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PubMed1983

Prorenin in plasma and kidney.

Circulating prorenin is an enzymatically inactive form of renin, also present in kidney, which can be activated in vitro. Its biochemical properties and physiological behavior suggest that it may be a biosynthetic precursor of active renin. However, in contrast to typical prohormones, the normal plasma concentrations of prorenin are much higher than the active hormone. The purposes and functions of prorenin are unclear. It may have no further role after its secretion into the circulation. On the other hand, it may be a transport form of renin that can enter or exit cells more easily than the active form. It is also possible that the activity of the renin-angiotensin system may be regulated by the conversion of prorenin to renin in the kidney (which may be under beta-adrenergic control) or at other possible sites. Irreversible activation of prorenin appears to be a proteolytic process. In addition, acidification causes reversible activation, perhaps through a change in molecular conformation. Such reversible activation might occur in vivo by unknown mechanisms. Future studies are needed to define the biochemical processes by which increased physiological demand for renin is translated into the production of more active enzyme.

Adrenergic beta-Antagonists↗
PubMed2005

Procoagulant stimulus processing by the intrinsic pathway of blood plasma coagulation.

Potentiation of the intrinsic pathway of human blood plasma coagulation in vitro by contact with a solid procoagulant surface leads to bolus release of thrombin (FIIa) in concentration proportion to the intensity of activation as measured by procoagulant surface area or energy (water wettability). This rather remarkable finding is confirmed using two different assays: one triggering coagulation substantially through the intrinsic pathway alone and the second triggering coagulation through the intrinsic pathway in the presence of exogenous FIIa spikes. Similarity of experimental outcomes of these assays strongly suggests that endogenous FIIa production through the intrinsic pathway is independent of the absolute amount of FIIa present in plasma. Furthermore, we corroborate previous work indicating that procoagulant surfaces remain activating after repeated use and are not poisoned or denatured in the process of activating plasma coagulation. It is concluded that the sharp control mechanism that gives rise to bolus-production of FIIa from the intrinsic pathway must occur between surface activation of FXII and the FII --> FIIa step, is not related to inhibition by FIIa, and does not involve deactivation of procoagulant surfaces.

Biocompatible Materials↗
PubMed2004

Homozygosity of the T allele of the 46 C-->T polymorphism in the F12 gene is a risk factor for acute coronary artery disease in the Spanish population.

Following new guidelines that contain recommendations on the desirable features of a genetic association study, we performed a case-control study to establish the risk of acute coronary artery disease (CAD) related to the polymorphism (46 C-->T) in the F12 gene. We found a 6-fold higher risk of acute CAD associated with the homozygosity of the T allele of the F12, 46C-->T polymorphism in the Spanish population.

Acute Disease↗
PubMed1996

Intracoronary thrombolysis in the treatment of graft closure immediately after CABG.

A patient with a hypercoagulable state underwent coronary artery bypass grafting and was recovering uneventfully until diffuse electrocardiographic changes and cardiogenic shock developed within hours of the operation. Because of severe hemodynamic compromise on high-dose inotropic drugs and intraaortic balloon pump support, she was taken to the catheterization laboratory, where the patient was discovered to have thrombotic occlusion of all grafts, including the left internal mammary artery to the left anterior descending artery. Multiple graft percutaneous transluminal coronary angioplasty and thrombolysis with urokinase successfully opened the grafts, without bleeding complication. Anastomoses were all free of significant anatomic lesion. She has remained free of cardiac symptoms for 3.5 years after operation.

Angioplasty, Balloon, Coronary↗
PubMed2001

In vitro factor XI activation mechanism according to an optimized model of activated partial thromboplastin time test.

Whether the in vitro activation of factor XI in plasma is mediated by thrombin or by auto-activation remains a controversial question. In this context, we have simulated theoretical activated partial thromboplastin time (aPTT) by means of a program based on a body of 22 essential elementary reactions implemented with rate constants quoted in current literature. To meet self-consistency in input data issued from varying sources, the results were optimized using the simplex treatment. The performance of the model was systematically evaluated considering the extent of the deviations observed between predicted aPTT and laboratory measurements conducted on normal and factor VIII, IX, XI and XII single-factor deficient plasma. The influence of the auto-activation or thrombin-mediated activation of factor XI on these aPTTs was tested separately after insertion of these reactions in the model. According to the best fits, a mechanism accounting for an auto-activation reaction of activated factor XI rather than a positive feedback reaction mediated by thrombin seemed more likely. Based on this conclusion, a chart of self-consistent rate constant values accounting for the intrinsic pathway of coagulation under static conditions is proposed.

Blood Coagulation↗
PubMed1983

The kallikrein-kinin system in the acutely-ill: (A) changes in plasma kininogen in acutely-ill patients. (B) the efficacy of pulmonary clearance of bradykinin.

These studies have indicated some quantitative aspects of the kallikrein kinin system in sepsis. While other investigators have noted the fall in plasma kininogen in patients with sepsis, e.g. Erdos and colleagues (23), this study has indicated that it is the fall in the LMWK that is significant in these patients. LMWK comprises of three-quarters of the total plasma kininogen and its consumption can lead to the production of 2.24 million picograms bradykinin/ml plasma. In health bradykinin concentration is of the order of 100-400 picograms/ml. It is not unreasonable to suggest therefore, that bradykinin levels are increased in acute disease and other investigators have shown this by direct assay of the peptide in such patients. The present study has shown that once bradykinin is generated in the circulation in terms of ng/ml, even with passage through the lung, systemic effects occur, namely reduction in TPR and a fall in CO and BP. Thus, bradykinin could be the humoral factor responsible for the hyperdynamic state and systemic hypotension in severe sepsis. It is apparent that metabolism of bradykinin involves more than simply clearance of the peptide. It appears that bradykinin can stimulate the production of other vasoactive mediators by the lung. The consumption of LMWK in sepsis indicates that it is not plasma kallikrein activity but rather non-specific kininogenase activity that is critical. This may be important not only from the viewpoint of kinin generation, but also because of the consumption of plasma protease inhibitors. A mechanism to control or inhibit such protease activity offers a possible therapeutic approach to circulatory failure in these patients.

Acute Disease↗
PubMed1981

Guinea pig Hageman factor as a vascular permeability enhancement factor.

Hageman factor was purified from guinea pig plasma by successive column chromatography. The guinea pig Hageman factor appeared homogeneous as a single-chain protein on polyacrylamide gels in the presence of sodium dodecyl sulfate (SDS) and beta-mercaptoethanol. The apparent molecular weight was 76,000 daltons by SDS--polyacrylamide gel electrophoresis and 105,000 daltons by gel filtration with a Sephadex G-150 column. Amino acid composition of the guinea pig Hageman factor was similar to that reported for human, bovine, and rabbit Hageman factors. The purified guinea pig Hageman factor, as well as guinea pig plasma, showed strong clotting time correction activity in Hageman-factor--deficient human plasma. The activity could be blocked by the IgG fraction of antiserums against guinea pig Hageman factor raised in rabbits or a goat. The concentration of Hageman factor in guinea pig plasma was determined to be 120 microgram/ml by quantitative radial immunodiffusion assay. The 28,000-dalton active form of Hageman factor (beta-HFa) was prepared from guinea pig Hageman factor by treatment with plasma kallikrein. beta-HFa caused an increase in vascular permeability when injected into guinea pig skin at concentrations as low as 3 x 10(-10) M (0.8 ng). Native, or zymogen Hageman factor did not cause an increase in permeability at concentrations of up to 2 x 10(-7) M. The increased permeability induced by beta-HFa was short lasting, with about a 50% decrease in activity apparent within 6 minutes after intradermal injection. The permeability enhancement activity of beta-HFa was inhibited by pretreatment of beta-HFa with diisopropylfluorophosphate. It may be concluded that active Hageman factor in the interstitial space of guinea pigs acts as a vascular permeability factor of far greater potency than bradykinin.

Animals↗
PubMed2003

The genetics of atherothrombotic disorders: a clinician's view.

The development of coronary artery disease is dependent on the interaction of multiple biochemical pathways that lead to the development of plaque in the arterial wall and ultimately plaque instability, plaque rupture and thrombosis. The latter stages lead to vascular obstruction, tissue death and the final phenotype of myocardial infarction. Hemostasis gene association studies of atherothrombotic disorders have been unrewarding, with largely underpowered studies reporting inconsistent results. Clinical studies such as the Multiple Risk Factor Intervention Trial clearly indicate that clustering of classical risk increases the likelihood of myocardial infarction, and the addition of diabetes mellitus to the risk profile exponentially increases the risk of a vascular event. The development of insulin resistance is considered to be a pivotal event in vascular risk with associated clustering of dysglycemia, hyperinsulinemia, systolic hypertension, raised triglyceride and low high-density lipoprotein cholesterol. Additionally, elevated levels of plasminogen activator inhibitor-1, factor (F)VII, FXII, fibrinogen and tissue plasminogen activator occur with insulin resistance to create an atherothrombotic risk cluster. Heritability studies of insulin resistance and the vascular risk profile demonstrate genetic pleitropy between diabetes and vascular risk, which indicate that common genes have an important role. Increasingly, it is felt that inflammation underpins both diabetes and cardiovascular disease and that the expression of the final phenotype(s) may depend on complex gene-environment interactions with regulatory genes, including those for nuclear transcription factors and RNA-binding proteins. The complexity of coronary artery disease and the risk factor interactions make it unlikely that genetic epidemiology will identify genes involved in these processes without a better understanding of environmental influences.

Cholesterol↗
PubMed2005

Role of hepatocyte nuclear factor 4alpha in control of blood coagulation factor gene expression.

Hepatocyte nuclear factor 4alpha (HNF4alpha) plays an important role in the maintenance of many liver-specific functions. Liver-specific HNF4alpha-null mice were used to determine whether hepatic HNF4alpha regulates blood coagulation in vivo. These mice exhibited reduced expression of hepatic coagulation factors V, IX, XI, XII, and XIIIB and a prolonged activated partial thromboplastin time but not prothrombin time. Promoter analysis of the mouse FXII and FXIIIB genes was performed to determine whether HNF4alpha directly regulates the genes encoding these coagulation factors. Sequence analysis revealed the presence of one and two HNF4alpha binding sites in the mouse FXII and FXIIIB genes, respectively. Using transient transfection and electrophoretic mobility shift analyses with the mouse FXII and FXIIIB promoters, it was established that the high levels of promoter activity were dependent on HNF4alpha binding sites and the expression of HNF4alpha. In conclusion, HNF4alpha has a critical role in blood coagulation homeostasis by directing transcription of the FXII and XIIIB genes.

Animals↗
PubMed1970

The role of chemical mediators in the inflammatory response induced by foreign bodies: comparison with the schistosome egg granuloma.

Both divinyl benzene copolymer (plastic) beads and schistosome eggs produce inflammatory reactions after intravenous deposition into the lung of a mouse. As reported previously, the schistosome egg granuloma is an immunologic reaction of the delayed hypersensitivity type; this inflammatory process is prevented by immunosuppressive measures, and characteristically demonstrates an anamnestic response. In contradistinction, the plastic bead granuloma appears to be characteristic of a foreign body reaction; it is unaffected by immunosuppressive measures and does not demonstrate an anamnestic response with repeated exposure. The data in this report suggest that the granuloma formation around plastic beads is a nonimmunologic reaction induced by chemical mediators of inflammation. This proposal is supported by the following findings: the plastic beads activate Hageman factor in normal human and mouse plasma; the plastic beads induce vascular permeability-enhancing activity as measured in guinea pig skin and kinin-like activity in normal human and mouse plasma that is dependent on Hageman factor; ellagic acid, an agent that activates Hageman factor in vivo and is reported to diminish kininogen by consumptive depletion, markedly depresses the plastic bead granuloma. These data are consistent with the idea that the plastic bead granuloma and perhaps other foreign body inflammatory reactions are in major part dependent on kinin formation. Ellagic acid also suppressed the schistosome egg granuloma, but not to the same degree as the plastic bead granuloma. The implications of this observation are discussed in the text. Silicosis and "blue velvet disease", pathologic processes associated with the deposition of silica and magnesium trisilicate, respectively, in the lung, and the induction of a foreign body reaction may also be dependent on the activation of chemical mediators of inflammation by the silica and magnesium trisilicate particles with immunologic mechanisms participating in only a minor way, if at all. The marked suppression of experimental silicosis and blue velvet disease in mice by ellagic acid supports this idea.

Animals↗