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HISTORY AND CLINICAL FINDINGS A 56-year-old woman was admitted for replacement of a previously implanted right hip prosthesis which had become loose (no infection). She limped painfully on a shortened leg whose mobility was markedly impaired. At the site of the previous operation the pelvis was lower by about 2 cm; the scar looked well healed. INVESTIGATIONS Routine laboratory tests were normal except for moderately raised erythrocyte sedimentation rate (18/ 27 mm). There was complete loosening of the prosthesis on X-ray. TREATMENT AND COURSE Intraoperative bleeding from a branch of the inferior gluteal artery required blood transfusion and further erythrocyte infusions became necessary. Jaundice developed on the 4th postoperative day and 7 days later the direct Coombs test was positive with demonstrable agglutination. Free irregular erythrocytic anti-Kidd(a) (anti-jk[a]) antibodies were found in the serum. To counteract the delayed haemolytic transfusion reaction, exclusively jk(a)-negative erythrocytes were infused. The jaundice gradually disappeared and the bilirubin values became normal. CONCLUSION Jaundice and signs of haemolysis after erythrocyte transfusion may be due to delayed transfusion reaction and should be investigated with the direct Coombs test.

In five patients with von Willebrand's disease the haemostatic effect of heat-treated factor VIII concentrates was examined. For comparison, small-pool cryoprecipitate was used. All three preparations (Factor VIII-HT Hyland, Factor VIII HS Behringwerke, Kryobulin SP) were shown to improve abnormal laboratory findings, especially bleeding time, and at times even normalize them. It was possible to prevent bleedings during operative procedures, and effectively treat spontaneous bleedings. Factor VIII-HT and Factor VIII HS could be used in dosages comparable to cryoprecipitate (20-40 U/kg); in patients undergoing surgery a dose interval of eight hours is recommended. Two of four patients suffering of chronic liver disease had raised transaminase activities after receiving Factor VIII-HT. Although the risk of hepatitis cannot be conclusively assessed, the preparations used provide, owing to their good blood-clotting effect, an advance in the treatment and prevention of serious complications in patients with von Willebrand's disease.

Decreased retention in the retention test Homburg (RTH) indicates a loss of platelet function; increase is associated with an increased activation of platelets, for example, in patients with vascular diseases. Compared with other materials (e.g., collagen, glass pearls, etc.) the filter surface in the retention tubes is nonthrombogenic. Therefore, the RTH seems to be well suited for measuring an in vivo over-reactivity of platelets. In a pilot study using the RTH we evaluated the postoperative over-reactivity of platelets in 14 patients and observed a significant heterogeneity of the platelet population concerning size and stickiness. Reliable platelet function tests are also necessary for "drug monitoring," since they deliver important clinical laboratory parameters for efficient control of a therapy with antiplatelet drugs. Therefore, we evaluated in vitro how, after administration of platelet aggregation-inhibiting medications (such as acetylsalicylic acid, Prostaglandin and ReoPro in various concentrations, the adenosine diphosphate (ADP), collagen, ristocetin, or suprarenin increased retention can be reduced. The reaction of the platelets in platelet-rich plasma of different patients or donors to the addition of ADP is variable. The platelet function inhibitor effect is dose dependent. In a clinical pilot study, a significant platelet-inhibiting effect of clopidogrel using the RTH has been shown.

To diagnose von Willebrand disease (vWD) and to monitor drug efficacy, several tests have been established that are not, however, focused on the platelet adhesion properties of von Willebrand factor (vWF). The new platelet retention test Homburg (RTH) is characterized by a nonthrombogenic filter that retains platelets from blood when it is pressed through this filter. It was the aim of this study to examine the capability of this test to monitor the adhesive properties of vWF after its substitution in vWD or its release by desmopressin infusion. The RTH demonstrated a striking sensitivity for vWF after its release from endogenous storage sites or its supplementation in vivo as well as in vitro, whereas it did not detect an inhibition of platelet aggregability due to aspirin. Desmopressin infusions led to an immediate and highly significant increase of RTH platelet retention, followed by a gradual decline to initial values during the next 4 hours. The transfusion of a vWF concentrate also resulted in RTH data that demonstrated different kinetics than established parameters such as vWF:antigen, vWF:RiCoF, or the PFA-100 in vitro bleeding analysis. Additional in vitro experiments confirmed the correlation of RTH values with vWF concentrations. In conclusion, the RTH may be efficient to complement presently used measures to monitor vWD therapy with desmopressin or vWF concentrates.

ZusammenfassungDie Plättchenpfropfbildung wird durch den Prozess der Plättchenadhäsion eingeleitet, der hauptsächlich vom von-Willebrand-Faktor (VWF) vermittelt wird. Neben etablierten Parametern ist daher die Fähigkeit zur Plättchenadhäsion ein weiteres Kriterium zur VWF-Bestimmung, z. B. in der Diagnostik und Therapie der von-Willebrand-Krankheit. Der neue Plättchen-Retentionstest Homburg (RTH) soll helfen, diese Lücke zu schließen. Er ist charakterisiert durch seinen nicht thrombogenen Filter mit interkonnektierenden Poren, der die Plättchen aus dem Blut aufgrund der Scherkraft zurückhält, die beim Strömen durch den Filter entsteht. Der RTH erwies sich als sehr empfindlich zur Erfassung der plättchenadhäsiven Eigenschaft des VWF nach dessen Freisetzung aus endogenen Speichern durch Desmopressin oder VWF-Infusion bei Patienten mit von-Willebrand-Krankheit sowie bei entsprechenden In-vitro-Versuchen.

Patients in intensive care may be at high risk of in vivo platelet activation because comorbid conditions, such as infections, septicemia, shock, disseminated intravascular co agulation, and cancer represent procoagulant states. Hyperre activity of platelets with or without a decline of cell count may result in thromboembolic complications potentially associated with the phenomenon of heparin-induced thrombocytopenia. We analyzed the data of 10 patients highly suspected of having heparin-induced thrombocytopenia during their intensive care treatment of 29 plus or minus 22 days. In seven patients, throm bocytopenia coincided with thromboembolic complications. Six patients had additionally undergone fibrinolytic therapy before starting activated partial thromboplastin time-adapted alternative anticoagulation with r-hirudin. In three patients, the platelet count decreased without a clinical manifestation. of heparin-induced thrombocytopenia. R-Hirudin treatment moni tored by activated partial thromboplastin time and prothrombin time (PT) was effective and safe. The target value for activated partial thromboplastin time was a twofold prolongation. In four of five patients with deep venous thrombosis, a partial recana lization of the lower extremity could be achieved. Three pa tients with pulmonary embolism associated with deep venous thrombosis in two cases and in one additional case with an acute myocardial infarction did clinically profit from fibrino lysis with recombinant tissue plasminogen activator (rtPA) and r-hirudin treatment. Two lethal events probably caused by the underlying multimorbidity could not be prevented. No recur rence of thrombosis occurred, and there were no severe bleed ing complications attributed to r-hirudin treatment. Platelet counts were significantly reduced on day 9.4 plus or minus 6.4 of heparin administration in all cases (>50% decrease related to the initial values) from 224,000 plus or minus 126,000/μL to 96,000 plus or minus 61,000/μL, and increased during r- hirudin treatment to mean values of 224,000 plus or minus 126,000/μL. The heparin-induced platelet activation assay (HIPAA) assay was positive in 8/10 cases, whereas the PF4 enzyme-linked immunosorbent assay showed a positive result in four of eight analyzed cases. In four cases, the assays were concordantly positive. The PF4 enzyme-linked immunosorbent assay was not performed in two cases.

Summary Objective: In order to minimize bleeding complications, virus transmission, alloimmunization or graft-versus-host disease, a more restrictive

Inherited factor VII (FVII) deficiency is a rare autosomal recessive disorder. Mutations and polymorphisms of the FVII gene were characterized in more than 40 unrelated patients with FVII deficiency. Among the 29 different mutations, the most frequent were Ala294 Val, Ala294Val;404delC, IVS7+7, and Val281 Phe. Four novel mutations (IVS2+1G>C, Arg247 Cys, Glu265 Lys, Asp343 His) were detected. The relationships between genotypes of mutations and polymorphisms of the FVII gene, FVII deficiency, and clinical phenotype were investigated. Homozygosity of the Phe4 Leu, IVS4+1G>A, Cys135 Arg, Ala244 Val, and Ala294 Val;404delC and the double heterozygosity of Tyr68 Cys / IVS3-1G>A, Val252 Met / IVS2+5G>T, Val281 Phe / Cys135 Arg, Ala294 Val / Val281 Phe, Ala294 Val;404delC / Val281Phe, Ala294 Val;404delC / Arg152 stop, Ala294Val;404delC / Gln(-35) stop, Ala294 Val / Val252 Met, Ala294 Val / Gly156 Asp, and Thr359 Met / Asp242 His were related to clinical symptoms. Double heterozygotes for Arg247 Cys / IVS2+1G>C, Ala206 Thr / Pro303 Arg, Leu(-20) Pro / Val252 Met as well as IVS7+7 /Ala294 Val, IVS7+7 /Ala206 Thr, and IVS7+7 / Met298 Ile were asymptomatic. The clinical symptomatology is rather poor in correlation with the FVII activity. Concerning the clinical phanotype, a correlation seems to exist between specific mutations and clinical symptoms.

The innovative "Phoenix" database system of the Drug Commission of the German Medical Profession (AkdA) permits rapid access to data on adverse drug reactions. It enables the user to conduct searches covering a wide variety of questions within a short period of time. No one needs to be an "expert" to extract scientific knowledge from a database that currently already contains some 106,000 reports on adverse drug reactions. While our traditional apprenticeship model of physician training has served us well, an adaptation will be required for the new millennium. New tools are needed to allocate the available resources. Clinical proposals of experts or opinion leaders, guidelines, and highly graded clinical studies, like the use of clinical databases may help to improve safety and efficacy of drug administration. Evidence-based critical care medicine is therefore a potential tool for improving the effectiveness of drug therapy and for the patient's outcome. Over and above, the Phoenix database might be interpreted as an initiative instrument, which is easy to use and contributes to highlight the determinants of clinical decisions.

The antithrombotic potential of oral anticoagulants is undisputed as the frequency of recurrent thrombosis is high unless anticoagulant therapy is continued after hospital discharge. However, the relationship between potency and/or changes in anticoagulant therapy and frequency of complications remains unclear. Optimizing the clinical management of oral anticoagulation information obtained by databases may be advantageous in addition to meeting safety criteria, as described in the "Saarland Model." The Phoenix-database implicates an association between bleeding complications and the hypertensive elderly. From 1968 to 1993 most reports about cerebral/intraspinal bleedings occurred at prothrombin (PT)-values below 20% in the elder patients (>60 years of age) (12%; 367 reports). In the Saarland Model, 60 patients were followed from our department during a 3-year period. Our findings suggest neither a correlation of the range of PT values and the bleeding events nor an association with age or hypertension. It became obvious that "stable phases" of International Normalized Ratio (INR) [+/-15% change of 4 serial controls using nearly constant weekly oral anticoagulant dosages (+/-15%)] might be considered as a valid criterion of safety. At least the individual risk profile determines the patient's fate.

A key tenet in the criticism of medieval and early modern courts is: “Let him who desires to be righteous retire from the court” (Exeat Aula, qui vult esse pius). How Enea Silvio Piccolimini and Ulrich von Hutten perceived, criticized and justified courtly life, is the subject of this book.

A key tenet in the criticism of medieval and early modern courts is: “Let him who desires to be righteous retire from the court” (Exeat Aula, qui vult esse pius). How Enea Silvio Piccolimini and Ulrich von Hutten perceived, criticized and justified courtly life, is the subject of this book.

A randomized, double-blind multicenter trial was performed to compare the safety and efficacy of a new low-molecular-weight heparin (LMWH) (LU 47311, Clivarine) and standard unfractionated heparin for the prophylaxis of postoperative venous thromboembolism. Altogether 1351 patients scheduled to undergo abdominal surgery were included. Main outcome measures included the incidence of thromboembolic events (deep vein thrombosis, pulmonary embolism, or both) and bleeding complications, including wound hematoma. A total of 655 patients received 1750 anti-Xa IU of LMWH plus a placebo injection daily; 677 patients received 5000 IU of unfractionated heparin (UFH) twice a day. Both drugs were found to be equally effective, as 4.7% of patients in the LMWH group and 4.3% in the UFH group developed postoperative thromboembolic complications. However, the incidence of bleeding complications was significantly reduced in the LMWH group: 55 (8.3%) patients in the LMWH group and 80 (11.8%) in the UFH group developed bleeding complications, a relative risk (RR) of 0.70 (95% CI 0.51-0.97;p = 0.03); wound hematoma occurred in 29 (4.4%) of the LMWH group compared with 55 (7.7%) in those in the UFH group for an RR of 0.57 (95% CI 0.37-0.88;p = 0.01). This study confirmed that a very low dose of 1750 anti-Xa IU daily of this new LMWH is as effective as 10,000 IU of UFH for preventing postoperative deep vein thrombosis. At this dose its administration is associated with a significant reduction in the risk of bleeding including wound hematoma.

Hydroxyethyl starch (HES) is often used for volume therapy. Since bleeding complications have been reported repeatedly, a strict dose limitation of a maximum of 1,500 ml 6% solution per day is recommended. However, many indications require higher dosages. Bleeding complications are known to be caused by an acquired von Willebrand syndrome. It has been shown that the accumulation of large molecules and their impairment in the coagulation system can be avoided by using HES preparations with a low in vivo molecular weight. However, the effects of a high-dose therapy have not been studied yet. We have investigated, how a 4-day high-dose therapy, using 3,000 ml 6% HES 70/0.5 on the 1st day and 1,500 ml on days 2-4, affects the coagulation system and hemorheological parameters of acute stroke patients. Thromboplastin time, activated partial thromboplastin time and thrombin time showed no significant changes, except for a slight, clinically irrelevant change due to dilution. The subunits of von Willebrand factor VIII showed no significant change. Hematocrit decreased from 42.3 ± 4.6 to 37.4 ± 3.9% (p < 0.05) after day 1, reaching 35.3 ± 4.2% (p < 0.01) at the end of the therapy, demonstrating a substantial volume effect. Plasmaviscosity and erythrocyte aggregation decreased slightly, however not significantly. Our study shows that even a high-dose therapy with 6% HES 70/0.5 has no influence on the coagulation system.

Objective: Fibronectin (Fn) plays an important part in unspecific defense mechanisms because of its ability to mediate the binding of foreign-body particles, bacteria, collagen, and other macromolecules to phagocytising cells of the reticulo-endothe-lial system (RES). The aim of the present study was to examine the effect of a 10-day hemodilution therapy on Fn concentration in humans. Design: The patients were randomized and treated with either 10% hydroxyethyl starch (HES) 200/0,62 or 6% HES 200/0,62. Setting: Neurology department of an university clinic. Patients: We examined 12 patients with cerebrovascular perfusion disturbances. Interventions: The Fn concentration was determined using simple radial immunodif-fusion. Results: The Fn concentration dropped significantly in all 12 patients (p < 0.01) in a dose-dependent manner beyond the dilution effect. 10% HES 200/0,62 caused a Fn decrease from 26.6 ± 9.2 to 10.0 ± 2.2 mg/dl (-62.2%), 6% HES reduced Fn from 25.5 ± 9.9 to 15.0 ± 3.2 mg/dl (-41.1%). In one patient there was a continuous decrease of Fn from 41.0 down to only 6.4 mg/dl. Conclusion: According to the results of animal experiments, the decrease of Fn seems to indicate depression of the RES. Besides its defense function, Fn probably plays a role in embryogenesis, wound healing, and blood clotting. Therefore, we assume that the drug-induced reduction of Fn possibly has clinical relevance.

ZusammenfassungDie beiden wichtigsten Maßnahmen, um den Einsatz von Blutkomponenten zu minimieren, sind eine gute intraoperative Blutstillung und eine restriktive Indikationsstellung vor der Transfusion. Die gesicherten Indikationen zur Anwendung von Erythrozytenkonzentraten, Thrombozytenkonzentraten und gefrorenem Frischplasma (GFP) werden vorgestellt. Zur Zeit werden in der Bundesrepublik Deutschland 3,7 Mio. Einheiten Erythrozytenkonzentrate, 250 000 Thrombozytenhochkonzentrate und fast 200 000 Liter GFP pro Jahr verbraucht (7). Für die Herstellung von Gerinnungsfaktorenkonzentraten werden weitere 1,6 Mio. Liter GFP benötigt. Hierzu sind jährlich ungefähr 5 Mio. Spenden notwendig. Diese Spenden werden von zirka 2 Mio. Spendern aufgebracht, also 2,5% der Bevölkerung der Bundesrepublik Deutschland (im internationalen Vergleich eine Spitzenstellung). Eine effektive Maßnahme, Fremdblut einzusparen, ist die Gewinnung von Eigenblut vor elektiven Eingriffen. Peri- und intraoperativ kann durch die isovolämische Hämodilution oder die Retransfusion von Wundblut mit Hilfe von »cell savern« der Einsatz von Fremdblut reduziert werden. In dieser Arbeit werden auch neue Strategien zur präoperativen Eigenblutgewinnung vorgestellt.

ZusammenfassungIn klinischen Studien ist die Wirksamkeit der Prophylaxe mit Heparin zur Verhütung von Venenthrombosen und Lungenembolien im Verlauf der letzten 20 Jahre statistisch überzeugend gesichert worden. Die Ergebnisse klinischer Studien dürfen allerdings nicht als Endresultat klinischer Forschung angesehen werden. Die Resultate einer randomisierten klinischen Studie lassen zunächst im Sinne eines Basiswertes die Nutzen-Risiko-Relation eines Medikamentes erkennen. In klinischen Studien werden spezielle Patientenkollektive geprüft, die Ergebnisse lassen sich daher häufig nicht unmittelbar in Indikation und Kontraindikation auf einen individuellen Patienten übertragen. Für den praktizierenden Kliniker ist es notwendig, diese Entscheidungshilfen der zugängigen Standardliteratur zu entnehmen. Es wird dargelegt, wie wenig informativ Indikationen und Kontraindikationen zur Heparinprophylaxe in Fachinformationen und Roter Liste, speziell unter dem Gesichtspunkt der Risikosituation des Patienten, dargelegt werden. Konsensus-Konferenzen und Empfehlungen von ärztlichen Experten sind notwendig, um in der Praxis die Resultate klinischer Studien auf individuelle Patienten und Risiko-Nutzen-Überlegungen zu übertragen. Endziel ist es, die Ergebnisse klinischer Studien bei der antithrombotischen Therapie so umzusetzen, daß die Sicherheit erhöht wird, ohne daß die Wirksamkeit vermindert wird.

The aim of this double blind placebo controlled crossover study is to show that apart from decreasing blood pressure felodipine improves microcirculation. 30 patients with essential hypertension and manifest microangiopathy were included. No patients dropped out on account of side effects although these occunocd in the expected frequencies. The study phases each extended for a week (10 mg/d felodipine or locspectively a placebo). Blood pressure, blood and serum values, nail fold capillary circulation and oxygen partial pressure in muscle welOC measUlocd. The blood pressure in the placebo phase remained constant. The increase of erythrocyte velocity in cutaneous capillaries and oxygen partial pressure in muscle and the decrease of poorly supplied muscle areas caused by felodipine relevantly improved the microcirculation of skin and muscle by 50% and 30%. The vasomotor reserve increased by 50% owing to an antispastic effect of the substance. A rheological effect was observed in the form of a decrease in plasma viscosity. Felodipine significantly and loclevantly decreased by 10% the systolic and diastolic blood pressures. Apart from decreasing blood pressure Felodipine causes a relevant and significant global improvement of microcirculation in skin and skeletal muscle tissue.

Objective: Since plateletpheresis is being used increasingly, it is important to regard quality control to check health risks for donors and to exclude these. Design: Controlled randomised prospective open comparative study. Setting: Department of Transfusion Medicine of a University Clinic. Participants: 112 platelet donors were examined. Interventions: Prior to and after plateletpheresis platelet reactivity was determined. The platelet concentrates in the two groups of 56 donors each were produced using either the cell separator ‘CS-3000’ and the collecting chamber PLT 30TM with the OmnixTM system (group I) or the cell separator ‘AS-104’ (group II). Results: In group I five donors showed a pathologically increased platelet reactivity (p = 0.1297) after plateletpheresis. In group II there were 10 donors with a pathologically increased platelet reactivity (p = 0.0046) after plateletpheresis. The mean concentration of platelets was reduced by separation using the CS-3000 Omnix from 238 ± 49 · 103/µl to 172 ± 32 · 103/µl (68 ± 27 · 103/µl) and from 243 ± 53 · 103/µl to 180+31 · 103/µl (63 ± 33 · 103/µl) using the AS-104. In the first case the platelet yield was 3.9 1011 platelets/concentrate, in the latter case it was 2.9 · 1011 platelets/concentrate. The ‘CS-3000 Omnix’ is significantly more effective in separating (58.4 ± 15.5%) than the ‘AS-104’ with 44.2 ± 7.2% (p < 0.0001). Conclusions: Since both donor groups were comparable regarding all factors recorded – especially the cardiovascular risk factors – the separation process could be responsible for the different traumatisation of platelets.

Ziel: Zur Verhütung einer Gefährdung der Gesundheit von Mensch und Tier bei Anwendung von Arzneimitteln fordert der Gesetzgeber im Arzneimittelgesetz die zentrale Erfassung und Auswertung von Arzneimittelrisiken, insbesondere von Nebenwirkungen und Wechselwirkungen mit anderen Mitteln. Bereits seit 1988 müssen die pharmazeutischen Unternehmen einen qualifizierten Stufenplanbeauftragten benennen, der für die Erfüllung der Anzeigepflichten von Arzneimittelrisiken verantwort-lich ist und gemäβ einem internen Maβnahmenplan («Stufenplan») geeignete Maβ-nahmen bei Auftreten von Beanstandungen ergreifen muβ. Quellen und Auswahlkriterien: Grundlagen dieser Übersicht sind die gesetzlichen Bestimmungen, insbesondere das Arzneimittelgesetz und ergänzende Vorschriften, die die Pflichten des Stufenplanbeauftragten präzisieren. Ergebnisse: Blutkomponenten unterliegen ohne Einschränkung den Vorschriften für Arzneimittel, so daβ die entsprechenden Richtlinien für transfusionsmedizinische Einrichtungen unverändert zur Anwendung kommen. In diesem Artikel werden die geltenden Vorschriften zusammengefaβt. Am Beispiel einer transfusionsmedizinischen Abteilung an einer Universitätsklinik wird die praktische Umsetzung dar-gestellt. Schluβfolgerungen: Im Zusammenhang mit der Übertragung viraler Infektions-krankheiten hat sich in den letzten Jahren mehrfach gezeigt, wie wichtig die Funk-tion des Stufenplanbeauftragten für die Ergreifung effektiver Maβnahmen beim Auftreten von schwerwiegenden Nebenwirkungen ist. Durch die in den transfusions-medizinischen Einrichtungen erfolgte Umsetzung der entsprechenden gesetzlichen Bestimmungen konnte die Arzneimittelsicherheit von Blutkomponenten entschei-dend verbessert werden.

SummaryThe plasma clearance of hydroxyethyl starch (HES) depends on the initial molecular weight and the degree of substitution. So far, little attention has been paid to the clinical relevance of the C2/C6 substitution ratio of hydroxyethyl starch.10 patients with cerebrovascular circulatory disturbance received hemodilution therapy for 10 days, consisting of 10% HES 200/0.5 (mean molecular weight 200 kD, degree of substitution 0.5) with a C2/C6 ratio of 13.4. A second group of 10 patients received a starch solution with identical initial molecular weight and degree of substitution but with a C2/C6 ratio of 5.7.After the administration of a single dose, no significant differences between the two groups were observed. After repeated administration, significant differences could be detected in hemorheology, coagulation and elimination (pThe higher C2/C6 ratio of HES 200/0.5/13.4 slows down enzymatic degradation. After repeated administration of this starch, large molecules accumulate which are inefficiently degraded. The same effect has been observed after therapy with highly-substituted HES. This accumulation of large molecules leads to a beneficial longer lasting volume effect. The disadvantages include an increase in plasma viscosity and coagulation disturbances, which cannot be explained with the respective dilution effect alone. For these reasons, the C2/C6 ratio is of clinical relevance and should be included in the product labeling in the future.

Crosslinking of fibrin monomers by activated factor XIII (F XIIIa) is a final event in blood coagulation. So the fibrin clot gains mechanical stability and resistance to plasmin degradation which is thought to be essential for normal blood clotting and wound healing (1-3). In addition, changes in plasma F XIII activity were found in several state of disease such as collagenoses, inflammatory bowel diseases, leukemias, subarachnoidal bleeding and delayed fracture healing (4-12). Because approximately 50% of the potential F XIII activity in plasma are present in platelets (1), the additional determination of F XIII activity in platelets is of clinical interest especially concerning platelet transfusions that may exert an additional benefit due to simultaneous substitution of platelet-bound F XIII. The latter differs from plasma F XIII as a dimer containing only a-chains (a2) compared to the plasmatic tetramer carrying additional b-chains (a2b2). We applied a recently described photometric assay suitable for the routine laboratory after adaption to an autoanalyser to determine F XIII activity in plasma and platelets of 64 healthy blood donors.

Ziel: Prüfung des Einflusses des C2/C6-Besetzungsverhältnisses und des Substitutionsgrades von zwei 6%igen Hydroxyäthylstärke-(HES-)Lösungen auf die Eliminationskinetik und die Fluidität des Blutes. Design: Einfach-blinde prospektive randomisierte Cross-over-Studie. Rahmen: Hämostaseologisch-angiologische Ambulanz der Universitätsklinik Homburg. Teilnehmer: 6 freiwillige, klinisch unauffällige Probanden. Interventionen: Es wurde jeweils eine Infusion von 500 ml zweier verschiedener HES-Lösungen (6% HES 200/0,5 bzw. 6% HES 200/0,62) intravenös innerhalb von einer Stunde verabreicht. Zwischen den beiden Infusionen wurde eine Auswasch-phase von 3 Monaten eingehalten. Gemessen wurden Konzentration und Moleku-largewichtsverteilung der intravasalen HES-Moleküle bis zu 24 h nach Infusion so-wie die Fluidität des Blutes vor und nach Infusion. Ergebnisse: Neben der molaren Substitution (MS), die für die beiden eingesetzten HES-Lösungen unterschiedlich ist, beeinflußt das Besetzungsverhältnis der C2- bzw. C6-Atome (C2/C6-Besetzungsverhältnis) am Glukosering den Abbau der HES-Moleküle. Die entstehenden Degradationsprodukte haben bei hohem C2/C6-Beset-zungsverhältnis und hoher MS ein im Mittel höheres Molekulargewicht. Dies beeinflußt die Fließfähigkeit des Blutes. Während die Hämatokritabnahme eine Stunde nach Infusionsende vergleichbar ist, bleibt die Hämatokriterniedrigung bei hohem C2/C6-Besetzungsverhältnis und hoher MS länger erhalten. Der Plasmaviskositäts-anstieg ist bei hohem C2/C6-Besetzungsverhältnis und hoher MS starker ausgeprägt. Schlußfolgerungen: Die Infusion von HES 200/0,62 führt zu einer wesentlich längeren Verweildauer im Vergleich zu HES 200/0,5, verbunden mit deutlich größeren Degradationsprodukten im Plasma, was einen stärkeren Verdünnungseffekt, aber auch einen stärkeren Anstieg der Plasmaviskosität bis zu 24 h nach Infusionsende bewirkt. Bei der Hämodilutionsbehandlung von Patienten mit arterieller Verschlußkrankheit wird der Einsatz von HES, die einen Plasmaviskositätsanstieg induziert, eher als unwillkommen diskutiert.

Ziel: Ziel der Studie ist die Erprobung und Qualitätssicherung einer speziellen Bocksprungtechnik als fremdblutsparende Maßnahme. Design: An 40 von 100 Patienten mit koronarer Herzkrankheit wurde vor einer aortokoronaren Bypassoperation in einer randomisierten doppelblinden placebokontrollierten Studie Eigenblut in «Bocksprung-Technik» gesammelt. Innerhalb von 8 Wochen wurde jeweils die Gewinnung von 3-4 Erythrozytenkonzentraten und 0,9-1,2 Liter Plasma vorgenommen. Das substituierte Volumen (Verum: HES 200/0,5 10%, Placebo: 0,9% NaCl) entsprach dem Volumen des entnommenen Blutes. Jeder Patient erhielt täglich 200 mg Fe2+ oral. Ergebnisse: Klinisch profitierten nur die mit HES behandelten Patienten in der Phase der Eigenblutgewinnung signifikant. Zwei Patienten zeigten unerwünschte Begleiterscheinungen. Der peri- und postoperative Verlauf war vergleichbar. Nur in der NaCl-Gruppe erhielt ein Patient homologe Erythrozytenkonzentrate. Kein Patient starb pr-ä, perioder postoperativ. Schlußfolgerungen: Von den kardiochirurgischen Patienten kamen nur 40% für eine Eigenblutspende in Frage; für diese scheint die isovolämische Hämodilution mit HES 200/0,5 10% eine geeignete und sichere Form der präoperativen Blutgewinnung zu sein. Eine körperliche Belastung sollte vor und nach jeder Eigenblutspende durchgeführt werden. Bei verschlechterter Belastbarkeit sollten keine weiteren Eigenblutspenden vorgenommen werden.

ZusammenfassungEs werden die Wirkungen von Knoblauch auf Theologische und hämostaseologische Variablen, Lipide und den Blutdruck sowohl aus eigenen Untersuchungen als auch aus der Literatur zusammengestellt. Erste deutlich dosisabhängige Effekte werden nach Einmaldosen von 300 mg bzw. Tagesdosen von 600 mg gefunden. Der maximale Wirkzeitpunkt liegt zwischen 4 und 6 Stunden nach der Einnahme. Knoblauch reduziert die spontane und die induzierte Thrombozytenaggregation, die Plasmaviskosität, den Hämatokritwert und läßt die fibrinolytische Aktivität, den Durchmesser präkapillärer Arteriolen und die Mikrozirkulation ansteigen. Eine signifikante lipidsenkende Wirkung ist bislang in kontrollierten klinischen Studien mit 423 Patienten belegt. Milde Blutdrucksenkungen sind in mehreren Untersuchungen beobachtet worden. Bei einer täglichen Dosis von 900 mg treten bei bis zu 25% der Patienten knoblauchbedingt Geruchsbelästigungen auf. Darüber hinaus werden von 5% der Patienten gastrointestinale Beschwerden, bei starker Überdosierung Blutdruckabfälle (in seltenen Fällen bis zum Kollaps) angegeben. Ein Wirksamkeitsnachweis im Sinne einer Antiatherosklerosewirkung liegt bisher nicht vor, eine Gehstrekkensteigerung konnte für die periphere arterielle Verschlußkrankheit in einer Pilotuntersuchung gezeigt werden.

+: Pentapharm Ltd., 4002 Basel, Switzerland (Received 31.1.1992; accepted 21.7.1992) In this study adhesivity of leucocytes, neutrophil granulocytes and lymphocytes was compared using 3 different anticoagulants (Li-Heparin, Hirudin, EDTA) in a filtration test. Samples of 10 apparently healthy subjects were used. The filtration rate of leucocytes depends significantly on the anticoagulant (p=O.001). Neutrophil granulocytes, in particular, show a strong adhesivity after use of hirudin. After filtration none of the 10 samples contained neutrophils. After heparin neutrophils were found in 2 samples, and after EDTA in 6 samples. Lymphocytes could be demonstrated in 2 of the heparin samples, in 2 of the hirudin samples, and in 8 of the EDTA samples. The results show that the choice of an anticoagulant has an essential influence on leucocyte adhesivity. In future it has to be found out which anticoagulant ressembles the most the in-vivo conditions.

According to their code of professional conduct, German physicians are obliged to report suspected cases of adverse drug reactions (ADRs) to the Drug Commission of the German Medical Association (AkdA). On the basis of an agreement between the German Medical Association and the Federal Institute for Drugs and Medical Devices (BfArM) a common pharmacovigilance database within the German spontaneous reporting system was created. A user-friendly application program developed in-house enables the user to conduct searches about reported ADRs covering a wide variety of questions within a short period of time. ADRs caused by anticoagulants and by antiplatelet drugs still belong to the most reported adverse events. The most frequently reported suspected drugs are heparins, followed by ticlopidine, phenprocoumon, acetylsalicylic acid, and clopidogrel. Bleeding complications are the most often described ADR symptoms of any anticoagulation therapy, especially of phenprocoumon and acetylsalicylic acid. Another serious ADR is heparin-induced thrombocytopenia or changes in blood counts (CBC) due to ticlopidine and clopidogrel. During the past few years a reduction in severe reactions, such as cerebral hemorrhage, especially with fatal outcome was detectable because of better clinical management of oral anticoagulant therapy and of adverse events concerning heparin.

Adhesion and aggregation are important parameters characterizing the function of intact platelets in flowing blood and in contact with a more or less thrombogenic surface. In the retention test Homburg (RTH), platelets are exposed to a standardized textured surface (Sysmex retention tubes) under defined conditions of flow. Platelet counts are performed before and after the Sysmex retention tube passage. The difference between these values indicates the percentage of retained platelets (retention index). Decreased retention in the RTH indicates a loss of function or defective platelet function; increase is associated with an increased activation of platelets, for example, in patients with vascular diseases. For further evaluation of the retention phenomenon the filters were fixed after cell passage and examined by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). SEM and TEM micrographs show activated platelets adhering and spreading on the filter surface, comparable with platelets on a disturbed endothelium. Also, we examined the influence of different G forces and centrifugation times on the retention behavior of the platelets in citrated platelet-rich plasma (PRP) and whole blood (WB). G forces influenced the retention index in PRP and WB significantly and in a different way. Finally, we used a platelet standard, as customary in the quality check, to determine the serial as well as the day-to-day precision.

Sodium pentosanpolysulfate (Fibrezym) and unfractionated heparin (Liquemin) had significant antithrombotic efficacy in rats. 1 mg/kg body weight (BW) FibrezymR had its maximal effect 2-4 hours after subcutaneous administration; 200 U/kg BW LiqueminR s.c. were most effective 4-6 hours after application. Both drugs caused frequent embolic break-offs of thrombi during the time periods of maximal antithrombotic efficiency.

The pharmacokinetics of urokinase (two-chain urokinase-type plasminogen activator, tcu-PA) and single-chain urokinase-type plasminogen activator (scu-PA) were studied in 20 patients with acute myocardial infarction (AMI). Ten consecutive patients received 2.5 million units tcu-PA by bolus injection within 5 min during the first 6 h after AMI (group I). Ten further consecutive patients received 250,000 U tcu-PA within 5 min, followed by 4.5 million U scu-PA by intravenous infusion over 40 min (group II). An enzyme immunoassay was developed for urokinase antigen determinations, and a fibrin plate assay for determinations of fibrinolytic activity was applied. Using a 3-compartment model, in group I 98% of urokinase antigen were cleared with a half-life of 60.8 min. After scu-PA, urokinase antigen was cleared with half-lives (area under the curve in parentheses) of 6.9 min (74.8%), 26.5 min (23.6%), and 329.7 min (2.2%). The half-disappearance times of fibrinolytic activity were 18 and 8 min in group I and II, respectively. A more pronounced decrease of plasminogen was observed after tcu-PA.

The influence of additional hirudin in low doses on platelet and coagulation parameters was studied in platelet concentrates (PC) prepared by cytapheresis using citrate-dextrose solution formula A. The in vitro release of platelet factor 4 and β-thromboglobulin was markedly lowered and morphological platelet alterations, as assessed by platelet size studies were considerably less accentuated in the presence of hirudin over a 5-day storage period; this suggests a possibly protecting effect on platelet function. No clear activation of the coagulation and fibrinolysis system was evident during PC storage with and without hirudin since thrombin-antithrombin III complexes and D-dimers did not markedly change.

The potency and tests for thrombogenicity were studied prospectively in 7 different (two lots of each brand, A - G) prothrombin complex concentrates (PCC). Human albumine (H) and a factor IX concentrate (I), served as controls. The potency of coagulation factors and inhibitors varied considerably. Two brands (E, F) contained no protein S, additionally one brand contained no protein C. Two preparations exhibited high amidolytic activities, especially towards the thrombin-sensitive chromogenic substrate S-2238, in vitro. These activities could be quenched in part by the addition of hirudin or antithrombin III. The heparin and antithrombin III content of the PCCs was significantly different, and, after addition of antithrombin III an increase of thrombin-antithrombin III complexes in 2 preparations (B, D) was observed in vitro. Additionally, three brands (B, D, F) caused more severe cardio-pulmonary reactions in rabbits, associated with an increase of fibrin split products for brands B and D. We conclude that the use of these preparations in patients, in whom an acquired protein C or S defect, or a hypercoagulable state, can be suspected, cannot be recommended.

The basic therapy of peripheral arterial occlusive disease stage IIb, according to Fontaine, is exercise. It should be determined whether a mild hypervolaemic haemodilution with hydroxyethyl starch or Ringer lactate can produce a further increase in walking distance. For this purpose, three groups of 25 patients each were formed. One group exercised three times weekly and the second group, in addition to exercise, underwent a mild hypervolaemic to isovolaemic dilution therapy with HES for a period of 6 weeks. In the final group the haematocrit was reduced to the same extent by venesections and volume substitution using Ringer lactate. The walking distance in the HES group increased from 216 m to 311 m (44%), in the Ringer lactate group from 214 m to 258 m (20%), and in the exercise group from 213 m to 242 m (14%). On comparison of the groups, the increase in pain-free walking distance in the HES group differs significantly (P less than 0.05) from that achieved in the other groups. It was demonstrated that haemodilution with HES in combination with exercise brings about a clinical effect three times that achieved by exercise alone. Venesection with subsequent administration of Ringer lactate and exercise is superior to exercise alone but markedly inferior to the combination therapy with HES.