Oral anticoagulant therapy. Fundamentals, clinical practice and recommendations.

Oral anticoagulant therapy remains one of the most frequent options for treatment and prevention in patients with arterial and venous thromboembolism. Clinical guidelines have been updated in recent years by various associations such as the American Heart Association (AHA), the American College of Cardiology (ACC) and the European Society of Cardiology (ESC), as well as organizations in several other countries. The authors present a review of therapy with vitamin K antagonists, focusing on their mechanism of action and metabolism, as well as on the fundamentals of such therapy. Clinical recommendations for the most frequent indications are described. One of the most important issues is the use of these drugs for atrial fibrillation therapy, which is a common indication. Prosthetic valvular disease is a compelling indication for anticoagulation, for which there is a broad consensus. Ischemic heart disease is another indication described for oral anticoagulation. Several practical issues in cardiac patients are discussed. These include the appropriate initial dose, schemes for reversal of anticoagulation, and management of surgical patients. Finally, risk factors for deep venous thrombosis and pulmonary embolism are detailed in this review, presenting current clinical recommendations for oral anticoagulation of these patients.

Comparative ability of human monocytes and macrophages to control the intracellular growth of Mycobacterium avium and Mycobacterium tuberculosis: effect of interferon-gamma and indomethacin.

Intracellular growth of Mycobacterium avium and M. tuberculosis H37Rv was compared both in human peripheral blood monocytes and in cultured macrophages. The cells were treated with 300 U of human recombinant interferon-gamma (IFN gamma) either 48 h prior to phagocytosis or after infection. In some cases, indomethacin (IND, a potent inhibitor of prostaglandin-E2 synthesis), was added immediately after infection of macrophages. IFN gamma pretreatment of monocytes resulted in about 50% lesser uptake of both pathogens, but had no effect in macrophages. Macrophages, as compared to monocytes, were more permissive to M. avium growth suggesting that monocytes may be innately more efficient in controlling the intracellular growth of this pathogen. About ten-fold higher growth of M. avium as compared to M. tuberculosis was observed in both culture systems. IFN gamma-treatment alone did not confer any anti-M. avium activity to monocytes and macrophages alike and addition of IND did not change this unresponsiveness. In the case of M. tuberculosis, the IFN gamma treatment alone endowed both monocytes and macrophages with significant bacteriostatic activity which was further potentiated by the addition of IND. These observations show innate differences in the ability of human monocytes and macrophages to control the growth of two major mycobacterial pathogens and the immunoregulatory mechanisms involved.

Intracellular growth of Mycobacterium avium in human macrophages is linked to the increased synthesis of prostaglandin E2 and inhibition of the phagosome-lysosome fusions.

A virulent strain of Mycobacterium avium grew actively inside human adherent peripheral blood monocyte-derived macrophages. Bacteria were always confined to the phagosome compartment and were encapsulated. Cytochemical labeling of acid phosphatase using transmission electron microscopy showed a strong inhibition of the phagosome-lysosome fusions (PLF) in macrophages as not more than 25-30% bacteria containing phagosome at any time effectively fused with lysosomes. In case of a positive fusion event, the bacterial capsule prevented the diffusion of the lysosomal contents to the bacterial surface. Moreover, the infection of macrophages both by living and gamma-killed M. avium was linked to an increased synthesis of prostaglandin E2 (PGE2); however the total amount of PGE2 synthesized in the latter case was significantly lower than that observed with viable organisms. Our results suggest that the inability of human macrophages to control M. avium infection is linked to immunosuppressive pathways, e.g. enhanced synthesis of PGE2 and also to an impairment of normal microbicidal functions of the infected macrophages.

Effect of indomethacin on the modulation of Mycobacterium avium growth in human macrophages by interferon gamma, retinoic acid and 1,25(OH)2-vitamin D3.

A virulent strain of Mycobacterium avium was grown actively inside human adherent peripheral blood monocyte-derived macrophages with enhanced synthesis of prostaglandin E2 (PGE2). We therefore decided to investigate if the inability of human macrophages to control M. avium infection could be reversed using various immunomodulators, i.e. retinoic acid (RA), 1,25 dihydroxyvitamin D3 (D3) and interferon gamma (IFN gamma) alone or in combination, and whether this reversal was further potentiated by the addition of indomethacin (IND), a potent inhibitor of PGE2 biosynthesis. Among the various immunomodulators employed, only RA alone or in association with D3 or both D3 and IFN gamma were able to induce a clear mycobacteriostatic effect, which was further potentiated by IND. Our data suggest that immunosuppressive pathways induced in macrophages infected by M. avium result partly from an increased synthesis of PGE2 occurring soon after infection.

Interrelationship of plasma triglyceride and coagulant factor VII levels in normotriglyceridemic hypercholesterolemia.

We have evaluated the potential relationships between plasma levels of certain coagulation factors, i.e. factor VII antigen (F VIIag) and factor VII coagulant activity (F VIIc), and parameters of lipid transport in a group of 90 normotriglyceridemic patients displaying hypercholesterolemia (Fredrickson's type IIa hyperlipoproteinemia). Levels of factor VIIc were significantly elevated (P less than 0.01) in this patient group as compared to a group of healthy normolipidemic subjects. By contrast, levels of factor VIIag were also increased, but such differences were not significant in relation to those of controls. Furthermore, concentrations of F VIIc and F VIIag in hypercholesterolemic males and females resembled each other. Similar observations were made when patients were divided into those either presenting or lacking symptoms of vascular disease. However, plasma levels of both F VIIc and F VIIag were positively correlated with circulating triglyceride concentrations in the hypercholesterolemic group, but not with other parameters of lipid transport such as serum cholesterol, HDL-cholesterol, and apolipoprotein B. When patients were treated with a lipid-lowering agent (cholestyramine), lower levels of both F VIIc and F VIIag were found concomitantly with a decrease of similar order in triglyceride concentrations. We conclude that serum triglyceride levels, even within the normal range, may be associated with elevation in the activity of factor VII in hypercholesterolemic patients, thereby increasing their risk of thrombosis.

Coagulation factor VII and plasma triglycerides. Decreased catabolism as a possible mechanism of factor VII hyperactivity.

High circulating levels of coagulation factor VII (FVII) are known to be associated with elevated concentrations of blood lipids. More specifically, hypertriglyceridemia is correlated with raised FVII coagulant activity (FVIIc). Recently, evidence has been described which suggests that elevation in FVIIc might reflect an increase in the total concentration of FVII, as evaluated by quantitation of FVII antigen (FVIIag). It is also known that FVIIc represents a risk factor for cardiovascular death, but the prediction of cardiovascular risk based on triglyceride estimation is the subject of conflicting results. Since dyslipidemia featuring abnormal triglyceride metabolism is pathophysiologically heterogeneous, we analyzed the possible relationships between FVII and triglyceride further and under standardized postprandial conditions. For this purpose we studied FVIIc and FVIIag in relation to triglyceridemia after a standardized test meal. Our results confirm that FVIIc and FVIIag levels are strongly correlated with each other (r = 0.714; p = 0.01). In addition, both were significantly increased (p less than 0.02) in patients who exhibited abnormal triglyceride levels 8 h after a standardized test meal, as compared to those who displayed normal triglyceridemia. Furthermore, we found that apolipoprotein B levels were also increased in such patients. The deficient postprandial catabolism of triglycerides, therefore, appears to be related to an increase in total FVII concentration, suggesting that some association between the metabolism of triglyceride-rich lipoproteins and FVII might underlie the mechanism of the elevation in FVII. Given the important contribution of FVII to hypercoagulability, then our results may be relevant to the understanding of the role of postprandial triglyceride in atherogenesis and in consideration of the circadian prevalence of cardiovascular thrombosis.

Phospholipase C sensitive FVII activity and FVII antigen in hypertriglyceridemia.

An increase in factor VII coagulant activity (FVIIc) was found in patients with high thrombotic risk and in hyperlipidemias, namely in Fredrickson's types IIb and IV. This elevation was correlated with the level of total cholesterol and triglyceride concentrations. It has been suggested that this increase is due to higher FVII coagulant activity related to the formation of a complex between factor VII (FVII) and phospholipids, since it was shown that FVIIc returns to normal levels after incubation of plasma with phospholipase C. In this respect we have studied the activity of FVII before and after phospholipase C plasma treatment and FVII related antigen (FVIIag) in patients with types IIa, IIb and IV hyperlipidemias. An elevation of FVIIc was found in hyperlipidemic patients compared to normal controls. FVIIag values were also higher in type IV patients, implicating an increase in FVII total concentration and not only an activation of FVII. Furthermore, Phospholipase C action on patients' plasma samples lowered FVIIc to levels very similar to those of FVIIag. In normal controls the same action was noted and it seems therefore likely that the proposed phospholipid contribution to FVIIc hyperactivity plays only a minor role in FVII changes in primary hyperlipidemia. Instead, FVIIag increase seems to be the major mechanism of FVII increase in primary hypertriglyceridemic patients.

Plasma factor VII, triglyceride concentration and fibrin degradation products in primary hyperlipidemia: a clinical and laboratory study.

There is evidence that the increase in coagulation factor VII (FVII) represents a predictive risk factor of arterial thrombosis in coronary heart disease. Its relative contribution to this multifactorial process and its relationship to other risk factors, namely cholesterol and triglycerides, is yet a matter of investigation. In this study we aimed to clarify whether FVII synthesis or activation correlated with plasma lipid concentrations. For this, we assayed the plasma levels of FVII antigen (FVII:ag) and FVII coagulant activity (FVIIc) in types IIa, IIb and IV hyperlipidemic individuals, together with the levels of cholesterol, triglycerides, high-density lipoproteins and apolipoprotein B. FVII activation state (FVIIa) was then assessed by FVIIc/FVII:ag. In order to assess the possible correlation of FVII levels with the generation of thrombin and formation of fibrin, we also assayed the plasma concentration of fibrin degradation products (D-dimers) in these patients. Considering all the patients studied, there was a fair correlation between FVIIc and FVII:ag (r = 0.704; p less than 0.01). The mean levels of FVIIc and FVII:ag were significantly higher in type IV hyperlipidemia than in controls (t = 4.260; p less than 0.001 and t = 3.015; p less than 0.01, respectively) and other types of hyperlipidemia. We also found that FVIIc and FVII:ag significantly correlated to triglyceride concentration. We could not detect an evident activation of FVII in these patients since FVIIc/FVII:ag was not elevated in comparison with controls, nor did it correlate with any of the lipid determinations in any of the types of hyperlipidemia studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Factor VII hyperactivity in acute myocardial thrombosis. A relation to the coagulation activation.

It has been shown that coagulation factor VII (FVII) has an increased coagulant activity (FVIIc) in cardiovascular high risk patients and that it is a important risk factor for the development of ischaemic heart disease (IHD) and cardiovascular death. In this study, we measured FVII coagulant (FVIIc) and immunological (FVIIag) activities during the acute phase of unstable angina (UA) and acute uncomplicated and complicated myocardial infarction (AMI). We have also studied its changes in relation to thrombin formation and coagulation activation, as assessed by determination of thrombin-antithrombin circulating complexes (T-AT) at the same time. Our results show a marked increase in FVIIc in all patients, with highest significant levels in complicated AMI. In fact, this increase was also different between groups, complicated AMI showing a significant degree of increase in FVIIc in relation to UA and uncomplicated AMI. FVIIag did not vary between groups and controls, implicating a progressive activation of FVII. As expected, we found comparable levels of T-AT in UA and in AMI patients, suggesting that a common thrombotic process is involved in both situations. FVIIc was strongly correlated to T-AT in all patients (r = 0. 750; p less than 0.001) and also within groups. This study underlines the important positive contribution of FVIIc to IHD and to the prognosis of its thrombotic acute events, and shows that the increase in FVII activity is associated with an increase of a thrombotic marker (thrombin-antithrombin). Further studies are needed to evaluate if FVII activation is the cause or the consequence of the thrombotic processes.