A. von Felten

Familial disturbance of fibrin monomer aggregation.

The investigation of the cause of an accidentally observed prolonged prothrombin time in a patient without a haemorrhagic diathesis led to the discovery of a familial disturbance of the aggregation of fibrin monomers (von Felten, Duckert and Frick, 1965). The observed defect differs from previously reported anomalies in the last phase of coagulation such as congenital afibrinogenaemia or hypofibrinogenaemia (Frick and McQuarrie, 1954), congenital fibrin‐stabilizing‐factor (FSF) deficiency (Duckert, Jung and Shmerling, 1960), and congenital dysfibrinogenaemia (Beck, 1964). It may be similar to the fibrinogen anomaly described by Ménaché (1963).

Neutropenia after penicillins: Toxic or immune-mediated?

SummaryEight patients treated with a total of 220–550 million U penicillin-G developed neutropenia. These cases have been compared with eight patients receiving a similar dose of penicillin-G with no adverse reactions and with eight untreated subjects. All penicillin-treated patients showed raised levels of antipenicillin IgG antibodies and lymphocyte culture stimulation indices. These values were highest in the neutropenia group. Both of the two tests significantly descriminated the three groups. Antineutrophil antibodies could be detected in four of seven neutropenic patients with a staphylococcal-slide-assay while indirect immunofluorescence and microcytotoxicity tests failed to reveal these antibodies. The literature dealing with neutropenias induced by penicillin-G and its congeners is reviewed. We conclude that (1) penicillin-G in doses exceeding a total of 200 million U frequently induces neutropenia, (2) an immune-mediated pathogenesis is highly probable, (3) neutropenia after penicillins is different from two hither-to accepted types of this side effect, (4) sufficiently high amounts of penicillin-G intravenously always induce sensitization against this drug.ZusammenfassungAcht Patienten entwickelten nach total 220–550 Millionen E Penicillin-G i.v. eine Neutropenie. Wir verglichen immunologische Daten dieser Fälle mit denjenigen von acht Patienten, die mit vergleichbaren Penicillin-G-Dosen ohne ersichtliche Nebenwirkungen behandelt wurden, sowie mit denjenigen von acht unbehandelten Gesunden. Alle mit Penicillin Behandelten zeigten im Vergleich zu den Unbehandelten erhöhte Spiegel von anti-Penicillin IgG und einen stark positiven Lymphozyten-Stimulationstest mit Penicillin. Beide Untersuchungen ergaben die höchsten Werte innerhalb der Neutropeniegruppe und unterschieden alle drei Gruppen signifikant voneinander. Bei vier von sieben Neutropenikern konnten mit einem Objektträgertest unter Verwendung von Protein A enthaltenden Staphylokokken, antineutrophile Antikörper nachgewiesen werden. Mit indirekter Immunfluoreszenz und Mikrozytotoxizitätstest gelang dagegen in keinem Fall ein Antikörpernachweis. Die Literatur über Neutropenie nach Penicillin und seinen Derivaten wurde durchgesehen. Schlußfolgerungen: (1) Über 200 Mio E Penicillin-G i.v. induziert häufig eine Neutropenie, (2) ein immunvermittelter Mechanismus ist sehr wahrscheinlich, (3) die Neutropenie nach Penicillinen ist nicht identisch mit einem der zwei bisher akzeptierten Typen der medikamentös induzierten Immunneutropenie (Amidopyrin-Typ resp. Procainamid-Typ), (4) genügend hohe Dosen von Penicillin-G erzeugen immer einen positiven Lymphozyten-Stimulationstest und einen Anstieg von Penicillin-spezifischen IgG.

No clinically relevant effect of lornoxicam intake on acenocoumarol pharmacokinetics and pharmacodynamics

AbstractObjective: To investigate the effect of lornoxicam co-administration on acenocoumarol pharmacokinetics and pharmacodynamics. Methods: In an open crossover study, six healthy male volunteers received racemic acenocoumarol (10 mg) orally without/with lornoxicam co-administration (8 mg twice daily). Results: The median (range) areas under the concentration-time curve (AUC) for (R)-acenocoumarol were 3458 (3035–7312) μg · h l−1 in the absence of and 3667 (2907–7741) μg · h l−1 in the presence of lornoxicam. The corresponding values for (S)-acenocoumarol were 479 (381–853) μg · h l−1 and 612 (425–1241) μg · h l−1. The differences were not statistically significant. Lornoxicam co-administration did not influence the free fractions or acenocoumarols effect on factor II and VII activities. Simulations based on the results of a model-based analysis predicted that in the case of lornoxicam co-administration, the factor VII activity of a person in steady-state at 26% will remain between 14% and 32%. Conclusion: Co-administration of lornoxicam at the upper limit of recommended doses does not alter the pharmocokinetics of the clinically relevant (R)-acenocoumarol or the anticoagulant activity of acenocoumarol. These data clearly differ from the results of previous studies, which showed clinically relevant influences of lornoxicam on warfarin kinetics and of piroxicam on acenocoumarol kinetics.

Studies on Fibrin Monomer Aggregation in Congenital Dysfibrinogenaemia (Fibrinogen ‘Zürich’): Separation of a Pathological from a Normal Fibrin Fraction

Further characterization of the delay in aggregation of fibrinogen ‘Zürich’ showed a potentiation of the defect by increasing ionic strength and an acceleration by calcium ions or protamine. A new type of paracoagulation due to soluble abnormal fibrin monomers in fresh serum is described.

Opposite effects of lornoxicam co-administration on phenprocoumon pharmacokinetics and pharmacodynamics

AbstractObjective: To investigate the effect of co-administration of the non-steroidal anti-inflammatory drug (NSAID) lornoxicam on the pharmacokinetics of (R)- and (S)-phenprocoumon and their effect on factor II and VII activities. Methods: Six healthy male volunteers completed an open crossover study. Plasma concentrations of (R)- and (S)-phenprocoumon and activities of coagulation factors II and VII were measured after a single oral dose of 9 mg phenprocoumon racemate. In the second session, lornoxicam administration was started 3 days before phenprocoumon administration and continued twice daily until the last blood sample was drawn. Results: Lornoxicam co-administration resulted in a statistically significant increase of the area under the concentration-time curve (AUC) of the more potent (S)-isomer of phenprocoumon from a median value of 100 (range 68–146) mg · h · l−1 to 124 (92–239) mg · h · l−1. For the (R)-isomer, the AUC increase from 96 (70–142) mg h · l−1 in the absence to 108 (75–155) mg · h · l−1 in the presence of lornoxicam was not statistically significant. In a model-based analysis, an increase of (S)-phenprocoumon and (R)-phenprocoumon bioavailability of 14% [95% CI (9%, 19%)] and 6% (2%, 10%) and a decrease of their clearances by 15% (8%, 21%) and 6% (0%, 13%) was obtained. Lornoxicam co-administration did not influence the free fractions of (R)- or (S)-phenprocoumon. Contrary to what was expected from the changes in pharmacokinetics, a statistically significant decrease in the effect of phenprocoumon on factor II and VII activity was observed for the sessions with lornoxicam co-administration. For factor VII, lornoxicam was found to increase the concentration causing half-maximal effect (C50) of phenprocoumon by 70% [95% CI (38%, 111%)]. Conclusion: Co-administration of lornoxicam at the upper limit of recommended doses mainly altered the pharmacokinetics of the more potent (S)-isomer and to a lesser degree those of (R)-phenprocoumon. Despite these changes in pharmacokinetics, a decrease of the effect on factor II and VII activity was observed. These results suggest that in the case of lornoxicam co-administration in a patient treated with phenprocoumon the prothrombin time should be monitored closely.

Autologous Hematologic Recovery from Aplastic Anemia following High Dose Cyclophosphamide and HLA-Matched Allogeneic Bone Marrow Transplantation

A 17-year-old woman with severe aplastic anemia was treated with high-dose cyclophosphamide followed by infusion of bone marrow cells from her HLA-identical, ABO-incompatible brother. The marrow graft failed to take. Subsequently, the patient revealed an autologous marrow reconstitution leading to a near-complete hematologic recovery which is now persisting for over 20 months.

Digoxin-associated thrombocytopaenia.

SummaryA 60-year-old male patient had two episodes of thrombocytopaenia whilst being treated with digoxin, each of them reversible upon with-drawal of the drug. Bone marrow examination was consistent with peripheral platelet destruction as the main mechanism of the thrombocytopaenia. The inhibition of clot retraction test was positive, with a declining titer, after cessation of digoxin therapy, and this plus the finding of circulating immune complexes after incubation of the patients serum with digoxin established digoxin as the offending agent. It is concluded that digoxin may be a rare cause of drug-induced immune-thrombocytopaenia.

Circulating immune complexes before and after kidney allotransplantation

In a prospective study circulating immune complexes (CIC) were analyzed before and serially after renal transplantation in 141 consecutive patients. CIC were measured using the Raji cell assay as originally described by Theofilopoulos and Dixon. The amount of CIC was expressed as microgram heat aggregated human immunoglobulin G (IgG) equivalent/ml serum. The upper limit of normal sera was 25 micrograms/ml. The values are expressed as geometric means (- 1 SD/ + 1 SD). In 86 of 133 rejection episodes a renal biopsy was performed and the histopathologic changes were semiquantitatively assessed and classified in a cellular or vascular type of rejection. Before transplantation CIC were detected in 104 of 141 patients (73.8%) and the mean value was 65.6 (27.8-154.9) micrograms/ml. The level of CIC was positively correlated with the number of grafts (r: 0.43; P less than 0.01) and the occurrence of chronic active hepatitis (r: 0.31; P less than 0.01). No correlation was found between CIC and the underlying kidney disease, the number of blood transfusions prior to transplantation, and the pre-existing lymphocytotoxic antibodies. Graft survival and number of rejection episodes were not influenced by the level of CIC prior to transplantation. After transplantation CIC were elevated in 60 patients (41%), appeared transiently in 49 patients (35%) and were never detectable in 32 patients (23%). In patients with a graft survival less than or equal to 11 months the average and peak post-transplant CIC levels were significantly higher than patients with a graft survival of 12 months: 64.4 (21.8-191.0); 87.7 (26.0-295.8) versus 39.6 (18.4-85.3); 56.8 (21.0-150.1) micrograms/ml; P less than 0.01.(ABSTRACT TRUNCATED AT 250 WORDS)SummaryIn a prospective study circulating immune complexes (CIC) were analyzed before and serially after renal transplantation in 141 consecutive patients. CIC were measured using the Raji cell assay as originally described by Theofilopoulos and Dixon. The amount of CIC was expressed as µg heat aggregated human immunoglobulin G (IgG) equivalent/ml serum. The upper limit of normal sera was 25 µg/ml. The values are expressed as geometric means (−1 SD/+1 SD). In 86 of 133 rejection episodes a renal biopsy was performed and the histopathologic changes were semiquantitatively assessed and classified in a cellular or vascular type of rejection. Before transplantation CIC were detected in 104 of 141 patients (73.8%) and the mean value was 65.6 (27.8–154.9) µg/ml. The level of CIC was positively correlated with the number of grafts (r:0.43;P<0.01) and the occurrence of chronic active hepatitis (r:0.31;P<0.01). No correlation was found between CIC and the underlying kidney disease, the number of blood transfusions prior to transplantation, and the pre-existing lymphocytotoxic antibodies. Graft survival and number of rejection episodes were not influenced by the level of CIC prior to transplantation. After transplantation CIC were elevated in 60 patients (41%), appeared transiently in 49 patients (35%) and were never detectable in 32 patients (23%). In patients with a graft survival ≦11 months the average and peak post-transplant CIC levels were significantly higher than patients with a graft survival of 12 months: 64.4 (21.8–191.0); 87.7 (26.0–295.8) versus 39.6 (18.4–85.3); 56.8 (21.0–150.1) µg/ml;P<0.01. There was a positive correlation between CIC and serum creatinine in the post-transplant period (P<0.001). The histopathologic severity and morphological type of rejection did not correlate with CIC. In patients without rejection episodes CIC were significantly lower: 41.2 (39.6–42.9) than patients with rejection episodes: 61.8 (56.2–68.0);P<0.05.

Immune Complex-Associated Platelet Disorder in Renal Allograft Recipients

39 renal allograft recipients were selected on the basis of normal coagulation profiles and absence of detectable antiplatelet antibodies. Platelet aggregation to adenosine diphosphate was impaired in 10 patients and raised levels of immune complexes (IC) were present in 19 patients; between these two pathological parameters, a significant association could be found. Mean platelet serotonin content was significantly decreased in platelets of IC-positive patients compared to platelets of IC-negative patients or normal individuals. In vitro release of serotonin from normal platelets could be induced by addition of Raji cells which had been preincubated with IC-positive sera; this platelet defect may therefore represent an IC-induced functional abnormality.

No Malabsorption of Inorganic Ferrous Iron in Patients with Achylia gastrica

No Malabsorption of Inorganic Ferrous Iron in Patients with Achylia gastrica Celada et al. [1] recently described in this journal a considerable malabsorption of 59pe2+ for subjects with achylia gastrica. The authors have used the same test dose of 0.56 mg 59Fe2+ and the technique of whole body counting of absorbed 5βFe as proposed by us [7] but their results are in contradiction with published work from our [3-6] and another laboratory [8]. Neither normal gastric juice nor an intrinsic factor is required for the intestinal absorption of 59Fe2+ or hemoglobin-39Fe in humans [3-6]. Subjects with histamine-re-fractive achylia gastrica and absolute intrinsic factor deficiency (pernicious anemia in remission) absorbed 27 ± 15% [3, 5, 6] and subjects with a partial gastrectomy (Billroth I and II) 32 ± 15% [6], which was identical with the absorption of 31 ± 12% as observed for the 10 μrnoi (= 0.56 mg) sθpe2+ test dose m normal subjects [2-6]. Magnusson did confirm our results since he found no indications for iron malabsorption from the 0.56 mg 59Fe2+-dose in patients with Billroth ∏-partial gastrectomy or an-trectomy and gastroduodenostomy with or without vagotomy [8]. 59Fe2+ malabsorption (5.1 ± 3.3%) was observed only in patients with a total gastrectomy [6]. Hemoglobin 59Fe was even better absorbed (2-fold) by subjects with achylia gastrica and absolute intrinsic factor deficiency (15 ± 5.6% from a 5 mg hemoglobin-Fe dose versus 7.5 ± 2.4% in normal subjects) [3, 5], since the acidity of normal gastric juice does reduce the bioavailability of hemoglobin-iron probably by heme-polymeri-zation and precipitation [4]. A 3-fold reduction of intrinsically 59Fe-labeled meat-(and liver-)iτon bioavailability was, however, demonstrated for subjects with gastric mucosa atrophy or Billroth II partial gastrectomy [4] and confirmed with an extrinsically 59Fe-labeled test meal for subjects after antrectomy or partial gastrectomy [8]. This reduced bioavailability is however caused by, e.g., meat iron mal-digestion and not by malabsorption since it can be corrected by an in vitro peptic pre-digestion of the 59Fe-labeled pork [4]. The normal absorption of ferrous iron, the doubled hemiglobin-iron absorption and the considerable reduction of meatand liver-iron favour the assumption that dietary iron maldigestion rather than malabsorption causes the development of iron deficiency in patients with achylia gastrica or partial gastrectomy [4]. Patients with achylia gastrica No Malabsorption of Inorganic Ferrous Iron in Patients with Achylia gastrica 57 and iron deficiency anemia do absorb iron from therapeutic oral ferrous sulphate iron preparations like normal subjects and are not resistant to oral iron therapy and do not require parenteral iron. References Celada, A.; Rudolf, H.; Herreros, V., and Donath, A.: Inorganic iron absorption in subjects with iron deficiency anemia, achylia gastrica and alcoholic cirrhosis using a whole body counter. Acta haemat. 60: 182-192 (1978).