Fibrinolytic Research Articles

INTRAOPERATIVE STATE OF THE HEMOCOAGULATION SYSTEM IN PATIENTS WITH OPEN AND ENDOVASCULAR REVASCULARIZATION OF INFRAINGUAL ARTERIAL SEGMENT IN THE PRESENCE OF STENOTIC-OCCLUSIVE PROCESS OF TIBIAL ARTERIES

Background. Among all postoperative complications associated with revascularization of atherosclerotic steno-occlusive process of the femoral-distal artery, thrombosis of the reconstruction segment is 6-32%. Objective. Prevention of thrombotic complications through vascular revascularization of the lower extremity by using a pathogenetically reasonable system of postoperative thromboprophylaxis. Methods. The study involved 97 patients with atherosclerotic stenotic-occlusive process of the infrainguinal artery in cases of stenotic-occlusive lesions of the tibial arteries. In order to study the state of the hemocoagulation system on patients, the methods for studying the indicators of coagulation, fibrinolytic and aggregation systems were used. Results. Development of hypercoagulable disorders in the patients who underwent endovascular revascularization of the arterial segment is more intense than in those who underwent open vascular revascularization methods. Hypercoagulation of blood at the intraoperative stage of revascularization takes place primarily due to the activity of factor IIa of the hemocoagulation cascade. Taking into account these circumstances, already at the surgery stage for thromboprophylaxis non-fractionated heparin (NFH) should be prescribed. At the same time for prevention of thromboembolic complications double anti-thrombocyte therapy: clopidogrel, acetylsalicylic acid should be prescribed. Conclusion. Hypercoagulant ability of the blood system, which develops after arterial reconstructive interventions, takes place against the background of low activity of the fibrinolytic blood system, nevertheless a gradual increase in the activity of the aggregation capacity of the blood. Development of hypercoagulable disorders at the intraoperative stage of surgery in the patients with endovascular methods of arterial reconstructions is more intense than in those treated with open methods of arterial revascularization. Taking into account these circumstances, already at the surgery stage for thromboprophylaxis an anticoagulant should be prescribed that has a targeted effect on factor IIa of the hemocoagulant cascade with simultaneous prevention of thromboembolic complications – double anti-thrombocyte therapy.

Production of Fibrinolytic Enzyme by Soil Actinobacteria

Thrombotic diseases are increasingly becoming among the prominent causes of death across the globe. Researchers are now turning attention towards fibrinolytic enzymes as potential alternative treatment for thrombolytic diseases. This present study focused on the production of extracellular fibrinolytic enzyme from soil Actinobacteria and evaluation of its hydrolytic activity on blood clot. The Actinobacteria was isolated from compost soil of semi-arid climate in Nigeria. Bacterial isolation was achieved using starch casein agar. Potent fibrinolytic enzyme producing Actinobacteria were identified and subjected to enzyme production using submerged fermentation method. The interactive effects of incubation time, temperature, pH and media components on enzyme production were analysed. Extracellular fibrinolytic enzyme produced by the selected Actinobacteria was partially purified by ammonium sulphate precipitation and subsequently assayed for blood clot lysis activity. Results of these studies indicated that fibrinolytic enzyme was produced optimally at pH 8 and temperature of 40 oC after 72 hour of fermentation. Partially purified fibrinolytic enzyme was able to degrade blood clot comparable to the positive control. These results shows that soil Actinobacteria of unexplored semi-arid climate of Nigeria present a prospect in search of novel microorganisms with potentials in the production of fibrinolytic enzyme that can serve as an alternative blood clot buster in treating thrombolytic diseases.

High Plasma tPAPAI-1C Levels May Be Related to a Poor Prognosis in Patients with Severe or Critical COVID-19: A Single-Center Retrospective Study

Severe novel coronavirus disease 2019 (COVID-19) patients have a high incidence of thrombotic complications and mortality. The pathophysiology of coagulopathy involves fibrinolytic system impairment and vascular endothelial damage. This study examined coagulation and fibrinolytic markers as outcome predictors. In an observational study of 164 COVID-19 patients admitted to our emergency intensive care unit, hematological parameters on days 1, 3, 5, and 7 were retrospectively compared between survivors and nonsurvivors. Nonsurvivors had a higher APACHE II score, SOFA score, and age than survivors. Nonsurvivors also had a significantly lower platelet count and significantly higher plasmin/α2plasmin inhibitor complex (PIC), tissue plasminogen activator/plasminogen activator inhibitor-1 complex (tPAPAI-1C), D-dimer, and fibrin/fibrinogen degradation product (FDP) levels than survivors throughout the measurement period. The 7-day maximum or minimum values of the tPAPAI-1C, FDP, and D-dimer levels were significantly higher in nonsurvivors. A multivariate logistic regression analysis showed that the maximum tPAPAI-1C (OR = 1.034; 95% CI,1.014-1.061; p = 0.0041) was an independent factor affecting mortality, with an area under the curve (AUC) of 0.713 (optimum cut-off of 51 ng/mL; sensitivity, 69.2%; and specificity, 68.4%). COVID-19 patients with poor outcomes exhibit exacerbated coagulopathy with fibrinolysis inhibition and endothelial damage. Consequently, plasma tPAPAI-1C might be a useful predictor of the prognosis in patients with severe or critical COVID-19.

Assessment of Endocrine, Metabolic, and Fibrinolytic Profile and Its Association with BMI in Polycystic Ovarian Syndrome

Polycystic ovarian syndrome is a typical endocrine disorder that occurs in women and has a significant impact on the reproductive, metabolic, endocrine, and fibrinolytic systems. It is a heterogeneous clinical condition caused by multiple factors, especially obesity. Furthermore, metformin is the classical treatment approach for PCOS, which has conflicted results. The current study aimed to find out the effect of the usage of metformin on metabolic, fibrinolytic, and reproductive profiles between obese women with PCOS and non-obese women with PCOS. A cross-sectional study was carried out on 200 women diagnosed with PCOS and divided into two groups based on BMI. Each group was further subdivided into three subgroups (A, B, and C) based on their prescribed treatment. In addition, 50 age-matched controls were selected to compare the outcome. The reproductive hormones, lipid profile, glycaemic index, and fibrinolytic profile were measured in each group and compared to find the desired association. The demographic variables did not show significant variation within or between the groups except BMI. Group IA has shown better metabolic variables, Group IB has an improved endocrine profile, and Group IC has a better fibrinolytic profile(p>0.01**). Group II B has shown a better metabolic and endocrine profile, whereas it is significantly higher in the fibrinolytic profile (p>0.01**). Cumulatively Group II has a drastic reduction in all variables than group I(p>0.01**) except few non-significant variables. Obese PCOS patients are at an increased risk for complications such as endometrial hyperplasia, metabolic syndrome, and vascular thrombosis. Metformin and OCP are highly beneficial as they reduce the risk of insulin resistance and glucose intolerance and improve ovarian functions for a better reproductive life.

Reversible Cerebral Vasoconstriction Syndrome Treated by Continuous Intravenous Milrinone

Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by severe headaches, with or without other acute neurological symptoms, and diffuse segmental constriction of cerebral arteries that resolves spontaneously within 3 months.[1] It can occur spontaneously, especially in middle-aged women[1]; at least half the cases occur after exposure to vasoactive drugs or post-partum. This syndrome is often associated with a favorable outcome in 95% of cases.[1] However, the prognosis of RCVS is especially determined by stroke occurrence. Its management is inspired by what is applied in aneurysmal subarachnoid hemorrhage (aSAH), whose main complication is vasospasm and delayed cerebral ischemia (DCI). Although the physiopathology of RCVS is unclear, it appears to be distinct from aSAH. Indeed, the vasoconstriction in RCVS may be dependent on the activity and sensitivity of vascular receptors, which can lead to a more systemic effect on all brain vessels, as opposed to being dependent on the vasospasm induced by local clot lysis, as has been suggested in aSAH.[2] As cerebral arteries are densely innervated, the release of norepinephrine or neuropeptide Y from the sympathetic nerve endings may cause vasoconstrictions.[3] Angiographically, SAH-induced vasospasm is more commonly long-segmental and mainly around the bleeding focus, compared with the multiple, short-segmental, and diffuse changes seen in RCVS.[4] However, by analogy, RCVS is treated by nimodipine, and in some rare cases, the use of milrinone might be considered.[3]

In Silico Study of Different Thrombolytic Agents for Fibrinolysis in Acute Ischemic Stroke.

Alteplase is the only FDA-approved drug for thrombolysis in acute ischemic stroke (AIS). Meanwhile, several thrombolytic drugs are deemed to be promising candidates to substitute alteplase. This paper evaluates the efficacy and safety of urokinase, ateplase, tenecteplase, and reteplase for intravenous AIS therapy by computational simulations of the pharmacokinetics and pharmacodynamics combined with a local fibrinolysis model. The performances of the drugs are evaluated by comparing clot lysis time, plasminogen activator inhibitor (PAI) inhibition resistance, intracranial hemorrhage (ICH) risk, and activation time from drug administration to clot lysis. Our results reveal that urokinase has the quickest lysis completion but the highest ICH risk due to excess fibrinogen depletion in systemic plasma. While tenecteplase and alteplase have very similar thrombolysis efficacy, tenecteplase has a lower risk of ICH and better resistance to PAI-1. Among the four simulated drugs, reteplase has the slowest fibrinolysis rate, but fibrinogen concentration in systemic plasma is unaffected during thrombolysis.

Характеристика деяких показників системи гемостазу у хворих на компенсоване хронічне легеневе серце бронхо-легеневого генезу та особливості їх змін в умовах коморбідності зі стабільною ішемічною хворобою серця

The purpose of the study was to research and analyze the peculiarities of changes of some hemostasis system indices and define their possible role in the formation of a vascular lesion in the patients with compensated chronic cor pulmolale of broncho-pulmonary genesis in conditions of its comorbidity with stable coronary heart disease. Materials and methods. The retrospective study and analysis of hemostasis system indices (platelet count, thrombin time, prothrombin time, antithrombin – III, plasma tolerance to heparin, plasmin lysis, fibrinogen, soluble fibrin) in 64 patients with chronic obstructive pulmonary disease and compensated chronic cor pulmonale (29 female, 35 male, mean age – 54.6 ± 2.3) were carried out. 32 patients with the isolated pathology formed the comparative group whereas 32 patients with the comorbid coronary heart disease (exertional angina, functional class II-III, postinfarction or aterosclerotic cardiosclerosis) built the main group. The obtained research results of the patients of the main and comparative groups were compared both in groups and with the indices of practically healthy individuals (n = 15) of the same gender and age. Results and discussion. The obtained results indicated the presence of a significant increase of coagulation potential (the changes of indices of platelets, fibrinogen, plasma tolerance to heparin, antithrombin – III, and soluble fibrin) and activation of fibrinolysis system (thrombin time) and, simultaneous, its more pronounced depression (plasmin lysis) and increase of prothrombin time in case of presence of comorbid coronary heart disease in the patients with chronic cor pulmonale in conditions of chronic inflammatory process. Comorbidity promoted to the formation of disbalance of systemic correlation hemocoagulation and fibrinolysis. Our results confirm to a certain extent the following ideas of scientists: there are hypercoagulation and “exhaustion of the anticoagulant system potential” in case of combination of coronary heart disease and chronic obstructive pulmonary disease; hypercoagulation together with the oxidative stress and chronic systemic inflammation are general pathogenic mechanisms of chronic obstructive pulmonary disease and cardiovascular diseases, particularly of the coronary heart disease. Conclusion. The analysis of the changes of the hemostasis system indices in patients with compensated chronic cor pulmonale of broncho-pulmonary genesis indicates the presence of an increase of coagulation potential; the most significant changes with suppression of fibrinolytic activity are typical of the patients with comorbid coronary heart disease. The peculiarities of the hemostasis system changes in the patients with compensated chronic cor pulmonale of broncho-pulmonary genesis should be considered as a marker of the increased risk of the thrombogenic vascular complications. It should be taken into account for treatment-diagnostic strategy formation

SARS-CoV-2 infection results in upregulation of Plasminogen Activator Inhibitor-1 and Neuroserpin in the lungs, and an increase in fibrinolysis inhibitors associated with disease severity.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection results in coagulation activation although it is usually not associated with consumption coagulopathy. D-dimers are also commonly elevated despite systemic hypofibrinolysis. To understand these unusual features of coronavirus disease 2019 (COVID-19) coagulopathy, 64 adult patients with SARS-CoV-2 infection (36 moderate and 28 severe) and 16 controls were studied. We evaluated the repertoire of plasma protease inhibitors (Serpins, Kunitz, Kazal, Cystatin-like) targeting the fibrinolytic system: Plasminogen Activator Inhibitor-1 (PAI-1), Tissue Plasminogen Activator/Plasminogen Activator Inhibitor-1 complex (t-PA/PAI-1), α-2-Antiplasmin, Plasmin-α2-Antiplasmin Complex, Thrombin-activatable Fibrinolysis Inhibitor (TAFI)/TAFIa, Protease Nexin-1 (PN-1), and Neuroserpin (the main t-PA inhibitor of the central nervous system). Inhibitors of the common (Antithrombin, Thrombin-antithrombin complex, Protein Z [PZ]/PZ inhibitor, Heparin Cofactor II, and α2-Macroglobulin), Protein C ([PC], Protein C inhibitor, and Protein S), contact (Kallistatin, Protease Nexin-2/Amyloid Beta Precursor Protein, and α-1-Antitrypsin), and complement (C1-Inhibitor) pathways, in addition to Factor XIII, Histidine-rich glycoprotein (HRG) and Vaspin were also investigated by enzyme-linked immunosorbent assay. The association of these markers with disease severity was evaluated by logistic regression. Pulmonary expression of PAI-1 and Neuroserpin in the lungs from eight post-mortem cases was assessed by immunohistochemistry. Results show that six patients (10%) developed thrombotic events, and mortality was 11%. There was no significant reduction in plasma anticoagulants, in keeping with a compensated state. However, an increase in fibrinolysis inhibitors (PAI-1, Neuroserpin, PN-1, PAP, and t-PA/PAI-1) was consistently observed, while HRG was reduced. Furthermore, these markers were associated with moderate and/or severe disease. Notably, immunostains demonstrated overexpression of PAI-1 in epithelial cells, macrophages, and endothelial cells of fatal COVID-19, while Neuroserpin was found in intraalveolar macrophages only. These results imply that the lungs in SARS-CoV-2 infection provide anti-fibrinolytic activity resulting in a shift toward a local and systemic hypofibrinolytic state predisposing to (immuno)thrombosis, often in a background of compensated disseminated intravascular coagulation.

Plasminogen activator inhibitor 1 is not a major causative factor for exacerbation in a mouse model of SARS-CoV-2 infection

Coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a global pandemic. Although several vaccines targeting SARS-CoV-2 spike proteins protect against COVID-19 infection, mutations affecting virus transmissibility and immune evasion potential have reduced their efficacy, leading to the need for a more efficient strategy. Available clinical evidence regarding COVID-19 suggests that endothelial dysfunction with thrombosis is a central pathogenesis of progression to systemic disease, in which overexpression of plasminogen activator inhibitor-1 (PAI-1) may be important. Here we developed a novel peptide vaccine against PAI-1 and evaluated its effect on lipopolysaccharide (LPS)-induced sepsis and SARS-CoV-2 infection in mice. Administration of LPS and mouse-adapted SARS-CoV-2 increased serum PAI-1 levels, although the latter showed smaller levels. In an LPS-induced sepsis model, mice immunized with PAI-1 vaccine showed reduced organ damage and microvascular thrombosis and improved survival compared with vehicle-treated mice. In plasma clot lysis assays, vaccination-induced serum IgG antibodies were fibrinolytic. However, in a SARS-CoV-2 infection model, survival and symptom severity (i.e., body weight reduction) did not differ between vaccine- and vehicle-treated groups. These results indicate that although PAI-1 may promote the severity of sepsis by increasing thrombus formation, it might not be a major contributor to COVID-19 exacerbation.

Association of arterial stiffness with a prothrombotic state in uncomplicated nondiabetic hypertensive patients.

Past studies reported a significant contribution of a prothrombotic state to the development and progression of target organ damage in hypertensive patients. Stiffening of arterial vessels is associated with aging and hypertension, and additional factors could contribute to this process. This study was designed to examine the relationships between arterial stiffening and the hemostatic and fibrinolytic system. In 128 middle-aged, nondiabetic, essential hypertensive patients without major cardiovascular and renal complications, we measured coagulation markers that express the spontaneous activation of the hemostatic and fibrinolytic system and assessed stiffness of the arterial tree by measurement of the carotid/femoral pulse wave velocity (cfPWV) and pulse wave analysis with calculation of the brachial augmentation index (AIx). Levels of fibrinogen (FBG), D-dimer (D-d), and plasminogen activator-inhibitor 1 (PAI-1) were significantly higher in patients with PWV and AIx above the median of the distribution. FBG, D-d, and PAI-1 were significantly and directly related with both cfPWV and AIx, and multivariate regression analysis indicated that the relationships of D-d and PAI-1 with both cfPWV and AIx and of FBG with AIx, were independent of age, body mass index, severity and duration of hypertension, use of antihypertensive drugs, blood glucose, and plasma lipids. In middle-aged, uncomplicated, nondiabetic patients with essential hypertension, spontaneous activation of plasma hemostatic cascade and impaired fibrinolysis is significantly and independently associated with stiffening of the arterial tree.

Intracardiac Thrombi in Preterm Infants-A Case Study and Review of the Literature.

Intracardiac thrombi in preterm infants are not common but may lead to fatal outcomes. Predisposing and risk factors include small vessel size, hemodynamic instability, immaturity of the fibrinolytic system, indwelling central catheters and sepsis. In this paper, we present our own experience with a case of a catheter-related right atrial thrombus in a preterm infant, which was successfully treated with an aspiration thrombectomy. Then, we review the literature on intracardiac thrombosis in preterm infants: epidemiology, pathophysiology, clinical signs, echocardiographic diagnostic features and treatment options are discussed.

Increased thrombin activatable fibrinolysis inhibitor activity is associated with hypofibrinolysis in dogs with sepsis.

Disorders of coagulation are well-recognized in dogs with sepsis, but data regarding fibrinolysis disorders are limited. We aimed to characterize fibrinolysis in dogs with sepsis compared to healthy controls. We hypothesized that dogs with sepsis would be hypofibrinolytic, and that hypofibrinolysis would be associated with non-survival. This was a prospective observational cohort study. We enrolled 20 client-owned dogs with sepsis admitted to the Cornell University Hospital for Animals and 20 healthy pet dogs. Coagulation and fibrinolytic pathway proteins including antiplasmin activity (AP), antithrombin activity (AT), thrombin activatable fibrinolysis inhibitor activity (TAFI), D-dimer concentration, fibrinogen concentration, and plasminogen activity were measured and compared between groups. Overall coagulation potential, overall fibrinolysis potential, and overall hemostatic potential were calculated from the curve of fibrin clot formation and lysis over time. Compared to healthy controls, dogs with sepsis had lower AT (P = 0.009), higher AP (P = 0.002), higher TAFI (P = 0.0385), and higher concentrations of fibrinogen (P < 0.0001) and D-dimer (P = 0.0001). Dogs with sepsis also had greater overall coagulation potential (P = 0.003), overall hemostatic potential (P = 0.0015), and lower overall fibrinolysis potential (P = 0.0004). The extent of fibrinolysis was significantly negatively correlated with TAFI. No significant differences were observed between survivors and non-survivors. Dogs with sepsis were hypercoagulable and hypofibrinolytic compared to healthy dogs, suggesting potential utility of thromboprophylaxis in this patient population. The association between high TAFI and low overall fibrinolysis potential might provide a potential mechanism for this hypofibrinolysis.

A computational framework for the multiphysics simulation of microbubble-mediated sonothrombolysis using a forward-viewing intravascular transducer

Sonothrombolysis is a technique that utilises ultrasound waves to excite microbubbles surrounding a clot. Clot lysis is achieved through mechanical damage induced by acoustic cavitation and through local clot displacement induced by acoustic radiation force (ARF). Despite the potential of microbubble-mediated sonothrombolysis, the selection of the optimal ultrasound and microbubble parameters remains a challenge. Existing experimental studies are not able to provide a complete picture of how ultrasound and microbubble characteristics influence the outcome of sonothrombolysis. Likewise, computational studies have not been applied in detail in the context of sonothrombolysis. Hence, the effect of interaction between the bubble dynamics and acoustic propagation on the acoustic streaming and clot deformation remains unclear. In the present study, we report for the first time the computational framework that couples the bubble dynamic phenomena with the acoustic propagation in a bubbly medium to simulate microbubble-mediated sonothrombolysis using a forward-viewing transducer. The computational framework was used to investigate the effects of ultrasound properties (pressure and frequency) and microbubble characteristics (radius and concentration) on the outcome of sonothrombolysis. Four major findings were obtained from the simulation results: (i) ultrasound pressure plays the most dominant role over all the other parameters in affecting the bubble dynamics, acoustic attenuation, ARF, acoustic streaming, and clot displacement, (ii) smaller microbubbles could contribute to a more violent oscillation and improve the ARF simultaneously when they are stimulated at higher ultrasound pressure, (iii) higher microbubbles concentration increases the ARF, and (iv) the effect of ultrasound frequency on acoustic attenuation is dependent on the ultrasound pressure. These results may provide fundamental insight that is crucial in bringing sonothrombolysis closer to clinical implementation.

Fibrinolysis-Related Bleeding Troubles

An intricate enzymatic process called fibrinolysis is used to eliminate blood clots and stop vascular clogging. Numerous cofactors that make up the fibrinolytic system regulate fibrin breakdown and uphold the hemostatic balance. Different disease events that promote prothrombotic or hemorrhagic states based on the form of aberration are linked to the dysregulation of fibrinolysis. This review is centered on fibrinolysis ailments that can be either heritable or acquired and affect both adults and children. A shortage of one of the fibrinolysis inhibitors deficiencies, such as Plasminogen Activator Inhibitor Type 1 (PAI-1) or 2-plasmin inhibitor, or an overabundance of one of the activators, such as tissue-type plasminogen activator or urokinase-type plasminogen activator, can lead in hyperfibrinolytic bleeding. Delayed bleeding following trauma, surgery and dental interventions is a hallmark of fibrinolytic illnesses with a bleeding phenotype. Bleeding in states like menorrhagia and epistaxis, which has significant fibrinolytic activity, is also frequent. The most extreme bleeding episodes are experienced by patients with 2-plasmin inhibitor deficiency. Interestingly, it was found that, particularly in patients with PAI-1 deficiency, hyperfibrinolytic diseases are linked to a high prevalence of obstetric problems such as miscarriage and preterm delivery. Due to ignorance and a lack of reliable diagnostic tools, hyperfibrinolytic diseases are likely to be underdiagnosed. The vast majority of individuals whose bleeding was deemed to be “of unknown origin” may have a hyperfibrinolytic disease. Because these conditions may typically be successfully treated with antifibrinolytic drugs, early detection is crucial.

Effect of high-dose statin therapy on coagulation factors: Lowering of factor XI as a modifier of fibrin clot properties in coronary artery disease

BackgroundMultiple pleiotropic effects of statins include antithrombotic properties with formation of looser fibrin networks more susceptible to lysis. Recently, rosuvastatin 20 mg/d has been reported to decrease coagulation factors (F) VII, FVIII and FXI in venous thrombosis patients. ObjectivesWe investigated how high-dose statin therapy recommended in coronary artery disease (CAD) alters plasma levels of coagulation factors and if such changes might affect fibrin clot properties. MethodsWe studied 130 advanced CAD patients, who initially did not achieve the target low-density lipoprotein cholesterol (LDL-C). Before high-dose statin therapy (rosuvastatin 40 mg/d or atorvastatin 80 mg/d) and 6–12 months after its initiation, FII, FV, FVII, FVIII, FIX, FX, FXI and fibrinogen were assessed. We evaluated the impact of statin-induced alterations to the factors on plasma fibrin clot permeability (Ks) reflecting a fibrin pore size, and clot lysis time (CLT) reflecting fibrinolytic potential. ResultsAt baseline LDL-C (median 3.2, interquartile range 2.7–3.7 mmol/L) was independently associated solely with FXI (β = 0.58, P < 0.001). Median LDL-C reduction by 25% (P < 0.001) on high-dose statin treatment was accompanied by lowering of FVII, FVIII, and FXI (for all P < 0.001). On high-dose statin treatment, Ks (R = 0.65, P < 0.001) inversely associated with CRP (β = −0.41, P < 0.001), LDL-C (β = −0.26, P = 0.001), and FXI (β = −0.18, P = 0.016). In turn, CLT (R = 0.45, P < 0.001) was positively associated with LDL-C (β = 0.19, P = 0.043) and FXI (β = 0.17, P = 0.049). ConclusionsHigh-dose statin therapy in CAD patients decreases FVII, FVIII, and FXI. The statin-induced reduction in FXI may contribute to less prothrombotic fibrin clot phenotype, indicating additional antithrombotic effect of high-dose statins.

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).

Plant-Derived Compounds and Extracts as Modulators of Plasmin Activity-A Review.

Functionality of the fibrinolytic system is based on activity of its central enzyme, plasmin, responsible for the removal of fibrin clots. Besides the hemostasis, fibrinolytic proteins are also involved in many other physiological and pathological processes, including immune response, extracellular matrix degradation, cell migration, and tissue remodeling. Both the impaired and enhanced activity of fibrinolytic proteins may result in serious physiological consequences: prothrombotic state or excessive bleeding, respectively. However, current medicine offers very few options for treating fibrinolytic disorders, particularly in the case of plasmin inhibition. Although numerous attempts have been undertaken to identify natural or to develop engineered fibrinolytic system modulators, structural similarities within serine proteases of the hemostatic system and pleiotropic activity of fibrinolytic proteins constitute a serious problem in discovering anti- or profibrinolytic agents that could precisely affect the target molecules and reduce the risk of side effects. Therefore, this review aims to present a current knowledge of various classes of natural inhibitors and stimulators of the fibrinolytic system being well-defined low-molecular plant secondary metabolites or constituents of plant extracts as well as plant peptides. This work also discusses obstacles caused by low specificity of most of natural compounds and, hence, outlines recent trends in studies aimed at finding more efficient modulators of plasmin activity, including investigation of modifications of natural pharmacophore templates.

Persistent fibrinolysis shutdown is associated with increased mortality in traumatic pancreatic injury

PurposeThe features of fibrinolytic system modifications and their relationship with prognosis are still unknown in traumatic pancreatic injury. The object of this prospective cohort research was to identify fibrinolytic characteristics in patients with pancreatic trauma and to identify the correlation to mortality. MethodA prospective screening of traumatic pancreatic injury patients was done for five years. The fibrinolytic status of patients was determined by thromboelastography (TEG). The percentage reduction in clot strength 30 min (LY30) after the time of maximal clot strength was utilized to distinguish the fibrinolytic phenotype of individuals, including fibrinolytic shutdown (SD), physiologic fibrinolysis (PHYS) and hyperfibrinolysis (HF). Two cohorts, transient fibrinolytic shutdown (TSD) and persistent fibrinolytic shutdown (PSD), were divided according to whether fibrinolytic shutdown persisted within one week. Demographics, injury severity, characteristics of pancreatic injury, treatment, and outcomes were compared. ResultA total of 180 cases enrolled, aged 42(interquartile range 32–51) years, 88% males, 97% were blunt trauma. The median ISS was 19(IQR 10–25), and 76% were AAST grade III to V (high-grade). At admission, there were 159 cases of SD (88%), 15 cases of PHYS (8%) while 6 cases of HF (3%). Of these, the TSD cohort included 54 patients (34%), while the PSD cohort included 105 patients (66%). Compared with the TSD cohort, the PSD cohort had more severe injury (ISS 21[IQR 12–27] vs 16[IQR 9–22], p = 0.006) and a higher proportion of AAST high-grade (83% vs 67%, p = 0.035). Persistent fibrinolytic shutdown was associated with operative treatment (odds ratio [OR] 3.111; 95%CI 1.146–8.447; p = 0.026), associated intra-abdominal injury (OR 8.331; 95% CI 1.301–53.336; p = 0.025) and admission LY30 (OR 0.016; 95% CI 0.002 - 0.120; p < 0.001). It was an independent predictor of mortality (adjusted odds ratio [AOR] 4.674; 95% CI 1.03 to 21.14; p = 0.045). ConclusionFibrinolytic shutdown especially persistence of this phenotype is more common in traumatic pancreatic injury than PHYS and HF, which related with mortality. Risk factors including LY30 at admission, intra-abdominal injury and operative treatment were associated with the persistent fibrinolytic shutdown. Sheltered the patients from these risk factors seems to be beneficial, which need to be confirmed by further large-scale studies.

Atorvastatin downregulates plasma procarboxypeptidase U concentrations and improves fibrinolytic potential dose-dependently in hyperlipidemic individuals

BackgroundStatins efficiently lower cholesterol and also exert pleiotropic effects that extend beyond lipid lowering. In a recent pilot study, valuable information on the carboxypeptidase U (CPU) system in hyperlipidemia and the effect of statin therapy was collected. It was shown that proCPU levels are increased in hyperlipidemic patients. Statins significantly decreased proCPU levels and improved plasma fibrinolysis. Furthermore, it was suggested that patients with high baseline proCPU levels are most likely to benefit from statin therapy. ObjectivesWe aimed to further substantiate the effect of hyperlipidemia and statin therapy on CPU-related parameters in a larger cohort of hyperlipidemic and statin-treated individuals. MethodsBlood was collected from 141 individuals treated with different dosages of atorvastatin (10-80 mg), 38 normolipidemic, and 37 hyperlipidemic controls. Lipid parameters and markers of fibrinolysis (proCPU and clot lysis time) were determined and compared between the groups. ResultsPilot study results of high proCPU concentrations in hyperlipidemic patients and the proCPU-reducing effect of atorvastatin were confirmed. Accordingly, an improvement in plasma fibrinolytic potential was seen under the influence of atorvastatin. High interindividual variation in proCPU concentrations was observed in the hyperlipidemic cohort, with up to 80% higher proCPU levels compared with normolipidemic controls. Furthermore, proCPU concentration and the dosage of atorvastatin were inversely correlated. ConclusionsThis study clearly shows that plasma proCPU concentrations and its expected effect on the fibrinolytic rate (as measured by clot lysis time) are increased in hyperlipidemic patients and that these effects can be normalized (and even further reduced compared with normolipidemic patients) by atorvastatin treatment.

Abstract TP13: Is Tenecteplase Associated Recanalization Dependent On Thrombus Length?

Introduction: Recent evidence supports that IV tenecteplase (TNK) is non-inferior to IV alteplase when administered to eligible patients with acute ischemic stroke (AIS). Studies suggest that alteplase does not effectively lyse clots ≥ 8mm. However, the neurovascular characteristics of TNK are rapidly evolving. The aim of this study was to evaluate the efficacy of TNK in clot lysis ≥ 8mm as measured by hyperdense sign on CT for internal carotid artery (ICA) and middle cerebral artery (MCA M1 and M2 segment) occlusion. Methods: We conducted a retrospective cohort study of prospectively collected AIS patients who presented to our comprehensive stroke center, received TNK, and had hyperdense sign on CT head. Hyperdense signs were detected using 0.625 mm slices in retrospective fashion, blinded to the clinical scenario with regards to laterality. Revascularization was defined as modified Thrombolysis in Cerebral Infarction (mTICI) score on first run of digital subtraction angiography prior to intervention, follow up CTA or MRA without large vessel occlusion (LVO), and/or with improved clinical symptoms that correlate with hyperdense sign. Social science statistics software was used for data analysis. Results: From October 2020 to June 2022, out of 77 AIS patients who received TNK, 25 subjects (≥ 8mm, n=19) had associated hyperdense signs. Mean age was 67.16 (95% CI 60.05, 74.27). Median NIHSS was 14 (95% CI 11.378, 19.50). Mean thrombus length was 17.64 mm (95% CI, 13.26, 22.02). Twenty-one percent (n=4) of 19 subjects with hyperdense signs ≥ 8mm recanalized post-TNK (n=3 angiography, n=1 MRA). Thirty-three percent (n=2) of 6 subjects with hyperdense signs &lt; 8mm recanalized post-TNK. There was not a statistically significant difference between recanalization rates in hyperdense signs ≥ 8mm or &lt; 8mm (Fisher exact test statistic=0.61). There was not a statistically significant difference between intracerebral hemorrhage rates in hyperdense signs ≥ 8mm or &lt; 8mm (Fisher exact test statistic=1). Conclusion: Our study suggests that tenecteplase may be associated with higher thrombolytic-related recanalization in thrombi measuring 8mm or greater as compared to historical alteplase experience. Larger, prospective studies are needed to corroborate our findings.