Sabine Ziemer

Intravenous administration of recombinant adenoviruses causes thrombocytopenia, anemia and erythroblastosis in rabbits

Recombinant adenoviruses are highly efficient gene transfer vehicles but their administration to mammals is accompanied by a strong inflammatory response. The present study reports additional side effects observed during adenoviral gene transfer studies in rabbits.

Intermittent high permeability hemofiltration in septic patients with acute renal failure

ObjectiveHigh permeability hemofiltration (HP-HF) is a new renal replacement modality designed to facilitate the elimination of cytokines in sepsis. Clinical safety data on this new procedure is still lacking. This study investigates the effects of HP-HF on the protein and coagulation status as well as on cardiovascular hemodynamics in patients with septic shock. In addition, the clearance capacity for interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) is analyzed.DesignProspective, single-center pilot trial.SettingUniversity hospital.PatientsSixteen patients with multiple organ failure (MOF) induced by septic shock were studied.InterventionPatients were treated by intermittent high permeability hemofiltration (iHP-HF; nominal cut-off point: 60xa0kilodaltons). Intermittent HP-HF was performed over 5xa0days for 12xa0h per day and alternated with conventional hemofiltration.Measurements and resultsIntermittent HP-HF proved to be a safe hemofiltration modality in regard to cardiovascular hemodynamics and its impact on the coagulation status. However, transmembrane protein loss occurred and cumulative 12-h protein loss was 7.60xa0g (IQR: 6.2–12.0). The filtration capacity for IL-6 was exceptionally high. The IL-6 sieving coefficient approximated 1 throughout the study period. The total plasma IL-6 burden, estimated by area under curve analysis, declined over time (p<0.001 vs baseline). The TNF-α elimination capacity was poor.ConclusionsHigh permeability hemofiltration is a new approach in the adjuvant therapy of sepsis that facilitates the elimination of cytokines. HP-HF alternating with conventional hemofiltration is well tolerated. Further studies are needed to analyze whether HP-HF is able to mitigate the course of sepsis.

Nutritional status as marker for disease activity and severity predicting mortality in patients with systemic sclerosis

Objective To assess and analyse nutritional status in patients with systemic sclerosis (SSc) and identify possible associations with clinical symptoms and its prognostic value. Methods Body mass index (BMI) and parameters of bioelectrical impedance analysis (BIA) were assessed in 124 patients with SSc and 295 healthy donors and matched for sex, age and BMI for comparisons. In patients with SSc, BMI and BIA values were compared with clinical symptoms in a cross-sectional study. In a prospective open analysis, survival and changes in the nutritional status and energy uptake induced by nutritional treatment were evaluated. Results Patients with SSc had reduced phase angle (PhA) values, body cell mass (BCM), percentages of cells, increased extracellular mass (ECM) and ECM/BCM values compared with healthy donors. Malnutrition was best reflected by the PhA values. Of the patients with SSc, 69 (55.7%) had malnutrition that was associated with severe disease and activity. As assessed by multivariate analysis, low predicted forced vital capacity and high N-terminal(NT)-proBNP values discriminated best between good and bad nutritional status. Among different clinical parameters, low PhA values were the best predictors for SSc-related mortality. BMI values were not related to disease symptoms or mortality. Fifty per cent of patients with SSc had a lower energy uptake related to their energy requirement, 19.8% related to their basal metabolism. Nutritional treatment improved the patients nutritional status. Conclusions In patients with SSc, malnutrition is common and not identified by BMI. BIA parameters reflect disease severity and provide best predictors for patient survival. Therefore, an assessment of nutritional status should be performed in patients with SSc.

Hirudin versus heparin for anticoagulation in continuous renal replacement therapy

Abstract Objective: To compare the efficacy and safety of hirudin and heparin for anticoagulation during continuous renal replacement therapy (CRRT) in critically ill patients. Design: Prospective, randomized controlled pilot study. Setting: Single centre; interdisciplinary intensive care unit at a university hospital. Patients: Seventeen patients receiving CRRT. Interventions: Patients were randomly allocated to two groups. Heparin group (nine patients): continuous administration of 250xa0IU/h heparin; dose was adjusted in 125xa0IU/h steps with a targeted activated clotting time (ACT) of 180–210xa0s. Hirudin group (eight patients): continuous infusion of 10xa0µg/kg/h hirudin, dose was adjusted in 2xa0µg/kg/h steps with a targeted ecarin clotting time (ECT) of 80–100xa0s. Observation time was 96xa0h. Measurements and main results: Measured filter run patency and haemofiltration efficacy did not significantly differ between the two groups. Three bleeding complications were observed in the hirudin group, none in the heparin group (P<0.01). At the onset of bleeding, which occurred 60 or more hours after the start of therapy, only one patient was still under continuous hirudin administration but levels were either in therapeutic range or below. Conclusions: Hirudin can be used efficiently for anticoagulation in CRRT. Late bleeding complications may have been caused by possible hirudin accumulation, but this was not evident from hirudin plasma and ECT levels. Since bleeding complications were observed only in the presence of documented coagulation disorders, not only adequate drug monitoring but also the plasmatic and cellular coagulation status of the patient should be taken into consideration for adjusting hirudin dosage.

Recombinant factor VIIa after aortic valve replacement in a patient with osteogenesis imperfecta

Abstract A 26-year-old man with osteogenesis imperfecta and severe aortic regurgitation was scheduled for aortic valve replacement. As previously described by other authors the operation was difficult owing to the friability and weakness of the tissues. Mean blood losses of 153 mL per hour during the first 7 postoperative hours were observed. Despite normal coagulation indicators the bleeding did not stop and recombinant factor VIIa was applied at 40 μg/kg. Bleeding was successfully stopped after this single application.

Bleeding after intermittent or continuous r-hirudin during CVVH

Objective: To demonstrate bleeding complications encountered in patients after cardiac surgery on continous venovenous haemofiltration (CVVH) treated with continuous versus intermittent r-hirudin for heparin-induced thrombocytopenia (HIT) type II.¶Design: Case description.¶Setting: Cardiothoracic intensive care unit at a university hospital.¶Patients: 5 consecutive patients with proven HIT type II on CVVH after major cardiac surgery.¶Interventions: Recombinant hirudin (r-hirudin) was given continuously at a dose of 0.01 mg/kg per h in three patients or in repeated bolus administration of 0.05 mg/kg in two patients.¶Measurements and results: Since the ecarin clotting time assay was not available at that time to monitor hirudin effects on coagulation, the activated partial thromboplastin time (normal range 26–38 s, target range 50–60 s) was used. The continuously treated patients suffered from major bleeding complications. Therefore, the regimen was changed to repeated bolus administration, reducing the incidence of bleeding complications probably due to a threefold diminished cumulative hirudin dose per day in comparison to continuous administration.¶Conclusions: If ecarin clotting time, the most suitable monitor for hirudin activation, is not available, we would prefer to give r-hirudin in repeated boluses to avoid major bleeding complications in cardiac surgery patients on CVVH.

Measurement and Reversal of Prophylactic and Therapeutic Peak Levels of Rivaroxaban An In Vitro Study

Background: Rivaroxaban (Xarelto, Bayer HealthCare, Leverkusen, Germany) is a new oral anticoagulant drug. Anticoagulants may cause bleeding, thereby requiring reliable monitoring and efficient therapy. We investigated thromboelastometry versus routine coagulation tests to measure prophylactic and therapeutic concentrations of rivaroxaban and their reversal with prothrombin complex concentrate (PCC) and activated recombinant factor VII (rFVIIa) in vitro. Methods: Rivaroxaban was solubilized, and PCC and rFVIIa were added in 2 concentrations to the rivaroxaban-spiked blood samples, and thromboelastometry and measurements were performed. Results: Rivaroxaban increased tissue factor–activated clotting time (CTExTEM) dose dependently. Activated partial prothrombin time (aPTT), prothrombin time ratio (PTR), and prothrombin time (PT) were changed significantly in both concentrations. Reversal with PCC in both dosages caused no significant change in the measured parameters. For prophylactic rivaroxaban dosage, rFVIIa changed the PT significantly but not CTExTEM, aPTT, and PTR. For therapeutic rivaroxaban dosage, the CTExTEM was significantly reduced. The other parameters remained unaffected. Conclusions: Thromboelastometry can detect rivaroxaban effects. In vitro rFVIIa seems highly effective for reversal in contrast to PCC.

Increased rate of factor V Leiden mutation in patients with cerebral venous thrombosis

We investigated the association between cerebral venous thrombosis and hereditary resistance to activated protein C (APC) in 12 consecutive German patients with non-fatal cerebral venous thrombosis and in 187 controls without a history of thrombotic disorder. Three patients (25%) had a mutation in the factor V Leiden gene against only one subject in the control group. This difference was significant (P< 0.05), with an odds ratio of 11.7 (1.5–87 ; 95% confidence interval). Two patients carrying the mutation had additional common risk factors for thrombosis, and 2 had a positive family history of thromboembolism. We conclude that inherited APC resistance by a mutation in factor V Leiden is an important risk factor in non-fatal cerebral venous thrombosis. We recommend testing for APC resistance and, if abnormal for factor V Leiden mutation in patients with cerebral venous thrombosis.

Hereditäre Thrombophilien bei ischämischem Schlaganfall und Sinusvenenthrombosen Diagnostik, Therapie und Meta-Analyse

ZusammenfassungHereditäre Thrombophilien sind eine heterogene Gruppe von erblichen Gerinnungsstörungen, die, selten als alleinige Ursache, in einer komplexen Interaktion mit erworbenen Risikofaktoren zu Thrombosen führen. Nach der Entdeckung von genetisch gut charakterisierten und häufigen Thrombophilien wie dem Faktor V-Leiden oder der Prothrombinmutation 20210GA wurden diese Mutationen in größeren Fallkontrollstudien auch bei Schlaganfall und zerebralen Sinus- und Venenthrombosen (SVT) untersucht. In unserer Meta-Analyse zeigt sich dabei, dass die heterozygote Faktor V-Leiden-Mutation die häufigste Gerinnungsstörung ist und für SVT (16,4% vs 4,9%; OR: 4,3; p<0,001) und weniger auch für arterielle Ischämien (5,9% vs 2,6%; OR: 1,6; p<0,001) ein schwacher, aber signifikanter Risikofaktor ist. Die Protrombinmutation 20210GA ist dagegen vermutlich nur für Sinusvenenthrombosen (12,1% vs 1,9%; OR: 5,8; p<0,001), nicht jedoch für Schlaganfälle (4,1% vs 3,3%; OR: 1,4; p=0,1) als eigenständiger Risikofaktor zu betrachten. Die homozygote Form der Methyltetrahydrofolatreduktase-Mutation (MTHFR C677T), einem homozysteinabbauendem Enzym, ist ein weiterer Risikofaktor für Schlaganfälle (16% vs 15%; OR: 1,5; p<0,001). Für die SVT liegen keine ausreichenden Daten vor. Ein Thrombophilie-Screening für APC-Resistenz und die Prothrombinmutation erscheint bei der SVT sinnvoll, beim arteriellen Schlaganfall sollte eine APC-Resistenz berücksichtigt werden. Weil kontrollierte Therapiestudien fehlen, muss die Therapie unter Berücksichtigung von genetischen und auslösenden Faktoren in enger Zusammenarbeit mit Hämostaseologen dem individuellen Thromboserisiko angepasst werden.SummaryHereditary thrombophilias are a heterogenous group of genetic coagulation disorders which, particularly in combination with acquired prothrombotic factors, induce a predisposition to thrombosis. After characterization of frequent thrombophilic syndromes like factor V-Leiden or the prothrombin 20210GA mutation, a number of case-control studies screened for the prevalence of these mutations in ischemic stroke and cerebral venous thrombosis (CVT). Our meta-analysis shows that factor V-Leiden and prothrombin are frequent and significantly associated with CVT (16.4% vs. 4.9% or 4.3, P<0.001, and 12.1% vs. 1.9% or 5.8, P<0.001). In ischemic stroke, only factor V-Leiden and not prothrombin is a weak but significant risk factor (5.9% vs. 2.6% or 1.6, P<0.001, and 4.1% vs. 3.3% or 1.4, P=0.1). The C677T homozygous point mutation in the MTHFR, a homocystein-degrading enzyme, was also associated with arterial stroke (16% vs. 15% or 1.5, P<0.001). For CVT, sufficient data are lacking. We therefore recommend screening for thrombophilia in CVT. In ischemic stroke, atrial premature complex (APC) resistance should be considered. As long as controlled studies are lacking, individual anticoagulant therapy must take hereditary and precipitating factors into account to assess potential thrombotic risk.

Influence of heparin and hirudin on endothelial binding of antithrombin in experimental thrombinemia.

ObjectiveDuring the last decade, experimental and clinical evidence has accumulated that antithrombin (AT) exerts anti-inflammatory effects when given in high doses. Meanwhile, AT substitution has been shown to significantly increase prostacyclin release. However, the link between endothelial AT binding and anti-inflammatory AT effects remains to be established in vivo, although heparin has been shown to counteract anti-inflammatory AT effects. We hypothesized that the administration of heparin in endotoxin-challenged rats would decrease endothelial AT binding and systemic prostacyclin concentrations. DesignProspective, randomized, controlled experimental in vivo study. SettingResearch laboratory of a university hospital. AnimalsFifty-six Wistar rats. InterventionsBaseline values of coagulation variables were measured in six animals. Forty of 50 Wistar rats in the study groups were given endotoxin (50 mg·kg−1 iv) and were treated with saline (group LPS), AT (15 units·kg−1·hr−1) (LPS+AT), AT and heparin (80 IU·kg−1·hr−1), or AT and hirudin (0.12 mg·kg−1 · hr−1); the other 10 received saline instead of endotoxin and were treated with AT alone. Before endotoxin application, a tracheostomy was performed, and venous and arterial catheters were inserted for blood sampling and infusion. MeasurementsIntravital endothelial AT binding was studied by using fluorescence isothiocyanate-marked antibodies during intravital microscopy of intestinal submucosal venules. Systemic prostacyclin, thrombin-AT complex, and fibrinogen concentrations were measured after 4 hrs. Intergroup differences were tested by Kruskal-Wallis analysis of variance on ranks. Main ResultsAT and AT + heparin were equally effective in inhibiting systemic procoagulant turnover as reflected by fibrinogen concentrations. Only the administration of AT + hirudin significantly prevented fibrinogen consumption (p < .05). In contrast with all other treatments, the administration of heparin significantly reduced intravital endothelial AT binding (p < .05). However, prostacyclin concentrations were similarly increased in all endotoxin-challenged study groups irrespective of the anticoagulatory treatment. ConclusionsThere is evidence that heparin in contrast with hirudin prevents AT from being bound to the endothelial cell surface in this experimental model. Under low-dose AT substitution, systemic prostacyclin concentrations do not depend on whether heparin or hirudin is used for thrombin inhibition. These results support the view that heparin may counteract anti-inflammatory AT effects by keeping AT away from its endothelial binding sites; however, the results question the view that decreased endothelial prostacyclin release is solely responsible.