Fibrinolysis Inhibitor Research Articles

Hemorrhagic shock and tissue injury provoke distinct components of trauma-induced coagulopathy in a swine model.

Tissue injury (TI) and hemorrhagic shock (HS) are the major contributors to trauma-induced coagulopathy (TIC). However, the individual contributions of these insults are difficult to discern clinically because they typically coexist. TI has been reported to release procoagulants, while HS has been associated with bleeding. We developed a large animal model to isolate TI and HS and characterize their individual mechanistic pathways. We hypothesized that while TI and HS are both drivers of TIC, they provoke different pathways; specifically, TI reduces time to clotting, whereas, HS decreases clot strength stimulates hyperfibrinolysis. After induction of general anesthesia, 50kg male, Yorkshire swine underwent isolated TI (bilateral muscle cutdown of quadriceps, bilateral femur fractures) or isolated HS (controlled bleeding to a base excess target of -5mmol/l) and observed for 240min. Thrombelastography (TEG), calcium levels, thrombin activatable fibrinolysis inhibitor (TAFI), protein C, plasminogen activator inhibitor 1 (PAI-1), and plasminogen activator inhibitor 1/tissue-type plasminogen activator complex (PAI-1-tPA) were analyzed at pre-selected timepoints. Linear mixed models for repeated measures were used to compare results throughout the model. TI resulted in elevated histone release which peaked at 120min (p = 0.02), and this was associated with reduced time to clot formation (R time) by 240min (p = 0.006). HS decreased clot strength at time 30min (p = 0.003), with a significant decline in calcium (p = 0.001). At study completion, HS animals had elevated PAI-1 (p = 0.01) and PAI-1-tPA (p = 0.04), showing a trend toward hyperfibrinolysis, while TI animals had suppressed fibrinolysis. Protein C, TAFI and skeletal myosin were not different among the groups. Isolated injury in animal models can help elucidate the mechanistic pathways leading to TIC. Our results suggest that isolated TI leads to early histone release and a hypercoagulable state, with suppressed fibrinolysis. In contrast, HS promotes poor clot strength and hyperfibrinolysis resulting in hypocoagulability.

Changes in fibrinolytic activity and coagulation factors after epicardial left atrial appendage closure in patients with atrial fibrillation.

The left atrial appendage (LAA) is known to be the primary source of thrombus formation in atrial fibrillation (AF). We investigate whether epicardial LAA occlusion (LAAO) from the cardiovascular system has an effect on coagulation and prothrombotic status in AF. Twenty-two patients with nonvalvular AF, who were not currently receiving oral anticoagulation (OAC) therapy, participated in a single-center prospective study. We measured fibrinogen and plasminogen levels along with plasma fibrin clot permeability, clot lysis time (CLT) and endogenous thrombin potential (ETP) before the LAAO procedure, at discharge and 1 month afterward. One month after the LAAO procedure, plasma fibrin clot permeability improved by 39.3% as measured by clots prepared from peripheral blood (P=0.019) and also after adjustment for fibrinogen (P=0.027). Higher plasma fibrin clot permeability was associated with improved clot susceptibility to lysis (r=-0.67, P=0.013). CLT was reduced by 10.3% (P=0.0020), plasminogen activator inhibitor-1 antigen levels were reduced by 52% (P=0.023) and plasminogen activity was increased by 8.9% (P=0.0077). A trend toward decreased thrombin generation, reflected by a decreased ETP and peak thrombin generated was also observed 1 month after LAAO procedure (P=0.072 and P=0.087, respectively). No differences were observed in tissue-type plasminogen activator and thrombin-activatable fibrinolysis inhibitor plasma levels (both P>0.05). Obtained results seem to confirm that LAA plays a key role in thrombogenesis. Elimination of LAA from the circulatory system may improve fibrin clot permeability and susceptibility to fibrinolysis in peripheral blood.

Visualization of Domain- and Concentration-Dependent Impact of Thrombomodulin on Differential Regulation of Coagulation and Fibrinolysis.

Thrombomodulin (TM) functions as a dual modulator-anticoagulant and antifibrinolytic potential-by the thrombin-dependent activation of protein C and thrombin-activatable fibrinolysis inhibitor (TAFI). Activated TAFI cleaves the C-terminal lysine of partially degraded fibrin and inhibits both plasminogen binding and its activation on the fibrin surface. We have reported previously that activated platelets initiate fibrin network formation and trigger fibrinolysis after the accumulation of tissue-type plasminogen activator and plasminogen. To analyze the effects of domain-deletion variants of TM on coagulation and fibrinolysis at different concentrations. Domain-deletion variants of TM, such as D123 (all extracellular regions), E3456 (minimum domains for thrombin-dependent activation of protein C and TAFI), and E456 (minimum domains for that of protein C but not TAFI), were used at 0.25 to 125 nM for turbidimetric assay to determine the clotting time and clot lysis time and to visualize fibrin network formation and lysis in platelet-containing plasma. A low concentration of either D123 or E3456, but not of E456, prolonged clot lysis time, and delayed the accumulation of fluorescence-labeled plasminogen at the activated platelets/dense fibrin area due to effective TAFI activation. Conversely, only the highest concentrations of all three TM variants delayed the clotting time, though fibrin network formation in the vicinity of activated platelets was almost intact. TAFI activation might be affected by attenuation in thrombin activity after the clot formation phase. These findings suggest that the spatiotemporal balance between the anticoagulant and antifibrinolytic potential of TM is controlled in domain- and concentration-dependent manners.

Antiviral activity of aminocaproic acid against SARS-CoV-2: review of the literature and results of the first experimental study

BACKGROUND. The SARS-CoV-2 pandemic has a significant impact on the global health care system, so effective treatments for coronavirus disease (COVID-19) are urgently needed. Nowadays, drug repurposing is widely considered for COVID-19 therapy; significant attention is paid to inhibitors of transmembrane serine proteases (TMPRSS2), which ensure the penetration of SARS-CoV-2 into the human cells and contribute to their infection. ε-aminocaproic acid (ACA), which has been used worldwide for many years to correct blood loss as a fibrinolysis inhibitor, is also known for its ability to block TMPRRS2. It is approved by the Ministry of Health of Ukraine for the treatment of influenza and acute respiratory viral infections.
 OBJECTIVE. The aim of our study was to evaluate the antiviral effect of ACA in vitro by staining of SARS-CoV-2 viral antigen (spike protein) and by visual scoring of cytopathogenic effect (CPE).
 RESULTS AND DISCUSSION. Using immunohistochemistry assay it was found that the mean value of EC50 for ACA on Caco-2 cells was 2.5 mg/ml and on Calu-3 cells – 17.3 mg/ml. Using CPE assay it was identified that the mean value of EC50 for ACA on Caco-2 cells was 6.4 mg/ml and on Calu-3 cells – 8.7 mg/ml. Additional analysis was shown that ACA has low cytotoxicity with CC50 values of >50 mg/ml on Caco-2 cells after 24h and 48h incubation and 37,57 and 41,29 mg/ml on Calu-3 cells after 24h and 48h incubation, respectively. Antiviral activity of ACA was detected when using non-toxic concentrations of the drug and did not depend on the time of introduction of ACA (before the introduction of the virus simultaneously with the pathogen after 1-hour incubation). ACA can be recommended for further in vivo studies on laboratory animals.

Enhanced Production of ECM Proteins for Pharmaceutical Applications Using Mammalian Cells and Sodium Heparin Supplementation.

The yields of soluble ECM proteins recombinantly produced with mammalian cells can be significantly enhanced by exploiting the stabilizing properties of heparin. Here, we propose a simple and straightforward scalable protocol for the mammalian cell production of ECM proteins with affinity for heparin, using heparin as a supplement. As proof of concept, we have demonstrated the high-level expression of four biomedically relevant human enzymes such as carboxypeptidase Z (CPZ), carboxypeptidase A6 (CPA6), beta-galactoside alpha-2,6-sialyltransferase 2 (ST6GAL1) and thrombin-activable fibrinolysis inhibitor (TAFI). We found a strong linear correlation between the isoelectric point (pI) of a protein and the improvement in protein expression levels upon heparin addition, providing a reference for selecting novel protein targets that would benefit from heparin supplementation. Finally, we demonstrated the compatibility of this approach with a three-step purification strategy that includes an initial heparin affinity purification step. Using CPZ as a representative example, we performed a preparative purification of this enzyme. The purified protein is enzymatically active and can be used for pharmaceutical applications as well as for high-throughput functional and structural studies.

Serum thrombin-activatable fibrinolysis inhibitor levels and its relation with pathogenesis and bleeding and prognosis in patients with Crimean Congo hemorrhagic fever.

Crimean-Congo hemorrhagic fever (CCHF) is a viral hemorrhagic fever, which is common in Turkey and globally. The pathogenesis of coagulation disorders, which is seen in viral hemorrhagic fevers remains to be elucidated. Thrombin-activatable fibrinolysis inhibitor (TAFI) has a key role in this process In this study, we aimed to evaluate whether TAFI levels contributed to bleeding and whether it is related to prognosis in CCHF patients.Eighty-four patients older than 15 years of age, who were admitted to our hospital who had positive immunoglobulin M (enzyme-linked immunosorbent assay [ELISA]) and/or polymerase chain reaction test results for CCHF between 2009 and 2010, were included in the study. The control group included 30 healthy adults. The plasma TAFI levels were compared between patients and controls, and also between patients with bleeding and no bleeding, and between patients with mild-moderate and severe disease. The mean TAFI levels were lower in patients (mean: 87.82 ng/ml, median: 61.69 ng/ml (interquartile range [IQR] 30.49-537.95) than controls (mean: 313.5 ng/ml with a median: 338.5 ng/ml (IQR 182-418). However, median TAFI levels were significantly higher in patients with bleeding compared to those without bleeding (78.99 and 50.28 ng/ml, respectively; p = 0.032). Median IQR TAFI levels were similar between patients with mild-moderate and severe disease (64.72 (41.37-113.85), and, 58.66 (42.44-118.93) ng/ml, respectively; p = 0.09) and survivors and nonsurvivors (86.14 ± 77.98 and 103.48 ± 69.92, respectively; p = 0.3). Although TAFI levels were lower in the patients with CCHF compared to healthy controls, it does not seem to be a major player in the prognosis.

Efficiency of targeted delivery of streptokinase based on fibrin-specific liposomes in the in vivo experiment.

Acute thrombosis has a narrow therapeutic window and remains the leading cause of morbidity and mortality, while thrombolytic therapy has limited efficacy and risk of side effects. We have developed and investigated new fibrin-specific systems for local drug delivery to increase efficiency while minimizing the side effects of streptokinase. The experiment was carried out on dogs with 2-h thrombi in the femoral artery received intravenous injections of streptokinase, liposome-bound and free streptokinase at 40/60% ratio, and immunoliposomes. The completeness of the vessel lumen restoration affected by the thrombus, and the risks of side effects were assessed. Fibrinolytic parameters (plasminogen, fibrinogen, alpha2-antiplasmin, and D-dimers levels) were measured at several time points after thrombus induction and the administration of the drug. There was a strong activation of fibrinolysis and consumption of fibrinolysis inhibitors after therapy with all liposomal forms of streptokinase. According to the ultrasound data, immunoliposomal form of streptokinase significantly reduces the degree of residual stenosis to 32% [30.5; 33.7] in 180min after injection. The high fibrinolytic effect of liposomal forms of streptokinase is not accompanied by a sharp drop in the fibrinogen concentration in the blood compared to the native streptokinase by 60min. The morphometric evaluation of the artery samples showed that immunoliposomal form of streptokinase induces a significant increase in the degree of free vascular lumen compared to the native streptokinase (71.3% (62.7; 77.5) vs. 47.7% (39.6; 55.7), p < 0.001). Thus, the study shows the efficacy of streptokinase-induced thrombolysis using immunoliposomal form of drug delivery system. Mechanism of action of the immunoliposomal delivery system.

Plasmin Inhibitor in Health and Diabetes: Role of the Protein as a Therapeutic Target.

The vascular obstructive thrombus is composed of a mesh of fibrin fibers with blood cells trapped in these networks. Enhanced fibrin clot formation and/or suppression of fibrinolysis are associated with an increased risk of vascular occlusive events. Inhibitors of coagulation factors and activators of plasminogen have been clinically used to limit fibrin network formation and enhance lysis. While these agents are effective at reducing vascular occlusion, they carry a significant risk of bleeding complications. Fibrin clot lysis, essential for normal hemostasis, is controlled by several factors including the incorporation of antifibrinolytic proteins into the clot. Plasmin inhibitor (PI), a key antifibrinolytic protein, is cross-linked into fibrin networks with higher concentrations of PI documented in fibrin clots and plasma from high vascular risk individuals. This review is focused on exploring PI as a target for the prevention and treatment of vascular occlusive disease. We first discuss the relationship between the PI structure and antifibrinolytic activity, followed by describing the function of the protein in normal physiology and its role in pathological vascular thrombosis. Subsequently, we describe in detail the potential use of PI as a therapeutic target, including the array of methods employed for the modulation of protein activity. Effective and safe inhibition of PI may prove to be an alternative and specific way to reduce vascular thrombotic events while keeping bleeding risk to a minimum. Key Points Plasmin inhibitor (PI) is a key protein that inhibits fibrinolysis and stabilizes the fibrin network.This review is focused on discussing mechanistic pathways for PI action, role of the molecule in disease states, and potential use as a therapeutic target.

The suboptimal fibrinolytic response in COVID‐19 is dictated by high PAI‐1

BackgroundSevere COVID‐19 disease is associated with thrombotic complications and extensive fibrin deposition. This study investigates whether the hemostatic complications in COVID‐19 disease arise due to dysregulation of the fibrinolytic system. MethodsThis prospective study analyzed fibrinolytic profiles of 113 patients hospitalized with COVID‐19 disease with 24 patients with non‐COVID‐19 respiratory infection and healthy controls. Antigens were quantified by Ella system or ELISA, clot lysis by turbidimetric assay, and plasminogen activator inhibitor‐1 (PAI‐1)/plasmin activity using chromogenic substrates. Clot structure was visualized by confocal microscopy. ResultsPAI‐1 and its cofactor, vitronectin, are significantly elevated in patients with COVID‐19 disease compared with those with non‐COVID‐19 respiratory infection and healthy control groups. Thrombin activatable fibrinolysis inhibitor and tissue plasminogen activator were elevated in patients with COVID‐19 disease relative to healthy controls. PAI‐1 and tissue plasminogen activator (tPA) were associated with more severe COVID‐19 disease severity. Clots formed from COVID‐19 plasma demonstrate an altered fibrin network, with attenuated fiber length and increased branching. Functional studies reveal that plasmin generation and clot lysis were markedly attenuated in COVID‐19 disease, while PAI‐1 activity was elevated. Clot lysis time significantly correlated with PAI‐1 levels. Stratification of COVID‐19 samples according to PAI‐1 levels reveals significantly faster lysis when using the PAI‐1 resistant (tPA) variant, tenecteplase, over alteplase lysis. ConclusionThis study shows that the suboptimal fibrinolytic response in COVID‐19 disease is directly attributable to elevated levels of PAI‐1, which attenuate plasmin generation. These data highlight the important prognostic potential of PAI‐1 and the possibility of using pre‐existing drugs, such as tenecteplase, to treat COVID‐19 disease and potentially other respiratory diseases.

Hemostatic Effects of Tranexamic Acid in Cesarean Delivery: An Ancillary Study of the TRAAP2 Study.

Fibrinolysis activation during delivery contributes to postpartum hemorrhage (PPH). Clot lysis time studied with the global fibrinolytic capacity device (GFC/LT) is a functional test which rapidly assesses fibrinolytic profile. Tranexamic acid (TXA) is an efficient antifibrinolytic therapy. We prospectively studied fibrinolysis and coagulation in 33 women included in the TRAAP2 trial, which aimed to assess the impact of TXA in preventing PPH following a cesarean delivery. TXA or placebo was randomly administered after childbirth as part of the TRAAP2 trial's protocol. Fibrinolytic (GFC/LT, plasma concentration of fibrinolysis activators and inhibitors) and hemostatic parameters were assayed at three sample times (TREF [T-reference] after anesthesia, T15 and T120minutes after TXA, or placebo administration). All cesarean deliveries were elective. In the placebo group, the clot lysis time assessed with GFC/LT significantly decreased between TREF and T120, indicating an activated fibrinolysis (44 [interquartile range, IQR: 40-48] vs. 34 [IQR: 30-36] minutes, p<0.001). In both TXA and placebo groups, significant fluctuations of the plasmatic concentrations of fibrinolytic mediators were noticed over time, suggesting fibrinolysis activation. Clot lysis time measured by GFC/LT was significantly increased in women of the TXA group as compared with those in the placebo group at T15 (120 [120-120] vs. 36 [34-41] minutes, p<0.001) and T120minutes (113 [99-120] vs. 34 [30-36] minutes, p<0.001) after drug administration, indicating a decreased in fibrinolysis in those women. GFC/LT evidenced fibrinolysis activation during cesarean delivery, linked to a decrease in fibrinolytic inhibitors. GFC/LT revealed a significant antifibrinolytic effect of TXA compared with placebo.

P145. The effect of tranexamic acid on operative and postoperative blood loss in transforaminal lumbar interbody fusion

P145. The effect of tranexamic acid on operative and postoperative blood loss in transforaminal lumbar interbody fusion

Elevated Pre- and Postoperative ROTEM™ Clot Lysis Indices Indicate Reduced Clot Retraction and Increased Mortality in Patients Undergoing Liver Transplantation.

Background: The ROTEM™ clot lysis index, describing the decrease in firmness of a clot with time, predicts mortality in various settings. The variability of the clot lysis index in surgical procedures and the involved pathophysiological mechanisms are unknown. We therefore compared pre- and postoperative clot lysis indices in liver transplantation (LTX) procedures, determined the eventual association with mortality, and investigated the mechanisms underlying decreased clot lysis index using inhibitors of fibrinolysis and clot retraction, respectively. Methods: In this retrospective cohort study, data on pre- and post-transplant ROTEM™ findings as obtained with EXTEM (tissue factor activation), INTEM (intrinsic system activation), FIBTEM (extrinsic system activation and inhibition of clot retraction), APTEM (extrinsic system activation and fibrinolysis inhibition), conventional laboratory coagulation tests, blood loss, transfusion of blood products, and outcome were registered. Results: Pre-transplant clot lysis indices showed a broad distribution ranging from 75% to 99% independent of the activator used (EXTEM, INTEM). During the surgical procedure, median clot lysis index values markedly increased from 92% to 97% (EXTEM) and 93% to 98% (INTEM), respectively (p < 0.0001 each). Aprotinin had no effect on either pre- or postsurgical clot lysis indices. Inhibition of platelet clot retraction with cytochalasin D (FIBTEM) markedly increased the preoperative clot lysis index. High pre- and post-transplantation clot lysis indices were associated with increased mortality irrespective of the activator used (EXTEM, INTEM) and the inhibition of fibrinolysis (APTEM). Inhibition of clot retraction (FIBTEM) abolished the association of clot lysis index with mortality in both pre- and post-transplantation samples. Conclusion: Both pre- and postoperative ROTEM™ clot lysis indices predict mortality in patients following liver transplantation. Inhibitor experiments reveal that the clot lysis index is not an indicator of fibrinolysis, but indicates platelet clot retraction. The marked increase of clot lysis index during liver transplantation is caused by a decrease in clot retraction with eventual consequences for clot stability, retraction of wound margins, and reperfusion of vessels in case of thrombosis.

Effects of tranexamic acid on coagulofibrinolytic markers during the early stage of severe trauma: A propensity score-matched analysis.

Tranexamic acid (TXA) reduces the risk of bleeding trauma death without altering the need for blood transfusion. We examined the effects of TXA on coagulation and fibrinolysis dynamics and the volume of transfusion during the early stage of trauma. This subanalysis of a prospective multicenter study of severe trauma included 276 patients divided into propensity score–matched groups with and without TXA administration. The effects of TXA on coagulation and fibrinolysis markers immediately at (time point 0) and 3 hours after (time point 3) arrival at the emergency department were investigated. The transfusion volume was determined at 24 hours after admission. TXA was administered to the patients within 3 hours (median, 64 minutes) after injury. Significant reductions in fibrin/fibrinogen degradation products and D-dimer levels from time points 0 to 3 in the TXA group compared with the non-TXA group were confirmed, with no marked differences noted in the 24-hour transfusion volumes between the 2 groups. Continuously increased levels of soluble fibrin, a marker of thrombin generation, from time points 0 to 3 and high levels of plasminogen activator inhibitor-1, a marker of inhibition of fibrinolysis, at time point 3 were observed in both groups. TXA inhibited fibrin(ogen)olysis during the early stage of severe trauma, although this was not associated with a reduction in the transfusion volume. Other confounders affecting the dynamics of fibrinolysis and transfusion requirement need to be clarified.

A missense mutation in lectin domain of thrombomodulin causing functional deficiency

Thrombomodulin (TM) functions in coagulation, fibrinolysis and inflammation by its cofactor activity for protein C, thrombin-activatable fibrinolysis inhibitor (TAFI) activation and high mobility group box 1 (HMGB1) degradation induced by thrombin. It has been widely reported that mutations in TM are related to thromboembolic diseases but hardly in lectin domain. Here we report our findings about the functional deficiencies in TM caused by substitution of aspartate with tyrosine at residue 126. Three patients suffering from recurrent thromboembolic diseases were identified with this mutation and their plasma soluble TM levels were decreased. Transfected cells expressing wild-type TM or the variant and corresponding proteins were used to examine TM functions in vitro. The cofactor activity of the mutant for protein C, TAFI activation was reduced to approximately 50% and 60% respectively. Loss in anti-inflammation due to weakened HMGB1 degradation was also observed. And the study with thrombosis models of mice suggested the decreased inhibition of thrombus development of the mutant. Together the results showed deleterious changes on TM function caused by this mutation, which may explain the thrombophilia tendency of the patients. This work provided supportive evidence that mutation in lectin domain of TM might be related to thrombotic diseases and may help us better understand the physiological roles of TM.

Tranexamic acid: Beyond antifibrinolysis.

Tranexamic acid (TXA) is a popular antifibrinolytic drug widely used in hemorrhagic trauma patients and cardiovascular, orthopedic, and gynecological surgical patients. TXA binds plasminogen and prevents its maturation to the fibrinolytic enzyme plasmin. A number of studies have demonstrated the broad life-saving effects of TXA in trauma, superior to those of other antifibrinolytic agents. Besides preventing fibrinolysis and blood loss, TXA has been reported to suppress posttraumatic inflammation and edema. Although the efficiency of TXA transcends simple inhibition of fibrinolysis, little is known about its mechanisms of action besides the suppression of plasmin maturation. Understanding the broader effects of TXA at the cell, organ, and organism levels are required to elucidate its potential mechanisms of action transcending antifibrinolytic activity. In this article, we provide a brief review of the current clinical use of TXA and then focus on the effects of TXA beyond antifibrinolytics such as its anti-inflammatory activity, protection of the endothelial and epithelial monolayers, stimulation of mitochondrial respiration, and suppression of melanogenesis.

Andrographolide Suppresses Expressions of Coagulation and Fibrinolytic Inhibition-Related Factors in LPS-Induced Alveolar Epithelial Cell Type II via NF-κB Signal Pathway In Vitro

BackgroundAndrographolide (Andro) has been confirmed to ameliorate alveolar hypercoagulation and fibrinolysis inhibition via NF-κB pathway in acute respiratory distress syndrome (ARDS), but the specific target of Andro is unknown.PurposeOur aim is to explore the specific target of Andro through which the drug exerted its effects on alveolar hypercoagulation and fibrinolytic inhibition in LPS-induced ARDS.MethodsAECII was treated with different doses of Andro for 1 h, and then stimulated with LPS for 24 h. Expressions of tissue factor (TF), plasminogen activator inhibitor (PAI)-1 and tissue factor pathway inhibitor (TFPI) were detected. Concentrations of thrombin-antithrombin complex (TAT), pro-collagen type III peptide (PIIIP), antithrombin III (ATIII) and activated protein C (APC) in cell supernatant were measured by enzyme linked immunosorbent assay (ELISA). NF-κB signaling pathways activation was simultaneously determined. AECII with p65 down-/over-expression were used as control.ResultsAndro effectively inhibited TF and PAI-1 and promoted TFPI expressions on AECII induced by LPS stimulation. Andro also significantly suppressed the productions of TAT and PIIIP but promoted ATIII and APC secretions from the LPS-treated cell. Furthermore, Andro application obviously inhibited NF-κB signaling pathway activation provoked by LPS, as shown by decreased level of phosphorylation (p‑)-IKKβ/IKKβ, p-p65/p65 and p65 DNA binding activity. The effects of Andro on those factors were obviously strengthened by down- but were weakened by up-regulation of p65 gene in AECII cell.ConclusionsOur data demonstrates that targeting AECII is the mechanism by which Andro ameliorates alveolar hypercoagulaiton and fibrinolytic inhibition via NF-κB pathway in ARDS. Andro is worth to be clinically further studied in ARDS treatment.

GnRH Antagonist Protocol Enhances Coagulation During Controlled Ovarian Stimulation for IVF.

Changes in coagulation and fibrinolysis have been reported in women undergoing controlled ovarian hyperstimulation (COH) supporting a potential hypercoagulable condition related to this treatment. This study aimed at evaluating the changes in fibrin clot properties and thrombin generation induced by two different COH protocols: long with gonadotropin-releasing hormone agonist (GnRH-a) and GnRH antagonist (GnRH-ant). Primary outcomes included determination of plasma fibrin clot properties, including clot permeability (Ks) and efficiency of fibrinolysis using clot lysis time (CLT), along with thrombin generation (prothrombin fragments 1 + 2) and endogenous thrombin potential (ETP) and fibrinolysis inhibitor levels. One hundred twenty-nine infertile women were included in the final analysis. The GnRH-ant protocol resulted in increased ETP (+ 9.8%) and reduced Ks (- 2.4%). Conversely, COH with the GnRH-a protocol reduced thrombin generation by decreasing both ETP (- 6.6%) and F1 + 2 (- 30.8%) together with favorably altered fibrin clot properties represented by increased Ks (+ 21.7%) and reduced CLT (- 13.8%) as well as decreased PAI-1 levels (by 2.5 times). The GnRH-ant compared to the GnRH-a protocol increased PAI-1 levels (+ 77.3%), thrombin generation (9.3% higher ETP), and Ks (+ 13.7%). In the GnRH-a group, post-COH Ks was 14.3% higher (Ks ≥ 7.92 × 10-9 cm2) in women with positive vs. negative pregnancy outcomes. Our results show that the GnRH-ant protocol enhanced thrombin generation and slightly decreased fibrin clot density. COH with the GnRH-a reduced thrombin generation and improved fibrin clot features. This trial was registered (NCT04166825). Clinical Trial Registration Number: NCT04166825.

Composition and Organization of Acute Ischemic Stroke Thrombus: A Wealth of Information for Future Thrombolytic Strategies.

During the last decade, significant progress has been made in understanding thrombus composition and organization in the setting of acute ischemic stroke (AIS). In particular, thrombus organization is now described as highly heterogeneous but with 2 preserved characteristics: the presence of (1) two distinct main types of areas in the core—red blood cell (RBC)-rich and platelet-rich areas in variable proportions in each thrombus—and (2) an external shell surrounding the core composed exclusively of platelet-rich areas. In contrast to RBC-rich areas, platelet-rich areas are highly complex and are mainly responsible for the thrombolysis resistance of these thrombi for the following reasons: the presence of platelet-derived fibrinolysis inhibitors in large amounts, modifications of the fibrin network structure resistant to the tissue plasminogen activator (tPA)-induced fibrinolysis, and the presence of non-fibrin extracellular components, such as von Willebrand factor (vWF) multimers and neutrophil extracellular traps. From these studies, new therapeutic avenues are in development to increase the fibrinolytic efficacy of intravenous (IV) tPA-based therapy or to target non-fibrin thrombus components, such as platelet aggregates, vWF multimers, or the extracellular DNA network.

Pathophysiology and Management of Hypercoagulation in Infectious Diseases

AbstractNumerous systemic infections may have hypercoagulation as one of the complications, which may range from asymptomatic presentation of elevation of biochemical markers of coagulation such as that of fibrin and thrombin generation, to a much severe, symptomatic, life-threatening, disseminated intravascular coagulation (DIC), which results in the formation of thrombi in the microvasculature of various organs. This phenomenon contributes to increase in morbidity and mortality in various infectious diseases. The current review discusses various mechanisms of hypercoagulation during infections such as tissue factor activation, endothelial cell activation, inhibition of physiological anticoagulant pathways, and fibrinolysis inhibition. The review also discusses pathophysiological changes in the coagulation system and its management in the recent pandemic of COVID-19. The article also discusses role of various parenteral and oral anticoagulants in the management of infectious diseases. The review provides clinical data on various anticoagulants used during hospitalization and extended prophylaxis for the management of venous thromboembolism in various infections. Methodology Because this is a review of published literature and no humans or animals were involved, ethical committee approval was not required and patient consent was not required.

Commentary on “Elevated plasma levels of plasminogen activator inhibitor‐1 are associated with risk of future incident venous thromboembolism”: A new role for plasminogen activator inhibitor‐1—An inhibitor of fibrinolysis predicts future venous thromboembolic events and links them to obesity

Commentary on “Elevated plasma levels of plasminogen activator inhibitor‐1 are associated with risk of future incident venous thromboembolism”: A new role for plasminogen activator inhibitor‐1—An inhibitor of fibrinolysis predicts future venous thromboembolic events and links them to obesity