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N Semeraro

Publications and source records attributed to N Semeraro.

At least 73 records · Page 4Linked to original sources
PubMed1985

Mechanisms of blood clotting activation in inflammation: the role of mononuclear phagocytes.

The authors review the procoagulant role of mononuclear phagocytes in the activation of blood clotting. Although the intrinsic pathway via the contact system has been considered the most important mechanism leading to fibrin formation, at least in acute inflammation, recent studies strongly suggest a role for the cells of the monocyte-macrophage series, which accumulate in the inflamed areas. These cells, when triggered in vitro by various stimuli (endotoxin, antigens, immune complexes, complement proteolytic products C5a and C3b, allogeneic leucocytes, lymphokines and others), respond with the production of selected procoagulant activities, thereby initiating the coagulation pathways. The most commonly described procoagulant activity has been identified as tissue factor, although prothrombinases and factor X activators have been reported. In addition mononuclear phagocytes can also produce and/or assemble on their surface coagulation factors including f. II, VII/VIIa, IX, X/Xa and V. Available evidence indicates that monocytes/macrophages can respond to appropriate signals and acquire the capacity to activate blood coagulation in vivo also. These "activated" cells expressing procoagulant activity appear to be directly responsible for the local fibrin deposition observed at sites of endotoxin-induced inflammation, of tumours, of cell-mediated immune reactions and possibly of other inflammatory processes.

Blood Coagulation↗
PubMed1984

Procoagulant activity of macrophages associated with different murine neoplasms.

Mononuclear phagocytes, an integral part of the lymphoreticular infiltrate of human and experimental tumors, might contribute to tumor-associated fibrin deposition through the development of procoagulant activity (PCA). We have investigated PCA of tumor-associated macrophages (TAM) in 6 transplanted murine tumors in syngeneic hosts; peritoneal macrophages from tumor-bearing and control animals were studied also, as reference cell populations. PCA was evaluated by a one-stage clotting assay immediately after preparation and following incubation in the absence and in the presence of endotoxin. TAM from 5 poorly immunogenic tumors (mFS6, MN/MCA1, R 80/44, M109 and MS2) had basal PCA levels comparable to or somewhat lower than those of peritoneal macrophages from the same animals. Similar PCA was found in peritoneal macrophages from both control and tumor-bearing animals. Unlike peritoneal macrophages, TAM in all instances failed to respond with increased PCA when exposed to endotoxin in vitro. Failure to respond to endotoxin could not be ascribed to contaminating tumor cells or their products, to the presence of suppressive macrophage populations or to the lack of lymphocyte "help". TAM from a strongly immunogenic, regressing tumor (MSV sarcoma), in contrast to its non-immunogenic variant, MS2, and to the 4 other tumors mentioned above, expressed high levels of PCA immediately after isolation. The latter did not increase further following in vitro stimulation with endotoxin. When MSV sarcomas were induced in nude mice, TAM showed PCA levels similar to those of the euthymic hosts, suggesting that the procoagulant response was largely independent of T-cell-mediated immunity.

Animals↗
PubMed1984

Increased production of procoagulant activity (tissue factor) by human peripheral blood monocytes after Intralipid infusion.

Intralipid can produce functional and structural changes in the mononuclear phagocyte system. We have investigated the effect of Intralipid on the capacity of peripheral blood human monocytes to produce procoagulant activity when incubated in short term cultures. Twenty-three patients were studied before and after a single infusion of Intralipid 10%. Procoagulant activity was measured on isolated mononuclear cells after incubation (4 h at 37 degrees C) with and without endotoxin, using a one-stage clotting assay. Mononuclear cells obtained after Intralipid infusion produced significantly increased procoagulant activity as compared to their pre-infusion control samples (p < 0.005). Similar results were obtained when freshly collected whole blood was incubated with and without endotoxin (4 h at 37 degrees C) and procoagulant activity was measured on subsequently isolated mononuclear cells (p < 0.005). In all instances procoagulant activity was identified as tissue factor. Patients in the need of Intralipid are often at increased risk for thromboembolic complications and/or disseminated intravascular coagulation because of malignant disease, surgery or infection and there is evidence that the procoagulant activity of mononuclear phagocytes could play a major role in these processes. Our findings suggest that Intralipid might cause a further accentuation of the thrombotic tendency as a result of increased procoagulant activity.

Journal Article↗
PubMed1984

Arachidonic acid and leukotriene B4 induce aggregation of human peripheral blood mononuclear leucocytes in vitro.

Peripheral human blood mononuclear leucocytes (MNL) aggregated in response to arachidonic acid (AA) in vitro. This phenomenon was similar to that already described for polymorphonuclear cells (PMN). The effect of AA was concentration-dependent and was shared only by the structurally related di-homo-gamma-linolenic acid among the other fatty acids tested. A number of agents able to induce platelet aggregation such as ADP, collagen, serotonin and a stable prostaglandin analogue all failed to stimulate MNL or PMN aggregation. Inhibitors of cyclo-oxygenase activity such as acetylsalicylic acid and indomethacin not only did not prevent AA-induced aggregation, but even potentiated it. In contrast, both nordihydroguaiaretic acid and BW 755C, two inhibitors of cyclo-oxygenase and lipoxygenase, strongly prevented MNL aggregation. Thus AA seems to aggregate MNL through the mediation of lipoxygenase products. This is supported by the observation that leukotriene B4 (LTB4) also induced MNL aggregation. When highly purified lymphocyte and monocyte preparations were assessed separately, the latter responded to AA similarly to mixed MNL whereas lymphocyte aggregation was inconsistent, small and reversible even at high concentrations of AA. Although the pathophysiological significance of the MNL aggregation described here is still obscure, assembly of these cells--particularly monocytes--at the site of injury might be a crucial event.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1984

Cancer cell procoagulants and their pharmacological modulation.

Cancer cells may promote fibrin formation in the tumor microenvironment through availability of procoagulant activities which are mainly of two types: tissue thromboplastin-like or direct activator of coagulation factor X. The pharmacological modulation of these activities could be potentially important in the control of metastasis growth. However, very limited information is available so far on this issue; it has recently been shown that the direct activator of coagulation factor X is a vitamin K-dependent activity which is depressed by warfarin treatment, not by anticoagulation with heparin or defibrinating enzymes. Whether the inhibition of this peculiar cancer procoagulant is involved in the antimetastatic activity of warfarin is a stimulating hypothesis which needs to be further substantiated.

Adenocarcinoma↗
PubMed1983

Warfarin inhibits both procoagulant activity and metastatic capacity of Lewis lung carcinoma cells. Role of vitamin K deficiency.

Chronic vitamin K deficiency, either dietary or pharmacologically induced with warfarin, depressed significantly the growth of lung secondaries in a spontaneously metastasizing murine tumor, the Lewis Lung Carcinoma. This effect was associated with a marked depression of the procoagulant activity of cancer cells, which could contribute to fibrin deposition around the tumor. Cellular anticoagulation may thus be an important mechanism in the antimetastatic effect of warfarin.

Animals↗
PubMed1983

Stroke in two young siblings with congenital dysfibrinogenemia.

Two young siblings (a male of 21 and his sister of 26 years) suffered from arterial thrombosis episodes of the carotid and abdominal aorta documented by angiographic studies. In the absence of any known predisposing factor in the family and personal history, the laboratory investigation of both patients revealed coagulation abnormalities compatible with a dysfibrinogenemia. The occurrence of a similar defect also in plasma of one of the propositi's asymptomatic relatives is suggestive of an inherited fibrinogen disorder.

Adult↗
PubMed1983

Increased production of mononuclear cell procoagulant activity in Hodgkin's disease.

Procoagulant activity of peripheral blood mononuclear leucocytes was studied in 24 consecutive patients with Hodgkin's disease. Mononuclear cells, tested immediately after isolation, expressed very low activity which was, however, somewhat higher than that of cells from a matched control group (P = 0.063). Procoagulant activity generated by patients' mononuclear cells following stimulation with bacterial endotoxin was significantly higher than that produced by control cells (P less than 0.01). There was no apparent relation between procoagulant activity and pathological staging. The increased capacity of mononuclear phagocytes to produce procoagulant activity might help explain activation of blood coagulation and subsequent fibrin deposition in patients with Hodgkin's disease.

Adult↗
PubMed1983

Thrombohaemorrhagic complications in 101 cases of myeloproliferative disorders: relationship to platelet number and function.

A series of 101 consecutive patients with chronic myeloproliferative disorders including polycythaemia vera, chronic myelogenous leukaemia, idiopathic myelofibrosis and essential thrombocythaemia have been studied. The aim was to establish the incidence of thrombotic and haemorrhagic complications and the possible role played by platelet number and function. The total incidence of haemostatic complications was 21% and the platelet functional tests investigated (platelet aggregation, generation of malondialdehyde, endogenous serotonin, beta-thromboglobulin and platelet coagulant activity) were of little help for predicting these clinical complications.

Adolescent↗
PubMed1983

Impaired production of mononuclear cell procoagulant activity in chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL) is associated with a low incidence of thrombotic complications, or disseminated intravascular coagulation (DIC), or both, despite the frequent occurrence of severe infections. We have investigated the capacity of blood mononuclear cells to produce procoagulant activity when stimulated with bacterial endotoxin in 16 patients with untreated chronic lymphocytic leukaemia (CLL). Procoagulant activity generated by patients' cells after prolonged incubation with endotoxin was significantly lower than that produced by cells from a matched control group (p less than 0.001). The defect could not be attributed to an inhibitory effect of leukaemic lymphocytes. It is suggested that in CLL the monocyte has an intrinsic functional abnormality of the procoagulant response to endotoxin and possibly to other stimuli. These findings help explain why CLL patients do not develop thrombotic complications despite the high incidence of severe infectious diseases.

Adult↗
PubMed1983

Cultured human endothelial cells generate tissue factor in response to endotoxin.

Bacterial infection is associated with disseminated intravascular coagulation and fibrin deposition in the microcirculation; the mechanism of these effects in humans is still unclear. We have studied the generation of procoagulant activity (PCA) by cultured human endothelial cells (EC) in response to endotoxin. Cells from umbilical cord veins were grown in Eagle's minimum essential medium with 20% fetal calf serum till confluence. Absence of fibroblasts and macrophages was carefully checked. Endotoxin (Salmonella enteritidis lipopolysaccharide (LPS) W or Escherichia coli 0111:B4 LPS W, 0.01-1.0 micrograms/ml) was added to culture dishes for 4-6 h. PCA of EC was measured by a one-stage clotting assay and/or a two-stage amidolytic assay with the chromogenic substrate S-2222. In the absence of endotoxin, EC generated little, if any PCA (2-5 units/10(5) cells). In contrast, the addition of endotoxin resulted in generation of strong PCA that reached a maximum within 4-6 h (185-241 units/10(5) cells) and was dose-dependent between 1 and 0.01 microgram endotoxin/ml of culture medium. The generation of PCA required RNA and protein synthesis but did not require the presence of serum. No activity was found in the culture medium. The activity was of tissue thromboplastin type, as indicated by biological and immunological criteria. These endotoxin effects were observed in the absence of endothelial damage, as shown by phase-contrast microscopy and lack of 51Cr release. These data could contribute to elucidate the pathogenesis of vascular complications associated with endotoxemia in man.

Cells, Cultured↗
PubMed1983

Direct induction of tissue factor synthesis by endotoxin in human macrophages from diverse anatomical sites.

On exposure to endotoxin and other stimuli, human peripheral-blood mononuclear cells generate a potent procoagulant activity (PCA), identified as tissue factor. Although it is now recognized that the monocytes are the source of PCA, the question whether these cells per se are capable of procoagulant response to endotoxin or require lymphocyte collaboration remains unsettled. We have investigated the capacity of highly purified human macrophages from diverse anatomical sites to generate PCA following endotoxin stimulation. Purified (greater than 99%) monocyte-derived macrophages were obtained by prolonged (3-10 days) in-vitro culture of adherent monocytes using medium supplemented with 50% human serum. Purified (greater than 95%) peritoneal and milk macrophages were isolated by adherence to plastic. PCA was measured before and after incubation (4 hr at 37 degrees) with endotoxin (Salmonella enteritidis LPS, W or Escherichia coli O111:B4LPS, W, 1 microgram/ml final concentration) using a one-stage clotting assay and/or a two-stage amidolytic assay. Monocyte-derived macrophages had low baseline PCA (14-19 units/10(5) cells) but, upon exposure to endotoxin, displayed an eight-fold increase in PCA over control. Peritoneal and milk macrophages expressed very low baseline activity (1-5 units/10(5) cells). The latter, however, increased 15-20 times over control following endotoxin stimulation. PCA was identified as tissue factor by biological and immunological criteria. Its generation was completely abolished by cycloheximide. It is concluded that in the human mononuclear phagocyte series the capacity to produce PCA is not restricted to circulating monocytes but is also expressed by macrophages obtained from diverse anatomical sites. These macrophages appear to be autonomous in their procoagulant response to endotoxin.

Ascitic Fluid↗
PubMed1983

Occurrence of disseminated intravascular coagulation in rat BNML leukaemia despite lack of leucocyte procoagulant activity.

Signs of disseminated intravascular clotting were observed during the development of BNML myelomonocytic leukaemia in rats, when the peripheral leucocyte count exceeded 20,000/microliters and more than 50% blasts were present in the circulation. BNML cells, harvested from blood and tested in appropriate systems, were found devoid of any procoagulant activity (PCA) even following prolonged in vitro incubation with endotoxin. Thus, it appears that these rat leukaemic cells share the same inability to express PCA which had been previously described in peripheral blood mononuclear cells from normal rats. Conceivably, in this rat model, leucocyte PCA does not represent a major trigger of intravascular coagulation and blood clotting is initiated by other, mainly plasmatic, pathways.

Animals↗
PubMed1983

Generation of procoagulant activity by mononuclear phagocytes: a possible mechanism contributing to blood clotting activation within malignant tissues.

This study investigated the procoagulant activity (PCA) of mononuclear phagocytes from rabbits bearing the V2 carcinoma. Macrophages harvested from either intraperitoneally or subcutaneously growing tumors were found to express a very strong procoagulant activity as compared with peritoneal macrophages and circulating mononuclear cells from the same animals. On the other hand, when incubated with or without endotoxin in short-term cultures, circulating mononuclear cells from tumor-bearing animals generated significantly more procoagulant activity than those from control animals. In all instances, procoagulant activity was identified as tissue factor by using assay systems with plasmas selectively deficient in the various clotting factors. These results indicate that, besides cancer cells, mononuclear phagocytes might also play an important role in the activation of blood coagulation and in the deposition of fibrin at the host-tumor interface.

Animals↗
PubMed1982

Legionella pneumophila and related organisms induce the generation of procoagulant activity by peripheral mononuclear cells in vitro.

We investigated the in vitro effect of various members of the genus Legionella on human peripheral mononuclear cells. All the strains tested induced the generation of strong procoagulant activity (tissue factor) when incubated for a prolonged period of time with pure mononuclear cell suspensions. This effect was dependent on the number of bacteria. The production of mononuclear cell procoagulant activity was also observed after the addition of bacteria to citrated whole blood. Escherichia coli 0111:B4 showed similar activity, but Staphylococcus aureus was much less effective. These findings suggest that the presence of endotoxin-like substance(s) in the outer cell wall of Legionellae could contribute to the stimulation of mononuclear cells. The production of tissue factor, a potent trigger of blood clotting, by these cells could help us to understand the mechanism(s) responsible for the activation of intravascular coagulation associated with severe legionellosis.

Escherichia coli↗