Associated thrombophilic defects in essential thrombocythaemia: their relationship with clinical manifestations.
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Biomedical subjects
Publications and source records attributed to L Kordich.
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Recent studies have shown that patients with antiphospholipid antibodies (aPL) have increased lipid peroxidation. We evaluated the urinary excretion of 11-dehydro thromboxane B2 (11-DH-TXB(2) and isoprostane F(2alpha)III (IPF(2alpha)III), reflecting platelet activation and lipid peroxidation in vivo, and plasma soluble markers of endothelial cell, platelet and blood coagulation activation: soluble vascular cell adhesion molecule-1 (sVCAM-1), P- and E-selectin (sPsel and sEsel), F1 + 2 fragment of prothrombin (F1 + 2), thrombin-antithrombin complexes (TAT) and D-Dimer (DD). We studied 79 patients with aPL (47 with previous thrombosis), 45 healthy volunteers (normal controls, NC), 12 patients with systemic lupus erythematosus (SLE) without aPL and a thrombosis control group (TCG) without thrombophilia (n = 16). Urinary levels (mean, range) of eicosanoids and isoeicosanoids were significantly increased in 39 patients with aPL compared with 25 NC, 11-DH-TXB(2) 164.0 ng/mmol creatinine (9.5-1162.8) versus 43.4 ng/mmol creatinine (4.2-87.6), P < 0.001; IPF(2alpha)III 56.9 pg/mg creatinine (5.5-388.7) versus 27.0 pg/mg creatinine (4.6-87.6), P = 0.03. Both metabolites were significantly correlated (rho = 0.49, P = 0.014), but none correlated with any clinical manifestation or antibody profile. The aPL group presented increased levels of sPsel, sEsel, sVCAM-1, TAT, F1 + 2 and DD, but any soluble marker correlated with IPF2alphaIII. Urinary 11-DH-TXB(2) correlated with sPsel (rho = 0.39, P = 0.04). Compared with SLE controls, the SLE group with aPL had higher levels of F1 + 2. Plasma levels of F1 + 2 and DD were significantly increased and a trend to higher sPsel was found in aPL patients with thrombosis compared with the TCG. Platelet activation, lipid peroxidation and blood coagulation activation seem to be important in the pathophysiology of antiphospholipid syndrome.
Hyperhomocysteinemia is a risk factor for arterial and venous thrombosis. The aim of this study was to evaluate plasmatic homocysteine levels in patients under chronic anticoagulant treatment with dietary restriction of green vegetables. This kind of food is a very important source not only of vitamin K but also of folates, which are involved in Hcy metabolism. It is known that the lower the folate levels, the higher the Hcy concentration, so we suspected that these patients could show hyperhomocysteinemia. A group of patients receiving oral anticoagulant treatment and a restricted diet (Group I, n = 20) was compared with a group of untreated subjects of a similar age that were not on a restricted diet (Group II, n = 35). Group I showed significantly higher levels of plasmatic Hcy and significantly lower levels of serum folate than Group II. Therefore, a diet restricted in vitamin K applied to oral anticoagulated patients could induce an unwanted increase of homocysteine levels.
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In recent years, the determination of homocysteine (Hcy) has become increasingly important, since high levels of Hcy in plasma or serum represent an independent risk factor for occlusive vascular diseases. Nowadays, clinical laboratories use several analytical techniques to measure Hcy, of which high-performance liquid chromatography (HPLC) is the most popular. Recently, assays for Hcy quantification based on enzyme immunoassays (EIA) have become commercially available. Our group carried out the validation of the Axis method and compared results with those obtained by an established HPLC assay. Intra- and inter-assay coefficients of variation were < or = 8.5%. Compared with HPLC, linear regression analysis showed r=0.984, slope=0.952, intercept = 1.24 /mol/l; Bland-Altman procedure, the mean of the difference EIA-HPLC results = 0.5 micromol/l. Our results suggest that Hcy determinations by both methods are equivalent, and that the Axis assay provides reproducible and reliable data.
BACKGROUND: Previously we observed in some but not all septic patients a low plasma concentration of plasminogen. OBJECTIVES: To investigate prospectively whether plasma levels of plasminogen or the ratio of plasminogen to alpha-2-antiplasmin have a prognostic value for survival from sepsis and to study the variation of other hemostatic parameters during septicemia. PATIENTS: The study population consisted of 45 consecutive patients with septicemia, 15 non-septic patients from the same intensive care unit and 30 healthy volunteers. MEASUREMENTS AND MAIN RESULTS: Plasminogen concentrations were significantly lower (p < 0.001) in plasma of septic patients (median 0,62 IU/ml range: 0.15-1,06) than in plasma of healthy controls (median 1.00 IU/ml, range: 0.75-1.10) or of non-septic intensive care patients (median 1.00 IU/ml, range: 0.82-1.08). Among the other parameters tested, plasminogen activator inhibitor (PAI-1) antigen concentration and PAI activity were similar in septic and non-septic intensive care patients, but higher than in healthy controls. Concentrations of elastase-alpha-1-protease inhibitor or of thrombin-antithrombin complexes were higher in septic patients than in non-septic intensive care patients or healthy controls. A degraded form of plasminogen of 38 kDa was detected by Western blot analysis in the plasma of septic patients, but not in plasma of non-septic intensive care patients or controls. Plasminogen alone or the ratio of plasminogen to antiplasmin were good markers for survival from septicemia. E.g. for plasminogen at a cut off of 0.65 IU/ml, sensitivity was 90.5% and specificity 66.7%, whereas for the ratio of plasminogen over antiplasmin at a cut off ratio of 0,65 IU/ml, sensitivity was 95.2% and specificity 70.8%. CONCLUSION: Plasminogen or the ratio of plasminogen to antiplasmin are sensitive markers for survival in patients with septicemia.
PURPOSE: Glanzmann thrombasthenia is a well-defined inherited disorder of platelet function characterized by a decrease or absence of functional platelet glycoprotein (GP) GPIIbIIIa. The diagnosis must be considered in patients presenting with mucocutaneous bleeding, purpura, a normal platelet count, abnormal platelet aggregation, and a prolonged bleeding time. In most of the patients, the presence of small amounts of either GPIIb or GPIIIa was detected in their platelets. These observations could provide a basis for determining the clinical and laboratory heterogeneity of the disease. PATIENTS AND METHODS: We studied 10 patients of seven unrelated families with the usual methods and an immunoalkaline phosphatase technique (APAAP) to analyze the biosynthesis of GP in megakaryocytes. RESULTS: The results allowed us to classify six patients as GT type I, three as type II, and one as a variant. CONCLUSION: The nature and severity of the bleeding manifestations, in our patients, were not predictible by the laboratory findings. These confirm the clinical and laboratory heterogeneity of the disease.
Levels of heparin cofactor II (HCII) activity and antigen and electrophoretic pattern were studied both in normal subjects and in type I diabetic patients with high and normal levels of glycosylated haemoglobin. There was a significant reduction in HCII activity (83 +/- 7%) in patients with high levels of glycosylated haemoglobin compared with controls (95 +/- 17%; P < 0.001). However, plasma HCII antigen levels were not decreased in these patients.
Total protein S (tPS), free protein S (fPS) and C4b-binding protein (C4b-BP) were measured by immunological assays in 73 patients with antiphospholipid (aPL) antibodies, in order to determine whether the previously reported abnormalities in PS levels in this group of patients could be related to the presence of lupus anticoagulant (LA) or anticardiolipin (aCL) antibodies. As compared with the normal controls (n = 44), the authors found a significant decrease of tPS, fPS and C4b-BP in 45 LA(+)aCL(+) patients (P < 0.001), a decrease of tPS (P < 0.001), fPS and C4b-BP (P < 0.01) in eight LA(-)aCL(+) patients and a decrease of only fPS (P < 0.05) in 20 LA(+)aCL(-) patients. There was no difference in the levels of tPS, fPS and C4b-BP between LA(+)aCL(+) and LA(-)aCL(+) patients. In contrast, the LA(+)aCL(+) patients had lower values of tPS, fPS and C4b-BP than LA(+)aCL(-) patients (P < 0.05). In some patients, protein S activity (PSact) was also measured and a high correlation was observed between fPS antigen and PSact (r = 0.93, P < 0.001). The data show that the presence of aCL antibodies is associated with a probably acquired deficiency of PS and C4b-BP. On the other hand, in LA patients without a CL antibodies, the fPS deficiency is unrelated to an increase in C4b-BP levels and may be due to abnormal binding of PS to C4b-BP.
Two high sulphated heparin-like polysaccharides (L1, MW 16,000 and L2, MW 11,700) were isolated from rat liver tissues, after DEAE-cellulose chromatography. Heparan sulphates from heart and lung tissues were isolated for comparison and fractionated according to their molecular weight. The anticoagulant activities in vitro were studied using clotting antifactor Xa, antifactor IIa, and APTT assay methods, falling in a narrow range (5-44 IU/mg) although the wide variability in molecular weight and sulphate content. The heparan sulphate nature of fractions L1 and L2 (sulphate/disaccharide ratio 2.05 and 2.48, respectively) has been verified by: a) low iduronic/glucuronic acid ratio; b) nitrous acid degradation followed by gel chromatography; c) heparinase treatment followed by gel chromatography; d) electrophoretic behaviour. Native proteoglycans have been isolated and the glycosidic chains compared with L1 and L2. Their anticoagulant activities in vitro and the fact that anti-Xa clotting activity was not neutralized by protamine sulphate are in accordance with the results of structural studies.
Plasminogen, alpha 2-antiplasmin, alpha 2-macroglobulin, alpha 1-antitrypsin and fibrinogen degradation products (FDP) were studied in 45 patients with Argentine hemorrhagic fever. Patients were grouped into: 17 mild, 14 moderate and 14 severe cases. Plasminogen antigen level and functional activity were found to be reduced in the moderate and severe groups, when compared to the results obtained at recovery. The functional activity of alpha 2-antiplasmin was within the normal range, except for a slight decrease on days 10-11, alpha 2-macroglobulin remained normal during the course of illness. alpha 1-antitrypsin also remained normal except on days 10-11, when an increase in the antigen level was noted. FDP titre was normal (less than 10 micrograms/ml) in all patients during the course of disease. Plasminogen decrease was not attributable to liver insufficiency neither to a primary nor secondary fibrinolysis. The decreased antigen and reduced functionality of plasminogen in these patients we believe is related to proteolytic degradation by leukocyte enzymes.
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We report a case of partial deficiency of alpha 2-antiplasmin. A 45 year old Spanish man had a life long severe bleeding tendency after trauma. Routine coagulation and platelet functional tests in symptomatic and asymptomatic periods were normal. During the bleeding there was a rapid whole blood clot lysis and the concentration of alpha 2-antiplasmin in plasma was 20 to 25% of normal controls. After recovery these levels showed a slight increase (35 to 45% of normal). Addition of normal plasma to the patient's plasma increased alpha 2-plasmin inhibitor activity. Bidimensional electrophoresis of alpha 2-antiplasmin in the patient's plasma showed a normal pattern. Family studies showed that one of the proband's two sons had a mild hemorrhagic tendency and 40% of functional and antigenic levels of alpha 2-antiplasmin.
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