Biomedical subjects
Publications and source records attributed to C Soria.
Two cases of pre-Sézary erythroderma of several years of evolution that evolved into Sézary syndrome are presented. The role of persistent antigenic stimulation in the development of T-cell lymphoproliferative disease in discussed. We also review the different therapeutic approach to Sézary syndrome.
The results of a clinic assay with an extract made out of propolis (bee glue) or "Propolisina" were showed with the aim of showing its effectivity against giardiasis. One hundred and thirty eight patients were studied 48 children and 90 adults, in 2 groups and they selected aleatorily to be treated with "Propolosina" or an imidazole derivate (tinidazole). The method for an exact diagnosis in children was duodenal aspiration and in adults duodenal mucosa frotis by means of duodenoscopy. Similar studies were carried out as a cure criterium in a 5-day term after being through with the treatment. Propolisina was used with different concentrations: in children (concentration at 10%) results showed a 52% cure. In 40 adults (concentration at 20%) it was obtained a similar result to that of tinidazole; and when propolisina concentration was elevated at 30% in the remaining 50 patients there was a higher effectivity (60 of cure Vs 40% with tinidazole). This work shows the success of this natural product, which is very easy to obtain in Cuba and with no side effects in the treatment of this intestinal parasitism, what is of great economical importance for our countries.
Cerebral infarcts in 3 patients revealed the presence of disseminated intravascular coagulation (DIVC) of cancerous origin before any clinical manifestations of the neoplasm. Neurologic manifestations of these consumption coagulopathies almost constantly produce a picture of diffuse encephalopathy, expression of disseminated microinfarcts; however, transient or constituted focalized ischemic accidents by occlusion of a medium sized artery are also possible, and this in the absence of non-bacterial thrombotic endocarditis. Biologic diagnosis of DIVC is not always simple, and screening tests (platelet count, prothrombin and fibrinogen levels) can remain within normal limits during chronic forms, as a result of a subjacent inflammatory syndrome, frequently associated with cancer. Two other specific serum tests are therefore of fundamental interest: assay of fibrin degradation products and tests for soluble complexes.
As observed for many proteins, glucose has been shown to bind non enzymatically to fibrinogen and to fibrin. The in vitro degree of glycosylation depends upon the concentration of glucose added to fibrinogen and also on the incubation period. This glycosylation induces a decrease in fibrin lysis by plasmin. On the contrary, it does not influence either fibrinogen activity as cofactor in ADP-induced platelet aggregation or the binding of thrombin onto a clot. Despite the 4 day half life of fibrinogen, since clearance of fibrinogen is exponential, it is assumed that very small quantities of fibrinogen may remain for a long time in the circulation leading to the presence of a low level of a highly glycosylated form of fibrinogen. Consequently, poorly degradable fibrin might be derived from this highly glycosylated fibrinogen and thus be responsible for capillary occlusion and also for atherosclerotic complications in the diabetic patient.
A CD9 monoclonal antibody described to aggregate human platelets was studied on different platelet functions in order to determine its mechanism of action. After a lag phase of 35 sec the mAb ALB6 induced a transient decrease in 32P-polyphosphoinositides, synthesis of 32P-phosphatidate (PA), phosphorylation of myosin light chain (P20) and of 43 KDa protein (P43) and the release reaction. Final biological and metabolic effects of ALB6 thus appear similar to that of thrombin but three differences bring additional information: (i) the lag phase, (ii) the kinetic of ALB6-induced release is identical for all granules whereas the release of dense granules is faster when induced by thrombin. (iii) no external Ca++ is required for ALB6 induced-activation.
The abnormal fibrinogen Haifa is characterized by the fact that calcium present during enzymatic digestion by plasmin does not protect the Haifa D gamma chain against further plasmin attack as it does in normal molecules. Since calcium binding to fibrinogen, ADP--platelet aggregation cofactor activity and gamma dimerization process induced by factor XIIIa are normal for fibrinogen Haifa, the corresponding sequences in the gamma chain are not involved. It seems rather that the anomaly resides near the gamma 302 plasmin cleavage site that is protected when calcium is bound to the gamma chain and that this affects the availability of the polymerization site located in the C terminal part of the chain.
It has been shown that myocardial infarction (MI) is caused by thrombotic occlusion of a coronary artery. A thrombotic process is also involved in the flow obstruction associated with peripheral embolization in unstable angina (UA). In UA, a local fibrinolytic process should occur, but biological evidence has never been reported. Therefore, we measured sequential changes in plasma fibrin degradation products (FDP) in patients with stable and unstable angina pectoris without MI and compared the levels to those in patients with MI. FDP determination was carried out by ELISA using a D neo monoclonal antibody allowing low amounts of FDP to be reliably and precisely detected. Our results show an early increase in FDP in UA indicating a thrombolytic process. In patients who presented only one episode of chest pain, a prompt decrease of FDP was noted whereas in patients with recurrent chest pain, the levels of FDP remained high. On the contrary, during the first 3 days of uncomplicated MI, FDP levels were not significantly different from those of normal control suggesting an absence of clot dissolution. This study underlines the important function of fibrinolysis in the spontaneous evolution of acute coronary syndrome.
We have demonstrated that the specific determination and identification of plasma FbDP alone is not sufficient to follow the effectiveness of thrombolytic therapy. Some patients who received an intravenous infusion of rt-PA for myocardial infarction had very high plasma FbDP levels, although no recanalization was observed angiographically. Since in many cases the FbDP levels increased after recanalization, it is assumed that rethrombosis may occur during and after t-PA treatment.
Activation of plasminogen by tissue-type plasminogen activator (tpA) is potentiated by fibrin. We have demonstrated the role of fibrin polymerization in the potentiating effect of tpA-induced fibrinolysis. Therefore a pathogenic mechanism of thrombotic disorder may be related to an abnormal fibrin polymerization: the abnormal clot being less accessible to fibrinolysis than normal one. This defective lysis may be due to a defective enhancement by the abnormal fibrin of plasminogen activation by tpA, as demonstrated for fibrinogen Dusard, a congenital dysfibrinogenemia associated with a very severe thrombotic disorder. In some other cases, a decrease in the availability of the plasmin cleavage sites in fibrin clot may be involved. On the contrary, some antithrombotic drugs such as pentosane polysulfate in modifying clot structure allow a better degradation of fibrin clot by fibrinolytic enzymes. It is speculated that this enhanced fibrinolysis could explain, almost in part, the antithrombotic action of these drugs.
A specific determination of fibrin degradation product (FbDP) is essential for the monitoring of thrombolytic therapy. In patients under thrombolytic therapy, even with tpA (tissue type plasminogen activator) fibrinogen is degraded, and fragment D derived from fibrinogen degradation, is evidenced in the plasma of treated patients. In order to determine specifically the FbDP, even in the presence of fragment D, we take into account the fact that FbDP are complexes such as DDE complex. Therefore a new Elisa technique is proposed. FbDP and fragment D are captured from plasma by immobilized anti D neo monoclonal antibody which recognizes an epitope accessible on fragment D but does not react with undegraded fibrinogen. DDE complexes are then detected specifically using a peroxidase-labelled anti E antibody. The advantage of this technique is discussed in this paper.
Major heparin-induced thrombocytopaenia (HIT) is a condition which is feared more for its thrombotic complications than for the risk of haemorrhage. The platelet count is part of routine surveillance of patients receiving this treatment which must be withdrawn if HIT occurs. The use of heparin remains essential for cardio-pulmonary bypass surgery. There are two possible scenarios: The thrombocytopaenia occurs in the postoperative period: the standard heparin may be relayed by oral anti-vitamin K anticoagulants, platelet antiaggregant drugs or by low molecular weight heparin (LMWH). The diagnosis of HIT is made before surgery: three therapeutic attitudes are discussed with respect to the urgency of surgery: surgery is deferred for 6 to 8 weeks to allow the platelet count to return to normal and the responsible circulating antibody to disappear; the use of LMWH providing the tests of platelet aggregation are negative with this product; in addition, there are other problems specific to their use in cardiopulmonary bypass to be considered; blood exchange at the beginning of cardiopulmonary bypass to eliminate the circulating factor responsible and so allow the use of standard heparin during and after the operation: this is the only possible solution in cases with in vitro aggregant activity of LMWH.
Release of fibrinopeptide B from fibrinogen by copperhead venom procoagulant enzyme results in a form of fibrin (beta-fibrin) with weaker self-aggregation characteristics than the normal product (alpha beta-fibrin) produced by release of fibrinopeptides A (FPA) and B (FPB) by thrombin. We investigated the ultrastructure of these two types of fibrin as well as that of beta-fibrin prepared from fibrinogen Metz (A alpha 16 Arg----Cys), a homozygous dysfibrinogenemic mutant that does not release FPA. At 14 degrees C and physiologic solvent conditions (0.15 mol/L of NaCl, 0.015 mol/L of Tris buffer pH 7.4), the turbidity (350 nm) of rapidly polymerizing alpha beta-fibrin (thrombin 1 to 2 U/mL) plateaued in less than 6 min and formed a "coarse" matrix consisting of anastomosing fiber bundles (mean diameter 92 nm). More slowly polymerizing alpha beta-fibrin (thrombin 0.01 and 0.001 U/mL) surpassed this turbidity after greater than or equal to 60 minutes and concomitantly developed a network of thicker fiber bundles (mean diameters 118 and 186 nm, respectively). Such matrices also contained networks of highly branched, twisting, "fine" fibrils (fiber diameters 7 to 30 nm) that are usually characteristic of matrices formed at high ionic strength and pH. Slowly polymerizing beta-fibrin, like slowly polymerizing alpha beta-fibrin, displayed considerable quantities of fine matrix in addition to an underlying thick cable network (mean fiber diameter 135 nm), whereas rapidly polymerizing beta-fibrin monomer was comprised almost exclusively of wide, poorly anastomosed, striated cables (mean diameter 212 nm). Metz beta-fibrin clots were more fragile than those of normal beta-fibrin and were comprised almost entirely of a fine network. Metz fibrin could be induced, however, to form thick fiber bundles (mean diameter 76 nm) in the presence of albumin at a concentration (500 mumol/L) in the physiologic range and resembled a Metz plasma fibrin clot in that regard. The diminished capacity of Metz beta-fibrin to form thick fiber bundles may be due to impaired use or occupancy of a polymerization site exposed by FPB release. Our results indicate that twisting fibrils are an inherent structural feature of all forms of assembling fibrin, and suggest that mature beta-fibrin or alpha beta-fibrin clots develop from networks of thin fibrils that have the ability to coalesce to form thicker fiber bundles.
Antithrombin III (AT-III) Rouen is a hereditary abnormal antithrombin with normal progressive inhibitory activity and reduced heparin cofactor activity. It was isolated from the plasma of a woman who suffered a sudden idiopathic sensorineural hearing loss and balance impairment. There was no familial history of thrombosis. By heparin-Sepharose chromatography, AT-III Rouen was separated from the normal antithrombin on elution with increasing concentrations of NaCl. AT-III Rouen eluted earlier than is normal at both pH 7.4 and pH 6.0. At the lower pH, the antithrombins bound more avidly to the column, with the abnormal AT-III eluting closer to the normal than at the higher pH. Two-dimensional peptide mapping of tryptic and Staphylococcus aureus V8 protease digests of carboxymethylated antithrombins was performed on thin-layer silica plates. The abnormal peptide was located by tryptophan staining, and amino acid analysis and sequence studies demonstrated a substitution of an arginine at residue 47 for a histidine. Results from this study suggest that replacement of arginine 47 by a partially positively charged histidine has less effect on the heparin binding affinity than dose replacing it with a neutral cysteine side chain as in AT-III Toyama, in which no heparin binding was observed. In addition, heparin binding per se is not a sufficient condition to activate AT-III.
We have developed a latex immunoassay using an anti D neo monoclonal antibody (F2C5) which recognizes an epitope present in fragment D but which is hidden in intact fibrinogen and in early fibrinogen degradation products. This technique was applied directly to plasma of both healthy donors and patients, and was shown to be very convenient for clinical investigation, especially in emergency cases for diagnosis of intravascular coagulation. The use of plasma samples instead of serum offers several advantages: it is not time consuming since blood clotting is not required; it avoids overestimation when fibrinogen cannot be totally clotted, and underestimation due to the binding of nonclottable fibrin degradation products to the clot during clotting in vitro. This monoclonal antibody, which reacts more with FbDP (expressed in fragment D) than with fragment D, does not allow fibrin and fibrinogen degradation products to be differentiated. However, this discrimination does not seem critical for its clinical use since the level of fragment D neo antigen remained within the normal range in 12 cases of spontaneous or venous occlusion-induced hyperfibrinolysis.
A large number of similarities have previously been noted between the blood and milk clotting phenomena [Jollès, P. (1975) Mol. Cell. Biochem. 7, 73-85; Jollès, P. & Henschen, A. (1982) Trends Biochem. Sci. 7, 325-328]: some analogous features have also been found between fibrinogen and kappa-casein. In this connection, the effect of a natural and a synthetic peptide derived from kappa-casein on platelet function was studied: the undecapeptide Met-Ala-Ile-Pro-Pro-Lys-Lys-Asn-Gln-Asp-Lys (residues 106----116 of cow kappa-casein) inhibited both aggregation of ADP-treated platelets and binding of 125I-fibrinogen to ADP-treated platelets: its behaviour was similar to that of the structurally related C-terminal dodecapeptide of human fibrinogen gamma-chain.
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Fifteen patients (9 females and 6 males) with the "lupus type" circulating anticoagulant have been studied. The underlying disease was an auto-immune disorder in 11 cases and a malignant hemopathy in 4 cases. The manifestations frequently associated with the lupus inhibitor, such as thrombosis, thrombocytopenia and false-positive VDRL test were analysed. Hemorrhagic syndrome occurred only when thrombocytopenia or acquired abnormality of Willebrand's factor was present. Thrombotic events (8 cases) were frequent. Deep venous thrombosis was complicated with pulmonary embolism in 4 patients. Platelet abnormality, decreased fibrinolytic response or acquired Willebrand's syndrome were found in all patients with a thrombotic event. These different manifestations followed diverging courses in some patients with persistent thrombocytopenia although the anticoagulant had disappeared in 3 cases, negativation of the false-positive VDRL test while the anticoagulant remained unchanged in 1 case, occurrence of a thromboembolic episode although the anticoagulant had disappeared in 1 case.
Analyses were made of the fibrinolytic, plasminogen-activating system in skeletal muscle to determine if a regulating influence of the nerve could be detected on these enzymes. Young male mice underwent right sciatic neurectomy. Extracts were prepared from denervated muscle at 2-17 d after axotomy and compared with controls. Using a cascade-style biochemical assay (Rånby, M., B. Norrman, and P. Wallén, 1982, Thromb. Res., 27:743-748) we found that low levels of plasminogen activator (PA) were present in adult, innervated mouse muscle, but that denervation resulted in a marked time-dependent increase in enzyme activity. Qualitative separation showed an eightfold increase in urokinase-like PA with moderate elevation of tissue PA activity after 10 d. Fibrin zymography (Granelli-Piperno, A., and E. Reich, 1978, J. Exp. Med., 148:223-234) revealed clear zones of lysis corresponding to molecular masses of 48 kD for urokinase-like PA and 75 kD for tissue PA, consistent with the molecular masses found for these enzymes in other tissues of the mouse (Danø, K., P. A. Andreasen, J. Grøndahl-Hansen, P. Kristensen, L. S. Nielsen, and L. Skriver, 1985, Adv. Cancer Res., 44:139-266). In other studies we have shown that PA-activated plasmin readily attacks critical adhesive basement membrane molecules. The present results indicate that enzymes involved in plasminogen activation, particularly urokinase-like PA, rapidly increase after axotomy, suggesting they may have a role early in muscle denervation. Similar alterations in PA activity might underlie the elimination of polyneuronal innervation during mammalian muscle development. Certain neuromuscular diseases may also involve activation of these enzymes, resulting in degradation of basement membrane zone components and, therefore, warrant further study.