Janti Koderisch

Hemostasis and thromboembolism in children with nephrotic syndrome: Differences from adults

Eleven of 204 children with nephrotic syndrome had thrombotic complications: arterial thrombosis in five, venous thrombosis in four, and pulmonary embolism in two. Fifty-one episodes of thromboembolism were recognized in 116 adult patients with nephrotic syndrome. Despite the lower incidence, thromboembolic complications tended to be more severe in children. In vitro indices of hemostasis and clinical evidence of thromboembolic complications were compared in children and adults. Antithrombin III concentrations and activities were abnormal in seven of 10 children, but in only two of 32 adults. In both groups, alpha 2-macroglobulin was elevated, but more markedly so in children. No evidence for circulating granulocyte-derived proteases (elastase/antielastase complexes) was noted in either group. Protein C was significantly elevated in children with nephrotic syndrome, but was normal in adults. Children also differed from adults with nephrotic syndrome in laboratory evidence of subthreshold disseminated intravascular coagulation (i.e., elevated soluble fibrinogen monomeric complexes and fibrin degradation products) and indicators of in vivo platelet activation (elevated beta-thromboglobulin). The more severe coagulation abnormalities in children may be linked to the more pronounced hypoalbuminemia.

Mechanism of cephalosporin-induced hypoprothrombinemia: relation to cephalosporin side chain, vitamin K metabolism, and vitamin K status

The mechanism of cephalosporin‐induced hypoprothrombinemia has been investigated in hospitalized patients, with respect to cephalosporin structure, vitamin K metabolism, and vitamin K status. Cephalosporins containing side chains of N‐methylthiotetrazole (latamoxef, cefmenoxime, cefoperazone, cefotetan, cefamandole) or methyl‐thiadiazole (cefazolin) all caused the transient plasma appearance of vitamin K1 2,3‐epoxide in response to a 10‐mg intravenous dose of vitamin K1, whereas two cephalosporins without a heterocyclic side chain (cefotaxime and cefoxitin) did not. The plasma accumulation of vitamin K1 2,3‐epoxide was qualitatively similar to, but quantitatively less than, that produced by the oral anticoagulant phenprocoumon. Patients eating normally had plasma vitamin K1 concentrations (176 to 1184 pg/mL) that were within the normal range (150 to 1550 pg/mL) and their clotting tests remained consistently normal for all antibiotics tested. Patients on total parenteral nutrition had lower plasma vitamin K1 concentrations (50 to 790 pg/mL) but normal clotting before starting antibiotic therapy. Of 19 parenterally fed patients, all seven treated with latamoxef developed hypoprothrombinemia, PIVKA‐II and a decrease of protein C within four days whereas 12 patients treated with cefotaxime or cefoxitin showed no clotting changes. Latamoxef‐associated hypoprothrombinemia was readily reversible by 1 mg of vitamin K1 given intravenously, but hypoprothrombinemia and sub‐normal plasma vitamin K1 could recur within two to three days. The data suggest that NMTT‐cephalosporins are inhibitors of hepatic vitamin K epoxide reductase and that a lower nutritional‐vitamin K status predisposes to hypoprothrombinemia.

Alteration of hemostasis associated with cefoperazone treatment

Summary21 Patients with normal and impaired renal function were given cefoperazone in a recommended dose of 4 g/day, irrespective of renal function. Platelet function and plasmatic coagulation were analyzed before and on day 7 of therapy. In patients with normal renal function on their usual diets, there was neither impairment of platelet function nor plasmatic coagulation. High serum antibiotic trough levels, prolongation of bleeding time and decreased vitamin K-dependent coagulation factors, as verified by the prolongation of prothrombin time and the appearance of descarboxyprothrombin, could be observed in those patients with impaired renal function whose insufficiency was far advanced and accompanied by a complex clinical picture. In this situation vitamin K deficiency may be due to poor oral intake, along with interference of hepatic vitamin K metabolism, showing an effect similar to that seen after coumarin therapy. Dosage reduction of the antibiotic in advanced renal failure and repeated control of prothrombin time is advised.Zusammenfassung21 Patienten erhielten eine tägliche Standarddosis von 4 g Cefoperazon ohne Rücksicht auf die Nierenfunktion. Thrombozytenfunktion und plasmatische Gerinnung wurden vor und am Tag 7 der Therapie mit Cefoperazon untersucht. Bei Patienten mit normaler Nierenfunktion blieb die Hämostase unverändert. Dagegen trat bei Patienten mit präterminaler Urämie und zusätzlicher komplexer klinischer Situation eine Hämostasestörung auf, welche durch hohe Antibiotikatalspiegel verursacht war. Die gestörte Hämostase war gekennzeichnet durch eine verlängerte Blutungszeit und durch eine Erniedrigung des Quickwertes, hervorgerufen durch einen erworbenen Vitamin-K-Mangel. Ursache des Vitamin-K-Mangels war eine verminderte Zufuhr mit der Nahrung und eine kumarinähnliche Hemmung der hepatischen reduktiven Regeneration von Vitamin K. Um Hämostasestörungen zu vermeiden, werden bei Patienten mit präterminaler Urämie eine Dosisreduktion von Cefoperazon und häufige Kontrollen des Quickwertes empfohlen.

Pharmacokinetics and hemostasis following administration of a new, injectable oxacephem (6315-S, flomoxef) in volunteers and in patients with renal insufficiency

SummaryFlomoxef is a new oxacephem of broad antibacterial activity. The compound is mainly excreted through the kidneys. Two dose finding studies in patients with various degrees of renal insufficiency revealed that the dosage of flomoxef has to be reduced exactly according to the renal function. Although the N-methylthiotetrazole group has been replaced by a hydroxyethyl group, an inhibitory effect of flomoxef on vitamin K metabolism persisted. This effect was, however, less pronounced than with latamoxef. Only patients with low vitamin K stores are endangered. For those in whom low vitamin K stores are suspected repeated controls of prothrombin time are advised during the treatment. In contrast to latamoxef the platelet system was not affected by flomoxef. With the exception of loose stools in some patients no other clinical side effects during treatment were observed.ZusammenfassungFlomoxef ist ein neues parenterales Oxacephem mit breiter antibakterieller Aktivität. Wegen seiner vorwiegend renalen Elimination muß die Dosierung von Flomoxef der Nierenfunktion angepaßt werden. Hierzu wurden zwei Dosisfindungsstudien durchgeführt. Obwohl in Position 3 des Oxacephemgerüsts N-methyl durch ein Hydroxyaethyl im Thiotetrazolring ersetzt wurde, ist die hemmende Wirkung auf den Vitamin K Metabolismus immer noch nachzuweisen. Dieser kumarinähnliche Effekt ist allerdings deutlich geringer als unter Latamoxef. Deshalb sind nur solche Patienten gefährdet, unter der Therapie mit Flomoxef einen Abfall des Quicktests zu entwickeln, die einen ausgeprägten Vitamin K Mangel aufweisen, wie zum Beispiel Patienten unter totaler parenteraler Ernährung. Bei diesen Patienten sollte der Quickwert unter der Therapie häufiger kontrolliert werden. Im Gegensatz zu Latamoxef hat Flomoxef keinen Einfluß auf die Thrombozytenfunktion. Außer Stuhlgangunregelmäßigkeiten bei einem Teil der Patienten konnten keine zusätzlichen Nebenwirkungen unter der Therapie mit Flomoxef beobachtet werden.

SSA (Ro)-antibodies in Wegener's granulomatosis.

SummaryIn 4 consecutive cases of Wegeners granulomatosis with glomerulonephritis, antibodies against the extractable nuclear antigen SSA (Ro) could be demonstrated with counter-immunoelectrophoresis. Antibodies were demonstrable on admission and paralleled disease activity while patients were under therapy. This potential serological marker may be of value for diagnosis and follow-up of patients with Wegeners granulomatosis.

Hemostasis in patients with normal and impaired renal function under treatment with cefodizime

SummaryTen patients (two with normal, eight with impaired renal function) on their usual diet were treated with cefodizime (HR 221) for seven days. The dosage was 4 g/day, adapted to renal function as appropriate. Platelet function, plasma coagulation and vitamin K metabolism were investigated before and on day 7 of therapy. Platelet function and plasma coagulation remained unchanged, regardless of the size of the serum antibiotic trough levels, in both normal and impaired renal function. Vitamin K1 metabolism remained unaffected, since no increase in vitamin K1 2,3 epoxide in the circulation was observed during the therapy. Cefodizime (HR 221), a parenteral aminothiazole cephalosporin, does not affect hemostasis.ZusammenfassungZehn Patienten (zwei mit normaler, acht mit eingeschränkter Nierenfunktion) wurden sieben Tage mit Cefodizim (HR 221), einem parenteralen Aminothiazol-Cephalosporin, behandelt. Die Dosierung wurde der Nierenfunktion angepaßt. Thrombozytenzahl, Thrombozytenfunktion und Blutungszeit, plasmatische Gerinnung und Vitamin-K-Metabolismus wurden vor und am Tag 7 der Therapie mit Cefodizim untersucht. Unabhängig von den Antibiotikaspiegeln blieb die Hämostase bei Patienten mit normaler und eingeschränkter Nierenfunktion unbeeinflußt. Weder Plättchenfunktion noch plasmatische Gerinnung änderten sich signifikant. Der Vitamin-K-Metabolismus wurde nicht beeinträchtigt.