Release Of Plasminogen Activator Research Articles

Abstract P523: Circulating Endothelial-Cell Derived Microvesicles Associated With Insufficient Sleep Impairs Cerebral Microvascular Fibrinolytic Capacity

Chronic insufficient sleep (< 7 hour/night) is associated with increased risk of ischemic stroke. Endothelial cell dysfunction, specifically impairment endothelial release of tissue-type plasminogen activator (t-PA), represents an important mechanism underlying cerebrovascular events such as ischemic stroke. Endothelial cells are the primary site of synthesis and release of t-PA, the plasminogen activator in fibrinolysis and, thus, a key regulator of endogenous thrombolysis. We have previously demonstrated that insufficient sleep is associated with impaired endothelial capacity to release t-PA, however the mechanisms for the sleep-related fibrinolytic impairment are not well understood. Clinical interest in endothelial cell-derived microvesicles (EMVs) has intensified due to their involvement in the development of endothelial dysfunction and, in turn, cardiovascular and cerebrovascular events. The aim of this study was to determine, in vitro, the effects of circulating EMVs isolated from adults with chronic insufficient sleep on brain endothelial cell t-PA release. Considering EMVs are known to cross the blood brain barrier and are associated with ischemic stroke incidence, severity and outcome; circulating EMVs associated with insufficient sleep may be a mediator of stroke risk. Twenty-four healthy, non-obese, normotensive, sedentary adults (age: 23-69 years) were studied: 12 normal nightly sleep duration (7M/5F; age: 47±5 yr; nightly sleep: 7.4±0.1 hour/night) and 12 with short nightly sleep duration (9M/3F; 53±4 yr; 5.9±0.2 hour/night). EMV identification (CD144+) and isolation from peripheral blood was performed by flow cytometry. Human cerebral microvascular endothelial cells (hCMECs) were cultured and separately treated with EMVs from each subject. Cultured hCMECs were treated with EMVs in the absence and presence of thrombin (1 unit/mL) for 24 hours. Intracellular expression of t-PA was significantly lower (~30%) in hCMECs treated with EMVs from adults with insufficient sleep (31±3 AU) compared with cells treated with EMVs from normal sleep adults (40±3 AU). Although the effect of EMVs on basal t-PA release was not different between the groups; thrombin-stimulated t-PA release was significantly lower in cells treated with EMVs from adults with insufficient sleep (from 57±3 to 59±4 ng/mL) compared with EMVs from adults with normal sleep (from 53±3 to 66±4 ng/mL). The capacity of hCMECs to release t-PA in response to thrombin was ~75% lower when treated with EMVs from adults with insufficient sleep. These results indicate that circulating EMVs associated with chronic insufficient sleep diminishes brain endothelial cell t-PA production and impairs t-PA release. Circulating EMVs represent a mechanistic factor in insufficient sleep-related fibrinolytic dysfunction and ischemic stroke risk.

Phenotypes of Disseminated Intravascular Coagulation.

Two phenotypes of disseminated intravascular coagulation (DIC) are systematically reviewed. DIC is classified into thrombotic and fibrinolytic phenotypes characterized by thrombosis and hemorrhage, respectively. Major pathology of DIC with thrombotic phenotype is the activation of coagulation, insufficient anticoagulation with endothelial injury, and plasminogen activator inhibitor-1-mediated inhibition of fibrinolysis, leading to microvascular fibrin thrombosis and organ dysfunction. DIC with fibrinolytic phenotype is defined as massive thrombin generation commonly observed in any type of DIC, combined with systemic pathologic hyperfibrinogenolysis caused by underlying disorder that results in severe bleeding due to excessive plasmin formation. Three major pathomechanisms of systemic hyperfibrinogenolysis have been considered: (1) acceleration of tissue-type plasminogen activator (t-PA) release from hypoxic endothelial cells and t-PA-rich storage pools, (2) enhancement of the conversion of plasminogen to plasmin due to specific proteins and receptors that are expressed on cancer cells and endothelial cells, and (3) alternative pathways of fibrinolysis. DIC with fibrinolytic phenotype can be diagnosed by DIC diagnosis followed by the recognition of systemic pathologic hyperfibrin(ogen)olysis. Low fibrinogen levels, high fibrinogen and fibrin degradation products (FDPs), and the FDP/D-dimer ratio are important for the diagnosis of systemic pathologic hyperfibrin(ogen)olysis. Currently, evidence-based treatment strategies for DIC with fibrinolytic phenotypes are lacking. Tranexamic acid appears to be one of the few methods to be effective in the treatment of systemic pathologic hyperfibrin(ogen)olysis. International cooperation for the elucidation of pathomechanisms, establishment of diagnostic criteria, and treatment strategies for DIC with fibrinolytic phenotype are urgent issues in the field of thrombosis and hemostasis.

Endothelial-derived extracellular vesicles associated with electronic cigarette use impair cerebral microvascular cell function.

The aim of this study was to determine the effect of circulating endothelial cell-derived microvesicles (EMVs) isolated from e-cigarette users on human cerebral microvascular endothelial cells (hCMECs) nitric oxide (NO) and endothelin (ET)-1 production and tissue-type plasminogen activator (t-PA) release. Circulating EMVs (CD144-PE) were isolated (flow cytometry) from 27 young adults (19-25 yr): 10 nonsmokers (6 M/4 F), 10 e-cigarette users (6 M/4 F), and 7 tobacco cigarette smokers (4 M/3 F). hCMECs were cultured and treated with isolated EMVs for 24 h. EMVs from e-cigarette users and cigarette smokers induced significantly higher expression of p-eNOS (Thr495; 28.4 ± 4.6 vs. 29.1 ± 2.8 vs. 22.9 ± 3.8 AU), Big ET-1 (138.8 ± 19.0 vs. 141.7 ± 19.1 vs. 90.3 ± 18.8 AU) and endothelin converting enzyme (107.6 ± 10.1 and 113.5 ± 11.8 vs. 86.5 ± 13.2 AU), and significantly lower expression of p-eNOS (Ser1177; 7.4 ± 1.7 vs. 6.5 ± 0.5 vs. 9.7 ± 1.6 AU) in hCMECs than EMVs from nonsmokers. NO production was significantly lower and ET-1 production was significantly higher in hCMECs treated with EMVs from e-cigarette (5.7 ± 0.8 µmol/L; 33.1 ± 2.9 pg/mL) and cigarette smokers (6.3 ± 0.7 µmol/L; 32.1 ± 3.9 pg/mL) than EMVs from nonsmokers (7.6 ± 1.2 µmol/L; 27.9 ± 3.1 pg/mL). t-PA release in response to thrombin was significantly lower in hCMECs treated with EMVs from e-cigarette users (from 38.8 ± 6.3 to 37.4 ± 8.3 pg/mL) and cigarette smokers (31.5 ± 5.5 to 34.6 ± 8.4 pg/mL) than EMVs from nonsmokers (38.9 ± 4.3 to 48.4 ± 7.9 pg/mL). There were no significant differences in NO, ET-1, or t-PA protein expression or production in hCMECs treated with EMVs from e-cigarette users and smokers. Circulating EMVs associated with e-cigarette use adversely affects brain microvascular endothelial cells and may contribute to reported cerebrovascular dysfunction with e-cigarette use.NEW & NOTEWORTHY In the present study, we determined the effect of circulating endothelial cell-derived microvesicles (EMVs) isolated from e-cigarette users on human cerebral microvascular endothelial cells (hCMECs) nitric oxide (NO) and endothelin (ET)-1 production and tissue-type plasminogen activator (t-PA) release. EMVs from e-cigarette users reduced brain microvascular endothelial cell NO production, enhanced ET-1 production, and impaired endothelial t-PA release. EMVs are a potential mediating factor in the increased risk of stroke associated with e-cigarette use.

Aging Is Associated with a Circulating Endothelial Cell-Derived Microvesicle Phenotype that Impairs Cerebral Fibrinolytic Capacity

Aging is associated with increased risk and prevalence of ischemic stroke. Endothelial cell dysfunction is considered to be a central mechanism underlying the age-related increase in cerebrovascular accidents (CVA). However, the direct, and indirect, effects of aging on endothelial cell biology are diverse and not completely understood. Reduced endogenous fibrinolytic activity is a central etiologic factor underlying ischemic stroke. Endothelial cells are the primary site of synthesis and release of tissue-type plasminogen activator (t-PA), the main plasminogen activator in fibrinolysis and central regulator. Clinical interest in circulating extracellular vesicles, particularly endothelial cell-derived microvesicles (EMVs), has intensified due to their involvement in the development and progression of endothelial dysfunction and CVA. The aim of this study was to determine, in vitro, the effect of circulating EMVs isolated from young and older adults on brain endothelial cell fibrinolytic capacity. We hypothesized that EMVs from older adults would reduce brain endothelial cell t-PA production and release and increase PAI-1 production compared with EMVs from young adults. Twenty-two healthy, non-obese, normotensive, sedentary adults were studied: 10 young (6M/4F; age: 25±1 yr) and 12 older (7M/5F; 64±2 yr). EMV identification (CD144 + ) and isolation from peripheral blood were performed by flow cytometry. Human cerebral microvascular endothelial cells (hCMECs) were cultured and separately treated with EMVs from each subject. Cultured hCMECs were treated with EMVs in the absence and presence of thrombin (1 unit/mL) for 24 hours. Basal expression of t-PA (25.2±1.5 vs 39.8±1.8 AU) and the t-PA response to thrombin (32.5±1.5 vs 57.2±2.2 AU) were significantly lower (~35%) in hCMECs treated with EMVs from older compared with young adults. Concordant with changes in cell protein expression, basal t-PA production (55.2±3.5 vs 70.1±3.7 ng/mL) and thrombin-stimulated t-PA production (61.9±3.7 vs 88.4±3.8 ng/mL) was significantly lower in cells treated with EMVs from older adults. In conclusion, circulating EMVs may contribute to the increased risk of ischemic stroke with aging by impairing brain endothelial cell fibrinolytic capacity. Diminished capacity of the endothelium to release t-PA is a key mechanistic factor underlying cerebral thrombosis. Nothing to Disclose This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

SHock-INduced Endotheliopathy (SHINE): A mechanistic justification for viscoelastography-guided resuscitation of traumatic and non-traumatic shock.

Irrespective of the reason for hypoperfusion, hypocoagulable and/or hyperfibrinolytic hemostatic aberrancies afflict up to one-quarter of critically ill patients in shock. Intensivists and traumatologists have embraced the concept of SHock-INduced Endotheliopathy (SHINE) as a foundational derangement in progressive shock wherein sympatho-adrenal activation may cause systemic endothelial injury. The pro-thrombotic endothelium lends to micro-thrombosis, enacting a cycle of worsening perfusion and increasing catecholamines, endothelial injury, de-endothelialization, and multiple organ failure. The hypocoagulable/hyperfibrinolytic hemostatic phenotype is thought to be driven by endothelial release of anti-thrombogenic mediators to the bloodstream and perivascular sympathetic nerve release of tissue plasminogen activator directly into the microvasculature. In the shock state, this hemostatic phenotype may be a counterbalancing, yet maladaptive, attempt to restore blood flow against a systemically pro-thrombotic endothelium and increased blood viscosity. We therefore review endothelial physiology with emphasis on glycocalyx function, unique biomarkers, and coagulofibrinolytic mediators, setting the stage for understanding the pathophysiology and hemostatic phenotypes of SHINE in various etiologies of shock. We propose that the hyperfibrinolytic phenotype is exemplified in progressive shock whether related to trauma-induced coagulopathy, sepsis-induced coagulopathy, or post-cardiac arrest syndrome-associated coagulopathy. Regardless of the initial insult, SHINE appears to be a catecholamine-driven entity which early in the disease course may manifest as hyper- or hypocoagulopathic and hyper- or hypofibrinolytic hemostatic imbalance. Moreover, these hemostatic derangements may rapidly evolve along the thrombohemorrhagic spectrum depending on the etiology, timing, and methods of resuscitation. Given the intricate hemochemical makeup and changes during these shock states, macroscopic whole blood tests of coagulative kinetics and clot strength serve as clinically useful and simple means for hemostasis phenotyping. We suggest that viscoelastic hemostatic assays such as thromboelastography (TEG) and rotational thromboelastometry (ROTEM) are currently the most applicable clinical tools for assaying global hemostatic function-including fibrinolysis-to enable dynamic resuscitation with blood products and hemostatic adjuncts for those patients with thrombotic and/or hemorrhagic complications in shock states.

Point-of-care diagnosis and monitoring of fibrinolysis resistance in the critically ill: results from a feasibility study

BackgroundFibrinolysisis is essential for vascular blood flow maintenance and is triggered by endothelial and platelet release of tissue plasminogen activator (t-PA). In certain critical conditions, e.g. sepsis, acute respiratory failure (ARF) and trauma, the fibrinolytic response is reduced and may lead to widespread thrombosis and multi-organ failure. The mechanisms underpinning fibrinolysis resistance include reduced t-PA expression and/or release, reduced t-PA and/or plasmin effect due to elevated inhibitor levels, increased consumption and/or clearance. This study in critically ill patients with fibrinolysis resistance aimed to evaluate the ability of t-PA and plasminogen supplementation to restore fibrinolysis with assessment using point-of-care ClotPro viscoelastic testing (VET).MethodsIn prospective, observational studies, whole-blood ClotPro VET evaluation was carried out in 105 critically ill patients. In 32 of 58 patients identified as fibrinolysis-resistant (clot lysis time > 300 s on the TPA-test: tissue factor activated coagulation with t-PA accelerated fibrinolysis), consecutive experimental whole-blood VET was carried out with repeat TPA-tests spiked with additional t-PA and/or plasminogen and the effect on lysis time determined. In an interventional study in a patient with ARF and fibrinolysis resistance, the impact of a 24 h intravenous low-dose alteplase infusion on coagulation and fibrinolysis was prospectively monitored using standard ClotPro VET.ResultsDistinct response groups emerged in the ex vivo experimental VET, with increased fibrinolysis observed following supplementation with (i) t-PA only or (ii) plasminogen and t-PA. A baseline TPA-test lysis time of > 1000 s was associated with the latter group. In the interventional study, a gradual reduction (25%) in serial TPA-test lysis times was observed during the 24 h low-dose alteplase infusion.ConclusionsClotPro viscoelastic testing, the associated TPA-test and the novel experimental assays may be utilised to (i) investigate the potential mechanisms of fibrinolysis resistance, (ii) guide corrective treatment and (iii) monitor in real-time the treatment effect. Such a precision medicine and personalised treatment approach to the management of fibrinolysis resistance has the potential to increase treatment benefit, while minimising adverse events in critically ill patients.Trial registration: VETtiPAT-ARF, a clinical trial evaluating ClotPro-guided t-PA (alteplase) administration in fibrinolysis-resistant patients with ARF, is ongoing (ClinicalTrials.gov NCT05540834; retrospectively registered September 15th 2022).

Conventional and Pro-Inflammatory Pathways of Fibrinolytic Activation in Non-Traumatic Hyperfibrinolysis.

Hyperfibrinolysis (HF) frequently occurs after severe systemic hypoperfusion during major trauma and out-of-hospital cardiac arrest (OHCA). In trauma-induced HF, hypoperfusion, the activation of protein C (APC), and the release of tissue plasminogen activator (t-PA) have been identified as the driving elements of premature clot breakdown. The APC pathway also plays a role in inflammatory responses such as neutrophil extracellular trap formation (NETosis), which might contribute to lysis through cleavage of fibrin by neutrophil elastases. We investigated whether the APC and the plasminogen pathway were general drivers of HF, even in the absence of a traumatic incident. Additionally, we were interested in inflammatory activation such as the presence of NETs as potential contributing factors to HF. A total of 41 patients with OHCA were assigned to a HF and a non-HF group based on maximum lysis (ML) in thromboelastometry. Thrombin-antithrombin (TAT)-complex, soluble thrombomodulin (sTM), APC-PC inhibitor complex, t-PA, PAI-1, t-PA-PAI-1 complex, plasmin-antiplasmin (PAP), d-dimers, neutrophil elastase, histonylated DNA (hDNA) fragments, and interleukin-6 were assessed via immunoassays in the HF group vs. non-HF. APC-PC inhibitor complex is significantly higher in HF patients. Antigen levels of t-PA and PAI-1 do not differ between groups. However, t-PA activity is significantly higher and t-PA-PAI-1 complex significantly lower in the HF group. Consistent with these results, PAP and d-dimers are significantly elevated in HF. HDNA fragments and neutrophil elastase are not elevated in HF patients, but show a high level of correlation, suggesting NETosis occurs in OHCA as part of inflammatory activation and cellular decay. Just as in trauma, hypoperfusion, the activation of protein C, and the initiation of the plasminogen pathway of fibrinolysis manifest themselves in the HF of cardiac arrest. Despite features of NETosis being detectable in OHCA patients, early pro-inflammatory responses do not appear be associated with HF in cardiac arrest.

Laser thrombolysis and in vitro release kinetics of tPA encapsulated in chitosan polysulfate-coated nanoliposome

A major challenge in managing coronary artery disease is to find an effective thrombolytic therapy with minimal side effects. Laser thrombolysis is a practical procedure to remove the thrombus from inside blocked arteries, although it can cause embolism and re-occlusion of the vessel. The present study aimed to design a liposome drug delivery system for the controlled release of tissue plasminogen activator (tPA) and delivery of drug system into the thrombus by Nd:YAG laser at a wavelength of 532 nm for the treatment of arterial occlusive diseases. In this study, tPA encapsulated into the chitosan polysulfate-coated liposome (Lip/PSCS-tPA) was fabricated by a thin-film hydration technique. The particle size of Lip/tPA and Lip/PSCS-tPA was 88 and 100 nm, respectively. The release rate of tPA from Lip/PSCS-tPA was measured to be 35 % and 66 % after 24 h and 72 h, respectively. Thrombolysis through the delivery of Lip/PSCS-tPA into the thrombus during the laser irradiation was higher compared to irradiated thrombus without the nanoliposomes. The expression of IL-10 and TNF-α genes was studied by RT-PCR. The level of TNF-α for Lip/PSCS-tPA was lower than that of tPA, which can lead to improved cardiac function. Also, in this study, the thrombus dissolution process was studied using a rat model. After 4 h, the thrombus area in the femoral vein was significantly lower for groups treated with Lip/PSCS-tPA (5 %) compared to the groups treated with tPA alone (45 %). Thus, according to our results, the combination of Lip/PSCS-tPA and laser thrombolysis can be introduced as an appropriate technique for accelerating thrombolysis.

Commentary on “The suboptimal fibrinolytic response in COVID‐19 is dictated by high PAI‐1”

Commentary on “The suboptimal fibrinolytic response in COVID‐19 is dictated by high PAI‐1”

Arterial stiffness, endothelial dysfunction and impaired fibrinolysis are pathogenic mechanisms contributing to cardiovascular risk in ANCA-associated vasculitis

Cardiovascular disease is a complication of systemic inflammatory diseases including anti-neutrophil cytoplasm antibody-associated vasculitis (AAV). The mechanisms of cardiovascular morbidity in AAV are poorly understood, and risk-reduction strategies are lacking. Therefore, in a series of double-blind, randomized case-control forearm plethysmography and crossover systemic interventional studies, we examined arterial stiffness and endothelial function in patients with AAV in long-term disease remission and in matched healthy volunteers (32 each group). The primary outcome for the case-control study was the difference in endothelium-dependent vasodilation between health and AAV, and for the crossover study was the difference in pulse wave velocity (PWV) between treatment with placebo and selective endothelin-A receptor antagonism. Parallel invitro studies of circulating monocytes and platelets explored mechanisms. Compared to healthy volunteers, patients with AAV had 30% reduced endothelium-dependent vasodilation and 50% reduced acute release of endothelial active tissue plasminogen activator (tPA), both significant in the case-control study. Patients with AAV had significantly increased arterial stiffness (PWV: 7.3 versus 6.4 m/s). Plasma endothelin-1 was two-fold higher in AAV and independently predicted PWV and tPA release. Compared to placebo, both selective endothelin-A and dual endothelin-A/B receptor blockade reduced PWV and increased tPA release in AAV in the crossover study. Mechanistically, patients with AAV had increased platelet activation, more platelet-monocyte aggregates, and altered monocyte endothelin receptor function, reflecting reduced endothelin-1 clearance. Patients with AAV in long-term remission have elevated cardiovascular risk and endothelin-1 contributes to this. Thus, our data support a role for endothelin-blockers to reduce cardiovascular risk by reducing arterial stiffness and increasing circulating tPA activity.

The complex role of kininogens in hereditary angioedema.

Human high molecular weight kininogen (HK) is the substrate from which bradykinin is released as a result of activation of the plasma “contact” system, a cascade that includes the intrinsic coagulation pathway, and a fibrinolytic pathway leading to the conversion of plasminogen to plasmin. Its distinction from low molecular weight kininogen (LK) was first made clear in studies of bovine plasma. While early studies did suggest two kininogens in human plasma also, their distinction became clear when plasma deficient in HK or both HK and LK were discovered. The light chain of HK is distinct and has the site of interaction with negatively charged surfaces (domain 5) plus a 6th domain that binds either prekallikrein or factor XI. HK is a cofactor for multiple enzymatic reactions that relate to the light chain binding properties. It augments the rate of conversion of prekallikrein to kallikrein and is essential for the activation of factor XI. It indirectly augments the “feedback” activation of factor XII by plasma kallikrein. Thus, HK deficiency has abnormalities of intrinsic coagulation and fibrinolysis akin to that of factor XII deficiency in addition to the inability to produce bradykinin by factor XII-dependent reactions. The contact cascade binds to vascular endothelial cells and HK is a critical binding factor with binding sites within domains 3 and 5. Prekallikrein (or factor XI) is attached to HK and is brought to the surface. The endothelial cell also secretes proteins that interact with the HK-prekallikrein complex resulting in kallikrein formation. These have been identified to be heat shock protein 90 (HSP 90) and prolylcarboxypeptidase. Cell release of urokinase plasminogen activator stimulates fibrinolysis. There are now 6 types of HAE with normal C1 inhibitors. One of them has a mutated kininogen but the mechanism for overproduction (presumed) of bradykinin has not yet been determined. A second has a mutation involving sulfation of proteoglycans which may lead to augmented bradykinin formation employing the cell surface reactions noted above.

Tissue-type plasminogen activator induces TNF-α-mediated preconditioning of the blood-brain barrier

Ischemic tolerance is a phenomenon whereby transient exposure to a non-injurious preconditioning stimulus triggers resistance to a subsequent lethal ischemic insult. Despite the fact that not only neurons but also astrocytes and endothelial cells have a unique response to preconditioning stimuli, current research has been focused mostly on the effect of preconditioning on neuronal death. Thus, it is unclear if the blood-brain barrier (BBB) can be preconditioned independently of an effect on neuronal survival. The release of tissue-type plasminogen activator (tPA) from perivascular astrocytes in response to an ischemic insult increases the permeability of the BBB. In line with these observations, treatment with recombinant tPA increases the permeability of the BBB and genetic deficiency of tPA attenuates the development of post-ischemic edema. Here we show that tPA induces ischemic tolerance in the BBB independently of an effect on neuronal survival. We found that tPA renders the BBB resistant to an ischemic injury by inducing TNF-α-mediated astrocytic activation and increasing the abundance of aquaporin-4-immunoreactive astrocytic end-feet processes in the neurovascular unit. This is a new role for tPA, that does not require plasmin generation, and with potential therapeutic implications for patients with cerebrovascular disease.

Negative Influence of Insufficient Sleep on Endothelial Vasodilator and Fibrinolytic Function in Hypertensive Adults.

[Figure: see text].

Coagulation and Fibrinolytic Disorder

Traumatic brain injury(TBI)is associated with coagulation and fibrinolytic disorder. It is characterized by consumptive coagulopathy and secondary hyperfibrinolysis associated with hypercoagulability and by hyperfibrinolysis due to the release of tissue plasminogen activator from the injured brain. Thrombin antithrombin III complex, a coagulation parameter, is abnormally high immediately after TBI and declines 6 hours after TBI. Fibrinogen, a coagulation factor, is rapidly consumed and degraded within 3 hours of TBI. D-dimer, a fibrinolytic parameter, is abnormally high on arrival at the hospital and reaches its maximum value 3 hours after TBI; during this time, bleeding tendency increases. Plasminogen activator inhibitor-1, a parameter of fibrinolysis shutdown, peaks at 6 hours after TBI. D-dimer is also known to be a prognostic factor. Patients with a high D-dimer level despite a good level of consciousness on admission are more likely to be "talk and deteriorate." Administration of tranexamic acid, an anti-fibrinolytic agent, early in the acute phase of TBI may reduce mortality. Fresh frozen plasma transfusion should be performed within 3 hours of TBI with monitoring of fibrinogen levels, and the administration dose should be set with a target fibrinogen level of ≧ 150 mg/dL. However, excessive administration should also be avoided. Thus, in the acute phase of TBI, coagulation and fibrinolytic activity changes dynamically and may adversely affect the complicated injury; therefore, monitoring coagulation and fibrinolytic parameters while conducting treatment is recommended.

Thromboplasminflammation in COVID-19 Coagulopathy: Three Viewpoints for Diagnostic and Therapeutic Strategies.

Thromboplasminflammation in coronavirus disease 2019 (COVID-19) coagulopathy consists of angiotensin II (Ang II)-induced coagulopathy, activated factor XII (FXIIa)- and kallikrein, kinin system-enhanced fibrinolysis, and disseminated intravascular coagulation (DIC). All three conditions induce systemic inflammation via each pathomechanism-developed production of inflammatory cytokines. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) downregulates angiotensin-converting enzyme 2, leading to an increase in Ang II levels. Ang II-induced coagulopathy comprising platelet activation, thrombin generation, plasminogen activator inhibitor-1 expression and endothelial injury causes thrombosis via the angiotensin II type 1 receptor. SARS-CoV-2 RNA and neutrophil extracellular trap (NET) DNA activate FXII, resulting in plasmin generation through FXIIa- and kallikrein-mediated plasminogen conversion to plasmin and bradykinin-induced tissue-type plasminogen activator release from the endothelium via the kinin B2 receptor. NETs induce immunothrombosis at the site of infection (lungs), through histone- and DNA-mediated thrombin generation, insufficient anticoagulation control, and inhibition of fibrinolysis. However, if the infection is sufficiently severe, immunothrombosis disseminates into the systemic circulation, and DIC, which is associated with the endothelial injury, occurs. Inflammation, and serine protease networks of coagulation and fibrinolysis, militate each other through complement pathways, which exacerbates three pathologies of COVID-19 coagulopathy. COVID-19 coagulopathy causes microvascular thrombosis and bleeding, resulting in multiple organ dysfunction and death in critically ill patients. Treatment targets for improving the prognosis of COVID-19 coagulopathy include thrombin, plasmin, and inflammation, and SARS-CoV-2 infection. Several drugs are candidates for controlling these conditions; however, further advances are required to establish robust treatments based on a clear understanding of molecular mechanisms of COVID-19 coagulopathy.

Vascular mechanisms and manifestations of COVID-19

Vascular mechanisms and manifestations of COVID-19

Assessment the role of tranexamic acid in prevention of postpartum hemorrhage

BackgroundPostpartum hemorrhage (PPH) is one of the leading causes of maternal mortality and morbidity worldwide. It is believed that hemostatic imbalance secondary to release of tissue plasminogen activator (tPA) and subsequent hyperfibrinolysis plays a major role in PPH pathogenesis. Antifibrinolytic drugs such as tranexamic acid (TXA) are widely used in hemorrhagic conditions associated with hyperfibrinolysis. TXA reduced maternal death due to PPH and its use as a part of PPH treatment is recommended, and in recent years, a number of trials have investigated the efficacy of prophylactic use of TXA in reducing the incidence and the severity of PPH.The study is aiming to assess the efficacy of tranexamic acid in reducing blood loss throughout and after the lower segment cesarean section and reducing the risk of postpartum hemorrhage.ResultsThe amount of blood loss was significantly lower in the study group than the control group (416.12±89.95 and 688.68±134.77 respectively). Also the 24-h postoperative hemoglobin was significantly higher in the study group (11.66±0.79 mg/dl) compared to the control group (10.53±1.07mg/dl), and the 24-h postoperative hematocrit value was significantly higher in the study group (34.99±2.40) compared to control (31.62±3.22).ConclusionProphylactic administration of tranexamic acid reduces intraoperative and postoperative bleeding in cesarean section and the incidence of postpartum hemorrhage.

Cytokine-Storm-Induced Coagulopathy In Critical COVID-19 and Septic Shock Patients: Head-to-Head Comparison

Background: A cytokine-storm-induced coagulopathy has been described in both critical COVID-19 and septic shock. Improving the understanding of the critical COVID-19 pathophysiology could help in finding new therapeutic targets already explored in the treatment of septic shock. Methods: This prospective observational was conducted between February 1, 2019, and June 1, 2020. Consecutive adult patients admitted to ICU for critical COVID-19 with acute respiratory distress syndrome (ARDS) (n=22), septic shock (n=48) and matched control patients (n=48) were enrolled. A between-group comparison of lung histopathology, clinical characteristics and outcomes and key plasmatic soluble biomarkers of inflammation and coagulopathy was performed. Findings: The histopathological findings showed microthrombi with NETosis in both COVID-19- and septic shock-related ARDS. In the prospective cohort, the critical COVID-19 patients exhibited a prolonged ICU length-of-stay, less organ failure, no sepsis-induced coagulopathy, a higher level of soluble tissue factor (106±57 versus 60±28pg/mL for septic shock, pInterpretation: Critical COVID-19 exhibits a prolonged disease course but less organ failure compared to septic shock. At ICU admission, COVID-19 is characterized by a lymphocytic immune response and distinct coagulopathy with less platelet or coagulation factor consumption, and fibrinolysis alterations. Clinical Trial Registration Details: NCT04107402.Funding Information: Fondation Saint-Luc (Brussels, Belgium) and QUALIblood s.a.Declaration of Interests: The Division of Cardiology at Cliniques universitaires Saint-Luc, Belgium, has received unrestricted research grants from AstraZeneca (Belgium). J.D. is the CEO and founder of QUALIblood s.a., a Belgian Contract Research Organization. The remaining authors declare no competing interests.Ethics Approval Statement: The ethics committee approved the study protocol, and all patients signed their informed consent (B403201938590, NCT04107402). Protocol amendment was done to include COVID-19 patients in the ongoing study.

Tranexamic acid is associated with reduced complement activation in trauma patients with hemorrhagic shock and hyperfibrinolysis on thromboelastography.

: Trauma with hemorrhagic shock causes massive tissue plasminogen activator release, plasmin generation, and hyperfibrinolysis. Tranexamic acid (TXA) has recently been used to treat bleeding in trauma by preventing plasmin generation to limit fibrinolysis. Trauma patients also have increased complement activation that correlates with mortality and organ failure, but the source of activation is not clear, and plasmin has recently been shown to efficiently cleave C3 and C5 to their activated fragments. We hypothesized that trauma patients in hemorrhagic shock with hyperfibrinolysis on thromboelastography (TEG) LY30 would have increased complement activation at early time points, as measured by soluble C5b-9 complex, and TXA would prevent this. Plasma samples were obtained from an unrelated, previously performed IRB-approved prospective randomized study of trauma patients. Three groups were studied with n = 5 patients in each group: patients without hyperfibrinolysis (TEG LY30 < 3%) (who therefore did not get TXA), patients with hyperfibrinolysis (TEG LY30 > 3%) who did not get TXA, and patients with hyperfibrinolysis who were then treated with TXA. We found that patients who did not receive TXA, regardless of fibrinolytic phenotype, had elevated soluble C5b-9 levels at 6 h relative to emergency department levels. In contrast, all five patients with initial TEG LY30 more than 3% and were then treated with TXA had reduced soluble C5b-9 levels at 6 h relative to emergency department levels. There were no differences in PF1 + 2, Bb, or C4d levels between groups, suggesting that coagulation and complement activation pathways may not be primarily responsible for the observed differences.

COVID-19 coagulopathy vs disseminated intravascular coagulation

Patients with severe COVID-19 infections frequently manifest coagulation abnormalities that are associated with respiratory deterioration and death. In addition, many patients with severe COVID-19 infections develop thromboembolic complications, which seem to be related to the coagulopathy. It has been suggested that undiagnosed pulmonary embolism contributes to a sudden deterioration of pulmonary oxygen exchange that is sometimes seen in patients with COVID-19 infections. The coagulation changes associated with COVID-19 mimic other systemic coagulopathies that are regularly seen during severe infections, such as disseminated intravascular coagulation or thrombotic microangiopathy. However, at the same time, the clinical and laboratory characteristics of the coagulation changes in COVID are distinctly different from those in the common presentation of these conditions. Severe COVID-19 infections seem to cause a profound coagulation abnormality caused by inflammation-induced changes in coagulation in combination with severe endothelial cell injury, with consequent massive release of von Willebrand factor and plasminogen activators. This coagulopathy likely contributes to pulmonary microvascular thrombosis, bronchoalveolar fibrin deposition (which is a hallmark of adult respiratory distress syndrome), and thromboembolic complications.