Coagulation-fibrinolysis System Research Articles

Phospholipids of inhaled liposomes determine the in vivo fate and therapeutic effects of salvianolic acid B on idiopathic pulmonary fibrosis

Since phospholipids have an important effect on the size, surface potential and hardness of liposomes that decide their in vivo fate after inhalation, this research has systematically evaluated the effect of phospholipids on pulmonary drug delivery by liposomes. In this study, liposomes composed of neutral saturated/unsaturated phospholipids, anionic and cationic phospholipids were constructed to investigate how surface potential and the degree of saturation of fatty acid chains determined their mucus and epithelium permeability both in vitro and in vivo. Our results clearly indicated that liposomes composed of saturated neutral and anionic phospholipids possessed high stability and permeability, compared to that of liposomes composed of unsaturated phospholipids and cationic phospholipids. Furthermore, both in vivo imaging of fluorescence-labeled liposomes and biodistribution of salvianolic acid B (SAB) that encapsulated in liposomes were performed to estimate the effect of phospholipids on the lung exposure and retention of inhaled liposomes. Finally, inhaled SAB-loaded liposomes exhibited enhanced therapeutic effects in a bleomycin-induced idiopathic pulmonary fibrosis mice model via inhibition of inflammation and regulation on coagulation-fibrinolytic system. Such findings will be beneficial to the development of inhalable lipid-based nanodrug delivery systems for the treatment of respiratory diseases where inhalation is the preferred route of administration.

Association of prothrombin time, thrombin time and activated partial thromboplastin time levels with preeclampsia: a systematic review and meta-analysis

BackgroundPreeclampsia (PE), an obstetric disorder, remains one of the leading causes of maternal and infant mortality worldwide. In individuals with PE, the coagulation-fibrinolytic system is believed to be among the most significantly impacted systems due to maternal inflammatory responses and immune dysfunction. Therefore, this systematic review and meta-analysis aimed to assess the association of prothrombin time (PT), thrombin time (TT) and activated partial thromboplastin time (APTT) levels with preeclampsia.MethodsThis systematic review and meta-analysis was conducted in accordance with the PRISMA guidelines. Articles relevant to the study, published from July 26, 2013, to July 26, 2023, were systematically searched across various databases including PubMed, Scopus, Embase, and Hinari. The methodological quality of the articles was evaluated using the Joanna Briggs Institute critical appraisal checklist. Utilizing Stata version 14.0, a random-effects model was employed to estimate the pooled standardized mean difference (SMD) along with the respective 95% CIs. The I2 statistics and Cochrane Q test were utilized to assess heterogeneity, while subgroup analyses were performed to explore its sources. Furthermore, Egger’s regression test and funnel plot were employed to assess publication bias among the included studies.ResultsA total of 30 articles, involving 5,964 individuals (2,883 with PE and 3,081 as normotensive pregnant mothers), were included in this study. The overall pooled SMD for PT, APTT, and TT between PE and normotensive pregnant mothers were 0.97 (95% CI: 0.65–1.29, p < 0.001), 1.05 (95% CI: 0.74–1.36, p < 0.001), and 0.30 (95% CI: -0.08-0.69, p = 0.11), respectively. The pooled SMD indicates a significant increase in PT and APTT levels among PE patients compared to normotensive pregnant mothers, while the increase in TT levels among PE patients was not statistically significant.ConclusionsThe meta-analysis underscores the association between PE and prolonged PT and APTT. This suggests that evaluating coagulation parameters like PT, APTT, and TT in pregnant women could offer easily accessible and cost-effective clinical indicators for assessing PE. However, multicenter longitudinal studies are needed to evaluate their effectiveness across various gestational weeks of pregnancy.

The Relationship between the Level of Coagulative Function Hypertensive Disorder Complicating Pregnancy.

Preeclampsia, a pregnancy complication associated with significant maternal and perinatal mortality and morbidity, has been found to be closely linked to dysfunction in the blood coagulation-fibrinolysis system. However, the relationship between hematologic data and severity and onset time of preeclampsia remains unclear. This study aimed to identify specific hematologic parameters in both preeclamptic and normotensive pregnant women and determine their potential significance in the pathogenesis of preeclampsia. A total of 112 patients with gestational hypertension disease were divided into two groups: early-onset preeclampsia (32 cases) and late-onset preeclampsia (80 cases). A control group of 82 normotensive pregnant women matched for age and parity was also selected. Blood samples were collected from all participants to test for specific hematologic parameters. Mild and severe preeclampsia were associated with lower hemoglobin level (P = 0.01 and P = 0.03, respectively), higher mean platelet volume (P = 0.01 and P = 0.01, respectively) and fibrinogen (P = 0.01 and P = 0.01, respectively), and shorter prothrombin time (P = 0.02 and P = 0.01, respectively) and activated partial thromboplastin time (P = 0.01 and P = 0.02, respectively). These findings have provided evidence on the hematologic coagulative actors in the pathogenesis and severity of preeclampsia.

Alterations of Hemostatic Molecular Markers During Acute Large Vessel Occlusion Stroke.

This study aimed to investigate regional levels of TAT (thrombin-antithrombin complex), PIC (plasmin-α2 plasmin inhibitor complex), t-PAIC (tissue plasminogen activator-plasminogen activator inhibitor complex), sTM (soluble thrombomodulin), and D-dimer, along with their associations with clinical and procedural characteristics in patients with acute ischemic stroke undergoing endovascular thrombectomy. We retrospectively analyzed 166 consecutive patients with acute ischemic stroke (62±11.54 years of age, 34.3% women) using prospectively maintained clinical databases and blood samples from local ischemic (proximal to thrombus) and systemic (femoral artery, self-control) arterial compartments. Levels of TAT, PIC, t-PAIC, and D-dimer were significantly elevated, whereas sTM was significantly reduced, in local ischemic regions compared with their systemic levels. Each 1-unit increase in ischemic TAT (adjusted odds ratio [aOR], 1.086 [95% CI, 1.03-1.145]; P=0.002; area under the curve [AUC], 0.833) and PIC (aOR, 1.337 [95% CI, 1.087-1.644]; P=0.006; AUC, 0.771) correlated significantly with higher symptomatic intracranial hemorrhage risk. Additionally, each 1-unit increase in ischemic TAT (aOR, 1.076 [95% CI, 1.016-1.139]; P=0.013; AUC, 0.797), PIC (aOR, 1.554 [95% CI, 1.194-2.022]; P=0.001; AUC, 0.798), and sTM (aOR, 0.769 [95% CI, 0.615-0.961]; P=0.021; AUC, 0.756) was significantly associated with an increased risk of an unfavorable 90-day outcome (modified Rankin scale of 3-6). These hemostatic molecules, individually or combined, significantly improved the predictive power of conventional risk factors, as evidenced by significant increases in net reclassification improvement and integrated discrimination improvement (all P<0.01). We observed a hyperactive state of the coagulation-fibrinolysis system within the local ischemic region during hyperacute stroke. Rapid automated measurement of hemostatic molecular markers, particularly TAT, PIC, and sTM, during intra-arterial procedures may provide additional information for stroke risk stratification and therapeutic decision-making, and warrants further investigation.

The Lectin Pathway of the Complement System-Activation, Regulation, Disease Connections and Interplay with Other (Proteolytic) Systems.

The complement system is the other major proteolytic cascade in the blood of vertebrates besides the coagulation-fibrinolytic system. Among the three main activation routes of complement, the lectin pathway (LP) has been discovered the latest, and it is still the subject of intense research. Mannose-binding lectin (MBL), other collectins, and ficolins are collectively termed as the pattern recognition molecules (PRMs) of the LP, and they are responsible for targeting LP activation to molecular patterns, e.g., on bacteria. MBL-associated serine proteases (MASPs) are the effectors, while MBL-associated proteins (MAps) have regulatory functions. Two serine protease components, MASP-1 and MASP-2, trigger the LP activation, while the third component, MASP-3, is involved in the function of the alternative pathway (AP) of complement. Besides their functions within the complement system, certain LP components have secondary ("moonlighting") functions, e.g., in embryonic development. They also contribute to blood coagulation, and some might have tumor suppressing roles. Uncontrolled complement activation can contribute to the progression of many diseases (e.g., stroke, kidney diseases, thrombotic complications, and COVID-19). In most cases, the lectin pathway has also been implicated. In this review, we summarize the history of the lectin pathway, introduce their components, describe its activation and regulation, its roles within the complement cascade, its connections to blood coagulation, and its direct cellular effects. Special emphasis is placed on disease connections and the non-canonical functions of LP components.

Transcriptome analysis of cultured human vascular endothelial cells after γ-ray irradiation and correlation analysis with ATP, ADP, and adenosine as secondary soluble factors.

Vascular endothelial cells serve as barriers between blood components and subendothelial tissue and regulate the blood coagulation-fibrinolytic system. Ionizing radiation is a common physical stimulant that induces a bystander effect whereby irradiated cells influence neighboring cells through signalings, including purinergic receptor signaling, activated by adenosine 5'-triphosphate (ATP), adenosine 5'-diphosphate (ADP), and adenosine as secondary soluble factors. Human vascular endothelial EA.hy926 cells were cultured and irradiated with γ-rays or treated with ATP, ADP, or adenosine under non-toxic conditions. RNA-seq, gene ontology, and hierarchical clustering analyses were performed. The transcriptome analysis of differentially expressed genes in vascular endothelial cells after γ-ray irradiations suggests that the change of gene expression by γ-irradiation is mediated by ATP and ADP. In addition, the expression and activity of the proteins related to blood coagulation and fibrinolysis systems appear to be secondarily regulated by ATP and ADP in vascular endothelial cells after exposure to γ-irradiation. Although it is unclear whether the changes of the gene expression related to blood coagulation and fibrinolysis systems by γ-irradiation affected the increased hemorrhagic tendency through the exposure to γ-irradiation or the negative feedback to the activated blood coagulation system, the present data indicate that toxicity associated with γ-irradiation involves the dysfunction of vascular endothelial cells related to the blood coagulation-fibrinolytic system, which is mediated by the signalings, including purinergic receptor signaling, activated by ATP and ADP.

Retracted: Effects of Shenkang Injection Combined with Jinshuibao on Early Diabetic Nephropathy and Effects on Coagulation Fibrinolysis System and Urinary Protein.

[This retracts the article DOI: 10.1155/2022/3958049.].

Effects of proprotein convertase subtilisin-kexin type 9 inhibitors on inflammatory and hemostatic parameters in post myocardial infarction patients

Despite progress in treatment, elevated levels of low-density lipoprotein cholesterol (LDL-C) and lipoprotein (a) (Lp(a)), represent a significant part of the residual risk. Both are associated with inflammation and the coagulation fibrinolytic system. The purpose of our research was to evaluate the effect of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) on lipid parameters and indicators of inflammation, coagulation and fibrinolysis. We included 100 post myocardial infarction (MI) patients with insufficiently controlled LDL-C values despite the maximum dose of statin, and highly elevated Lp(a). Patients received alirocumab or evolocumab (150 mg sc or 140 mg sc every two weeks, respectively), or placebo for 6 months.In patients receiving PCSK9i, a significant decrease in total cholesterol (TC), LDL-C, triglycerides (TG) and Lp(a), and an increase in high density lipoprotein cholesterol (p < 0.001 for all) was found. Before treatment, the concentrations of TC, LDL-C and TG correlated with the concentrations of thrombin activatable fibrinolysis inhibitor (r = 0.41, p < 0.001; r = 0.353, p < 0.001; r = 0.311, p = 0.003, respectively), and plasminogen activator inhibitor-1 (r = 0.302, p = 0.007; r = 0.218, p = 0.049; r = 0.278; p = 0.013, respectively). The concentrations of TC and LDL-C correlated with overall fibrinolytic potential (r = −0.220, p = 0.034; r = −0.207, p = 0.047, respectively). The concentration of TG was related to the concentration of interleukin 6 (r = 0.290, p = 0.004) and interleukin 8 (r = 0.332, p = 0.001). No correlations between Lp(a) and inflammatory or hemostatic variables were found. No associations were found after treatment. Our results show that inflammatory cytokines and fibrinolytic parameters are related to LDL-C and not Lp(a) in post-MI patients before and with neither of them following PCSK9i treatment.The trial registration number: NCT04613167, Date of registration: November 3, 2020.

Hypercoagulability in Rheumatoid Arthritis: A Bibliometric Analysis and Retrospective Data Mining Study.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic systemic inflammation, leading to joint deformities and functional loss. RA progression is accompanied by abnormalities in the coagulation-fibrinolysis system, clinically manifested as a hypercoagulable state. However, there are currently no bibliometrics or visualization analysis in this field. The present study aims to reveal the knowledge structure, research status, and research trends related to hypercoagulability in RA through bibliometric analysis and to evaluate the utility of inflammatory and coagulation markers in RA disease activity through retrospective data mining. English articles and reviews on RA hypercoagulability published from 2010 to 2023 were extracted from the Web of Science Core Collection (WoSCC) database on March 1, 2023. VOSviewer and CiteSpace software were used for knowledge mapping analysis of the included papers in terms of countries/regions, institutions, journals, authors, keywords, research hotspots, and frontiers. A retrospective analysis was conducted on the general information on RA patients. The demographic and clinical indicators of all participants were collected to determine the correlation of inflammatory and coagulation markers with the Chinese patient-reported activity index for rheumatoid arthritis (CPRI-RA). A total of 957 papers were retrieved. The United States was the most productive country in this field and had the highest h-index, and the most prolific institution was the Karolinska Institute. The Annals of the Rheumatic Diseases was the journal with the most publications, and KLARESKOG L. was the most productive author. From keyword analysis, it could be seen that "inflammation", "activation", "disease-activity", and "risk" had long been the focuses of RA hypercoagulability research. "Criteria", "validation", "coagulation", "target", and "anemia" were the latest popular keywords in the past 5 years. Retrospective data mining revealed that the levels of inflammation (RF, ESR, and CRP) and coagulation (PLT and DD) were significantly increased in RA patients. FBG, CRP, and ESR were significantly correlated with CPRI-RA. Additionally, ESR, CRP, and FBG were identified as independent risk factors for CPRI-RA. The mechanism and application of hypercoagulability in RA have been research hotspots in recent years. Inflammation and coagulation markers are independent risk factors for CPRI-RA.

Abstract 16617: Effects of Proprotein Convertase Subtilisin-Kexin Type 9 Inhibitors on Inflammatory and Haemostatic Parameters in Coronary Artery Disease Patients

Background and aims: Despite progress in treatment, elevated levels of low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) (Lp(a)) represent a significant part of the residual risk. Both are associated with inflammation and the coagulation fibrinolytic system. The purpose of our research was to evaluate the effect of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) on lipid parameters and indicators of inflammation, coagulation and fibrinolysis. Methods: We included 100 patients after a myocardial infarction with insufficiently controlled LDL-C values despite the maximum dose of statin, and highly elevated Lp(a). Patients received alirocumab or evolocumab (150mg sc or 140g sc every two weeks; respectively) or placebo for 6 months. Results: In the group receiving PCSK9i, a significant decrease in total cholesterol (TC), LDL-C, triglycerides (TG) and Lp(a), and an increase in high density lipoprotein cholesterol (p&lt;0.001 for all) was found. Before treatment concentrations of TC, LDL-C and TG correlated with the concentration of thrombin activatable fibrinolysis inhibitor (r=0.41, p&lt;0.001; r=0.353, p&lt;0.001; r=0.311, p=0.003; respectively), and plasminogen activator inhibitor-1 (r=0.302, p=0.007; r=0.218, p=0.049; r=0.278; p=0.013; respectively). The concentration of TC and LDL-C correlated with overall fibrinolytic potential (r=-0.220, p=0.034; r=-0.207, p=0.047; respectively). The concentration of TG was related to the concentration of interleukin 6 (r=0.290, p=0.004) and interleukin 8 (r=0.332, p=0.001). No correlations between Lp(a) and inflammatory or haemostatic variables were found. No associations were found after treatment. Conclusion: Our results show that fibrinolytic parameters and inflammatory cytokines are related to the concentration of LDL-C and not Lp(a) before and with neither of them after treatment with PCSK9i.

Cancer associated thrombosis: crosstalk between cancer and blood coagulation-fibrinolysis system

Cancer associated thrombosis: crosstalk between cancer and blood coagulation-fibrinolysis system

Effects of Shenkang Injection Combined with Jinshuibao on Early Diabetic Nephropathy and Effects on Coagulation Fibrinolysis System and Urinary Protein.

Purpose To explore the effect of Shenkang injection (SKI) combined with Jinshuibao for early diabetic nephropathy (DN) and its effect on the coagulation fibrinolysis system and urinary protein. Methods 136 patients with early DN admitted to our hospital from March 2018 to October 2019 were divided into the observation group (n = 68) and the control group (n = 68) randomly. On the basis of the conventional treatment, the control group was treated with SKI, and the observation group was treated with SKI and Jinshuibao. Two weeks later, the therapeutic effects of the 2 groups were compared. The prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (FIB), tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), and D-dimer (D-D) were observed and compared before and after the treatment. 24 hour urine total protein (24 h-UTP), urine albumin excretion rate (UAER), and urine β2 microglobulin (β2-MG) were measured and compared before and after the treatment. Adverse reactions in the two groups were recorded during the treatment. Results The effective rate of the observation group after treatment was 92.65% higher than the control group 79.41%. the difference was statistically significant (P < 0.05). The levels of PT, APTT, TT, FIB, PAI-1, and D-D in the two groups after treatment were lower, and t-PA levels after treatment were higher than those before, and all of the above indicators were significantly changed in the observation group than in the control group. The difference was statistically significant (P < 0.05). The 24 h-UTP, UAER, and β2-MG in the two groups after treatment were lower than those before, and all of the above indicators were significantly changed in the observation group than in the control group. The difference was statistically significant (P < 0.05). There was no statistically significant difference during the treatment for 2 groups in terms of adverse reactions. The difference was statistically significant (P > 0.05). Conclusion SKI combined with Jinshuibao has a significant effect in the treatment of early DN, which can reduce the risk of hyperfunction of coagulation and fibrinolysis system, further reduce the content of urine protein, and delay the process of DN.

OP-9 - Correlation between antiphospholipid antibodies and the coagulation-fibrinolysis system in women with a history of miscarriage - comparison between conventional antiphospholipid antibodies and neo-self antibodies.

The clinical diagnostic criteria for antiphospholipid antibody syndrome (APS) include thrombosis and obstetric complications; alterations in the coagulation-fibrinolysis system due to pathogenic autoantibodies have been described as a common background for the clinical presentation of APS. Recently, autoantibodies against β2-glycoprotein I (β2GPI) in complex with HLA class II molecules (β2GPI/ HLA-DR) (neo-self antibodies) have been reported to be a novel autoantibody associated with APS. The present study investigated the relationship between conventional antiphospholipid antibodies and neoself antibodies and coagulation/fibrinolysis markers in women with a history of miscarriage. Serum antibody titres of conventional antiphospholipid antibodies (anti-cardiolipin IgG/IgM, anti-β2GPI and lupus anticoagulant) and neo-self antibodies were measured in 58 women with a history of miscarriage. Coagulation and fibrinolysis status was assessed by TAT, AT and D-dimer and APTT. In addition, the relationship with subsequent pregnancy outcome was investigated. Ten women were positive for conventional antiphospholipid antibodies and six were positive for neo-self antibodies, including one patient who was positive for both. 28 patients had elevated TAT levels and none of them showed APTT elongation. The frequency of elevated TAT was 80% (8/10) in the conventional antiphospholipid antibody-positive group and 83% (5/6) in the neo-self antibody-positive group. Those ratios were higher than the TAT positivity of 37% (16/43) in the antibodies-negative group. During the observational period, clinical pregnancy was confirmed in 23 cases, including 16 with TAT elevation. Among them, three cases resulted in early miscarriage, two of which had a TAT elevation, one of which was positive for neo-self-antibodies. Both the traditional antiphospholipid antibody-positive group and the neo-self antibody-positive group had a high frequency of TAT elevation. Alteration in coagulation/fibrinolytic system could be shared as the pathogenic background between the two groups and is possibly involved in the incidence of miscarriage.

Effect of sera from lupus patients on the glomerular endothelial fibrinolysis system.

Dysregulation of the coagulation fibrinolysis system in resident glomerular cells is associated with the pathogenesis of lupus nephritis. However, the role of plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (tPA) in resident glomerular cells remains undetermined. We examined the expression of PAI-1 and tPA mRNA in cultured normal human glomerular endothelial cells (GECs) treated with serum from patients with systemic lupus erythematosus (SLE) using quantitative reverse transcription polymerase chain reactions. We determined the relationship between PAI-1/tPA mRNA expression and several clinical/laboratory parameters. Serum from 16 patients (nine patients with new-onset SLE and seven patients with stable SLE) was used in the study. Plasminogen activator inhibitor-1 and tPA mRNA expression was significantly higher in GECs treated with serum of patients with new-onset SLE than other groups. The PAI-1 and tPA mRNA levels were also significantly correlated in GECs treated with serum from patients with SLE. Interestingly, both PAI-1 and tPA mRNA levels in GECs were inversely correlated with serum C4 level and positively correlated with SLE disease activity. These results suggest that serum from patients with SLE may activate the fibrinolysis system in glomerulus, which may be involved in the pathogenesis of lupus nephritis.

TGF-β1 Potentiates the Cytotoxicity of Cadmium by Induction of a Metal Transporter, ZIP8, Mediated by the ALK5-Smad2/3 and ALK5-Smad3-p38 MAPK Signal Pathways in Cultured Vascular Endothelial Cells.

Vascular endothelial cells cover the luminal surface of blood vessels in a monolayer and play a role in the regulation of vascular functions, such as the blood coagulation-fibrinolytic system. When the monolayer is severely or repeatedly injured, platelets aggregate at the damaged site and release transforming growth factor (TGF)-β1 in large quantities from their α-granules. Cadmium is a heavy metal that is toxic to various organs, including the kidneys, bones, liver, and blood vessels. Our previous study showed that the expression level of Zrt/Irt-related protein 8 (ZIP8), a metal transporter that transports cadmium from the extracellular fluid into the cytosol, is a crucial factor in determining the sensitivity of vascular endothelial cells to cadmium cytotoxicity. In the present study, TGF-β1 was discovered to potentiate cadmium-induced cytotoxicity by increasing the intracellular accumulation of cadmium in cells. Additionally, TGF-β1 induced the expression of ZIP8 via the activin receptor-like kinase 5-Smad2/3 signaling pathways; Smad3-mediated induction of ZIP8 was associated with or without p38 mitogen-activated protein kinase (MAPK). These results suggest that the cytotoxicity of cadmium to vascular endothelial cells increases when damaged endothelial monolayers that are highly exposed to TGF-β1 are repaired.

COT-9 Prognostic impact of hypercoagulation in glioblastoma and molecular mechanism thereof

Introduction: Pathological features of glioblastoma include intravascular thrombosis, suggesting that the thrombus formation in tumor microenvironment contributes to progression of gliomas. Meanwhile, glioblastoma has been known to be high risk malignant tumor for venous thromboembolism, however, it remains unclear how the coagulation-fibrinolysis system is disrupted, which essentially grow within the cranium in a localized manner, and how the disruption contributes to the malignant transformation. Methods: Total 64 patients with glioblastoma between January 2014 and April 2021 who underwent a D-dimer test before the therapeutic intervention were divided into two groups: the high D-dimer group (D-dimer level >3.0μg/ml) and the low D-dimer group (D-dimer level <3.0μg/ml). We compared the two groups in the maximum gadolinium-enhanced MRI lesions, MIB-1 index, and gene abnormalities (IDH mutation, TERT promoter mutation, and MGMT promotor methylation). The progression-free survival (PFS) and overall survival were analyzed using the Kaplan-Meier method. Furthermore, in 23 patients who underwent a D-dimer test at recurrence, the time to death after recurrence was analyzed. Results: The PFS in high D-dimer group was significantly shorter than that in the low D-dimer group (log-rank p = 0.0075). The D-dimer increase at the time of recurrence significantly correlated with the decrease in post-recurrence survival duration (log-rank p = 0.0226). Moreover, the gadolinium-enhanced lesions in the high D-dimer group were significantly larger. Conclusion: The Pre-intervention D-dimer levels and PFS suggest that glioblastoma-induced systemic enhancement of the coagulation-fibrinolysis system plays a role in the malignant transformation. The D-dimer increase during the treatment was found to be a predictor of poor prognosis after recurrence. Furthermore, the MRI findings revealed a correlation between the D-dimer increase and the size of intratumoral necrosis. Meanwhile, no correlation with the MIB-1 index was found, suggesting that the mechanism of malignant transformation by hypercoagulation differ from enhanced cell proliferation.

A study of changes in the coagulation-fibrinolysis system in patients with uterine adenomyosis using platelet indices

A study of changes in the coagulation-fibrinolysis system in patients with uterine adenomyosis using platelet indices

Framing Cause-Effect Relationship of Acute Coronary Syndrome in Patients with Chronic Kidney Disease.

The main causes of death in patients with chronic kidney disease (CKD) are of cardiovascular nature. The interaction between traditional cardiovascular risk factors (CVRF) and non-traditional risk factors (RF) triggers various complex pathophysiological mechanisms that will lead to accelerated atherosclerosis in the context of decreased renal function. In terms of mortality, CKD should be considered equivalent to ischemic coronary artery disease (CAD) and properly monitored. Vascular calcification, endothelial dysfunction, oxidative stress, anemia, and inflammatory syndrome represents the main uremic RF triggered by accumulation of the uremic toxins in CKD subjects. Proteinuria that appears due to kidney function decline may initiate an inflammatory status and alteration of the coagulation—fibrinolysis systems, favorizing acute coronary syndromes (ACS) occurrence. All these factors represent potential targets for future therapy that may improve CKD patient’s survival and prevention of CV events. Once installed, the CAD in CKD population is associated with negative outcome and increased mortality rate, that is the reason why discovering the complex pathophysiological connections between the two conditions and a proper control of the uremic RF are crucial and may represent the solutions for influencing the prognostic. Exclusion of CKD subjects from the important trials dealing with ACS and improper use of the therapeutical options because of the declined kidney functioned are issues that need to be surpassed. New ongoing trials with CKD subjects and platelets reactivity studies offers new perspectives for a better clinical approach and the expected results will clarify many aspects.

Syndecan-1 downregulates syndecan-4 expression by suppressing the ERK1/2 and p38 MAPK signaling pathways in cultured vascular endothelial cells

Syndecan-1 and syndecan-4 are members of the syndecan family of transmembrane heparan sulfate proteoglycans. Vascular endothelial cells synthesize both species of proteoglycans and use them to regulate the blood coagulation-fibrinolytic system and their proliferation via their heparin-like activity and FGF-2 binding activity, respectively. However, little is known about the crosstalk between the expressions of the proteoglycan species. Previously, we reported that biglycan, a small leucine-rich dermatan sulfate proteoglycan, intensifies ALK5–Smad2/3 signaling by TGF-β1 and downregulates syndecan-4 expression in vascular endothelial cells. In the present study, we investigated the crosstalk between the expressions of syndecan-1 and other proteoglycan species (syndecan-4, perlecan, glypican-1, and biglycan) in bovine aortic endothelial cells in a culture system. These data suggested that syndecan-1 downregulated syndecan-4 expression by suppressing the endogenous FGF-2-dependent ERK1/2 pathway and FGF-2-independent p38 MAPK pathway in the cells. Moreover, this crosstalk was a one-way communication from syndecan-1 to syndecan-4, suggesting that syndecan-4 compensated for the reduced activity in the regulation of vascular endothelial cell functions caused by the decreased expression of syndecan-1 under certain conditions.

Novel Coronavirus Disease 2019 (COVID-19) and Cytokine Storms for More Effective Treatments from an Inflammatory Pathophysiology.

The Novel Coronavirus Disease 2019 (COVID-19) has swept the world and caused a global pandemic. SARS-CoV-2 seems to have originated from bats as their reservoir hosts over time. Similar to SARS-CoV, this new virus also exerts its action on the human angiotensin-converting enzyme 2. This action causes infections in cells and establishes an infectious disease, COVID-19. Against this viral invasion, the human body starts to activate the innate immune system in producing and releasing proinflammatory cytokines such as IL-6, IL-1β, IL-8, TNF-α, and other chemokines, such as G-CSF, IP10 and MCPl, which all develop and increase the inflammatory response. In cases of COVID-19, excessive inflammatory responses occur, and exaggerated proinflammatory cytokines and chemokines are detected in the serum, resulting in cytokine release syndrome or cytokine storm. This causes coagulation abnormalities, excessive oxidation developments, mitochondrial permeability transition, vital organ damage, immune system failure and eventually progresses to disseminated intravascular coagulation and multiple organ failure. Additionally, the excessive inflammatory responses also cause mitochondrial dysfunction due to progressive and persistent stress. This damages cells and mitochondria, leaving products containing mitochondrial DNA and cell debris involved in the excessive chronic inflammation as damage-associated molecular patterns. Thus, the respiratory infection progressively leads to disseminated intravascular coagulation from acute respiratory distress syndrome, including vascular endothelial cell damage and coagulation-fibrinolysis system disorders. This condition causes central nervous system disorders, renal failure, liver failure and, finally, multiple organ failure. Regarding treatment for COVID-19, the following are progressive and multiple steps for mitigating the excessive inflammatory response and subsequent cytokine storm in patients. First, administering of favipiravir to suppress SARS-CoV-2 and nafamostat to inhibit ACE2 function should be considered. Second, anti-rheumatic drugs (monoclonal antibodies), which act on the leading cytokines (IL-1β, IL-6) and/or cytokine receptors such as tocilizumab, should be administered as well. Finally, melatonin may also have supportive effects for cytokine release syndrome, resulting in mitochondrial function improvement. This paper will further explore these subjects with reports mostly from China and Europe.