Endothelin, vasoconstriction, and endothelial damage in Raynaud's phenomenon.
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Biomedical subjects
Publications and source records attributed to C Cimminiello.
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Tissue plasminogen activator (t-PA) and its inhibitor (PAI) were assessed in venous blood drawn before and after venous occlusion (bvo, avo) for 33 patients with Raynaud's phenomenon (RP), 14 with primary RP (PRP), 9 with suspected secondary RP (SSRP), and 10 with definite collagen disease and secondary RP (SRP). There were significant differences in PAI values avo between PRP (and controls), SSRP, and SRP. PAI activity decreased significantly avo only in controls and in PRP, and there was significant t-PA antigen elevation avo in the same groups. In addition, since PAI is neutralized by activated protein C (PC), both PC antigen and PC activity were assessed avo and bvo. PC Ag remained unchanged in all groups, with PC activity significantly lower than controls in SRP and SSRP. Finally the authors looked for interference of anticardiolipin antibodies (ACA) and lupus-like anticoagulant (LAC) with the PC system in collagen disease-associated RP. Specific IgG ACA were found in only 1 patient with SRP. In conclusion, there is an endothelial derangement, involving t-PA release and PAI, in SSRP and SRP patients. The reduced PC activity in these latter groups appears to be due to increased PAI influence rather than to ACA/LAC.
The clinical benefit of aspirin in the acute phase of myocardial infarction is dramatically suggested by the results of the ISIS-2 trial. However, the time course of pathophysiological events that lead to such a determining involvement of platelets still appears uncertain and further study is needed to single out exactly how early and how long antiplatelet drugs should be given, since there is a risk of bleeding complications due to the combination of the different antithrombotic therapies. Thrombolytic agents and heparin are in fact widely used for patients with acute myocardial infarction, even if the optimal schedule of treatment, including anti-aggregating therapy, is not yet firmly established. To avoid rethrombosis and to enhance the efficacy of coronary thrombolysis, thus reducing early mortality, several newer antiplatelet agents other than aspirin, such as antibodies against the platelet receptor of adhesive proteins, the glycoprotein IIb/IIIa and the RGD peptides, are currently under investigation.
Twenty outpatients presenting with Raynaud's phenomenon secondary to clinical or preclinical inflammation of connective tissue were treated orally with defibrotide 400 mg three times daily or a matching placebo in a randomized double-blind study. The test product defibrotide (a polydeoxyribonucleic acid compound of animal origin with demonstrated profibrinolytic activity when administered parenterally) was administered orally for 3 weeks in order to explore its effects on the parameters of extrinsic fibrinolysis before and after venous stasis. The antigen of t-PA and its inhibitor PAI, free and total, and the biologic activity of PAI were assayed in basal conditions and after treatment. Although a marked increase of t-PA was seen with the active treatment, PAI activity was significantly reduced by defibrotide. Immunoreactive PAI was not significantly modified by treatment, even though it dropped considerably after venous stasis in the defibrotide group. Thus, the disturbance of endothelial function that seems to occur in vasculitis and in Raynaud's phenomenon secondary to inflammation of connective tissue (or so suspected to be) would constitute the basis of a disturbance of fibrinolysis, which oral defibrotide seems able to correct. Further studies are warranted to define the clinical effectiveness of this treatment in patients with Raynaud's phenomenon.
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We conducted a controlled multicenter trial with central randomization and evaluation of events under blind conditions involving 652 patients with unstable angina. Patients were treated either with conventional therapy alone (group C) (n = 338) or with conventional therapy combined with an inhibitor of platelet aggregation, ticlopidine 250 mg b.i.d. (group C + T) (n = 314). Patients were assigned randomly within 48 hours of admission and followed up for 6 months. With the "intention-to-treat" approach, the primary end points, vascular death and nonfatal myocardial infarction, were observed in 13.6% of the patients in group C and in 7.3% of the patients in group C + T, which is a reduction in risk of 46.3% (p = 0.009). Vascular mortality was 4.7% in patients in group C and 2.5% in patients in group C + T, which is a reduction in risk of 46.8% (p = 0.139). The risk of nonfatal myocardial infarction was reduced by 46.1% (p = 0.039), with a frequency of 8.9% in patients in group C and 4.8% in patients in group C + T. New Q wave myocardial infarction occurred with a frequency of 6.8% in patients in group C and 3.8% in patients in group C + T, which is a reduction in risk of 44.1% (p = 0.091). Fatal and nonfatal myocardial infarction was 10.9% in patients in group C and 5.1% in patients in group C + T, which is a reduction in risk of 53.2% (p = 0.006). These findings confirm the importance of platelets in the pathogenesis of unstable angina and the usefulness of antiplatelet treatment for the prevention of cardiovascular events.
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Plasma fibronectin (FN) was measured in 17 patients with essential mixed cryoglobulinaemia (EMC) and in 17 normal subjects by single radial immunodiffusion (RID) and enzyme-linked immunosorbent assay (ELISA). In 9 patients the presence of FN in the cryoprecipitates was also assessed by immunoblotting. In the EMC group, plasma FN levels were significantly lower than in control subjects, using both methods, and FN was constantly demonstrated in EMC cryoprecipitates. Capillaroscopic observation of the capillary bed in skin and bulbar conjunctiva, performed in all cases, showed severe alterations of microcirculation in EMC patients. A negative correlation between plasma FN and capillaroscopic abnormalities of skin capillaries was observed. These data support the hypothesis that plasma fibronectin plays a role in the pathogenesis of systemic vasculitis in EMC.
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Inhibition of monocyte function is known to have important clinical consequences and to be present in a variety of diseases: Accordingly we evaluated the effect of Ticlopidine, a powerful and widely employed inhibitor of platelet aggregation, on the capacity of peripheral blood monocytes to ingest IgG-coated erythrocytes. Our results show that in vivo administration of this drug has no effect on monocyte phagocytosis, when tested with an in vitro assay. This finding suggests that Ticlopidine can be safely used in patients with depressed monocyte function and in those in whom an impairment of monocyte phagocytosis could lead to a deterioration of the clinical picture.
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Peripheral blood lymphocyte subpopulations and IgA production in vitro have been studied in 30 elderly subjects. Fifteen patients were treated with Bacillus subtilis (Enterogermina, Midy) and 15 with a placebo preparation. At the end of the treatment, a significant increase was noticed in lymphocytes bearing membrane IgA and Ia+ cells in the group treated with Bacillus subtilis, but not in the controls. Similarly, a significantly enhanced spontaneous production of IgA in vitro was seen in the treated subjects. The relevance of these findings to the understanding of the mode of action of Bacillus subtilis and its usefulness in different immunodeficiency states is discussed.
The specificity and immunoglobulin isotype distribution of antiphospholipid (aPL) antibodies have been evaluated in 68 patients with systemic lupus erythematosus (SLE) by ELISA which employed a panel of 7 different PL antigens. A total of 49 patients (72%) were positive for aPL antibodies of different isotypes and directed to one or more PL epitopes. Prevalence of IgG anticardiolipin (aCL, 37%) was similar to that of the other negatively charged PLs phosphatidylserine (PS, 35%), phosphatidylinositol (PI, 35%), phosphatidylglycerol (PG, 35%) and phosphatidic acid (PA, 40%); prevalence reduced to 9-12% and 7-16% respectively for IgM and IgA isotypes to the same antigens. aPL antibodies to the zwitterionic PLs phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were also observed, though their prevalence was lower than that demonstrated for negatively charged PLs. Of the 36 SLE patients who were aCL negative (53%), 17 (25% of all patients and 47% of aCL-negative patients) were positive for aPL antibodies of different isotypes to one or more non-CL epitopes. During a mean follow-up period of 30 months, 10 patients had deep vein thrombosis (DVT) with a total of 21 events. By chi 2 test, a significant correlation was found between DVT and IgG aCL (p = 0.03) and between this event and the presence of lupus anticoagulant (LA) antibody (p = 0.04). However, stronger correlations were demonstrated between DVT and IgA aCL (p = 0.007), IgG anti-PS (p = 0.02), and IgA anti-PC, -PI and -PG (p = 0.02, 0.003 and 0.02, respectively), whereas no correlation was found between thrombotic events and aPL antibodies with PE and PA specificities.(ABSTRACT TRUNCATED AT 250 WORDS)
As Ca2+ is known to play a fundamental role in platelet function, the effect of combining two platelet aggregating agents (adrenaline and the ionophore A23187) with different effects on Ca2+ was studied at levels subthreshold for aggregation using platelet-rich plasma from eight atherosclerotic patients. Adrenaline lowered the A23187 threshold required to induce aggregation. The effects of treating patients with the antiplatelet agents, indobufen and ticlopidine, on A23187 and adrenaline induced aggregation of platelets prepared in hirudin or sodium citrate was also evaluated. Aggregation was also studied using platelets resuspended in Ca2(+)-free and Ca2(+)-enriched Tyrode solution. Before treatment hirudin treated platelet-rich plasma, which has physiological extraplatelet Ca2+ levels, was more sensitive to A23187 and adrenaline than was citrated platelet-rich plasma, which has suppressed Ca2+ levels. Ticlopidine significantly raised the concentration of A23187 required to induce aggregation in citrated but not hirudin treated platelet-rich plasma. Indobufen did not significantly affect A23187 induced aggregation. Ticlopidine acts by inhibiting the glycoprotein IIb-IIIa complex on the platelet membranes. Low levels of extracellular Ca2+ and ticlopdine may act synergistically to reduce the aggregatory response of stimulated platelets.
A new classification for microvascular lesions assessment by means of capillaroscopy is proposed in this research. The new method, offering a numerical score for microvascular lesions, was used in patients affected by isolated Raynaud Phenomenon (RP). RP can often be associated with scleroderma and, therefore, the new classification has been compared to the Maricq one for what concerns this connective tissue disorder. The numerical method is as sensitive as that by Maricq, but, as easily expected, its specificity is quite low. It appeared to be satisfactory also the positive predictive value of the new capillaroscopy classification combination with the clinical examination and with the immunologic biohumoral investigation. It is particularly easy to apply this method, as it presents to the examinator a restricted range of answers, for the capillaroscopic picture description, but it needs further studies in different microcirculation damages to be proved definitely valuable.
Antiplatelet agents have been studied in a number of clinical trials to evaluate their efficacy in the prevention of ischemic cardiovascular events related to platelet-rich thrombi. Acetylsalicylic acid (ASA) is definitely effective in the hospital phase of acute myocardial infarction; it also prevents cardiovascular events but not anginal attacks in patients with unstable angina and reduces the rate of occlusion of coronary artery bypass grafts. ASA is often used in the post-infarction period, even though anticoagulant therapy is probably more effective; it is also effective in patients with transient ischemic attacks in the brain. Ticlopidine is the treatment of choice in patients with major stroke and in those with peripheral vascular ischemia; it can also be considered a valid alternative to ASA in the management of transient ischemic attacks and unstable angina. There is at the moment little role for antiplatelet agents in the primary prevention of cardiovascular disease.