Flemming Knudsen

Protein C activity in renal disease

Protein C activity was determined in 19 healthy controls and in 52 patients with renal diseases, clinically divided into three groups I) Nephrotic syndrome, II) Renal insufficiency, III) Terminal uremia, requiring maintenance dialysis. In the nephrotic syndrome protein C levels were found to be normal, but in renal insufficiency and terminal uremia the protein C activity was significantly decreased. A correlation between decreasing protein C and progressive renal failure is suggested. The reduced protein C activity may play an important role in the thrombotic tendency seen in renal diseases and uremia.

Haemostatic activation in patients with head injury with and without simultaneous multiple trauma.

In a prospective study including 16 patients with multiple trauma and head injury and 14 patients with isolated head injury we measured plasma levels of prothrombin fragment 1 and 2 (F1 + 2) and thrombin/antithrombin III complex (TAT) on admission and on days 1, 2, 3, and 7 after the incident. On admission, all patients had values of F1 + 2 and TAT above the reference range. Admission levels of both F1 + 2 and TAT were significantly higher compared with levels on the following days. Admission levels of F1 + 2 was significantly correlated to the Injury Severity Score. TAT was higher in patients with multiple trauma than in patients with isolated head injury and were significantly correlated to the Injury Severity Score on admission and on day 3. Levels of F1 + 2 were significantly lower on day 1 in four patients with post-traumatic pulmonary dysfunction compared with patients without pulmonary dysfunction. With respect to levels of TAT, no differences were detected between patients with and without pulmonary dysfunction.

Angiotensinogen is an acute-phase protein in man

Accumulating information concerning the structure of angiotensinogen suggests a resemblance of this component of the renin-angiotensin system to the acute-phase protein alpha 1-antitrypsin. Compared to a group of age- and sex-matched controls without signs of infection, markedly elevated levels of angiotensinogen (increase in median value: 70%), alpha 1-antitrypsin (102%), caeruloplasmin (76%), haptoglobin (261%), and orosomucoid (162%) were found in plasma from 14 patients with acute inflammatory disease. This finding indicates that angiotensinogen should be included in the list of acute-phase proteins in man, and raises the question whether angiotensinogen is involved in the regulation of the renin-angiotensin system during inflammation and tissue injury.

Neurogenic Pulmonary Edema: Treatment with Dobutamine

In the case of a patient with complicating subarachnoid hemorrhage, an infusion of dobutamine was followed by a massive diuresis and regression of severe neurogenic pulmonary edema. It is suggested that the reduction in total peripheral vascular resistance and the increase in cardiac contractility accounts for the observed beneficial effect and indicate that dobutamine is a suitable drug for the treatment of neurogenic pulmonary edema.

The effect of dialyser membrane material on intradialytic changes in platelet count, platelet aggregation, circulating platelet aggregates and antithrombin. III

Blood surface interaction during hemodialysis leads to impairment of platelet function and decrease in platelet number, which besides heparinization, may cause or exacerbate bleeding in risk patients. Furthermore, antithrombin III has been shown to increase during dialysis, probably due to vascular endothelial injury caused by infusion of activated platelets into the patient. 23 patients were examined during two successive dialyses, using membranes based on regenerated cellulose (RC) and cellulose acetate (CA). In 12 of the patients, platelet aggregation induced by ADP, circulating platelet aggregates and immunological AT III and AT III activity were determined. Irrespective of the membrane used, hemodialysis was associated with deterioration of platelet function, reflected by a decrease in platelet aggregation with return to predialysis values at the end of dialysis. However, the decline in platelet count and the increase in circulating platelet aggregates were membrane dependent, with RC causing greater changes than CA. No changes in threshold concentration of ADP inducing secondary platelet aggregation or in either immunological AT III or AT III activity were seen during dialysis.

On the kinetics of complement activation, leucopenia and granulocyte-elastase release induced by haemodialysis.

In order to elucidate the kinetics of haemodialysis-induced activation of complement, leucopenia and release of granulocyte-elastase, 10 patients (three females and seven males; mean age 47.8 years) were extensively studied during a 4 h haemodialysis treatment and for the following 24 h, and further compared with a healthy control group. Prior to dialysis patients had normal leucocyte count, plasma elastase bound to alpha 1-proteinase inhibitor (E-alpha 1P1) and total haemolytic complement, whereas plasma C3d was higher and plasma C5a lower than in controls. Haemodialysis induced initial leucopenia and subsequent rebound phenomenon lasting 24 h post treatment. These alterations were due to almost selective changes in neutrophile count as monocyte and lymphocyte counts, apart from decrease in the first 30 min, were unchanged. Total haemolytic complement decreased initially during dialysis and rose at the end. Generation of C5a within the dialyser was evident by demonstration of high levels of this anaphylatoxin in dialyser effluent plasma; maximal values observed coincided with the nadir of leukopenia. Plasma C3d and E-alpha 1P1 both progressively rose during dialysis. After termination of extracorporeal circulation the disappearance rates (T/2) were approximately 6 h and 2.5 h respectively. Haemodialysis thus induces changes in the complement and leucocyte system resembling an acute inflammation, which out-lasts the treatment period.

Protein C assays in uremia

Protein C was determined in 42 patients with terminal uremia and 20 healthy controls in three different ways 1) anticoagulant activity 2) amidolytic activity 3) antigen level. Protein C anticoagulant activity was markedly decreased in uremia, but was partly normalized during hemodialysis treatment, whereas the amidolytic activity and antigen level of protein C were normal and without changes during dialysis. The activities and antigen levels of factor II and X were normal before and after hemodialysis. In anticoagulated patients we found a good correlation between prothrombin levels and protein C levels determined with three different assays. We did not find any evidence for a defect carboxylation of protein C as the cause for the defective protein C in uremia. The BaCl2 precipitation in the Protein C anticoagulant assay was incomplete both in uremia and in controls but without differences between the two groups. In vitro addition of urea and creatinine did not decrease protein C activity. The cause of the defective protein C in uremia is still not known but it might contribute to thromboembolic complications.

Platelets and antithrombin III in uraemia: the acute effect of haemodialysis.

In 14 haemodialysis patients, platelet count, secondary platelet aggregation rate, immunological antithrombin III and antithrombin III activity were lower and plasma beta-thromboglobulin higher than in 14 age- and sex-matched controls. In contrast, primary platelet aggregation, the degree of secondary aggregation and circulating platelet aggregates did not differ. Haemodialysis was associated with signs of platelet damage reflected by increase in plasma beta-thromboglobulin, extraction of platelets in the dialyser and decline in platelet count. Platelets in the dialyser effluent line were less aggregable than platelets in arterial blood. Circulating platelet aggregates and immunological antithrombin III were unchanged during dialysis whereas antithrombin III activity showed a minor rise. In conclusion, uraemics show a decreased rate of secondary platelet aggregation, and haemodialysis confers further platelet injury due to blood/surface interactions during extracorporeal circulation. The defective platelet function and low antithrombin III activity may help to explain the paradoxical occurrence of both haemorrhagic and thrombotic complications in uraemia.

Leukopenia and Release of Granulocyte Elastase: Interlinked Membrane-Dependent Events during Hemodialysis

In order to investigate the effect of dialyzer membrane material on hemodialysis-induced leukopenia and release of granulocyte elastase, 12 patients were studied during two successive dialyses using membranes based on regenerated cellulose (RC) and cellulose acetate (CA). RC membranes induced greater and more prolonged leukopenia than did CA membranes. Release of granulocyte elastase, assessed as changes in plasma levels of elastase in complex with α1-proteinase inhibitor (E-α1-PI), increased with both membranes, but significantly more with RC membranes. The demonstrated liberation of granulocyte elastase could contribute to the deterioration of pulmonary function reported during hemodialysis. Furthermore, we suggest that measurement of E-α1-PI may be used to evaluate biocompatibility of dialyzer membranes.

Protein C in renal allotransplantation during the perioperative period

Abstract Sørensen PJ. Nielsen AH. Knudsen F. Schmitz O. Dyerberg J (Department of Nephrology. and Department of Clinical Chemistry. Aalborg Hospital. Aalborg. and Department of Nephrology. University Hospital of Århus. Århus. Denmark). Protein C in renal allotransplantation during the perioperative period.