactive protein (p < 0.001), interleukin-6 (p = 0.032), and NLR (p = 0.019). Conclusions: Preoperative plasma VWF:Ag concentration is linked to biomarkers of inflammation and may be valuable in predicting complications in microvascular flap surgery.

Erythrophagocytosis-induced ferroptosis contributes to pulmonary microvascular thrombosis and thrombotic vascular remodeling in pulmonary arterial hypertension

BackgroundWhether primary or just as a complication from the progression of pulmonary arterial hypertension (PAH), thrombosis seems to be an important player in this condition. The crosstalk between red blood cells (RBCs) and pulmonary microvascular endothelial cells (PMVECs) and their role in PAH remain undefined. ObjectivesThe goals of this study were to assess the role of RBC–PMVEC interaction in microvascular thrombosis and thrombotic vascular remodeling under hypoxic conditions. MethodsWe established an in vitro hypoxic coincubation model of RBC and PMVEC as well as a hypoxic mouse model. We investigated erythrophagocytosis (EP), ferroptosis, thrombosis tendency, and pulmonary hemodynamics in experimental PAH. ResultsIncreased EP in PMVEC triggered ferroptosis, enhanced procoagulant activity, and exacerbated vessel remodeling under hypoxic conditions. In the PAH mouse model induced by chronic hypoxia, EP-induced ferroptosis followed by upregulated TMEM16F led to a high tendency of thrombus formation and thrombotic vascular remodeling. Inhibition of ferroptosis or silencing of TMEM16F could alleviate hypercoagulable phenotype, reverse right ventricular systolic pressure, right ventricular hypertrophy index, and remodeling of pulmonary vessels. ConclusionThese results illustrate the pathogenic RBC–PMVEC interactions in PAH. Inhibition EP, ferroptosis, or TMEM16F could be a novel therapeutic target to prevent PAH development and thrombotic complications.

Elevated level of extracellular vimentin is associated with an increased fibrin formation potential in sepsis: ex vivo swine study

BackgroundSepsis can lead to coagulopathy and microvascular thrombosis. Prior studies, including ours, reported an increased level of extracellular vimentin in blood derived from septic patients. Moreover, we identified the contribution of extracellular vimentin to fibrin formation and to the fibrin clot structure ex vivo in plasma from septic patients. Here, we tested the status of plasma vimentin and its impact on fibrin clots using our recently described swine model of methicillin-resistant Staphylococcus aureus (MRSA) sepsis-induced coagulopathy.ResultsWe employed ELISA, size-exclusion chromatography, vimentin antibodies, confocal microscopy, and turbidity assays on piglet plasma obtained at pre- and post-MRSA inoculation. Plasma vimentin level at 70 h post-MRSA inoculation was on average twofold higher compared to pre-infection (0 h) level in the same animal. Anti-vimentin antibody effectively reduced fibrin formation ex vivo and increased porosity in the fibrin clot structure generated from septic piglet plasma. In contrast to plasma at 0 h, the size-exclusion chromatography revealed that phosphorylated vimentin was in-complex with fibrinogen in septic piglet plasma.ConclusionsThus, our swine model of sepsis-induced coagulopathy, reproduced increased extracellular circulating vimentin and subsequent potentiation of fibrin formation, often observed in septic patient. These outcomes validate the use of large animal models to investigate the dysregulated host immune response to infection leading to coagulopathy, and to develop new therapies for sepsis-induced disseminated microvascular thrombosis.

The COVID-19 thrombus: distinguishing pathological, mechanistic, and phenotypic features and management.

A heightened risk for thrombosis is a hallmark of COVID-19. Expansive clinical experience and medical literature have characterized small (micro) and large (macro) vessel involvement of the venous and arterial circulatory systems. Most events occur in patients with serious or critical illness in the hyperacute (first 1-2weeks) or acute phases (2-4weeks) of SARS-CoV-2 infection. However, thrombosis involving the venous, arterial, and microcirculatory systems has been reported in the subacute (4-8weeks), convalescent (>8-12weeks) and chronic phases (>12weeks) among patients with mild-to-moderate illness. The purpose of the current focused review is to highlight the distinguishing clinical features, pathological components, and potential mechanisms of venous, arterial, and microvascular thrombosis in patients with COVID-19. The overarching objective is to better understand the proclivity for thrombosis, laying a solid foundation for screening and surveillance modalities, preventive strategies, and optimal patient management.

The Phenomenon of Thrombotic Microangiopathy in Cancer Patients.

Thrombotic microangiopathy (TMA) encompasses a range of disorders characterized by blood clotting in small blood vessels, leading to organ damage. It can manifest as various syndromes, including thrombotic thrombocytopenic purpura (TTP), hemolytic-uremic syndrome (HUS), and others, each with distinct causes and pathophysiology. Thrombo-inflammation plays a significant role in TMA pathogenesis: inflammatory mediators induce endothelial injury and activation of platelet and coagulation cascade, contributing to microvascular thrombosis. Primary TMA, such as TTP, is primarily caused by deficient ADAMTS13 metalloproteinase activity, either due to antibody-mediated inhibition or intrinsic enzyme synthesis defects. In cancer patients, a significant reduction in ADAMTS13 levels and a corresponding increase in VWF levels is observed. Chemotherapy further decreased ADAMTS13 levels and increased VWF levels, leading to an elevated VWF/ADAMTS13 ratio and increased thrombotic risk. Drug-induced TMA (DITMA) can result from immune-mediated or non-immune-mediated mechanisms. Severe cases of COVID-19 may lead to a convergence of syndromes, including disseminated intravascular coagulation (DIC), systemic inflammatory response syndrome (SIRS), and TMA. Treatment of TMA involves identifying the underlying cause, implementing therapies to inhibit complement activation, and providing supportive care to manage complications. Plasmapheresis may be beneficial in conditions like TTP. Prompt diagnosis and treatment are crucial to prevent serious complications and improve outcomes.

Comparison of clinical and serological features in thrombotic antiphospholipid syndrome patients, with and without associated systemic lupus erythematosus, followed for up to 42 years: A single centre retrospective study.

To assess the impact of concomitant systemic lupus erythematosus (SLE) on the clinicopathological manifestations of thrombotic antiphospholipid syndrome (APS). This single-centre, retrospective study compared clinical and antiphospholipid antibody (aPL) data from 118 patients, 58 with SLE-associated APS (SLE-APS), and 60 with primary APS. Median follow-up was 13.9 (IQR 7.7-19.3) and 8.6years (3.5-10.6) for the SLE-APS cohort and PAPS cohort, respectively. Age at diagnosis of APS was lower in the SLE-APS cohort (mean 35.9 vs PAPS: 46.7years; p < 0.05). Distribution of aPL subtypes was similar across cohorts. 198 thrombotic events were identified overall (index plus recurrent), with venous thromboembolism (VTE) and arterial thrombosis each occurring in just over half of patients in both cohorts. Microvascular thrombosis (12.1% vs 0%), and a mixed (any combination of venous, arterial and microvascular) thrombotic phenotype (19.0% vs 6.7%, p = 0.05) were more prevalent in SLE-APS patients. Recurrent thrombosis incidence rates (∼0.5 events/10-patient years), and Kaplan-Meier recurrence-free survival after index thrombosis, were similar. In the PAPS cohort, only: (i) triple-aPL-positivity was associated with a significantly higher recurrent thrombosis event rate (incidence rate ratio 2.22, p = 0.03) and lower recurrence-free survival after first thrombosis (log-rank test p = 0.01); (ii) lupus anticoagulant (LA)-positivity was associated with higher prevalance of arterial thrombosis (RR 2.69, p = 0.01), and lower prevlance of VTE (RR 0.48, p < 0.001), versus LA-negativity. Concomitant SLE does not appear to modify long-term recurrent thrombosis risk, or aPL phenotypes, in patients with APS. Triple-aPL-positivity and LA-positive status may have less influence on thrombotic outcomes in patients with SLE-APS compared to PAPS.

Rising total leukocyte counts correspond with rising platelet counts in thrombotic thrombocytopenic purpura

AbstractThrombotic thrombocytopenic purpura (TTP) is a rare disorder involving pathological platelet–von Willebrand factor interaction, resulting in microvascular thrombosis. The consumption of platelets in TTP microthrombi results in severe thrombocytopenia which resolves with resolution of the microvascular thrombosis. Over the course of treatment, patient platelet counts often rise and fall multiple times before stable remission is achieved. On casual inspection, we noted that total leukocyte counts follow a pattern that appears to correspond to platelet counts. To explore whether changing leukocyte counts track significantly with changing platelet counts, we examined paired daily platelet counts and total leukocyte counts in 27 episodes of TTP in 13 patients across 2 institutions comprising 423 days of data. We modeled the nonlinear behavior in the data using a threshold mixed-effects regression model, in which we found a significant temporal relationship between total leukocyte counts and platelet counts. The model proved that, on a day when platelet counts were rising in previous days, the total leukocyte count is predictive of the rise in platelet count. The higher the total leukocyte count, the greater the rise in platelet count. Our results support the hypothesis that leukocytes play a role in the resolution of TTP microvascular thrombosis.

Soluble platelet selectin and platelets in COVID-19: a multifaceted connection.

The COVID-19 pandemic has brought to light the intricate relationship between platelets, soluble platelet selectin (sP-selectin), and disease pathogenesis. Platelets, traditionally recognized for their role in hemostasis, have emerged as key contributors to the immunothrombotic complications observed in COVID-19 patients. Concurrently, elevated levels of sP-selectin, indicative of platelet activation and endothelial injury, have been consistently identified in COVID-19 patients and have shown associations with disease severity and adverse outcomes. This multifaceted connection underscores the pivotal role of platelets and sP-selectin in orchestrating thromboinflammation, vascular dysfunction, and disease progression in COVID-19. Platelet activation triggers the release of inflammatory mediators and promotes platelet-leukocyte interactions, amplifying the systemic inflammatory response and exacerbating endothelial injury. Additionally, platelet-derived factors contribute to microvascular thrombosis, further exacerbating tissue damage and organ dysfunction in severe COVID-19. Elevated sP-selectin levels serve as biomarkers for disease severity and prognostication, aiding in risk stratification and early identification of patients at higher risk of adverse outcomes. Therapeutic strategies targeting platelet dysfunction and sP-selectin-mediated pathways hold promise in mitigating thromboinflammation and improving outcomes in COVID-19 patients. Antiplatelet agents, platelet inhibitors, and anti-inflammatory therapies represent potential interventions to attenuate platelet activation, inhibit platelet-leukocyte interactions, and alleviate endothelial dysfunction. A comprehensive understanding of the multifaceted connection between platelets, sP-selectin, and COVID-19 pathogenesis offers opportunities for tailored therapeutic approaches aimed at mitigating thromboinflammation and improving patient outcomes in this complex and challenging clinical setting.

The Use of Fibrinolytic Agents in the Salvage of Free Flaps: A Systematic Review.

Microvascular thrombosis following free tissue transfer presents a complex challenge for surgeons and carries the potential risk of flap failure. The application of fibrinolytic agents represents a robust therapeutic option. The aim of this systematic review is to provide a comprehensive overview of the clinical use of fibrinolytic drugs in the rescue of compromised free flaps. A systematic literature search for clinical studies detailing the utilization of fibrinolytic agents for salvaging free flaps was conducted using the PubMed and Web of Science databases. The inclusion criteria encompassed English-language publications that specifically addressed the clinical application of fibrinolytic agents for free-flap salvage. A total of 331 articles were screened after excluding duplicates, with 56 meeting the inclusion criteria. Among these, 21 were clinical trials (evidence level III), and 35 were case studies (evidence level IV/V). In total, 459 flaps underwent treatment with fibrinolytic agents. The application of fibrinolytic agents appears to be a valuable intervention for rescuing compromised free flaps attributable to microvascular compromise. Notably, no prospective randomized trials have been published on this subject, and the evidence within the existing literature is characterized by its limited and heterogeneous nature. Further research is imperative to gather data on the efficacy, dosage, and safety profile of fibrinolytic agents.

Antiphospholipid syndrome, monoclonal gammopathy, and cryoglobulinemia overlap leading to recurrent cutaneous microvascular thrombosis: A case report and retrospective cohort study.

Antiphospholipid syndrome (APS), cryoglobulinemia, and monoclonal gammopathies are variably accompanied by thrombotic complications. We describe a patient with recurrent skin microvascular thrombosis, APS, cryoglobulinemia, marginal zone lymphoma, and IgMκ monoclonal gammopathy, responsive to chemoimmunotherapy. The cryoglobulin fraction contained the IgMκ paraprotein, while antiphospholipid antibodies (aPL) were predominantly in the cryosupernatant. A retrospective analysis of aPL-positive patients in our institution showed that 8.1% co-expressed monoclonal gammopathy. These overlap patients had thrombotic complications and most had recurrences. Patients with multiple gammopathies of thrombotic significance may have several autoantibodies and constitute a high-risk group.

ADAMTS13 in the New Era of TTP.

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening, often immune-mediated disease that affects 2-13 persons per million per year. Hemolytic anemia, thrombocytopenia, and end-organ damage due to the formation of microthrombi are characteristic of TTP. ADAMTS13 is a disintegrin, metalloproteinase, cleaving protein of von Willebrand factor (VWF) that processes the VWF multimers to prevent them from interacting with platelets and, in turn, to microvascular thrombosis. Prompt diagnosis of TTP is critical yet challenging. Thrombotic microangiopathies have similar clinical presentation. Measurement of ADAMTS13 activity helps in the differential diagnosis. Less than 10% ADAMTS13 activity is indicative of TTP. Laboratory ADAMTS13 activity assays include incubating the test plasma with the substrate (full-length VWM multimers) and detection with direct or indirect measurement of the cleavage product. The purpose of this study is to examine the diagnostic potential, advantages, and weaknesses of the ADAMTS13 potency in TTP.

THE ROLE OF GLYCOCALYX IN THE PATHOGENESIS OF DIABETES MELLITUS COMPLICATIONS

Glycocalyx (GC) is represented by protein-polysaccharide compounds lining the inner surface of endothelial cells in the form of a gel. GC plays an important role in the regulation of vascular homeostasis, controls vascular wall permeability and microvascular tone, prevents microvascular thrombosis and participates in the regulation of leukocyte adhesion. Damage of endothelial HA is a part and initial link of pathophysiological processes underlying the development of complications of diabetes mellitus (DM). In most cases of DM is accompanied by degradation of HA caused by hyperglycemia, which leads to impaired microcirculatory perfusion and organ dysfunction. Further study of HA, determination of its contribution to the development of diabetes complications is a very promising area of research. In this review, we analyze the main mechanisms of destruction and the role of HA in the pathophysiological mechanisms of the development of DM complications. Although numerous studies indicate a significant role of HA dysfunction in the development of micro- and macroangiopathies in the outcome of diabetes, many aspects of pathophysiological processes are still unexplored and require further research.

Thromboinflammation in COVID-19: Unraveling the interplay of coagulation and inflammation.

The coronavirus disease 2019 (COVID-19) pandemic has not only challenged global health systems but also spurred intense scientific inquiry into its pathophysiology. Among the multifaceted aspects of the disease, coagulation abnormalities have emerged as a significant contributor to morbidity and mortality. From endothelial dysfunction to dysregulated immune responses, various factors contribute to the hypercoagulable state seen in severe COVID-19 cases. The dysregulation of coagulation in COVID-19 extends beyond traditional thromboembolic events, encompassing a spectrum of abnormalities ranging from microvascular thrombosis to disseminated intravascular coagulation (DIC). Endothelial injury induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection triggers a cascade of events involving platelet activation, coagulation factor consumption, and fibrinolysis impairment. Moreover, the virus direct effects on immune cells and the cytokine storm further exacerbate the prothrombotic milieu. Unraveling this intricate web of interactions between viral pathogenesis and host responses is essential for elucidating novel therapeutic targets and refining existing management strategies for COVID-19-associated coagulopathy. In the quest to unravel the complex interplay between coagulation and COVID-19, numerous clinical and laboratory studies have yielded invaluable insights into potential biomarkers, prognostic indicators, and therapeutic avenues. Anticoagulation therapy has emerged as a cornerstone in the management of severe COVID-19, although optimal dosing regimens and patient selection criteria remain subjects of ongoing investigation. Additionally, innovative approaches such as targeting specific components of the coagulation cascade or modulating endothelial function hold promise for future therapeutic development.

Optimizing DCD Liver Grafts With Prolonged Warm Ischemic Time Using Stabilized Plasmin in a Static Cold Storage Orthotopic Rat Liver Transplant Model.

The clinical success of liver transplantation has led to increased demand, requiring further expansion of the donor pool. Therapeutic interventions to optimize organs from donation after circulatory death (DCD) have significant potential to mitigate the organ shortage. Dysfunction in DCD liver grafts is mediated by microvascular thrombosis during the warm ischemic period, and strategies that reduce this thrombotic burden may improve graft function. We hypothesized that the administration of the fibrinolytic enzyme plasmin to the donor organ during the cold storage period would reduce the thrombotic burden and improve DCD liver graft function. In 2 separate cohorts, 32 syngeneic orthotopic rat liver transplants were performed in Lewis rats. Livers were procured from donors with 45 min of warm ischemic injury. Liver grafts were flushed with histidine-tryptophan-ketoglutarate preservation solution mixed with either plasmin (experimental group) or albumin (control group). All investigators were blinded to treatment group. After preparing the liver for implant using a modified cuff technique, the liver was stored for 1 h by static cold storage at 4 °C. Immediately before implantation, the liver graft was flushed, and this effluent was analyzed for fibrin degradation products to determine graft clot burden. Twenty-four hours following transplantation, animals were euthanized, and samples were collected. Recipient survival was significantly higher for DCD liver grafts treated with plasmin compared with control. Moreover, histology of liver graft tissue immediately before implant reflected significantly reduced congestion in plasmin-treated livers (score, mean ± SD: 0.73 ± 0.59 versus 1.12 ± 0.48; P = 0.0456). The concentration of fibrin degradation products in the final flush before implantation was significantly reduced in plasmin-treated livers (743 ± 136 versus 10 919 ± 4642 pg/mL; P = 0.0001), reflecting decreased clot burden in the graft. The present study demonstrates that plasmin improves survival and may reduce thrombotic burden in DCD liver grafts with prolonged warm ischemic injury, meriting further study.

A narrative review of chemokine receptors CXCR1 and CXCR2 and their role in acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a severe form of acute respiratory failure characterised by extensive inflammatory injury to the alveolocapillary barrier leading to alveolar oedema, impaired gas exchange and, ultimately, hypoxaemia necessitating the use of supplemental oxygen combined with some degree of positive airway pressure. Although much heterogeneity exists regarding the aetiology, localisation and endotypic characterisation of ARDS, what remains largely undisputed is the role of the innate immune system, and in particular of neutrophils, in precipitating and propagating lung injury. Activated neutrophils, recruited to the lung through chemokine gradients, promote injury by releasing oxidants, proteases and neutrophil extracellular traps, which ultimately cause platelet aggregation, microvascular thrombosis and cellular death. Among various neutrophilic chemoattractants, interleukin-8/C-X-C motif ligand 8 and related chemokines, collectively called ELR+ chemokines, acting on neutrophils through the G protein-coupled receptors CXCR1 and CXCR2, are pivotal in orchestrating the neutrophil activation status and chemotaxis in the inflamed lung. This allows efficient elimination of infectious agents while at the same time minimising collateral damage to host tissue. Therefore, understanding how CXCR1 and CXCR2 receptors are regulated is important if we hope to effectively target them for therapeutic use in ARDS. In the following narrative review, we provide an overview of the role of ELR+ chemokines in acute lung injury (ALI) and ARDS, we summarise the relevant regulatory pathways of their cognisant receptors CXCR1/2 and highlight current preclinical and clinical evidence on the therapeutic role of CXCR1 and CXCR2 inhibition in animal models of ALI, as well as in ARDS patients.