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BACKGROUND: The prevalence of medical misinformation on the Internet has received much attention among researchers concerned that exposure to such information may inhibit patient adherence to prescriptions. Yet, little is known about information people see when they search for medical information and the extent to which exposure is directly related to their decisions to follow physician recommendations. These issues were examined using statin prescriptions as a case study. METHODS: We developed and used a tool to rank the quality of statin-related web pages based on the presence of information about side effects, clinical benefits, management of side effects, and misinformation. We then conducted an experiment in which students were presented with a hypothetical scenario in which an older relative was prescribed a statin but was unsure whether to take the medication. Participants were asked to search the web for information about statins and make a recommendation to this relative. Their search activity was logged using a web-browser add-on. Websites each participant visited were scored for quality using our tool, quality scores were aggregated for each participant and were subsequently used to predict their recommendation. RESULTS: Exposure to statin-related benefits and management of side effects during the search was significantly associated with a higher probability of recommending that an older relative adhere to their physician's recommendation. Exposure to misinformation and side effects were not associated, nor were any other participant characteristics. Bigram analyses of the top reasons participants gave for their recommendation mirrored the statistical findings, except that among participants who did not recommend following the prescription order, myriad side effects were mentioned. CONCLUSIONS: Our findings suggest that units of information people see on health-related websites are not treated equally. Our methods offer new understanding at a granular level about the impact of Internet searches on health decisions regarding evidence-based recommended medications. Our findings may be useful to physicians considering ways to address non-adherence. Preventive care should include actively engaging patients in discussions about health information they may find on the web. The effectiveness of this strategy should be examined in future studies.
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Comunicação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Inibidores de Hidroximetilglutaril-CoA Redutases , Cooperação do Paciente , Análise Custo-Benefício , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Internet , Masculino , MédicosRESUMO
BACKGROUND: Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death in the United States. Case-based learning using electronic delivery of the modules can educate clinicians and improve translation of evidence-based guidelines into practice for high-risk ASCVD patients. OBJECTIVE: To develop and optimize module design, content, and usability of e-learning modules to teach clinicians evidence-based management in accordance with multi-society guidelines for high-risk ASCVD patients that will be implemented and evaluated in U.S. health systems in the TEACH-ASCVD study. METHODS: Seven e-learning modules were created by a committee of lipid experts. Focus groups were conducted with lipid experts to elicit feedback on case content followed by interviews with a target audience of clinicians to assess usability of the online module platform. Responses from both groups were evaluated, and appropriate changes were made to improve the e-learning modules. Design of the TEACH-ASCVD study is presented. RESULTS: Feedback regarding case content by lipid experts included providing more detailed patient histories, clarifying various diagnostic criteria, and emphasizing clinical best practices based on evidence-based guidelines. The target audience clinician group reported an agreeable experience with the e-learning modules but noted a discordance between the evidence-based guidelines and clinical decision-making in their own practices. Participants felt the modules would help educate clinicians in managing high-risk ASCVD patients. CONCLUSION: Clinicians must be informed of best practices as the field of lipidology continues to evolve. E-learning modules provide a concise, valuable, and accessible mechanism for educating clinicians regarding changes in the field to deliver the best patient care.
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Aterosclerose , Instrução por Computador , Humanos , Estados Unidos , LipídeosRESUMO
BACKGROUND: Procoagulant activity attributed to tissue factor (TF, CD142) bound to lipid microvesicles has previously been shown to be elevated in urine of patients with various solid cancers. The phosphorylation of the C-terminal signal transduction peptide (STP) at Ser253 and Ser258 has been determined to be important for the formation of TF-microvesicles. The purpose of this work was to investigate the marker potential of the TF-STP domain in urine of patients with cancer using immunologic methods to quantitate unphosphorylated TF and TF phosphorylated at Ser253 and Ser258. MATERIALS AND METHODS: We developed monoclonal and polyclonal antibodies directed against the 3 C-terminal STP species of TF and constructed 3 enzyme-linked immunosorbent assays (ELISAs) that specifically recognize unphosphorylated TF and TF phosphorylated at either Ser253 or Ser258. As proof of principle, a preliminary pilot study with stored Biobank-sourced urinary specimens from 45 healthy individuals and 38 patients with bladder cancer were studied using these ELISAs. RESULTS: We report that all 3 species of TF were found in the urine. Two species, TF-pSer258 and unphosphorylated TF, were significantly elevated in the cohort with bladder cancer. The sensitivity of TF-pSer258 by the receiver operator characteristic technique was 86.8%, with a specificity of 97.8% at a cutoff value of 0.55 ng/mL. Using a simplified sample preparation method for the ELISAs on the same clinical specimens, the sensitivity of TF-pSer258 was 86.8%, with a specificity of 93.3% at a cutoff value of 0.53 ng/mL. The unphosphorylated TF species was significantly elevated in later stage bladder cancer with best results seen for the unfractionated preparation technique (95% confidence interval, 10.55-15.74; N = 20) but not early stage non-muscle-invasive bladder cancer (95% confidence interval, 4.71-10.73; N = 18; P < .02). CONCLUSIONS: The development of these new ELISAs allows the quantitation of the urinary biomarkers TF-pSer258 and unphosphorylated TF, which may lead to a new diagnostic approach to the early detection of bladder cancer and warrant further investigation in a prospective trial.
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Biomarcadores Tumorais/urina , Serina/metabolismo , Tromboplastina/urina , Neoplasias da Bexiga Urinária/urina , Biomarcadores Tumorais/química , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Estadiamento de Neoplasias , Fosforilação , Projetos Piloto , Estudos Prospectivos , Sinais Direcionadores de Proteínas , Tromboplastina/química , Neoplasias da Bexiga Urinária/patologiaRESUMO
The presence of fibrin degradation products, thrombin-like enzyme, prothrombin fragments, thrombin-activatable fibrinolysis inhibitor, plasmin and other active components of blood coagulation and fibrinolysis in seminal plasma has been reported. In the present study we investigate the presence of thrombomodulin in human semen. Using an Imubind thrombomodulin enzyme-linked immunosorbent assay (American Diagnostica Inc., Stamford, Connecticut, USA), seminal thrombomodulin levels were measured in 47 semen specimens obtained from subfertile individuals, normally fertile individuals, semen donors as well as vasectomized individuals, and in a further group defined by normality in several parameters derived from the World Health Organization fertility criteria. Conventional semen parameters were analysed in all semen samples. Thrombomodulin is quantifiable in human semen at a concentration lower than that normally found in citrated blood plasma samples. Slightly higher levels were seen for fertile stratifications compared with infertile individuals but without significant difference, given the numbers accrued. A vasectomized group showed the lowest value. In conclusion, our results establish the presence of thrombomodulin in human semen and suggest its production both upstream and downstream from the level of a vasectomy lesion.
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Sêmen/química , Trombomodulina/análise , Humanos , Infertilidade Masculina , Masculino , Contagem de Espermatozoides , VasectomiaRESUMO
Plasminogen activator inhibitor-1 (PAI-1) is the major specific inhibitor of tissue-type plasminogen activator (tPA) which mediates fibrin clot lysis through activation of plasminogen. Wild-type-PAI-1 (wPAI-1) is rapidly converted to the latent form (half-life of approximately 2 h) and loses its ability to inhibit tPA. We developed a very long half-life PAI-1 (VLHL PAI-1), a recombinant protein with a half-life >700 h compared with wPAI-1. In this study, VLHL PAI-1 was assessed for its ability to inhibit clot lysis in vitro. Clot formation was initiated in normal plasma supplemented with tPA by the addition of either tissue factor or human recombinant FVIIa. Clot lysis time, monitored turbidimetrically in a microtiter plate reader, was determined at various concentrations of wPAI-1 and VLHL PAI-1. Both wPAI-1 and VLHL PAI-1 caused a significant increase in clot lysis time, although the latter was somewhat less effective at lower concentrations. The VLHL PAI-1, but not wPAI-1, maintained its anti-fibrinolytic activity after preincubation overnight at 37 degrees. These studies demonstrate that VLHL PAI-1 is an effective inhibitor of fibrin clot degradation. Due to the high stability of VLHL PAI-1 compared with wPAI-1, this novel inhibitor of tPA-mediated fibrinolysis may have therapeutic applications for treating surgical and trauma patients when used directly or in conjunction with the procoagulant recombinant FVIIa.
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Coagulação Sanguínea/efeitos dos fármacos , Fibrina/metabolismo , Fibrinólise/efeitos dos fármacos , Inibidor 1 de Ativador de Plasminogênio/farmacologia , Proteínas Recombinantes/farmacologia , Ativador de Plasminogênio Tecidual/farmacologia , Eletroforese em Gel de Poliacrilamida , Meia-Vida , Humanos , Inibidor 1 de Ativador de Plasminogênio/isolamento & purificação , Espectrofotometria , TermodinâmicaRESUMO
Several active components of the haemostatic system have been identified in human semen. Here we investigated the presence of thrombin-activatable fibrinolysis inhibitor (TAFI) in seminal plasma. Using an enzyme-linked immunosorbent assay, TAFI levels were measured in 36 semen specimens obtained from subfertile, normally fertile, fertile sperm donor and vasectomized individuals. TAFI was detectable in human semen. Its levels were highest in vasectomized individuals compared with the other groups, including a pooled normal semen parameter stratification group (by World Health Organization criteria). This elevation in the vasectomy group was found to be statistically significant in comparison with the normally fertile (P < 0.01) and the pooled normal semen parameter groups (P < 0.05). Seminal TAFI levels showed a significant positive correlation with total sperm count and sperm density. In contrast, a negative association was observed with semen volume, days of sexual abstinence and liquefaction time. The highly motile sperm group showed low TAFI levels. Our results establish the presence of TAFI in seminal plasma with a probable role in the protection of the seminal clot against lysis. It also suggests a downstream (post-testicular) source for its production. This reinforces the involvement of the conventional haemostatic system in the coagulation and liquefaction properties of human semen.
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Carboxipeptidase B2/metabolismo , Fertilidade/fisiologia , Peptídeo Hidrolases/metabolismo , Sêmen/enzimologia , Humanos , Masculino , Contagem de Espermatozoides , Motilidade dos Espermatozoides/fisiologiaRESUMO
In 2003, select families with familial hypercholesterolemia were first identified to have gain-of-function mutations for proprotein convertase subtilisin kexin type 9 (PCSK9) followed, in 2006, by the identification of those with lifelong low levels of LDL-C and lowered atherosclerotic cardiovascular disease (ASCVD) risk who had loss-of-function PCSK9 mutations. These discoveries led to the rapid development of PSCK9-targeted monoclonal antibody (PCSK9 mAb) therapies and, in 2015, 2 'fully-humanized' PCSK9 mAbs (alirocumab and evolocumab) were marketed in the United States, Europe, and other countries. In a wide range of high risk patients, with and without ASCVD, these PCSK9 mAbs, as once or twice monthly subcutaneous injections, potently reduce LDL-C 50-65% beyond levels achieved by maximally tolerated statin therapy; approximately one-third of patients achieve LDL-C levels <25 mg/dL. In the US, PCSK9 mAb therapy has current limited indications for persons with ASCVD or familial hypercholesterolemia requiring additional LDL-C reduction beyond maximally tolerated statin therapy. The first of the ASCVD outcomes-driven trials, the FOURIER trial has very recently shown in over 27,000 subjects randomized to evolocumab or placebo on top of moderate or high intensity statin therapy, a 15% risk reduction in the primary and 20% reduction in the secondary outcome over 2.2 years of treatment. Also of interest in patients with coronary artery disease on statin therapies, once-monthly evolocumab treatment, for only 76 weeks, resulted in significant plaque atheroma volume regression, as assessed by serial intravascular ultrasonography imaging, in approximately two-thirds of treated patients. Finally, in development is a highly durable RNA interference therapeutic inhibitor of PCSK9 synthesis which from a single dosage has been shown to maintain, for 6 months, a 75% reduction in PCSK9 levels and 50% reductions in LDL-C levels. The potential role of this vaccination-like product, as well as currently available PCSK9 mAb therapies, represents significant therapeutic advances to address ASCVD residual risk.
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Functional assays are commonly used to measure the antibodies of ADAMTS13 found in patients of thrombotic thrombocytopenic purpura (TTP). In this study we used an enzyme-linked immunoassay to analyze the ADAMTS13-binding IgG levels in six groups of individuals: normal, random hospitalized patients, acute TTP, TTP after receiving plasma therapy, TTP in remission, and other types of thrombotic microangiopathy (TMA). The results showed that ADAMTS13-binding IgG levels were elevated in 100% of the acute TTP group, 75% of the TTP group after receiving plasma therapy, and 40% of the remission group. Overall, the ADAMTS13-binding IgG levels correlated with the inhibitory activity levels againstADAMTS13 (r = -0.69, P < 0.0001). The assay also detected elevated IgG binding levels in 5% - 15% of the normal, random, and other TMA control groups. Addition of purified ADAMTS13 protein to the plasma samples suppressed the IgG binding in each of the acute TTP patients, but in none of the non-TTP groups. Serial measurement in a patient that had two exacerbations of TTP within the first three weeks revealed that the ADAMTS13 activity levels remained <0.1 U/ml during this period, and the ADAMTS13-binding IgG remained elevated, suggesting that ADAMTS13 analysis may provide valuable insight to the disease status during the course of therapy. Analysis of ADAMTS13-binding IgG is helpful for the diagnosis and management of TTP.
Assuntos
Proteínas ADAM/imunologia , Autoanticorpos/sangue , Imunoglobulina G/imunologia , Púrpura Trombocitopênica Trombótica/imunologia , Proteína ADAMTS13 , Complexo Antígeno-Anticorpo/sangue , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Síndrome Hemolítico-Urêmica/imunologia , Humanos , Imunoglobulina G/sangue , Contagem de Plaquetas , PrevalênciaRESUMO
Plasminogen activator inhibitor-1 (PAI-1), a member of the serpin super-family, forms a covalent complex with its target proteinases, such as tissue and urokinase plasminogen activators. Thus, PAI-1 controls the physiological and pathological proteolysis. An abnormal expression of PAI-1 has been observed in different diseases, which can be treated by returning the proteolysis back to normal physiological levels. It has been reported that some PAI-1 inhibitors neutralize its activity by accelerating the conversion of PAI-1 into a latent form. We have found small organic chemicals that also neutralize PAI-1 activity, but by a different mechanism. Using the NBD fluorescent probe [N,N'-dimethyl-N-(acetyl)-N'-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)] incorporated into the reactive center loop (RCL) of PAI-1, we measured the kinetics of conversion from an active to a latent form. Unexpectedly, we found that some inhibitors of PAI-1 arrest this serpin in its active form instead of increasing the speed of conversion. Using docking calculations, we located two possible binding sites for these chemicals. The sites are in proximity of the P1/P1' amino acids of the RCL of PAI-1. Binding in this area can inactivate PAI-1 and additionally create a steric obstacle on the RCL making insertion of this loop between the A3 and A5 strands more difficult; hence abolishing a necessary step in the conversion of this protein into the latent form. Additionally, PAI-1 inhibitors link the RCL of one PAI-1 molecule with the strand 3C and strand 4C or helix A and strand 1B regions of the other PAI-1 molecule aiding polymerization or stabilizing the junction of the two. The polymerization of PAI-1 reduces PAI-1 activity by encapsulating the critical RCL fragment inside the formed PAI-1/PAI-1 polymers.
Assuntos
Biopolímeros/metabolismo , Inibidor 1 de Ativador de Plasminogênio/química , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Inativadores de Plasminogênio/metabolismo , Sequência de Aminoácidos , Sítios de Ligação/efeitos dos fármacos , Corantes Fluorescentes , Cinética , Ligantes , Espectrometria de Massas , Modelos Moleculares , Dados de Sequência Molecular , Ligação Proteica/efeitos dos fármacos , Conformação Proteica , Estrutura Secundária de Proteína , Análise de Sequência de Proteína , Espectrometria de FluorescênciaRESUMO
There is already evidence that a few components of the haemostatic system exist in semen. If these comprise a functional system, they may have a role in seminal clotting and liquefaction processes and ultimately may influence fertility. What might be expected in semen as collected from fertility clinics i.e., after having both coagulated and subsequently liquefied is uncertain. It does however still contain significant amounts of Tissue Factor (TF) although its effect on semen quality remains poorly understood. The present study analyses semen for Tissue Factor Pathway Inhibitor (TFPI). Measurements were made in seminal plasma, swim-up sperm and prostasomes and its relationship with conventional fertility parameters assessed. TFPI antigen levels in seminal plasma were measured in a total of 176 subjects using an Enzyme-linked immunosorbent assay (ELISA). These include sub-fertile (n=37), normally fertile (n=40), fertile sperm donor (n=34), vasectomized subjects (n=65) and in a further group defined by normality in several parameters derived from the World Health Organization (WHO) fertility criteria and termed "pooled normal semen parameters" (PNSP). For characterization studies, both TFPI activity and antigen were measured on whole semen, swim-up sperm and prostasome-rich fraction (n=5). TFPI levels were significantly higher in normal men as compared to sub-fertile (P<0.01) or vasectomized subjects (P<0.001). TFPI levels were even higher in the donor quality semen and the PNSP group. TFPI levels also correlated with semen liquefaction time, normal semen viscosity, sperm progression, percentage of motile sperm and sperm counts (density). In conclusion, the present finding substantiates the concept of an active clotting system in human semen. TFPI could regulate the activity of abundant TF, as it does elsewhere. Given a functional set of coagulation factors in semen, the TF/TFPI balance might impinge on its liquefaction and hence on global fertility.
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Hemostasia , Lipoproteínas/sangue , Lipoproteínas/metabolismo , Sêmen/metabolismo , Adulto , Ensaio de Imunoadsorção Enzimática , Fertilidade , Humanos , Infertilidade Masculina , Masculino , Pessoa de Meia-Idade , Contagem de Espermatozoides , Motilidade dos Espermatozoides , Espermatozoides , Tromboplastina/metabolismo , Fatores de Tempo , VasectomiaRESUMO
Coagulation factor (F) IX is a zymogen of the plasma serine proteases, one that plays an essential role in the regulation of normal blood coagulation. Congenital defects of FIX synthesis or function cause hemophilia B (originally called hemophilia C). Factor IX is activated by Tissue Factor (TF):FVII/FVIIa complex and FXIa. Subsequent to its activation, FIXa combines with FVIIIa on the platelet surface and activates FX to FXa. Human semen forms a semi-solid gelatinous coagulum, which then liquefies within 5-20 minutes in vitro. In spite of evidence demonstrating the importance of the seminal coagulation and liquefaction process in terms of global fertility and despite the fact that the seminal coagulum is composed of fibrin-like material, it has always been addressed from the perspective of High Molecular Weight Seminal Vesicle (HMW-SV) proteins (Semenogelin I and II) and their cleavage by prostate-specific antigen rather than the conventional hemostatic factors. In this study and as part of our continuing investigation of human seminal clotting factors, we report here on seminal FIX and FIXa in normal, subfertile, and vasectomized subjects. Factors IX and FIXa were studied in a total of 119 semen specimens obtained from subfertile (n=18), normally fertile (n=34), and fertile sperm donors (n=27) and vasectomy subjects (n=40). Seminal FIX and FIXa levels were also measured in a group defined by normality in several parameters derived from the World Health Organization fertility criteria and termed "pooled normal semen parameters." Both FIX and FIXa were quantifiable in human semen. There was a wide individual variation in FIX and FIXa levels within groups. Despite the group size, statistically significant associations with fertility-related parameters were infrequent. There is a positive correlation between FIX and its activation product, FIXa (n=36; r=0.51; P <.05). Factor IXa elevation in the high sperm-clump group was significant (P <.05), and days of abstention correlated with FIXa levels (n=63; r=0.3; P <.05). The key finding of the present study is that both FIX and FIXa are present in concentrations that are not dissimilar to plasma levels and that are apparently functional, as the activated form is also present. This fact, taken with other reports of coagulation factors in semen, raises the likelihood that a functional set of hemostatic coagulation proteins exists in semen, potentially to interact with the HMW-SV proteins and the prostate-specific antigen system.
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Fator IX/análise , Fator IXa/análise , Fertilidade/fisiologia , Sêmen/química , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , VasectomiaRESUMO
Statins are one of the most commonly prescribed drugs in clinical practice. They are usually well tolerated and effectively prevent cardiovascular events. Most adverse effects associated with statin therapy are muscle-related. The recent statement of the European Atherosclerosis Society (EAS) has focused on statin associated muscle symptoms (SAMS), and avoided the use of the term 'statin intolerance'. Although muscle syndromes are the most common adverse effects observed after statin therapy, excluding other side effects might underestimate the number of patients with statin intolerance, which might be observed in 10-15% of patients. In clinical practice, statin intolerance limits effective treatment of patients at risk of, or with, cardiovascular disease. Knowledge of the most common adverse effects of statin therapy that might cause statin intolerance and the clear definition of this phenomenon is crucial to effectively treat patients with lipid disorders. Therefore, the aim of this position paper was to suggest a unified definition of statin intolerance, and to complement the recent EAS statement on SAMS, where the pathophysiology, diagnosis and the management were comprehensively presented.
RESUMO
Statins are one of the most commonly prescribed drugs in clinical practice. They are usually well tolerated and effectively prevent cardiovascular events. Most adverse effects associated with statin therapy are muscle-related. The recent statement of the European Atherosclerosis Society (EAS) has focused on statin-associated muscle symptoms (SAMS), and avoided the use of the term 'statin intolerance'. Although muscle syndromes are the most common adverse effects observed after statin therapy, excluding other side effects might underestimate the number of patients with statin intolerance, which might be observed in 10 - 15% of patients. In clinical practice, statin intolerance limits effective treatment of patients at risk of, or with, cardiovascular disease. Knowledge of the most common adverse effects of statin therapy that might cause statin intolerance and the clear definition of this phenomenon is crucial to effectively treat patients with lipid disorders. Therefore, the aim of this position paper was to suggest a unified definition of statin intolerance, and to complement the recent EAS statement on SAMS, where the pathophysiology, diagnosis and the management were comprehensively presented.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Doenças Musculares/induzido quimicamente , Doenças Cardiovasculares/prevenção & controle , Dislipidemias/tratamento farmacológico , Humanos , Doenças Musculares/epidemiologiaRESUMO
Semen contains enzymes and inhibitors of the haemostatic system as well as the high molecular weight seminal vesicle (HMW-SV) proteins. The former may have roles in seminal clotting and in liquefaction through "fibrinolytic" activity, which may ultimately affect fertility. Although a limited number of studies have addressed the subject, the role of clotting and fibrinolytic factors in semen remains poorly understood. The liquefaction time and the distribution of components vary across split ejaculates. This may have an important bearing on the way clotting/fibrinolytic factors in semen are assessed. Semen contains tissue factor (TF, Thromboplastin, CD142), which originates from the prostate and is associated with prostasomes. The function of TF (and prostasomes) in semen is still a matter for speculation. Recently the presence of minute amounts of factor VII in semen has been demonstrated but its importance is uncertain. Semen also contains a thrombin-like enzyme, prothrombin fragments 1 and 2 (F1+2), D-dimer (DD) and thrombin-antithrombin (TAT) complexes. The presence of several fibrinolytic factors has been demonstrated in semen but few questions about their potential impact on semen quality have been raised. Factors found include tissue plasminogen activator (t-PA), urinary plasminogen activator (u-PA) and plasmin. There are also traces of fibrinogen, plasminogen, plasminogen activator inhibitor-1 (PAI-1), factor VIII coagulant activity (VIII:c) and fibrin monomers. The co-ordinate expression of both TF and PAI-1 by decidual cells of the endometrium is believed to be important in maintaining haemostasis during endovascular trophoblast invasion. Kallikrein-like serine protease inhibitors including prostate specific antigen (PSA) are known to be present in semen at high concentrations. In semen PSA is also found in a complex form with protein C inhibitor (PCI) with mutually inhibitory consequences. A better understanding of the spectrum of coagulating and liquefaction agents in semen to include classical haemostatic processes and the pathogenesis resulting from any imbalances between or within either system may provide the basis for the development of more selective and efficient agents affecting global fertility. Here we review aspects of male reproductive physiology in the light of recent findings concerning conventional clotting/fibrinolytic systems in human semen with a view to stimulating further research.
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Coagulação Sanguínea , Sêmen/fisiologia , Fibrinólise , Humanos , Masculino , Reprodução/fisiologia , Serina Endopeptidases/fisiologia , Inibidores de Serina Proteinase/fisiologiaRESUMO
Human semen spontaneously coagulates into a semisolid mass and then wholly liquefies in a process that may have some similarity to that of normal blood. This well described phenomenon is referred to as coagulation and liquefaction of semen. Besides other active components of the haemostatic system, semen contains a significant amount of functional tissue factor (TF). However, TF needs factor (F)VII in order to exert it actions. In this study, we assessed human semen for the presence of FVII and FVIIa, and related their levels to conventional fertility parameters. Using a functional, one stage, clotting assay based upon the prolongation of the prothrombin clotting time, using the ACL 300R analyser and an Imubind FVIIa ELISA assay, FVII and FVIIa levels were measured in 97 semen specimens obtained from sub-fertile (sperm counts <20 x 10(6)/mL), normally fertile (sperm counts >or=20 x 10(6) but <60 x 10(6)/mL), fertile sperm donors (sperm counts >or=60 x 10(6)/mL), vasectomized subjects and in a pooled normal semen parameters group (categorization into groups was based on the World Health Organization guidelines on fertility criteria). In addition, conventional semen parameters were analysed on all semen samples. Both FVII and FVIIa were quantifiable in human semen. The mean levels of FVII and FVIIa were 4.4 IU/dL and 12 ng/mL respectively. Despite the observed variations of FVIIa levels in the studied groups they did not meet statistical significance when the groups were tested against each other. However, seminal FVIIa levels showed a significant positive association with semen liquefaction time, sperm motility and semen volume. The anti-sperm antibodies and sperm-agglutination groups were also associated with raised seminal FVIIa levels. We observed no significant relationship between FVIIa levels and total sperm concentration, sperm count per mL (sperm density), sperm progression and days of sexual abstinence. This study demonstrates that human semen contains appreciable amounts of FVII and FVIIa. It is possible to quantify these using commercially available assays. There also appears to be a direct correlation between the levels of these factors and certain seminal parameters. This finding reinforces the concept of an active clotting system in human semen, by establishing the missing link in the activation of a TF-dependent pathway.
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Fator VII/análise , Fator VIIa/análise , Fertilidade/fisiologia , Sêmen/química , Proteínas Secretadas pela Vesícula Seminal/análise , Espermatozoides/fisiologia , Tromboplastina/análise , Autoanticorpos/análise , Humanos , Masculino , Abstinência Sexual , Aglutinação Espermática , Contagem de Espermatozoides , Motilidade dos Espermatozoides , Espermatozoides/imunologia , VasectomiaRESUMO
Factor (F) VIII circulates in blood complexed with von Willebrand Factor (vWF). Deficiency or defect accounts for haemophilia A and vWF disease. In blood, FVIII functions as a co-factor for FIXa in the activation of FX. Human semen coagulates and liquefies in a process that resembles and has some links with the conventional haemostatic process. A study elsewhere has detected traces, but not measurable levels, of FVIII coagulant activity (FVIII:C). In the present study we have assessed FVIII antigen (FVIII:Ag), FVIII:C and vWF antigen (vWF:Ag) levels in 159 semen specimens obtained from sub-fertile (n = 21), normally fertile (n = 38), fertile donors (n = 32), and vasectomized men (n = 57). Seminal FVIII:Ag levels were also measured in a group defined by several parameters derived from the World Health Organization (WHO) fertility criteria, termed "pooled normal semen parameters" (PNSP). Factor VIII:Ag levels were compared with conventional fertility parameters. In addition, both FVIII:C and vWF:Ag were assessed in a separate group of normal individuals (n = 11). Factor VIII:Ag, FVIII:C and vWF were present and quantifiable in human semen. Factor VIII:Ag levels were significantly lower in vasectomy subjects compared with donors (p = 0.01) or PNSP group (p = 0.01). Several trends taken together suggest an associations between FVIII:Ag and semen quality. Parallel investigations demonstrate FV, FVII, FVIIa, FIX, FIXa, FXa, FXI, FXII, tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in semen. The present report therefore provides further evidence for the presence of a functioning clotting system in human semen.