Coagulation Activation Research Articles

Dependence of Clot Structure and Fibrinolysis on Apixaban and Clotting Activator

BackgroundAnticoagulants prevent the formation of potentially fatal blood clots. Apixaban is a direct oral anticoagulant that inhibits Factor Xa (FXa), thereby impeding the conversion of prothrombin into thrombin and the formation of blood clots. Blood clots are held together by fibrin networks that must be broken down (fibrinolysis) to restore blood flow. Fibrinolysis is initiated when tissue plasminogen activator (tPA) converts plasminogen to plasmin, which binds to and degrades a fibrin fiber. The effects of apixaban on clot structure and lysis have been incompletely studied. ObjectivesWe aimed to study apixaban effects on clot structure, kinetics, and fibrinolysis using thrombin (low or high concentration) or tissue factor (TF) to activate clot formation. MethodsWe used a combination of confocal and scanning electron microscopy and turbidity to analyze the structure, formation kinetics, and susceptibility to lysis when plasma was activated with low concentrations of thrombin, high concentrations of thrombin, or TF in the presence or absence of apixaban. ResultsWe found that the clotting activator and apixaban differentially modulated clot structure and lytic potential. Low thrombin clots with apixaban lysed quickly due to a loose network and FXa cleavage product’s cofactor with tPA; high thrombin clots lysed faster due to FXa cleavage product’s cofactor with tPA; TF generated loose clots with restricted lysis due to their activation of thrombin activatable fibrinolytic inhibitor. ConclusionOur study elucidates the role of apixaban in fibrinolytic pathways with different clotting activators and can be used for the development of therapeutic strategies using apixaban as a cofactor in fibrinolytic pathways.

Steps Toward Recapitulating Endothelium: A Perspective on the Next Generation of Hemocompatible Coatings.

Endothelium, the lining in this blood vessel, orchestrates three main critical functions such as protecting blood components, modulating of hemostasis by secreting various inhibitors, and directing clot digestion (fibrinolysis) by activating tissue plasminogen activator. No other surface can perform these tasks; thus, the contact of blood and blood-contacting medical devices inevitably leads to the activation of coagulation, often causing device failure, and thromboembolic complications. This perspective, first, discusses the biological mechanisms of activation of coagulation and highlights the efforts of advanced coatings to recapitulate one characteristic of endothelium, hereafter single functions of endothelium and noting necessity of the synergistic integration of its three main functions. Subsequently, it is emphasized that to overcome the challenges of blood compatibility an endothelium-mimicking system is needed, proposing a synergy of bottom-up synthetic biology, particularly synthetic cells, with passive- and bioactive surface coatings. Such integration holds promise for developing advanced biomaterials capable of recapitulating endothelial functions, thereby enhancing the hemocompatibility and performance of blood-contacting medical devices.

Effect of Temperature on the Coagulation Activity of Blood Plasma in Rainbow Trout (Oncorhynchus mykiss), Common Carp (Cyprinus carpio), and North African Catfish (Clarias gariepinus) in vitro

Effect of Temperature on the Coagulation Activity of Blood Plasma in Rainbow Trout (Oncorhynchus mykiss), Common Carp (Cyprinus carpio), and North African Catfish (Clarias gariepinus) in vitro

Rupture mechanics of blood clots: Influence of fibrin network structure on the rupture resistance

Embolization is a leading cause of mortality, yet we know little about clot rupture mechanics. Fibrin provides the main structural and mechanical stability to blood clots. Previous studies have shown that altering the concentration of coagulation activators (thrombin or tissue factor (TF)) has a significant impact on fibrin structure and viscoelastic properties, but their effects on rupture properties are mostly unknown. Toughness, which corresponds to the ability to resist rupture, is independent of viscoelastic properties. We used varying TF concentrations to alter the structure and toughness of human plasma clots. We performed single-edge notch rupture tests to examine fibrin toughness under a constant strain rate and we assessed viscoelastic mechanics using rheology. We utilized fluorescent confocal and scanning electron microscopy (SEM) to quantify the fibrin network structure under varying TF concentrations. Our results revealed that increased TF concentration resulted in increased number of fibrin fibers with a reduction in network pore size, thinner and shorter fibrin fibers. Increasing TF concentration yielded a maximum toughness at mid-TF concentration, such that fibrin diameter and number of fibers underlie a complex role in influencing the rupture resistance of blood clots, resulting in a nonmonotonic relationship between TF and toughness. A simple mechanical model, built on our findings from our Fluctuating Spring (FS) computational model, adopted to estimate the fracture toughness (critical energy release rate) as a function of TF predicts trends that are in good agreement with experiments. The differences in mechanical responses point to the importance of studying the structure-function relationships of fibrin networks, which may be predictive of the tendency for embolization. Statement of significanceFibrin, a naturally occurring biomaterial, is the main mechanical and structural scaffold of blood clots that provides the necessary strength and stability to the clot, ensuring effective stemming of bleeding. The rupture of blood clots can result in the blockage of downstream vessels thereby blocking blood flow and oxygen supply. The fibrin network structure has been shown to influence the viscoelastic mechanical properties of clots, but has not been explored for fracture mechanics. Here, we modulate the fibrin network structure by varying the concentration of Tissue Factor (TF). Interestingly, the association between TF concentration and maximum toughness of the clots is non-monotonic. The variations in mechanical responses highlight the importance of studying the structure-function relationships of fibrin networks, as these may predict the tendency for embolization.

Evaluating the Role of Silymarin in Coordinating the Relationship between Inflammation and Thrombosis by Affecting Endothelial Cells

Background: A widespread crosstalk between inflammation and coagulation has been shown in numerous studies. This suggests that coagulation can trigger an inflammatory response which ultimately leads to coagulation activation. Previous research has shown that polyphenols can affect blood pressure and endothelial dysfunction, resulting in reduced risk of cardiovascular diseases. This study aimed to investigate whether Silymarin, a flavonolignans, could play a role in the interaction between inflammation and coagulation by influencing endothelial cells. Materials and Methods: In this experimental study, human umbilical vein endothelial cells (HUVECs) were seeded with and without various concentrations of silymarin. In vivo, treatment with silymarin was also carried out. Coagulative and fibrinolytic factors, including Von Willebrand factor (VWF) and Factor VIII (FVIII), tissue plasminogen activator-1 (TPA-1), and inflammatory factors, including interleukin 8 (IL-8) and tumor necrosis factor-alpha (TNF-α), were evaluated by flow cytometry, Real-Time Polymerase Chain Reaction (qPCR), Enzyme-Linked Immunosorbent Assay (ELISA) and Immunocytochemistry (ICC). Results: Silymarin increased the gene expression, release, and storage of VWF while diminishing the gene expression, release, and storage of TPA-1 (P ˂ 0.05). The activity of FVIII was dramatically increased, and IL-8 and TNF-α levels were augmented. The in vivo study also indicated an elevated plasma level of VWF and IL-8 by silymarin administration. Conclusion: The results showed that, although silymarin reduces inflammatory factors, it can affect coagulation factors by increasing the levels of VWF and FVIII activity and inhibiting TPA-1 production, thereby making thrombosis probable. Consequently, it is advisable to prescribe this medication with caution for individuals who are susceptible to thrombotic events.

Comparative Analysis of Coagulation Activation in Rheumatoid Arthritis Patients Treated With TNF Inhibitors Versus JAK Inhibitors: A Prospective Study.

This study aims to investigate the activation of the coagulation system of RA patients and assess changes during anti-inflammatory treatment with tumor necrosis factor blockers (anti-TNF) and Janus kinase inhibitors (JAKi). Biomarkers for the coagulation system, including D-dimer, fibrinogen, prothrombin time, activated partial thrombin time, prothrombin fragment 1 + 2, thrombin-antithrombin complex (TAT), activated factor IX, antithrombin complex, and von Willebrand factor (vWF), were longitudinally measured in 83 RA patients treated with anti-TNF and 38 RA patients with JAKi. Data were collected at baseline, after 1, 3, and 6 months. The mean age was 57 (±14) years; 76% was female. The mean DAS28-CRP was 3.6 (±1.3) for anti-TNF users and 4.1 (±1.4) for JAKi users at baseline and declined in both groups. Baseline coagulation markers levels were comparable between groups. In anti-TNF users, D-dimer and fibrinogen levels significantly declined (-0.31 mg/L, p = 0.01 and -0.71 g/L, p < 0.001, respectively), whereas TAT significantly increased after 6 months follow-up (1.46 μg/L, p = 0.03) and no effect on vWF (p = 0.98). In JAKi users, vWF declined significantly during the 6 months follow-up (-37.41%, p < 0.001); additionally, there were reductions of D-dimer, fibrinogen, and TAT that did not reach significance (-0.17 mg/L, p = 0.59; -0.49 g/L, p = 0.12; and 0.68 μg/L, p = 0.27, respectively). The prothrombotic tendency in active RA declined during effective treatment with both anti-TNF and JAKi. Altogether, the biomarkers used in this study suggest that an increased VTE risk in the first 6 months due to either treatment with anti-TNF or JAKi is unlikely.

Construction of a Kluyveromyces lactis strain with multi-copy integration for enhanced bovine chymosin production by CRISPR/Cas9 and UV mutagenesis

Bovine chymosin is an essential food enzyme widely used in cheese production in the dairy industry. This study used a codon-optimized prochymosin gene to construct an expression cassette for extracellular expression of bovine chymosin in Kluyveromyces lactis. After integration of the prochymosin gene into the host cell genome, the single-copy integration strain KLUcym showed the clotting activity of 40 U/mL in a shake flask. The CRISPR/Cas9 system was employed to delete amdS and construct the double-copy integration strain and triple-copy integration strain, which achieved the clotting activities of 70 U/mL and 78 U/mL in shake flasks, separately. Subsequently, multiple rounds of UV mutagenesis were performed on the double-copy strain KLUcymD, and a recombinant K. lactis strain with a high yield of bovine chymosin was obtained. This strain achieved the clotting activity of 270 U/mL in a shake flask and 600 U/mL in a 5 L bioreactor after 76 h. In summary, we construct a strain KLUcymD-M2 for high production of bovine chymosin, which lays a foundation of industrial fermentation.

Modulating Coagulation via Bioinspired Mesoporous Calcium-Decorated Silica Nanoparticles for Efficient Fibrin Clot Formation.

Blood clotting is vital for preventing bleeding after an injury. Hemostasis is a complex cascade involving numerous plasma proteins. Uncontrolled bleeding leads to mortality. The presence of Ca (calcium) activates and promotes the different phases in the coagulation cascade. Even nonbiological surfaces such as silicates may activate coagulation factor XII (FXII). This causes the clotting of the blood. The exceptional hemostatic ability of the mesoporous calcium-decorated silica nanoparticles (MCSNs) is achieved by stimulating the factors needed to form fibrin mesh, a durable clot, thereby establishing hemostasis. This may be used as a hemostatic agent during an accident surgical procedure and other bleeding-related trauma conditions. This study investigates the mechanistic activation of the coagulation cascade by MCSN through blood coagulation index, clotting time, and coagulation activation studies like PT and aPTT. Our finding demonstrates that MCSN induces platelet adhesion and RBC aggregation and activates thrombin generation through distinct pathways.

Comparison of tissue factor-activated versus citrated native thromboelastography in dogs with suspected hemostatic abnormalities.

Viscoelastic testing methods, including thromboelastography (TEG) and rotational thromboelastometry, have an advantage over traditional tests of coagulation due to their ability to reflect in vivo hemostasis and predict need for transfusion of blood products more accurately. TEG in clinical settings is most often performed on citrated whole blood samples that are recalcified at the time of analysis, with or without the addition of an activator of coagulation. To date, superiority of the use of an activator in canine patients with abnormal hemostasis has not been demonstrated. We compared the use of tissue factor-activated (TF) TEG with citrated native (CN) TEG in dogs with suspected hemostatic abnormalities. Forty-five of 79 enrolled dogs with suspected abnormal hemostasis had an abnormal MA value. There was very high correlation between CN samples and TF-activated samples for alpha, K, MA, and R; there was a high correlation for LY30 and LY60. Categorical agreement for CN- and TF-activated TEG classification of hypercoagulable and hypocoagulable cases based on MA was good to very good, with 91% and 97% categorical agreement, respectively. No difference was found in the variance for any TEG variable between the 2 methods of analysis. For canine patients with suspected abnormal hemostasis, use of CN or TF-activated TEG appears acceptable. Monitoring of coagulation should be done with the same method; methods may not be used interchangeably.

COVID-19 and Pulmonary Embolism: A Comprehensive Review of Epidemiology, Pathophysiology, and Management

Global public health has suffered greatly as a result of the coronavirus illness 2019 (Covid-19) pandemic; yet when vaccinations against Covid-19 are available, they have contributed to the containment of the spread of SARS Coronavirus 2 (SARS-CoV-2) infection. However, there have been isolated reports of vaccine-induced cerebral venous sinus thrombosis (CVST) and vaccine-induced immune thrombotic thrombocytopenia (VITT) following viral vector vaccinations (Ad26.COV2 vaccine, AdOx1 nCoV-19 vaccine).One of the most effective ways to address the global health issue as the new SARS-CoV-2 virus spreads around the world is immunization against COVID-19.This condition manifests as thrombocytopenia, the formation of an autoantibody against platelet-factor 4,and widespread thrombosis in unusual places, mainly in the cerebral venous. (PF4). The human Freia receptor on platelets can be bound by the PF4 autoantibody, which can then cause the platelets to aggregate. This is an uncommon side effect that closely mimics the clinical presentation of the traditional immune-mediated HIT illness that develops after heparin exposure. We will talk about the recently reported side effect known as vaccine-induced immune thrombotic thrombocytopenia (VITT),which can happen after receiving specific COVID-19 vaccinations, in this Spotlight. Since the vaccinations have been employed, questions have been raised about their safety. Following the COVID-19 vaccine, the most frequent side effects include local reactions at the injection site and general systemic symptoms like fever, headache, weariness, and myalgia. These side effects could appear shortly after immunization and go away quickly. Nonetheless, a few uncommon cases of vaccine-induced immune thrombotic thrombocytopenia (VITT) have been documented, mostly in relation to vaccinations utilizing viral vectors. Platelet expression of spike protein and subsequent immune response, platelet expression of other adenoviral proteins and subsequent reactions, the role of antibodies against platelet factor 4 (PF4), the direct interaction between adenoviral vector and platelets, the cross-reactivity of antibodies against SARS-CoV-2 spike protein with PF4, the cross-reactivity of anti-adenovirus antibodies and PF4 interaction between spike protein and platelets. Because severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can activate platelets, thrombocytopenia while rare in the first presentation may also be an indicator of the severity of the disease. The spike protein-angiotensin converting enzyme 2 (ACE2) connection causes this directly, and the activation of coagulation and inflammation causes it indirectly. In COVID-19, dysregulation of the innate and adaptive immune systems is a significant contributing factor to thrombosis and thrombocytopenia.

Reconfigurable DNA Nanocage for Protein Encapsulation and Regulation.

Creating nanomachines capable of precisely capturing, organizing, and regulating the activity of target biomolecules holds profound significance for advancing nanotechnology and therapeutics. Here, we develop a multistage reconfigurable DNA nanocage that can enclose and modulate proteins through multivalent interactions, activated by specific molecular signals. By strategically designing and manipulating the strut architecture of the DNA nanocages, we can achieve precise control over their reconfiguration among pyramid, square, and linear branch shapes. Additionally, we demonstrated its ability to capture thrombin and effectively inhibit its coagulation activity by incorporating two thrombin-targeting aptamers into the designed arms of the DNA nanocage. The activity of thrombin can be recovered by rearranging the conformation of the DNA nanocage and exposing the protein, thereby activating the coagulation process. This approach enriches the design toolbox for dynamic nanomachines and inspires a new strategy for protein encapsulation and regulation with potential future therapeutic applications.

Multivariate regression analysis of risk factors for the development of polyposisrhinosinusitis

Introduction. Chronic rhinosinusitis with nasal polyps is a group of chronic recurrent inflammatory diseases of the nasal mucosa and paranasal sinuses with an incompletely understood etiopathogenesis. Despite various theories on the development of this disease and principles of pathogenetic therapy, some patients continue to suffer from the disease, which is resistant to both medical and surgical treatment.The aim of this study was to identify the most significant risk factors for the development of polypoid rhinosinusitis in patients with chronic purulent rhinosinusitis using binary logistic regression.Materials and methods. The study included patients diagnosed with chronic purulent rhinosinusitis (n=40) and chronic purulent-polypoid rhinosinusitis (n=40) who were treated at the otorhinolaryngology department of the Chita Clinical Hospital "RZD-Medicine" from 2016 to 2020. The control group consisted of 20 healthy volunteers, matched by sex and age with the study groups. All subjects underwent comprehensive clinical examinations, bacteriological analysis, endoscopic examination, and measurements of interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, defensins (HAD 1-3), heat shock protein 70 (HSP70), and autoantibodies to it in serum and nasal secretions, as well as the coagulation activity of nasal secretions. Binary logistic regression was used to analyze risk factors for the development of polypoid rhinosinusitis.Results. We demonstrated that high predictive significance for the development of nasal mucosal polyps in patients with purulent rhinosinusitis is associated with concentrations of heat shock protein 70, IL-10, and HAD 1-3 in serum.Conclusion. A test set that includes levels of HSP70, IL-10, and HAD 1-3 in serum can predict the development of chronic polypoid rhinosinusitis with 99% accuracy.

Promoted coagulant activity and disrupted blood-brain barrier depending on phosphatidylserine externalization of red blood cells exposed to ZnO nanoparticles

Zinc oxide nanoparticles (ZnO-NPs) are nanomaterials mainly produced and used worldwide. They translocate to circulatory systems from various exposure routes. While blood and endothelial cells are persistently exposed to circulating ZnO-NPs, the potential risks posed by ZnO-NPs to the cardiovascular system are largely unknown. Our study identified the potential risk of thrombosis and disturbance of the blood-brain barrier (BBB) by coagulant activity on red blood cells (RBCs) caused by ZnO-NPs. ZnO-NPs promoted the externalization of phosphatidylserine and the generation of microvesicles through an imbalance of intracellular mechanisms regulating procoagulant activity in human RBCs. The coagulation cascade leading to thrombin generation was promoted in ZnO-NPs-treated human RBCs. Combined with human RBCs, ZnO-NPs caused coagulant activity on isolated rat RBCs and rat venous thrombosis models. We identified the erythrophagocytosis of RBCs into brain endothelial cells via increased PS exposure induced by ZnO-NPs. Excessive erythrophagocytosis contributes to disrupting the BBB function of endothelial cells. ZnO-NPs increased the procoagulant activity of RBCs, causing venous thrombosis. Excessive erythrophagocytosis through ZnO-NPs-treated RBCs resulted in the dysfunction of BBB. Our study will help elucidate the potential risk ZnO-NPs exert on the cardiovascular system.

Blood Coagulation Activities and Influence on DNA Condition of Alginate-Calcium Composites Prepared by Freeze-Drying Technique.

The aim of this research was to synthesize and characterize alginate-calcium composites using a freeze-drying method, with a focus on their potential applications in biomedicine. This study specifically explored the biochemical properties of these composites, emphasizing their role in blood coagulation and their capacity to interact with DNA. Additionally, the research aimed to assess how the cross-linking process influences the structural and chemical characteristics of the composites. Detailed analyses, including microscopic examination, surface area assessment, and atomic absorption spectrometry, yielded significant results. The objective of this study was to examine the impact of calcium chloride concentration on the calcium content in alginate composites. Specifically, the study assessed how varying concentrations of the cross-linking solution (ranging from 0.5% to 2%) influence the calcium ion saturation within the composites. This investigation is essential for understanding the physicochemical properties of the materials, including calcium content, porosity, and specific surface area. The results are intended to identify the optimal cross-linking conditions that maximize calcium enrichment efficiency while preserving the material's structural integrity. The study found that higher calcium chloride concentrations in alginate cross-linking improve the formation of a porous structure, enhanced by two-stage freeze-drying. Increased calcium levels led to a larger surface area and pore volume, and significantly higher calcium content. Furthermore, assays of activated partial thromboplastin time (aPTT) showed a reduction in clotting time for alginate composites containing calcium ions, indicating their potential as hemostatic agents. The aPTT test showed shorter clotting times with higher calcium ion concentrations, without enhanced activation of the extrinsic clotting pathway. The developed alginate material with calcium effectively supports hemostasis and reduces the risk of infection. The study also explored the capacity of these composites to interact with and modify the structure of plasmid DNA, underscoring their potential for future biomedical applications.

Antivenom Properties and Chemical Profiling via Molecular Networking of Mimosa gracilis Extracts.

The species Mimosa gracilis var. capillipes (Benth.) Barneby is used for its antivenom properties in the Coqueiros community, municipality of Catalão, state of Goiás. This study focused on three varieties: M. gracilis Benth. var. gracilis, M. gracilis var. capillipes (Benth.) Barneby, and M. gracilis var. invisiformis Barneby. The chemical profiles of extracts from these varieties were analysed using molecular networking through liquid chromatography with tandem mass spectrometry. Additionally, the study investigated the inhibitory potential of these three varieties against the proteolytic, coagulant, and phospholipase activities of Bothrops and Crotalus venoms. In vitro results confirmed the antivenom potential of nine extracts. Remarkably, the ethanolic extracts of roots from M. gracilis var. capillipes (Benth.) Barneby and the leaves from M. gracilis Benth. var. gracilis exhibited 100 % inhibition of the tested activities. The study also revealed 19 annotated compounds through molecular networking, reported for the first time in the species M. gracilis.

Photothermal and Antibacterial PDA@Ag/SerMA Microneedles for Promoting Diabetic Wound Repair.

Diabetic foot ulcer (DFU) is a common and severe complication of diabetes characterized by wound neuropathy, ischemia, and susceptibility to infection, making its treatment difficult. Dressings are commonly used in treating diabetic wounds; however, they have disadvantages, including lack of flexibility and mechanical strength, lack of coagulation activity, resistance to biodegradation, and low drug delivery efficiency. Developing more effective strategies for diabetic wound treatment has become a new focus. Microneedles (MN) can be used as a drug delivery platform for DFU wounds, allowing safe, effective, painless and minimally invasive medication administration through the skin. Herein, PDA@Ag/SerMA microneedles were prepared by combining the photothermal properties of polydopamine (PDA), the antimicrobial properties of argentum (Ag), and the ability of sericin methacryloyl (SerMA) to promote cell mitosis to accelerate wound healing and treat diabetic ulcer wounds. The results revealed that PDA@Ag/SerMA microneedles exhibited approximately 100% antimicrobial efficacy against Staphylococcus aureus and Escherichia coli under 808 nm near-infrared (NIR) irradiation. Furthermore, the wound healing rate of mice reached 95% within 12 days, which demonstrated the excellent antibacterial properties and wound healing efficacy of PDA@Ag/SerMA microneedles at cellular and animal levels, providing a potential solution for treating DFU.

Circulating microRNAs targeting coagulation and fibrinolysis in patients with severe COVID-19

BackgroundCoronavirus-19 disease (COVID-19) frequently causes coagulation disturbances. Data remains limited on the effects of microRNAs (miRNAs) on coagulation during COVID-19 infection. We aimed to analyze the comprehensive miRNA profile as well as coagulation markers and blood count in hospitalized COVID-19 patients.MethodsCitrated plasma samples from 40 patients (24 men and 16 women) hospitalized for COVID-19 were analyzed. Basic coagulation tests, von Willebrand factor (VWF), ADAMTS13, blood count, C-reactive protein, and 27 miRNAs known to associate with thrombosis or platelet activation were analyzed. MiRNAs were analyzed using quantitative reverse transcription polymerase chain reaction (RT qPCR), with 10 healthy controls serving as a comparator.ResultsAmong the patients, 15/36 (41%) had platelet count of over 360 × 109/L and 10/36 (28%) had low hemoglobin of < 100 g/L, while 26/37 (72%) had high VWF of over 200 IU/dL. Patients had higher levels of the miRNAs miR-27b-3p, miR-320a-3p, miR-320b-3p, and miR-424-5p, whereas levels of miR-103a-3p and miR-145-5p were lower than those in healthy controls. In total, 11 miRNAs were associated with platelet count. Let-7b-3p was associated with low hemoglobin levels of < 100 g/L. miR-24-3p, miR-27b-3p, miR-126-3p, miR-145-5p and miR-338-5p associated with high VWF.ConclusionCOVID-19 patients differentially express miRNAs with target genes involved in fibrinolysis inhibition, coagulation activity, and increased inflammatory response. These findings support the notion that COVID-19 widely affects hemostasis, including platelets, coagulation and fibrinolysis.

Association of biomarkers of endothelial function, coagulation activation and kidney injury with persistent albuminuria in sickle cell anaemia.

Persistent albuminuria (PA) is common in sickle cell anaemia (SCA). With the association of chronic kidney disease (CKD) with increased mortality, biomarkers that predict its development or progression are needed. We evaluated the association of select biomarkers with PA in adults with SCA using Kruskal-Wallis rank-sum test and logistic regression models, with adjustment for multiple testing. Of 280 subjects, 100 (35.7%) had PA. Median plasma levels of soluble vascular cell adhesion molecule-1 (VCAM-1) (1176.3 vs. 953.4 ng/mL, false discovery rate [FDR] q-value <0.003), thrombin-antithrombin complex (5.5 vs. 4.7 ng/mL, FDR q-value = 0.04), and urinary angiotensinogen (AGT) (12.2 vs. 5.3 ng/mg, FDR q-value <0.003), urinary nephrin (30.6 vs. 27.2 ng/mg, FDR q-value = 0.04), and urinary kidney injury molecule-1 (KIM-1) (0.8 vs. 0.5 ng/mg, FDR q-value <0.003), normalized to urine creatinine, were significantly higher in subjects with PA. In multivariable analysis, only urinary AGT (odds ratio = 1.058, FDR q-value <0.0001) remained a significant predictor of PA. In addition, soluble VCAM-1 (FDR q-value <0.0001), D-dimer (FDR q-value <0.0001), urinary AGT (FDR q-value <0.0001), KIM-1 (FDR q-value <0.0001), and nephrin (FDR q-value <0.0001) were significantly associated with urine albumin-creatinine ratio in multivariable analyses. Longitudinal studies to evaluate the predictive capacity of biomarkers for the development and progression of CKD in SCA are warranted.

Decreased Protein C Pathway Activity in COVID-19 Compared to Non-COVID Sepsis: An Observational and Comparative Cohort Study.

Sepsis-associated coagulopathy increases risk of mortality. Impairment of the anticoagulant protein C (PC) pathway may contribute to the thrombotic phenotype in coronavirus disease 2019 (COVID-19) sepsis. This study assessed the functionality of this pathway in COVID-19 and non-COVID sepsis by measuring its key enzymes, thrombin and activated PC (APC). The study population included 30 patients with COVID-19, 47 patients with non-COVID sepsis, and 40 healthy controls. In healthy controls, coagulation activation and subsequent APC formation was induced by 15 µg/kg recombinant activated factor VII one hour before blood sampling. APC and thrombin in plasma were measured using oligonucleotide-based enzyme capture assays. The indirect thrombin markers prothrombin-fragment 1+2 (F1+2) and thrombin-antithrombin complex (TAT) were also measured. Compared with stimulated healthy controls, median thrombin, F1+2, and TAT levels were higher in patients with COVID-19 (up to 6-fold, p < 2 × 10-6) and non-COVID sepsis (up to 4.7-fold, p < 0.010). APC levels were 2.4-fold higher in patients with COVID-19 (7.44 pmol/L, p = 0.011) and 3.4-fold higher in non-COVID sepsis patients (10.45 pmol/L, p = 2 × 10-4) than in controls (3.08 pmol/L). Thrombin markers and APC showed correlation in both COVID-19 (r = 0.364-0.661) and non-COVID sepsis patients (r = 0.535-0.711). After adjustment for PC levels, median APC/thrombin, APC/F1+2, and APC/TAT ratios were 2-fold (p = 0.036), 6-fold (p = 3 × 10-7) and 3-fold (p = 8 × 10-4) lower in the COVID-19 group than in the non-COVID sepsis group, and the latter two were also lower in the COVID-19 group than in stimulated healthy controls. In conclusion, it was found that a comparatively lower anticoagulant APC response in COVID-19 patients as compared to non-COVID sepsis patients, potentially linked to endothelial dysfunction, contributes to the prothrombotic phenotype of COVID-19 sepsis.

Plasma-Induced Enhanced Coagulation and Complement Activation of Blood Streams by Platinum Nanoparticles

Plasma-Induced Enhanced Coagulation and Complement Activation of Blood Streams by Platinum Nanoparticles