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Biomedical subjects

E Marciniak

Publications and source records attributed to E Marciniak.

10 recordsLinked to original sources
PubMed1989

Impaired catalytic function of activated protein C: a new in vitro manifestation of lupus anticoagulant.

Lupus anticoagulant (LA), an antibody against anionic phospholipid with anticoagulant laboratory manifestations, is paradoxically associated with a high incidence of thrombosis. In the present study we analyzed the phospholipid- and platelet-dependent degradation of factor Va following clotting in plasma from 15 consecutive patients with LA to provide evidence for a distinct procoagulant effect of the antibody. After clotting with 25 micrograms phospholipid/mL, all samples containing LA showed markedly decreased rates of factor Va degradation (k = 0.01 to 0.14 min-1 v 0.27 to 0.35 min-1 in controls). Also with higher phospholipid concentrations (up to 100 micrograms/mL), as well as in the presence of platelets (5 to 33 x 10(7)/mL), significantly less of the procoagulant activity disappeared per unit of time in samples with LA than in controls. Plasma with LA was to a variable extent capable of decreasing or abolishing factor Va inhibition in normal plasma. Most importantly, exogenous activated protein C failed to correct the ineffective factor Va destruction despite adequate protein S levels. These data suggest that LA prevents the formation of the complex essential for rapid proteolysis of factor Va both on phospholipid and on the platelet membrane, thereby compromising the catalytic function of activated protein C. Our findings offer a new opportunity for a more comprehensive evaluation of patients with antiphospholipid antibody in defining the pathogenesis of thrombosis in this clinical condition.

Autoantibodies↗
PubMed1988

Laboratory control in predicting clinical efficacy of T cell-depletion procedures used for prevention of graft-versus-host disease: importance of limiting dilution analysis.

In an attempt to assess the usefulness of partial elimination of T lymphocytes from histocompatible donor bone marrow as a sole method of graft-versus-host disease prophylaxis in patients undergoing bone marrow transplantation, we compared in vitro and clinically the efficacy of two depletion protocols, each resulting in a different degree of T cell reduction. The protocols were based on complement-dependent T cell lysis induced either by one (T10B9) or two (T10B9 and T12A10) monoclonal antibodies, contributing respectively to 95% and 99% depletion of T cells defined functionally by limiting dilution analysis. Phenotypic analysis was unsuitable for detecting differences in the efficiency of the two depletion modalities due to very low numbers of residual OKT3-positive cells generally present. Of the 34 patients with advanced leukemias transplanted with marrow from HLA-matched sibling donors, 26 (ages 15-52) received two-antibody depleted grafts (group I) with subsequent incidence of severe acute graft-versus-host disease of 8% (in two of 24 engrafted). The T cell dose for two patients of this group whose grafts were directly evaluated by limiting dilution analysis was less than 2 x 10(5)/kg and presumably did not exceed 3.2 x 10(5)/kg for others, based on the depletion efficiency of the protocol estimated in additional small marrow samples. The remaining eight patients (ages 8-55) received one-antibody depleted grafts (group II) with 5-18 x 10(5) T cells/kg defined functionally in five grafts. Severe acute graft-versus-host disease (grade 3-4) developed in all seven engrafted subjects. Although with phenotypic analysis several grafts in this group revealed no residual T lymphocytes, they apparently carried doses of donor T cells not tolerable in a HLA-identical host unprotected by additional immunosuppression. Careful evaluation by functional T cell analysis should be considered in choosing a depletion protocol as a method for reducing the risk of graft-versus-host disease in allogeneic bone marrow transplantation.

Adolescent↗
PubMed1979

Acquired coagulation inhibitor delaying fibrinopeptide release.

A 14-yr-old girl Down syndrome developed a unique type of circulating inhibitor causing a mild bleeding tendency and interfering strongly with coagulation tests, including reptilase time, and with the reaction of purified fibrinogen and thrombin. The concentration of all coagulation factors was normal. The inhibitor had no direct effect on thrombin activity or on the aggregation of fibrin monomer in plasma. Chromatography on DEAE-cellulose and neutralization by immune sera revealed that the inhibitor was an immunoglobulin of IgG class with both kappa and lambda determinants. Isolated inhibitor delayed the release of fibrinopeptide A from a normal fibrinogen reacting with thrombin and retarded the onset of visible clotting, but had no effect on the the final degree of clottability. The clinical and laboratory features of this patient resemble those of patients with congenital dysfibrinogenemia associated with abnormal fibrinopeptide release.

Adolescent↗
PubMed1977

Heparin-induced decrease in circulating antithrombin-III.

Plasma-antithrombin-III (AT-III) concentrations were measured throughout therapy in 24 patients receiving continuous intravenous heparin infusion and in 2 patients treated with repeated intravenous heparin injections. In all patients, including 1 with congenital AT-III deficiency, heparin therapy was associated with a considerable progressive reduction in AT-III-binding capacity and antigenic protein. The net individual decrease in plasma-AT-III was 0-31 +/- 0-05 units/ml (normal plasma-AT-III was 1-00 units/ml) or 9-5 +/- 2-0 mg/dl and the decrease was independent of initial concentration. Plasma-AT-III returned to normal two to three days after heparin was stopped. There was no decrease in plasma-AT-III after a single dose of intravenous heparin. When present in blood for long periods heparin significantly reduced AT-III, the proteinase inhibitor that is responsible for the anticoagulant effect of this drug. The finding is very relevant to the interpretation of clinical data in patients treated with heparin and suggests that AT-III depletion may underly the thromboembolic complications sometimes encountered during heparin therapy.

Antigens↗
PubMed1977

Antithrombin III and heparin inactivation in thrombin involving reactions.

The inhibitory capacity of antithrombin III (AT III) was measured by a quantitative method independent of the velocity of inhibition. When AT III was in excess of thrombin in plasma or in purified system the capacity of inhibitor decreased quantitatively in proportion to the amount of thrombin neutralized. Heparin present in reaction together with thrombin invariably induced a more extensive utilization of inhibitor than thrombin alone. The extent of this additional loss of inhibitory capacity was to a limited degree related to the concentration of heparin. Heparin itself was neutralized in thrombin-AT III reaction losing its anticoagulant property in proportion to the amount of thrombin bound by inhibitor. This quantitative neutralization of heparin occurred not only when the anticoagulant participated in thrombin-AT III binding but also when heparin was added to a medium containing a preformed thrombin-AT III complex. These results suggest that acceleration of binding and increased utilization of binding capacity are the two regular effects of heparin on thrombin-involving reactions of AT III. Both of these effects may be abolished by quantitative binding of heparin to thrombin-AT III complex.

Antithrombins↗
PubMed1975

Adverse effect of heparin in thrombin-antithrombin III interaction.

Thrombin, while reacting in the presence of hepatin, impairs the inhibitory capacity of antithrombin III so that subsequent inhibition of thrombin or factor Xa is decreased or abolished. This adverse effect of hepatin has been observed directly with at least 1.5 Iowa units of thrombin per each unit of purified human antithrombin III participating in the reaction. The inhibitory capacity was then totally destroyed and some residual thrombin remained in the active form. With a lower enzyme/inhibitor ratio inactivation of thrombin in the presence of hepatin was fast and complete, however, a significant decrease of inhibitory capacity below that found in reaction without heparin, has been established by measuring the residual antithrombin III activity. In defibrinated human plasma at least 2 units of thrombin per each antithrombin III unit were required to demonstrate directly the adverse effect of heparin but a fast depletion of inhibitory capacity has been also observed after repeated additions of small thrombin portions into plasma heparinized in vitro or in vivo. Portions of enzyme initially added disappeared with great velocity; subsequent portions, however, accumulated building up a high thrombin level not seen in the absence of heparin. The accumulation of residual enzyme was more extensive in plasma containing about 1 heparin unit per ml than anticoagulant at lower concentrations and was particularly noticeable in antithrombin III deficient plasma. These results may have some bearings on the approach to heparin therapy in the event when thrombin continuously generates or when a marked deficiency of antithrombin III exists.

Antithrombins↗