The cytoprotective protein C pathway Mosnier, Laurent O.; Zlokovic, Berislav V.; Griffin, John H.
Blood,
04/2007, Letnik:
109, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Protein C is best known for its mild deficiency associated with venous thrombosis risk and severe deficiency associated with neonatal purpura fulminans. Activated protein C (APC) anticoagulant ...activity involves proteolytic inactivation of factors Va and VIIIa, and APC resistance is often caused by factor V Leiden. Less known is the clinical success of APC in reducing mortality in severe sepsis patients (PROWESS trial) that gave impetus to new directions for basic and preclinical research on APC. This review summarizes insights gleaned from recent in vitro and in vivo studies of the direct cytoprotective effects of APC that include beneficial alterations in gene expression profiles, anti-inflammatory actions, antiapoptotic activities, and stabilization of endothelial barriers. APC's cytoprotection requires its receptor, endothelial cell protein C receptor, and protease-activated receptor-1. Because of its pleiotropic activities, APC has potential roles in the treatment of complex disorders, including sepsis, thrombosis, and ischemic stroke. Although much about molecular mechanisms for APC's effects on cells remains unclear, it is clear that APC's structural features mediating anticoagulant actions and related bleeding risks are distinct from those mediating cytoprotective actions, suggesting the possibility of developing APC variants with an improved profile for the ratio of cytoprotective to anticoagulant actions.
Experimental data indicate that reducing factor XI levels attenuates thrombosis without causing bleeding, but the role of factor XI in the prevention of postoperative venous thrombosis in humans is ...unknown. FXI-ASO (ISIS 416858) is a second-generation antisense oligonucleotide that specifically reduces factor XI levels. We compared the efficacy and safety of FXI-ASO with those of enoxaparin in patients undergoing total knee arthroplasty.
In this open-label, parallel-group study, we randomly assigned 300 patients who were undergoing elective primary unilateral total knee arthroplasty to receive one of two doses of FXI-ASO (200 mg or 300 mg) or 40 mg of enoxaparin once daily. The primary efficacy outcome was the incidence of venous thromboembolism (assessed by mandatory bilateral venography or report of symptomatic events). The principal safety outcome was major or clinically relevant nonmajor bleeding.
Around the time of surgery, the mean (±SE) factor XI levels were 0.38±0.01 units per milliliter in the 200-mg FXI-ASO group, 0.20±0.01 units per milliliter in the 300-mg FXI-ASO group, and 0.93±0.02 units per milliliter in the enoxaparin group. The primary efficacy outcome occurred in 36 of 134 patients (27%) who received the 200-mg dose of FXI-ASO and in 3 of 71 patients (4%) who received the 300-mg dose of FXI-ASO, as compared with 21 of 69 patients (30%) who received enoxaparin. The 200-mg regimen was noninferior, and the 300-mg regimen was superior, to enoxaparin (P<0.001). Bleeding occurred in 3%, 3%, and 8% of the patients in the three study groups, respectively.
This study showed that factor XI contributes to postoperative venous thromboembolism; reducing factor XI levels in patients undergoing elective primary unilateral total knee arthroplasty was an effective method for its prevention and appeared to be safe with respect to the risk of bleeding. (Funded by Isis Pharmaceuticals; FXI-ASO TKA ClinicalTrials.gov number, NCT01713361.).
Highlights • Normalization of international normalized ratio (INR) was associated with improved mortality in acute traumatic coagulopathy (ATC) patients in the setting of isolated traumatic brain ...injury (iTBI). • There was substantial lag time between product delivery and eventual coagulation normalization. • Specific management of coagulopathy should be implemented as early as possible.
A good understanding of the possible risk factors for coronavirus disease 19 (COVID-19) severity could help clinicians in identifying patients who need prioritized treatment to prevent disease ...progression and adverse outcomes. COVID-19-linked coagulopathy is one of the life-threatening severe acute respiratory syndrome coronavirus 2 infections. Growing evidence indicates a correlation between abnormal coagulation and increased risk of venous thromboembolism; in COVID-19-infected patients, yet a clear understanding of the role of coagulopathy in the severity of COVID-19 illness is still unresolved. This retrospective cohort study was thus undertaken to investigate the role of coagulation dysfunction with COVID-19 mortality/severity. Blood samples from 1000 hospitalized patients with COVID-19 pneumonia were collected. The study participants were both male and female in equal ratios with a mean age of 48.94. Patients were followed-up until discharge either for recovery or death. All biochemical investigations-complete blood count and coagulation profile including D-dimers, prothrombin time, partial prothrombin time, and international normalized ratio was performed in COVID-19 survivors and in non-survivors admitted in intensive care unit. In the survivor group, all coagulation parameters were within normal limits, and 8.7% had a low red blood count. The most common risk factors associated with COVID-19 patients were diabetes mellitus (2.8%), hypertension (10.8%), and heart disease (3%). In the non-survivor group, the coagulation parameters were above the normal range (prothrombin in 31.5%, PTT in 10.5%, international normalized ratio in 26.3%, D-dimer in 36.8%) with thrombocytopenia in 21.04% of patients. Other complications were pulmonary embolism in 21.05% and venous thromboembolism in 15.7% of non-survivors. A significant association was found between increased markers of coagulopathy and the severity of SARS-CoV2 infection. Furthermore, the severity of infection was observed to increase with risk factors such as age, heart disease, hypertension, and DM eventually affecting COVID-19 prognosis and mortality.
The association between coagulopathy and either isolated traumatic brain injury (TBI) or progressive hemorrhagic injury (PHI) remains controversial. The aims of this study were to evaluate whether ...isolated TBI induces pronounced coagulopathy, in comparison with non-TBI or TBI in conjunction with other injuries (TBI + other injuries), and to examine whether there is any evidence of a relationship between coagulopathy and PHI in patients who have experienced TBI. The MEDLINE(®) and Embase databases, and the Cochrane Central Register of Controlled Trials (Central), were trawled for relevant studies. Searches covered the period from the inception of each of the databases to June 2015, and were conducted using appropriate combinations of terms and key words based on medical subject headings (MeSH). Studies were included if they compared isolated TBI with a similar severity of injury to other body regions, or compared PHI with non-PHI, with regard to coagulation tests and the prevalence of coagulopathy. We extracted the means and standard deviations (SD) of coagulation test levels, as well as their ranges or the percentage of abnormal coagulation tests, in both cases and controls. A total of 19 studies were included in our systematic review and meta-analysis. Only the mean fibrinogen (FIB) in isolated TBI was found to be significantly higher than in TBI + other injuries (pooled mean difference MD 32.09; 95% confidence interval CI 4.92-59.25; p = 0.02); in contrast, it was also significantly higher than in non-TBI (pooled MD 15.44; 95% CI 0.28-30.59; p = 0.05). We identified 15 studies that compared coagulopathy between a PHI group and a non-PHI group. The PHI group had a lower platelet count (PLT) value (pooled MD -19.21; 95% CI: -26.99 to -11.44, p < 0.001) and a higher international normalized ratio (INR) value (pooled MD 0.07; 95% CI: 0.02-0.13, p = 0.006) than the non-PHI group, but no differences were observed in the mean activated partial thromboplastin time (APTT) and prothrombin time (PT) between the PHI and non-PHI patients. In addition, PHI was significantly associated with a higher percentage of INR >1.2 (pooled OR 3.49 95% CI 1.97-6.20, p < 0.001), PLT <100 × 109/L (pooled OR 4.74 95% CI 2.44-9.20, p < 0.001), and coagulopathy (pooled OR 2.52; 95% CI 1.88- 3.38; p < 0.001), compared with non-PHI. The current clinical evidence does not indicate that the prevalence of coagulopathy in TBI is significantly higher than in injuries of similar severity to other areas of the body, or in multiple injuries with TBI. With respect to the association between coagulopathy and PHI, the occurrence of coagulopathy, INR, and PLT was significantly associated with PHI, but APTT and PT were not found to be associated with PHI. In the future, high quality research will be required to further characterize the effects of coagulopathy on TBI and subsequent PHI.
•We highlight the current knowledge in the field of blood–materials interactions.•We highlight the role of surface chemistry, energy and topography in mediating blood–material interactions.•We ...highlight novel methods for measuring biological responses.
Blood coagulation and platelet adhesion remain major impediments to the use of biomaterials in implantable medical devices. There is still significant controversy and question in the field regarding the role that surfaces play in this process. This manuscript addresses this topic area and reports on state of the art in the field. Particular emphasis is placed on the subject of surface engineering and surface measurements that allow for control and observation of surface-mediated biological responses in blood and test solutions. Appropriate use of surface texturing and chemical patterning methodologies allow for reduction of both blood coagulation and platelet adhesion, and new methods of surface interrogation at high resolution allow for measurement of the relevant biological factors.
Early clot amplitudes measured on thromboelastometry (ROTEM®) predict maximum clot firmness (MCF) in adults. In this multicentre, retrospective study, we aimed to confirm the suspected relationship ...between early ROTEM® variables and MCF, in children undergoing cardiac or non-cardiac surgery.
4762 ROTEM® tests (e.g. EXTEM, INTEM, FIBTEM, APTEM, and HEPTEM) performed in children undergoing cardiac or non-cardiac surgery at three University hospitals between January 2011 and June 2014 were reviewed. To assess the correlation between clot amplitudes measured after 5, 10 and 15 min and MCF, each variable was compared with the corresponding MCF by calculating Spearman’s correlation coefficient.
For the EXTEM® test, we observed that amplitude measured after 5 min (A5: r=0.91, P<0.001), 10 min (A10: r=0.95, P<0.001) and 15 min (A15: r=0.96, P<0.001) were strongly correlated to MCF. The same correlations were observed for INTEM® test (A5: r=0.93, P<0.001; A10: r=0.97, P<0.001; A15: r=0.97, P<0.001), and FIBTEM® test (A5: r=0.93, P<0.001; A10: r=0.94, P<0.001; A15: r=0.96, P<0.001). In addition, the amplitudes measured after five, 10 and 15 min were also strongly correlated with MCF in the APTEM® and the HEPTEM® tests. Receiver operating characteristics (ROC) analysis confirmed that A5, A10, A15 strongly predicted decreased MCF on all ROTEM® tests.
This study confirmed that early values of clot amplitudes measured as soon as five, 10 or 15 min after clotting time could be used to predict maximum clot firmness in all ROTEM® tests.
Dabigatran is a reversible and selective, direct thrombin inhibitor (DTI) undergoing advanced clinical development as its orally active prodrug, dabigatran etexilate. This study set out to determine ...the molecular potency and anticoagulant efficacy of dabigatran and its prodrug dabigatran etexilate. This was achieved through enzyme inhibition and selectivity analyses, surface plasmon resonance studies, platelet aggregation, thrombin generation and clotting assays in vitro and ex vivo. These studies demonstrated that dabigatran selectively and reversibly inhibited human thrombin (Ki: 4.5 nM) as well as thrombin-induced platelet aggregation (IC(50): 10 nM), while showing no inhibitory effect on other platelet-stimulating agents. Thrombin generation in platelet-poor plasma (PPP), measured as the endogenous thrombin potential (ETP) was inhibited concentration-dependently (IC(50): 0.56 microM). Dabigatran demonstrated concentration-dependent anticoagulant effects in various species in vitro, doubling the activated partial thromboplastin time (aPTT), prothrombin time (PT) and ecarin clotting time (ECT) in human PPP at concentrations of 0.23, 0.83 and 0.18 microM, respectively. In vivo, dabigatran prolonged the aPTT dose-dependently after intravenous administration in rats (0.3, 1 and 3 mg/kg) and rhesus monkeys (0.15, 0.3 and 0.6 mg/kg). Dose- and time-dependent anticoagulant effects were observed with dabigatran etexilate administered orally to conscious rats (10, 20 and 50 mg/kg) or rhesus monkeys (1, 2.5 or 5 mg/kg), with maximum effects observed between 30 and 120 min after administration, respectively. These data suggest that dabigatran is a potent, selective thrombin inhibitor and an orally active anticoagulant as the prodrug, dabigatran etexilate.
Cause of trauma-induced coagulopathy Davenport, Ross A; Brohi, Karim
Current opinion in anaesthesiology,
04/2016, Letnik:
29, Številka:
2
Journal Article
Trauma-induced coagulopathy (TIC) is a multifactorial, global failure of the coagulation system to sustain adequate haemostasis after trauma haemorrhage. Damage control resuscitation is associated ...with improved outcomes although the mechanisms of how it corrects TIC have yet to be fully characterized. Identification of predominant pathophysiological pathways in TIC is required to develop effective treatment algorithms for trauma haemorrhage.
TIC is described by varying degrees of dysfibrinogenaemia, hyperfibrinolysis, endothelial dysfunction and impaired platelet activity, dependent on the magnitude of trauma, and severity of haemorrhagic shock. Acute traumatic coagulopathy is the early endogenous process mediated by the protein C pathway in response to tissue injury and hypoperfusion. Thrombin generation appears maintained with altered fibrinogen utilization and activation of fibrinolytic pathways representing key components of TIC. Shedding of the endothelial glycocalyx appears capable of triggering systemic thrombin generation, protein C activation and hyperfibrinolysis and may itself represent a therapeutic target.
Further advances in TIC treatment require an enhanced understanding of the dynamic changes in the equilibrium between pro and anticoagulant factors, downstream effectors, and the host response. Delineating the interaction between fibrinolysis, fibrinogen utilization, platelet activity, and thrombin generation may provide opportunity for targeted intervention.
Genomics of bleeding disorders Goodeve, A. C.; Pavlova, A.; Oldenburg, J.
Haemophilia,
20/May , Letnik:
20, Številka:
s4
Journal Article
Recenzirano
Odprti dostop
Summary
Molecular genetic tools are widely applied in inherited bleeding disorders. New genes involved in haemorrhagic disorders have been identified by genome wide linkage analysis on families with ...a specific phenotype. LMNA1 or MCFD in combined FV/FVIII‐deficiency and VKORC1 in vitamin K coagulation factor deficiency type 2 are two examples. Identification of the causative gene mutation has become standard for most bleeding disorders. Knowledge of the causative mutation allows genetic counselling in affected families and most importantly adds to the pathophysiological understanding of phenotypes. Haemophilia A represents a model as the F8 gene mutation predicts the risk of developing an inhibitor and more recently also the bleeding phenotype. In this review novel genetic diagnostic strategies for bleeding disorders are outlined and inhibitor formation is presented as an example for clinical relevant phenotype/genotype correlation studies.
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