Biomedical subjects
Publications and source records attributed to M Schleuning.
Stored single-donor platelets are characterized by a progressive cell activation. The data presented indicate that activation of plasma coagulation and complement system could contribute to this storage lesion process.
A patient in an intensive care unit experienced severe esophageal bleeding caused by erosion of a lusorian artery. The lusorian artery is a rare variant of the right subclavian artery. It originates in the descending aortic arch and crosses behind the esophagus to the right, sometimes generating esophageal compression. The patient's condition required respirator therapy and placement of a duodenal tube. At the point of crossing over of the lusorian artery and the esophagus, the duodenal tube caused esophageal necrosis, leading to erosion of the lusorian artery. This resulted in extensive esophageal bleeding, which at last required surgical intervention. To attain proper treatment and to avoid unnecessary diagnostic and therapeutic approaches, a lusorian artery lesion has to be included in the differential diagnosis of upper gastrointestinal bleeding.
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During the last decade, the trend toward intensifying chemotherapeutic regimens in patients with hematologic malignancies rapidly increased the demand for single-donor platelet concentrates (PCs). The logistics of such supply, however, necessitated the storage of these blood components prior to transfusion. Today, most blood centers use di(2-ethylhexyl)phthalate-free blood bags, which are assumed to allow a storage period of up to 5 days. This report describes biochemical and functional changes of stored single-donor PCs, which may influence the expected quality of PCs. The acid-base status is characterized by an initial respiratory alkalosis compensated by a metabolic acidosis. Changes in extracellular electrolyte, lactate dehydrogenase, glucose, lactate, elastase, and complement levels, as well as in the release of alpha granule content and the initial activation of plasma coagulation, are demonstrated. These changes result in a functional impairment of stored PCs as reflected by thromboxane and serotonin release reaction and by aggregation and in vitro bleeding time studies. In contrast, in vivo recovery and survival rates have been reported to be unaffected. Whether the good recovery and survival rates are caused by a rejuvenescence of stored PCs in vivo or are due to injured circulating platelets has not yet been proven.
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During storage of CPD-A1 preserved whole blood factors of the complement cascade become activated, as evidenced by a rapid increase in the concentrations of C3a-desArg and C4a-desArg. After 10 to 14 days of whole blood storage, the elevations of C3a and C4a levels were highly significant. This increase was paralleled by an increase in the concentration of the lysosomal proteinase elastase from polymorphonuclear (PMN) granulocytes. By contrast, the concentration of the C3 activator complex C4b2b remained unchanged even after 3 weeks of storage. The supplementation of the anticoagulant CPD-A1 with the polyvalent-proteinase-inhibitor aprotinin and the specific elastase-inhibitor eglin C failed to inhibit complement activation, whereas leukocyte depletion could partially abolish the increase of the concentration of C4a, but had no effect on C3a concentrations. These observations support the notion that cleavage of C4 during storage of whole blood is partially leukocyte dependent, whereas the activation of C3 is possibly caused by the activation of the alternate pathway of the complement system by contact of plasma with plastic surfaces.
Previous studies of sensitization to RhD by RhD-positive platelet transfusions in RhD-negative cancer patients have shown different frequencies of alloimmunization (max. 19%). We studied 37 RhD-negative patients who received RhD-incompatible platelet transfusions and simultaneously anti-D-immune globulin. We provide evidence that in this setting RhD-prophylaxis is highly effective in preventing alloimmunization due to RhD antigen, since none of the patients studied developed anti-D. Detection of other red blood cell antibodies than anti-D proves the possibility of immunization in these patients. Prevention of isoimmunization in patients with malignant diseases is recommended especially in young females, since an increasing number of patients are having successful pregnancies, despite prior or even during cytotoxic therapy.
As reported earlier, factors of the complement cascade get activated in CPD-A1-stabilized whole blood. As early as after 10 days of storage under normal blood bank conditions the elevations of the concentrations of C3a-desArg and C4a-des-Arg were highly significant. By contrast, the concentration of the C3 activator complex C4b2b remained unchanged even after 3 weeks of storage. Leukocyte depletion partially inhibited the activation of C4 but had no effect on C3a concentrations. Therefore, cleavage of C4 during storage of whole blood seems to be partially leukocyte-dependent, whereas the activation of C3 is possibly due to the activation of the alternate pathway of the complement system by contact of blood to plastic surfaces. Even through the radioimmunologically measured C3a might be inactive as an anaphylatoxin, these observations are of clinical importance since the inactivated C3a-desArg still possesses biological activities such as activation of platelets which may lead to hypercoagulability and thrombosis.
As reported earlier, factors of the complement cascade get activated in CPD-A1-stabilized whole blood. While leukocyte depletion inhibited partially the activation of C4, it had no effect on C3a concentrations. Therefore cleavage of C4 during storage of whole blood seems to be partially leukocyte-dependent, whereas the activation of C3 is possibly due to the activation of the alternate pathway of the complement system by contact of blood to plastic surfaces. Even though the radioimmunologically measured C3a might be inactive as an anaphylatoxin, these observations are of clinical importance since the inactivated C3a-desArg still possesses biological activities, like activation of platelets which may lead to hypercoagulability and thrombosis.
Tumor necrosis factor is one of the recently cloned cytokines with pleiotropic effects on normal and malignant cells. Our knowledge about the scope of cells producing or responding to this cytokine has enormously expanded. In critically ill patients with acute hepatic failure, acute graft-versus-host disease, or septic shock, circulating tumor necrosis factor can be measured and useful prognostic correlations do exist. Despite promising in vitro results, early clinical trials with tumor necrosis factor for the treatment of cancer have failed thus far to reveal major antineoplastic activity in cancer patients. However, more clinical trials are necessary, since different routes of administration and combinations with other cytokines may lead to favorable results.
We have provided evidence that tumor necrosis factor alpha (TNF-alpha) enhances the proliferation and the state of activation of human thymocytes cultured with concanavalin A or interleukin 2 (IL-2), as evidenced by an increase in the expression of the c-myc gene and the gene of the IL-2 receptor (alpha-chain, Tac antigen) and by the expression of Tac antigen on the cell surface. Our observations suggest that TNF-alpha interacts with IL-2 and with another factor(s) which is induced in the course of activation by concanavalin A, since the immunosuppressant drug cyclosporin A-, which inhibits thymocyte activation, prevents the effect of TNF-alpha on thymocytes activated with concanavalin A, whereas anti-Tac, which prevents the binding of IL-2 to its receptor without affecting the production of IL-2 or the expression of IL-2-specific mRNA, inhibits proliferation only partially. By contrast, anti-Tac inhibits the response to TNF-alpha of thymocytes induced with IL-2 completely. These observations show that TNF-alpha exerts a potentially important immunoregulatory effect in synergy with IL-2 on thymocytes, which could contribute to tumor rejection. In addition, we show that activated human thymocytes express the TNF-alpha gene and that the expression of this gene is inhibited by cyclosporin A and dexamethasone.
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Transfusion of frozen blood has become a routine method. As the cost is high, the method is restricted to autologus transfusion and storage of rare blood groups. Transfusion of frozen platelets will become a routine method in near future. Especially large pools of HLA-identical platelets should be of great advantage in many cases.
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Enzymatically active or diisopropyl fluorophosphate-inactivated pig pancreatic kallikrein were infused intravenously into dogs. Pig pancreatic kallikrein in plasma and urine was measured by a radioimmunoassay. The total excreted pig pancreatic kallikrein was 0.8-3.1% of the administered dose when active kallikrein was infused and 21.6% when inactive kallikrein was infused. The renal clearance of the administered kallikrein was found to be between 0.9 and 4.1 ml/min, which corresponds to 2.4-6.4% of the inulin or creatinine clearance. These results indicate that renal synthesis of tissue kallikrein and its direct secretion into the urine is not the exclusive mechanism of the excretion of tissue kallikrein into the urine. A second mechanism, the renal transfer of endogenous tissue kallikrein from the blood into the urine, can also contribute to the total amount of excreted urinary kallikrein.