Rationale and design of "Can Very Low Dose Rivaroxaban (VLDR) in addition to dual antiplatelet therapy improve thrombotic status in acute coronary syndrome (VaLiDate-R)" study : A randomised trial modulating endogenous fibrinolysis in patients with acute coronary syndrome.

Impaired endogenous fibrinolysis is novel biomarker that can identify patients with ACS at increased cardiovascular risk. The addition of Very Low Dose Rivaroxaban (VLDR) to dual antiplatelet therapy has been shown to reduce cardiovascular events but at a cost of increased bleeding and is therefore not suitable for all-comers. Targeted additional pharmacotherapy with VLDR to improve endogenous fibrinolysis may improve outcomes in high-risk patients, whilst avoiding unnecessary bleeding in low-risk individuals. The VaLiDate-R study (ClinicalTrials.gov Identifier: NCT03775746, EudraCT: 2018-003299-11) is an investigator-initiated, randomised, open-label, single centre trial comparing the effect of 3 antithrombotic regimens on endogenous fibrinolysis in 150 patients with ACS. Subjects whose screening blood test shows impaired fibrinolytic status (lysis time > 2000s), will be randomised to one of 3 treatment arms in a 1:1:1 ratio: clopidogrel 75 mg daily (Group 1); clopidogrel 75 mg daily plus rivaroxaban 2.5 mg twice daily (Group 2); ticagrelor 90 mg twice daily (Group 3), in addition to aspirin 75 mg daily. Rivaroxaban will be given for 30 days. Fibrinolytic status will be assessed during admission and at 2, 4 and 8 weeks. The primary outcome measure is the change in fibrinolysis time from admission to 4 weeks follow-up, using the Global Thrombosis Test. If VLDR can improve endogenous fibrinolysis in ACS, future large-scale studies would be required to assess whether targeted use of VLDR in patients with ACS and impaired fibrinolysis can translate into improved clinical outcomes, with reduction in major adverse cardiovascular events in this high-risk cohort.

Using a Radial Diffusion Method to Investigate the Role of Plasmin Degradation of Fibrin in a Physical Model of an Early-phase Wound.

BACKGROUND: Fibrin clot formation, which acts to stabilize a wound following injury, is among the key early aspects of dermal wound healing. This preliminary matrix is eventually degraded via a process known as fibrinolysis and replaced with a collagen-rich matrix that continues to be remodeled to minimize scarring. Disruptions in these carefully coordinated events lead to certain undesirable conditions such as fibrosis and the formation of abnormal scars that are associated with excess amounts of collagen. The hypothesis proposed herein is that the presence of collagen (and potentially other molecules) in an early-phase model of healing alters fibrinolysis and that this effect can be attenuated with mediators of the process. MATERIALS AND METHODS: Laboratory in vitro experiments were conducted using agarose-fibrin gel systems with and without collagen to study fibrinolysis caused by plasmin (a serine protease that degrades fibrin) and the effects of aprotinin (a serine protease inhibitor) and bromelain (an extract from pineapple) on fibrin clot breakdown. The extent of fibrinolysis was monitored at various times (0.5, 1, 2, 4, 8, 12, 24, 48, and 72 hours) by measuring the size of rings of fibrinolysis following the diffusion of plasmin. The data obtained at 0.5, 12, and 24-hour time points were considered (because there was no difference found in the data collected for closer intermediates nor for the longer times beyond 24 hours) and were compared using the nonparametric Mann-Whitney U statistical significance test. RESULTS: The results obtained showed aprotinin significantly inhibited fibrinolysis in systems containing collagen, while bromelain improved fibrinolysis. In general, the presence of increasing amounts of collagen in the system decreased the extent of fibrinolysis. CONCLUSIONS: These findings support the notion that early-phase deposition of collagen contributes to disrupted fibrinolysis, which could lead to impaired healing as well as potentially facilitate control of fibrinolysis.

The effects of acute garlic supplementation on the fibrinolytic and vasoreactive response to exercise.

BACKGROUND: The purpose of this project was to examine the effects of acute garlic supplementation on fibrinolysis and vasoreactivity both at rest and following maximal exercise. METHODS: Eighteen healthy trained males (20.9 ± 2.2 years, 178 ± 7.7 cm, 75.5 ± 9.6 kg, VO2max = 59.8 ± 6.7 ml • kg(-1) • min(-1)) performed a graded treadmill test to volitional exhaustion. Blood samples were taken at rest, within two minutes post-exercise, and one hour post-exercise. Eleven of the subjects also had a brachial vasoreactivity test performed immediately after the blood sample to assess flow-mediated dilation (FMD) of the brachial artery. Participants were randomly assigned to ingest either 900 mg of powdered garlic or a placebo three hours before the exercise session. The supplement was distributed in a double-blind, crossover fashion. Participants repeated the protocol with the other treatment after a 14-day washout period. Paired t-tests were used to compare VO2max between the two trials. A two-factor (treatment and time) repeated measures analysis of variance (ANOVA) was used to assess changes in FMD, tPA activity, tPA antigen, and PAI-1 activity. A priori statistical significance was set at P <0.05. RESULTS: VO2max was greater for the garlic treatment trial vs. placebo (Placebo = 59.8 ± 6.7 ml • kg(-1) • min(-1); Garlic = 61.4 ± 6.6 ml • kg(-1) • min(-1)). There was no main effect for treatment and no treatment x time interaction for FMD or any fibrinolytic variables examined. CONCLUSION: Acute garlic supplementation does not alter vasoreactivity, fibrinolytic potential or the fibrinolytic response to exercise in young healthy trained males. Acute garlic supplementation does, however, cause a small but statistically significant increase in VO2max. It remains unclear if this increase in VO2max is of functional importance.

Dosing time-dependent effect of raloxifene on plasma plasminogen activator inhibitor-1 concentrations in post-menopausal women with osteoporosis.

Raloxifene, a selective oestrogen receptor modulator commonly used for the treatment of post-menopausal osteoporosis, affects the coagulation and fibrinolytic systems and consequently increases the risk of venous thromboembolism. Because both the coagulation and fibrinolytic systems exhibit circadian rhythms, the aim of the present study was to investigate the effects of dosing time of raloxifene on markers of coagulation and fibrinolysis, as well as on markers of bone metabolism. Thirty-nine post-menopausal patients with osteoporosis were randomly allocated to two groups: one received 60 mg raloxifene once daily in the morning, whereas the other received 60 mg raloxifene once daily in the evening, for 12 months. In both groups, the activity of coagulation Factors IX and XII was increased significantly after 12 months treatment compared with baseline. The activity of coagulation Factors II and V and levels of markers of bone metabolism (i.e. bone alkaline phosphatase and tartrate-resistant acid phosphatase 5b) decreased in both groups. The changes in these markers did not differ between the two groups. In contrast, the plasma concentration of plasminogen activator inhibitor (PAI)-1 increased in the group receiving the morning dose (mean change 40.9%; 95% confidence interval (CI) 9.4, 72.5), but not in the groups receiving the evening dose (mean change -0.3%; 95% CI -31.5, 30.9); these percentage changes differed significantly (P < 0.05). Because an elevated concentration of PAI-1 is known to be associated with the risk of venous thromboembolism, the findings of the present study suggest that the dosing time of raloxifene influences its safety. Further larger-scale studies are needed to determine the clinical usefulness of chronotherapy with raloxifene.

Effects of Ω-3 fatty acids on endothelial function, arterial wall properties, inflammatory and fibrinolytic status in smokers: a cross over study.

BACKGROUND: Smoking is associated with endothelial dysfunction and arterial stiffness. Supplementation of Ω-3 PUFAs is associated with better prognosis. Aim of this study was to evaluate the effects of Ω-3 polyunsaturated fatty acids (PUFAs) supplementation on smoking-induced impairment of arterial function. METHODS: We studied the effect of a 12 weeks oral treatment with 2gr/day of Ω-3 PUFAs in 20 healthy smokers on three occasions (day 0:baseline, day 28 and day 84). The study was carried out on two separate arms (Ω-3 fatty acids and placebo), according to a randomized, placebo-controlled, double-blind, cross-over design. Measurements were carried out before (pSm), immediately and 20min after cigarette smoking. Endothelial function was evaluated by flow-mediated dilation (FMD) of the brachial artery. Carotid-femoral pulse wave velocity (PWV) was measured as an index of aortic stiffness and augmentation index (AIx) as a measure of arterial wave reflections. Circulating levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and plasminogen activator inhibitor-1 (PAI-1) were measured. RESULTS: Compared with placebo, Ω-3 PUFAs treatment resulted in a significant improvement in pSm values of FMD (p<0.05), AIx (p<0.001) and PWV (p<0.01). Although, acute cigarette smoking decreased FMD and caused an increase in AIx and PWV, Ω-3 PUFAs treatment blunted the acute smoking-induced impairment of FMD (p<0.001), AIx (p<0.05) and PWV (p<0.05) and significantly decreased levels of TNFα (p<0.05) and IL-6 (p=0.01) and increased levels of PAI-1 (p=0.05). CONCLUSIONS: Ω-3 PUFAs improved endothelial function and the elastic properties of the arterial tree in healthy smokers, with a parallel anti-inflammatory effect.

Estudio Ebrictus. Resultados funcionales, supervivencia y años potenciales de vida perdidos después del primer episodio de ictus / Ebrictus study. Functional results, survival, and potential years of life lost after the first stroke

Objetivo: Conocer la mortalidad, el grado de dependencia, la supervivencia y los años potenciales de vida perdidos (APVP) después de un primer episodio de ictus. Diseño: Estudio de cohorte fija. Emplazamiento: Base comunitaria. Participantes: Entre el 1/4/2006 y el 31/3/2008 fueron incluidas 553 personas entre 15-90 años, con un primer episodio de ictus definitivo o transitorio. Mediciones principales: Grado de dependencia según la escala de Barthel (EB) al año, APVP (1-70 años) a partir de las medias de las esperanzas de vida al nacer, análisis de supervivencia por curvas de Kaplan-Meier, bivariante entre pacientes fallecidos y supervivientes, y multivariante de Cox. Resultados: Edad media, 73,3; DE: 11,6 años. El tiempo medio de seguimiento fue 29,7; DE:13,4 meses, en el que un 26,6% de los pacientes fallecieron. El valor medio EB descendió > 20%, especialmente entre las mujeres. El 41,5% (IC 95% 30,6-52,8%) tenía una dependencia moderada o más. La probabilidad de supervivencia global acumulada fue de 0,96 (IC 95% 0,94-0,97) el primer mes y 0,69 (IC 95% 0,65-0,72) al final. La fibrinólisis mejoró significativamente la curva de supervivencia a los 3 años post-episodio, en particular entre las mujeres. Los factores pronósticos independientes para la supervivencia global fueron la edad (riesgo relativo [RR] 1,08, IC 95% 1,001-1,179) y la incidencia de un nuevo episodio cardiovascular (RR 6,97, IC 95% 2,23-21,7). La tasa de APVP fue 11,5/104, DE 7,2, significativamente mayor en los hombres. Conclusiones: La evolución funcional, la mortalidad y la tasa de APVP son diferentes por género. La incidencia de un nuevo episodio cardiovascular es un factor pronóstico independiente de la supervivencia(AU)

Aim: To determine the mortality, degree of dependence, survival, and years of life lost (YLL) after first episode of stroke. Design: Cohort study. Location: Community based register. Participants: A total of 553 subjects between 15-90 years with a first episode of definitive or transitory stroke were recruited between 01/04/2006 and 31/03/2008.MeasurementsThe analyses were performed with the use of time-to-event methods, according to the intention-to-treat principle. The level of dependency was assessed according to the Barthel Scale one year after stroke; YLL (1-70 years) from the mean life expectancies at birth; survival analysis by Kaplan-Meier's curves, bivariate analysis comparing the variables between patients who had survived and those who died, and Cox's multivariate.: Results: The mean age was 73.3 (±11.6 years. The mean time of follow-up was 29.7±13,4 months, during which 26.6% of the patients died. The mean Barthel score fell by >20%, particularly among women. There was moderate or greater dependence in 41.5% (95%CI 30.6-52.8%) of the subjects. The overall accumulative probability of survival was 0.96 (95% CI 0.94-0.97) in the first month and 0.69 (95% CI 0.65-0.72) in the fourth year. The thrombolytic treatment showed a protective effect on mortality, particularly among the women. The main predictive variables were, history of recurrent cardiovascular event (RR 6.7, 95% CI 2.2-21.7) and aging (RR 1.08, 95% CI 1.01-1.2). The average YLL was 11.5/10000/year SD7.2, and higher among men. Conclusion: There are differences in functional outcome, mortality, and potential years of life lost by gender. A new cardiovascular event is an independent prognostic factor of survival(AU)

[Influence of tea polyphenols on the damage of fibrinolytic system induced by homocysteine in human umbilical vein endothelial cells].

OBJECTIVE: To study the influence of tea polyphenols (TP) on cells form and fibrinolytic system which focused on tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) induced by homocysteine (Hcy) in human umbilical vein endothelial cells (HUVEC). METHODS: HUVEC were divided into two groups, one was administered with TP and Hey at the same time, the other was firstly treated with Hey for 12 hours and followed by administering TP. Each group was divided into some groups depending on different concentrations of TP. The t-PA and PAI-1 levels of HUVEC supernatant were determined by ELISA assay. RESULTS: Compared with the groups that just treated with Hcy, medium concentration (4 and 8 microg/ml) and high concentration (16 microg/ml) of TP could strengthen cells stereoscopic effect and decrease endochylema particles; the results of ELISA demonstrated that the concentrations of PAI-1 were increased in the groups that just treated with Hey compared with control group (P < 0.05), administrations of medium and high dose of TP could decrease the concentration of PAI-1, and the concentration of PAI-1 were decreased depending on the increase of TP concentration (P < 0.05), there was no difference between low concentration TP group and the group only treated with Hcy. There were no differences on the concentrations of t-PA among each groups. CONCLUSION: The proper concentration of TP could restore the damage of HUVEC form and decrease the concentration of PAI-1 induced by Hey.

Ajo y riesgo cardiovascular / Garlic and cardiovascular risk

El ajo es una de las plantas curativas más antiguas de la que tenemos referencia. En el presente trabajo, revisaremos las evidencias existentes sobre el consumo de ajo y el riesgo cardiovascular, analizando su papel sobre el perfil lipídico, el endotelio vascular y la agregación plaquetaria. El consumo regular de 5 g de ajo crudo dos veces al día durante 42 días disminuye los niveles de colesterol total y triglicéridos, no obstante la mayor parte de los estudios realizados en el campo de los lípidos han sido llevados a cabo en animales. En modelos animales (perros y ratas) se ha demostrado los efectos hipotensores del ajo de manera dosis dependiente. Algunos trabajos han demostrado que el ajo activa la fibrinolisis, además de suprimir el sistema de coagulación previniendo así la formación de trombos. Estos resultados se han corroborado en otro trabajo, en el cual se demuestra que el extracto alcohólico de ajo es un potente inhibidor de la agregación plaquetaria. En resumen, los efectos del ajo sobre la disminución del riesgo cardiovascular son importantes. No obstante los estudios en humanos son escasos y todavía falta por demostrar que estos efectos disminuyan los eventos cardiovasculares así como la cantidad necesaria de ajo para obtener estos beneficios

Garlic is one of the oldest dietary vegetables. In this article, we´ll review the evidences of cardiovascular risk factors and garlic consumption, analizing the influence on lipid levels, vascular endothelium and platelet aggregation. Regular consumption of 5 g (raw garlic) twice per day during 42 days decreases levels of cholesterol and triglyceride. However, almost all lipid studies have been realized in animals. In animal models (dogs and rats), it has been demonstrated a dose depending hypotensive effect, too. Garlic consumption has demonstrated an activation of fibrinolisis and a down regulation of coagulation, with a decrease in the rate of thrombogenesis. These results have been repeated by otherwork, in which a garlic alcoholic extract is a potent inhibitor of platelet aggregation. In summary, the effects of garlic on cardiovascular risk are important. However, it is necessary to demonstrate a decrease on cardiovascular events and to elucidate the amount of garlic to obtain benefict effects, most studies are necessary

Effects of isoflavones on the coagulation and fibrinolytic system of postmenopausal women.

OBJECTIVE: We evaluated the effects of soy isoflavone supplementation on hemostasis in healthy postmenopausal women. METHODS: In this double-blinded, placebo-controlled study, 47 postmenopausal women 47-66 y of age received 40 mg of soy isoflavone (n = 25) or 40 mg of casein placebo (n = 22) once a day for 6 mo. Levels of factors VII and X, fibrinogen, thrombin-antithrombin complex, prothrombin fragments 1 plus 2, antithrombin, protein C, total and free protein S, plasminogen, plasminogen activator inhibitor-1, and D-dimers were measured at baseline and 6 mo. Urinary isoflavone concentrations (genistein and daidzein) were measured as a marker of compliance and absorption using high-performance liquid chromatography. Baseline characteristics were compared by unpaired Student's t test. Within-group changes and comparison between the isoflavone and casein placebo groups were determined by a mixed effects model. RESULTS: The levels of hemostatic variables did not change significantly throughout the study in the isoflavone group; however, the isoflavone group showed a statistically significant reduction in plasma concentration of prothrombin fragments 1 plus 2; both groups showed a statistically significant reduction in antithrombin, protein C, and free protein S levels. A significant increase in D-dimers was observed only in the isoflavone group. Plasminogen activator inhibitor-1 levels increased significantly in the placebo group. However, these changes were not statistically different between groups. CONCLUSION: The results of the present study do not support a biologically significant estrogenic effect of soy isoflavone on coagulation and fibrinolysis in postmenopausal women. However, further research will be necessary to definitively assess the safety and efficacy of isoflavone.

A multiparameter test of clot formation and fibrinolysis for in-vitro drug screening.

A large spectrum of methods has been used in both routine and scientific studies of the hemostatic system. The particular interest of the investigators has been focused on methods simultaneously evaluating clotting and fibrinolysis processes. The aim of the present study was to develop an optical method for overall evaluation of clot formation and lysis (CL-test) that could be used in drug screening. The CL-test was performed in citrate plasma diluted with Tris-buffered saline. Thrombin was applied for plasma clotting (0.5 IU/ml), while tissue plasminogen activator (60 ng/ml) was used for fibrinolysis activation. Clot formation and lysis were monitored in thermostatic conditions (37 degrees C) as a continuous record of transmittance change. By means of own computer program, kinetic parameters of the processes studied and plasma overall clot formation and fibrinolysis potential, expressed as the area under the clotgeneration and fibrinolysis curves, were calculated. The CL-test was developed and checked by evaluation of the effect, on clot formation and lysis, of various concentrations of acetylsalicylic acid (a drug that affects hemostasis), aprotinin (fibrinolysis activator) and venoruton (fibrinolysis inhibitor). The obtained results confirmed that the test we propose for monitoring clot formation, stabilization and lysis is sensitive and enables precise estimation of the processes studied. In our opinion, it can be a useful tool in drug screening investigations.

A novel extracellular protease with fibrinolytic activity from the culture supernatant of Cordyceps sinensis: purification and characterization.

A novel serine protease with fibrinolytic activity named CSP was purified from the culture supernatant of the fungus Cordyceps sinensis, a kind of Chinese herbal medicine. Analysis of the purified enzyme by SDS-PAGE indicated that CSP was a single polypeptide chain with an apparent molecular weight of 31 kDa, and N-terminal sequencing revealed that the first ten amino acid residues of the enzyme were Ala-Leu-Ala-Thr-Gln-His-Gly-Ala-Pro-Trp-. When casein was used as a substrate, the proteolytic activity of CSP reached its maximum at pH 7.0 and 40 degrees C. The effect of chemical agents on the enzyme activity indicated that CSP is a serine protease with a free cysteine residue near the active site. It hydrolysed fibrinogen, fibrin and casein with a high efficiency, while hydrolysing bovine serum albumin (BSA) and human serum albumin (HSA) to a lesser extent. CSP was found to be a plasmin-like protease, but not a plasminogen activator, and it preferentially cleaved the A alpha chain of fibrinogen and the alpha-chain of fibrin. Therefore, the extracellular protein CSP may represent a potential new therapeutic agent for the treatment of thrombosis.

Decreased levels of PAI-1 and alpha 2-antiplasmin contribute to enhanced fibrinolytic activity in divers.

BACKGROUND: There are a number of reported cases of decompression sickness (DCS) with haemorrhages. These cases have not been sufficiently investigated and thus bleeding complications could not be directly correlated to the enhanced fibrinolysis. OBJECTIVES: The effect of hyperbaric exposition and decompression on the main components of fibrinolytic system has been measured. METHODS: Two groups of 25 male divers each were subjected to hyperbaric exposures to the pressure of either 400 kPa - group I - or 700 kPa - group II followed by a staged decompression. The divers were monitored for clinical symptoms of DCS and checked for Doppler-detected venous gas bubbles. Venous blood was drawn from divers before exposition and 15 min after decompression. The concentrations and activities of t-PA and PAI-1 as well as concentrations of PAP and alpha2-antiplasmin and activity of factor XIIa were measured. RESULTS: In all groups of divers no cases of DCS as well as detectable gas bubbles were noted. We observed elevated concentration of PAP, decreased concentration of alpha2-AP, decreased PAI-1 concentration and activity. There were no significant changes in factor XIIa activity as well as of t-PA concentration and activity. CONCLUSIONS: Hyperbaric exposition and decompression induce activation of fibrinolysis, even in the absence of detectable gas bubbles. Fibrinolytic activity increases mainly due to decrease of PAI-1 concentration and activity. Further clinical trials are necessary for the estimation of the importance of activation of fibrinolysis with decreased level of PAI-1 and alpha2-AP as a possible risk factor for bleeding in divers.

Dietary fatty acids and the haemostatic system.

Studies of the effects of dietary fatty acids on the haemostatic system, and their potential relevance for the thrombotic component of coronary heart disease (CHD), have a pedigree as long as those linking dietary fat, plasma lipoprotein metabolism and atheroma. Achievements have not been as impressive, however, partly owing to the relatively slow evolution of our understanding of the complicated physiology, biochemistry and pathology of haemostasis and fibrinolysis, which remains incomplete. Progress was also retarded up to 1980 by a general reluctance to acknowledge the pathogenic importance of thrombosis for myocardial infarction. Interest in dietary fat and the haemostatic mechanism re-emerged with reports of associations of haemostatic variables with plasma triacylglycerol levels and risk of CHD. This review summarises the history, focuses on evidence for dietary C18-unsaturated fatty acids as important determinants of factor VII (FVII) activation and plasminogen activator inhibitor type 1 (PAI-1) levels, and discusses possible underlying mechanisms involving ATP binding cassette (ABC) transporters and peroxisome proliferator-activated receptors. The potential relevance of these effects for CHD is discussed. In the presence of unstable atheromatous plaques, increased levels of activated FVII and PAI-1 induced by diets rich in mixtures of saturated and unsaturated fats may raise the risk of occlusive thrombosis in the event of plaque rupture.

Effects of HMG-CoA reductase inhibitors on coagulation and fibrinolysis processes.

Recent large clinical trials have demonstrated that HMG-CoA reductase inhibitors, or statins, markedly reduce morbidity and mortality when used in the primary and secondary prevention of cardiovascular disease. It has been established that the benefits of statin therapy in cardiovascular disease can be explained not only by the lipid-lowering potential of statins but also by nonlipid-related mechanisms (so-called "pleiotropic effects") that contribute to the positive effect of statins on the incidence of cardiovascular events. The coagulation and fibrinolytic systems are two separate but reciprocally linked enzyme cascades that regulate the formation and breakdown of fibrin. Numerous studies have demonstrated that disturbances of coagulation and fibrinolysis contribute to the development and progression of atherosclerosis, and that they affect the incidence of atherosclerosis-related clinical events. High plasma levels or activities of fibrinogen, factor VII, factor VIII, von Willebrand factor (vWF), soluble thrombomodulin, tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) are thought to be associated with increased morbidity and mortality related to cardiovascular disease. Experimental studies and many clinical studies have recently shown that statins produce favourable effects on haemostatic parameters, including those that are risk factors for cardiovascular disease. Statins diminish procoagulant activity, which is observed at different stages of the coagulation cascade, including tissue factor (TF) activity, conversion of prothrombin to thrombin and thrombin activity. In some studies, statins also reduced fibrinogen levels. By altering the levels and activities of tPA and PAI-1, statins seem to stimulate fibrinolysis. The data on the effects of combined treatment with statins and other drugs on haemostasis are rather limited. They suggest that statins combined with fibric acid derivatives, omega-3 fatty acids and 17beta-estradiol are superior to statins alone. The only two clinical studies performed in patients with acute coronary syndromes showed a relatively weak effect of statins on haemostasis in those patients. Although various statins may produce different effects on individual variables, there are no convincing data showing that differences in their physicochemical and pharmacokinetic properties significantly alter their net effect on excessive procoagulant activity. Apart from the lipid-lowering effect, statins suppress the synthesis of several important nonsterol isoprenoids derived from the mevalonate pathway, especially farnesyl and geranylgeranyl pyrophosphates, which via enhanced protein prenylation, are involved in the regulation of many cellular processes. It is presumed that the inhibitory effect of statins on the mevalonate pathway is involved in the regulation of some key steps of coagulation and fibrinolysis processes. In this way they probably regulate the synthesis of TF, tPA and PAI-1, and perhaps they also control the generation and activity of thrombin. The beneficial effects of statins on coagulation and fibrinolysis may be responsible for their ability to decrease the number of cardiovascular events. The lipid-independent effects of statins on haemostasis may contribute to the marked decrease in the incidence rates of mortality, hospitalisation and revascularisation in patients treated with these drugs.

Reversible inhibitors of TAFIa can both promote and inhibit fibrinolysis.

The plasma carboxypeptidase activated thrombin-activable fibrinolysis inhibitor (TAFIa), is thermally unstable at 37 degrees C, with a half-life of 8 or 15 min depending on the isoform. The arginine analog, 2-guanidinoethylmercaptosuccinate (GEMSA), not only inhibits TAFIa but also slows the spontaneous inactivation of the enzyme, thereby reducing the activity of TAFIa, while extending its apparent half-life. Because, as shown in previous work, the ability of TAFIa to prolong clot lysis can be more dependent on its half-life than its concentration, in this study we determined whether reversible inhibitors of TAFIa could paradoxically prolong clot lysis. Potato tuber carboxypeptidase inhibitor (PTCI) or GEMSA were titrated into normal pooled human plasma, in the presence of soluble thrombomodulin. Both inhibitors mediate a biphasic antifibrinolytic effect, prolonging clot lysis at lower concentrations and enhancing clot lysis at higher concentrations. The antifibrinolytic effect of GEMSA is maximized at 1 mmol L-1, increasing clot lysis time from 100 min to 350 min. The antifibrinolytic effect of PTCI is maximized at 100 nmol L-1, increasing clot lysis time from 100 min to 240 min. To further characterize the nature of this biphasic effect, TAFI at various concentrations was added to TAFI-immunodepleted human plasma in the presence of PTCI or GEMSA. The magnitude of the effect depends on the concentration of TAFIa, the concentration of inhibitor, and the potency of the inhibitor. We propose that the biphasic antifibrinolytic effect is mediated by the dynamic equilibrium of free TAFIa that inactivates quickly, and TAFIa bound to inhibitor that inactivates slowly. TAFIa inhibitors used as therapeutic agents might not only enhance lysis at higher concentrations, but also stabilize fibrin clots at intermediate concentrations.

[Coagulative and fibrinolytic changes in patients with essential hypertension and the effect of sustained-release nifedipine].

OBJECTIVE: To investigate the changes of coagulation and fibrinolysis status in patients with essential hypertension (EH) and observe the therapeutic effect of sustained-release nifedipine. METHODS: Ninety-nine EH patients were divided according to their diastolic blood pressure (DBP) into mild group (48 cases), moderate group (29 cases) and severe group (22 cases), and 25 patients among the groups were chosen at random to receive sustained-release nifedipine for 2 weeks. Twenty healthy subjects served as control group. Plasma D-dimer (DD), fibrin monomer (FM) and tissue-type plasminogen activator (tPA) levels were determined in all the subjects by enzyme-linked immunosorbent assay (ELISA). RESULTS: The plasma DD and FM levels were much higher, while tPA level was much lower in hypertensives than those of normal controls, exacerbating with the severity of the disease. DBP was positively correlated with plasma FM level (r=0.374,P<0.001). In patients with left ventricular hypertrophy, left ventricular enlargement and left atrial enlargement, higher levels of DD, FM and tPA were detected. Nifedipine treatment produced significant reduction in plasma DD and FM levels along with the increase in tPA level [DD: (40.7+/-23.5) mg/dl vs (23.8+/-16.5) mg/dl; FM: (7.0+/-1.6) ng/microliter vs (4.8+/-1.5) ng/microliter tPA: (0.31+/-0.14) ng/ml vs(0.41+/-0.05) ng/ml, P<0.001]. CONCLUSION: Enhanced coagulative activity and lowered fibrinolytic activity characterize EH patients and nifedipine may correct this disorder.

Effects of recombinant human erythropoietin therapy on blood coagulation and fibrinolysis system.

This study was designed to examine the effects of recombinant human erythropoietin (rHuEPO) therapy on blood coagulation and fibrinolysis in patients scheduled for elective heart surgery and undergoing preoperative autologous blood donation. Twenty-seven patients were studied, of whom 16 patients received rHuEPO (group E) and 11 patients no rHuEPO therapy (group N). The patients in group E were given 6000 units of rHuEPO intravenously every other day, three times a week, beginning from two weeks prior to the operation. In both groups, 400 ml of blood was collected preoperatively for predeposit once a week for two weeks, and the self-donated blood was returned to the patient intra- and postoperatively. Blood samples were drawn at the beginning of the study, immediately before the operation and two weeks after the operation. They were analyzed to assess blood coagulation, fibrinolysis, platelet function and vascular endothelial cell function, in order to examine the effects of the administration of rHuEPO. No significant difference was observed between the two groups in the degree of changes in these parameters following the operation. As enhancement of blood coagulability and fibrinolytic activity was evident postoperatively in both groups, changes in these parameters during the preoperative autologous blood donation period were also assessed excluding the postoperative data. Again, there was no significant intergroup difference in any of the markers evaluated. It was concluded that the administration of rHuEPO during preoperative autologous blood donation is unlikely to affect coagulation and fibrinolysis.

Ginger, fat and fibrinolysis.

Administration of 50 gm of fat to 30 healthy adult volunteers decreased fibrinolytic activity from a mean of 64.20 +/- 5.31 to 52.10 +/- 3.20 units (P < 0.001). Supplementation of 5 gm of ginger powder with fatty meal not only prevented the fall in fibrinolytic activity but actually increased it significantly (P < 0.001). This fibrinolytic enhancing property is a further addition to the therapeutic potential of ginger.

Protein C anticoagulant pathway and its role in controlling microvascular thrombosis and inflammation.

OBJECTIVE: To review the physiologic and biochemical mechanisms that suggest that protein C and activated protein C (APC) have unique properties that make them good candidates for the treatment of microvascular thrombosis, disseminated intravascular coagulation, and sepsis. DATA SOURCES: A summary of published medical literature from MEDLINE search files and published reviews on protein C physiology, biochemical properties, and activity in experimental and human sepsis. DATA SUMMARY: Protein C is critical to the regulation of microvascular coagulation, as seen most clearly in humans born with congenital deficiency of protein C, who develop neonatal purpura fulminans. Protein C supplementation reverses the lesion formation. In primate models of sepsis, APC blocks disseminated intravascular coagulation initiated by Escherichia coli infusion, and inhibition of APC function exacerbates both the coagulant and inflammatory responses of the animals to sublethal levels of E. coli. In vitro experiments have shown that APC can inhibit neutrophil binding to selectins: Endothelial cell protein C receptor, a protein C/APC binding receptor, can bind to proteinase 3 bound to Mac-1 on leukocytes, potentially blocking tight leukocyte adhesion; and APC can inhibit tumor necrosis factor-alpha secretion by monocytes and other cell lines by interfering with nuclear factor-kappaB nuclear translocation. By blocking nuclear factor-kappaB nuclear translocation, cytokine- and endotoxin-mediated adhesion molecule up-regulation is decreased. These properties of APC are consistent with a large number of animal studies demonstrating that APC can diminish complications of crush injury and leukocyte damage to lung and other tissues in response to sepsis and decrease the inflammatory response. The animal studies are consistent with the phase 2 studies reported on APC use in the treatment of human sepsis. CONCLUSIONS: The protein C pathway is uniquely poised to interfere with the microvascular coagulation and inflammation that follows challenge with endotoxin. By limiting leukocyte activation, cytokine elaboration, and microvascular coagulation, APC has been shown to prevent organ damage in experimental models of sepsis. These results are consistent with the initial phase 2 reports of APC therapy in human sepsis suggesting a clinical benefit and demonstrating anti-inflammatory activity with several reports of apparent protein C effectiveness in severe sepsis, especially meningococcemia.