PubMed · 7048490
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M Steinbuch. 1982. Heparin - plasmaprotein interactions. Current status.. https://doi.org/10.1016/s0338-4535(82)80010-x
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The recent demonstration of a protein disulfide isomerase (PDI) on the surface of and secreted from blood platelets raises the possibility that proteins involved in hemostasis and wound healing are also substrates of this enzyme. In this study purified preparations of platelet PDI, thrombospondin-1 (TSP), alpha-thrombin, and antithrombin III (AT) were used to demonstrate that PDI catalyzes formation of a TSP-thrombin-AT complex consistent with previous results with supernatant platelet activation. Concentrations of 1.25 microg/ml of PDI were sufficient to convert almost 50% of thrombin to TSP-thrombin-AT complex. Complex formation requires low concentrations of a reduced thiol and the reaction can be prevented by N-ethymaleimide. The complex is dissociated by reducing agents such as mercaptoethanol. Absence of Ca2+ and the addition of EDTA increased the rate of complex formation, indicating that TSP in the Ca2+-free form is most effective. In the absence of AT a small amount of TSP-thrombin complex formed which was only 0-13% of maximal complex formation in the presence of AT. This result, in combination with kinetic studies showing rapid formation of thrombin-AT complex followed by conversion to ternary complex, suggests that the thrombin-AT complex is an obligatory intermediate in the reaction. Under optimal conditions over 70% of the thrombin is incorporated into the complex in 60 min. Heparin accelerated the reaction largely by enhancing formation of thrombin-AT complexes and had little effect on TSP. PDI coprecipitated with TSP from the supernatant solution of activated platelets, suggesting an association between PDI and its substrate. In summary, these data are consistent with a role for PDI-catalyzed formation of disulfide-linked complexes of TSP with other proteins.
Dialysis membranes made from regenerated cellulose are under dispute because of their alleged lack of hemocompatibility. The introduction of membranes from synthetically modified cellulose, like cellulose acetate or Hemophan, has proven, however, that hemocompatible membranes can be fabricated from cellulose by means of chemical surface modifications. In addition to membranes made from modified cellulose like ethers or esters, which were investigated in earlier experiments, we looked for further cellulose modifications to be assessed for their hemocompatibility. For this purpose, we synthesized a series of cellulose carbamate derivatives to profit from the excellent hemocompatibility pattern of the urethane family. In vitro investigations on membranes made from these cellulose modifications proved a direct relationship between the degree of modification and hemocompatibility. This was proven for the following 3 representative hemocompatibility parameters: complement C5a generation, thrombin-antithrombin (TAT) III formation, and platelet count (PC). As already shown for modifications made from cellulose esters, a direct dependency between improved hemocompatibility and the degree of substitution (DS) in the cellulose molecule could be found. In our experiments, a degree of substitution below a value of 0.1 led to a nearly complete suppression of complement activation for all cellulose carbamates under investigation. In contrast to data on cellulose esters, we observed that molecular weight or molecular conformation of chemical substituents exerted only a minor effect on the hemocompatibility pattern. In addition, data on cellulose carbamate esters (e.g., cellulose succinate-phenyl-carbamate) show that a simultaneous but balanced substitution with hydrophilic and hydrophobic groups at the surface of the cellulose polymer is a further prerequisite for optimal hemocompatibility. It seems that the carbamate configuration per se has a positive effect on the hemocompatibility pattern of synthetically modified cellulose membranes.
Plasmodium falciparum malaria is associated with procoagulant activity but not with thromboembolism. We measured coagulation factor XIII, i.e., fibrin-stabilizing factor, in 45 patients with falciparum malaria over time. Of these, 22 had organ complications. The factor XIII antigen (subunits A and B) and plasma activity levels were abnormally low in those with falciparum malaria. They increased during antiparasitic therapy. In 14 of 22 patients with complications, but in no patient with mild disease (P < 0.001), subunit A and activity was < 50%. The factor X.III levels were inversely correlated with clinical severity, parasitemia, and human neutrophil elastase (HNE), but not with thrombin-antithrombin III levels. Thus, low factor XIII levels may reflect proteolysis by HNE, rather than procoagulant activity. One could speculate that factor XIII degradation in severe malaria prevents thromboembolism. On the other hand, factor XIII deficiency might reduce protection of the vascular endothelium against HNE and reactive oxygen species, which would promote organ damage.