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ZusammenfassungVor allen operativen oder anderen invasiven Eingriffen, die mit gefährlichen Blutungen einhergehen können, muss eine hämorrhagische Diathese anamnestisch, ggf. anhand der klinischen Symptomatik und laboranalytisch ausgeschlossen werden. Auf keine dieser Maßnahmen kann verzichtet werden. Die Blutungsanamnese wird mit einem standardisierten Fragebogen unter Verwendung eines Scores und unter ärztlicher Anleitung erhoben. Falsch positive und falsch negative Blutungsanamnesen kommen häufig vor. Das laboranalytische Minimalprogramm besteht aus Thrombozytenzahl, aktivierter partieller Thrombo plastinzeit (aPTT) und Quick-Wert in % der Norm. Eine Ergänzung durch die Bestimmung des Fibrinogens ist sinnvoll. Ein zuverlässiges Screening für häufige Thrombozytopathien und das von-Willebrand-Syndrom steht nicht zur Verfügung. Ergeben Anamnese oder Symptomatik oder Labor-Screening den Verdacht auf eine hämorrhagische Diathese, muss eine präoperative Abklärung in einem hämo staseologischen Labor erfolgen.

A randomized and controlled study was undertaken to test whether substitution with factor XIII concentrates influences the clinical course in patients with acute leukaemia and acquired factor XIII deficiency (less than or equal to 60%). A control group of 31 patients was compared with a factor XIII-treated group of 29 patients. Partial factor XIII deficiency was successfully corrected by substitution. On the other hand, there was no statistically significant difference between the two patient groups in the frequency and severity of bleeding complications, transfusion requirements, and the number of remissions. Undesirable side-effects as a result of substitution treatment were not observed.

During postoperative prophylaxis of thrombosis using subcutaneous low-dose heparin thrombocytopenia and consumption coagulopathy without manifest haemorrhage were observed in a female patient with gynaecologic problems on the tenth postoperative day. Using gel-electrophoresis, demonstration of cross-linked fibrin derivatives, which occur only after contact with thrombin, was proof that disseminated intravascular coagulation must have been present. Cancellation of heparin prophylaxis was sufficient for regression of the haemostatic disorder. Platelet function tests performed two months later showed as the only reproducible abnormality that the patient's plasma caused inhibition of desaggregation of normal platelets only when heparin was present. The remarkably close chronologic connection of heparin prophylaxis with thrombocytopenia and consumption coagulopathy suggests a possible causal connection. However, at present the possibly heterogeneous aetiology cannot be explained satisfactorily.

HISTORY An 80-year-old woman had been hospitalized in a psychiatric clinic where, on the 22nd day, she sustained a fracture of the neck of the left femur, which was treated by internal screw fixation. The postoperative course was at first without complication. But 9 days postoperatively her platelet count had fallen to 59,000/microliter. As heparin induced type II thrombocytopenia (HIT II) was suspected, the thrombosis prophylaxis with low-molecular heparin was replaced by sodium danaparoid (twice 750 units subcutaneously). Despite this, ischaemia of the right lower leg developed and required amputation. On the following day the left lower leg and foot also became ischemic, where upon she was admitted to the author's hospital (37 days after her admission to the psychiatric clinic). ADMISSION FINDINGS The patient was in a reduced general condition (body-mass index 19.5 kg/m2). She was disoriented as to place and time. Her blood pressure was 140/80 mmHg, her pulse irregular with a ventricular rate of 100/min. The skin below the middle of the left lower leg was cold and livid and the pedal pulses were not palpable. LABORATORY TESTS Haemoglobin content was 9.7 g/dl, the white cell count 9,200/microliter, and platelet count 54,000/microliter. Electrolytes and creatinine were within normal limits. TREATMENT AND COURSE Thrombendarterectomy was performed once via the left groin under danaparoid anticoagulation. There was no re-occlusion and the patient was able to walk again.--It was ascertained subsequently, she had already been given ordinary heparin in the psychiatric clinic for 20 days. Her platelet count of around 70,000/microliter returned to normal even though heparin administration was continued. CONCLUSION A reduction in platelet count by more than half during heparin treatment suggests heparin-induced thrombocytopenia, in which case heparin should be discontinued at once. In high-risk patients adequate treatment should be initiated with other anticoagulants even before the occurrence of thromboembolism.

Argatroban is a direct, selective and reversible active site thrombin inhibitor derived from L-arginine. It is a representative of a new class of antithrombotic drugs which offer inhibition of clot-bound as well as fluid-phase thrombin. Argatroban is characterised by favourable pharmacokinetics (beta-elimination half-time approximately 40-50 min) undergoing hepatic metabolism and mainly biliary excretion. Renal impairment will not result in altered or delayed elimination. For many years, argatroban has been used in Japan and in the United States and is approved by the FDA for anticoagulation in patients with heparin-induced thrombocytopenia (HIT type II). The ease of monitoring with the activated partial thromboplastin time, lack of induction of antibodies and adequate safety in renal failure patients, make this drug a favourable mode therapy in comparison with other anticoagulants such as lepirudin or heparinoids. Since June 2005 argatroban has been approved in Germany for the treatment of patients with HIT type II. The main characteristics of the drug with special considerations for anaesthesiologists and intensive care physicians are presented in this review.

Melagatran is a direct inhibitor of thrombin and-like its oral prodrug ximelagatran-a newly developed dipetide with high antithrombotic efficacy. They present a linear dose-response, a short plasma half-life and the therapeutic range may be advantageous compared with classic anticoagulants such as heparins or vitamin K antagonists. The results of clinical studies for prevention and treatment of thromboembolic complications are encouraging. The use of melagatran and ximelagatran will gain significance in the perioperative management, thus being of particular importance for anaesthesiology and critical care medicine in the near future.

Purpose: To investigate the influence of two non-ionic radiographic contrast media with different osmolality on thrombocytic function and the plasmatic coagulation system. Material and Methods: The study was carried out as a randomised, prospective, comparative study with two contrast media in a heart catheter laboratory. Results: Activating influences on platelet aggregation, procoagulatory or profibrinolytic functions or injury to the endothelium could be ruled out. Apparently, also differences in substance properties, such as the media's ionic character or osmolality had no demonstrable influence on the interaction with haemostatis and blood vessels. An adjuvant, antithrombotic therapy was carried out, which consisted of platelet aggregation inhibitors and heparins. Conclusion: Our findings agree with the results of recent clinical trials, which demonstrated no relevant disadvantage of non-ionic contrast media as regards thrombotic complications.

Functionally active antithrombin can be quantified by chromogenic substrate assays utilizing the heparin cofactor activity of antithrombin and the inhibition rates of thrombin or of activated factor X (FXa). Thrombin-based assays but not FXa-based assays may overestimate the antithrombin activity due to their sensitivity toward heparin cofactor II. We focused on the question whether an overestimation of antithrombin activity by thrombin-based assays involves the risk of misdiagnosing antithrombin-deficient individuals as being non-deficient. We determined antithrombin using two thrombin-based assays and one FXa-based assay in 27 plasma samples from patients with acquired antithrombin deficiency spiked with lepirudin, in antithrombin-deficient plasma and in mixtures of antithrombin-deficient plasma and normal plasma. We also measured antithrombin in healthy subjects, in patients with inherited and acquired antithrombin deficiency and in patients under high-dose heparin treatment. At therapeutic final concentrations of lepirudin, antithrombin activities were considerably overestimated by the thrombin-based assays but not by the FXa-based assay. The residual antithrombin activities in antithrombin-deficient plasma determined by the thrombin-based assays were markedly higher than the corresponding values obtained with the FXa-based assay. The thrombin-based assays also overestimated antithrombin activity in patients under high-dose heparin. However, the degree of overestimation in the range between 50 and 100 IU/dl was too low to misidentify individuals with inherited or acquired antithrombin deficiency as normal. We conclude that functionally active antithrombin can be reliably determined using FXa-based chromogenic substrate assays in all settings examined. Thrombin-based assays must not be used in patients under treatment with hirudin or other direct thrombin inhibitors.

BACKGROUND: After the application of high volumes of high-molecular- weight starch (hetastarch), bleeding complications have repeatedly been observed. Later studies showed that the application of medium-molecular- weight starch led to far fewer disturbances of the blood coagulation system. However, the relationships among the degree of hydroxyethyl substitution, the rate of degradation, and the average in vivo molecular weight have not been investigated. STUDY DESIGN AND METHODS: A 10-day hemodilution treatment (n = 20) was carried out using two medium-molecular-weight hydroxyethyl starches (HES) with a degree of hydroxyethyl substitution of 0.5 and 0.62, respectively (10% HES 200 was used for a substitution of 0.5 and 6% HES 200 for a substitution of 0.62). After a loading dose of 500 mL was administered, 1000 mL of HES was infused daily for 4 days, and then 500 mL was infused daily for 6 days. RESULTS: The more highly substituted starch was broken down more slowly and eliminated renally. This resulted in a higher intravascular molecular weight than for the less highly substituted HES (120 vs. 84 kDa) and a greater increase in serum concentration (20.3 vs. 9.0 mg/mL). Initially, the more highly substituted 6-percent HES had a lesser effect on plasma volume (p < 0.01). Because of HES accumulation, there was no longer a significant difference between the starches by the end of treatment, even though a higher dose of the 10-percent low- substitution starch was infused. Six-percent HES caused an increase in plasma viscosity (+9%, p < 0.01) that was due to an accumulation of macromolecules. Ten-percent HES 200/0.5 had no effect on the coagulation system beyond the dilution effect. Six-percent HES, on the other hand, led to an acquired von Willebrand syndrome during the course of the 10-day therapy. Factor VIII function was reduced by 72.2 percent, von Willebrand ristocetin cofactor by 61.3 percent, and von Willebrand factor antigen by 64 percent (p < 0.01). CONCLUSION: It is the intravascular and not the initial (in vitro) molecular weight that determines the properties of HES. Especially after repeated administration, a high degree of hydroxyethyl substitution leads to an accumulation of macromolecules that affect hemorrheologic measures and the coagulation system just as adversely as high-molecular-weight starch does. Depending on the degree of substitution, medium-molecular- weight starches can have widely differing properties.

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.

Haemorrhagic disorders must be excluded prior to any operation or other invasive procedure that has the potential to involve serious bleeding. When assessing the individual risk of bleeding, screening tests of hemostasis must be combined with the patient's clinical history and symptoms, and any history of bleeding must be explored under direct medical supervision using a standardized questionnaire. However, this bleeding history is neither very specific, nor is it particularly sensitive. Screening tests that have been found to be useful include platelet count, activated partial thrombo plastin time (aPTT), prothrombin time (PT) and clottable fibrinogen. No reliable, sensitive and specific screening test is however available today to screen for platelet dysfunction or von Willebrand disease. A specialized coagulation laboratory should be involved when the bleeding history or laboratory screening indicate a potential haemorrhagic disorder.

Argatroban is a direct, selective and reversible active site thrombin inhibitor derived from L-arginine. It is a representative of a new class of antithrombotic drugs which offer inhibition of clot-bound as well as fluid-phase thrombin. Argatroban is characterised by favourable pharmacokinetics (beta-elimination half-time approximately 40-50 min) undergoing hepatic metabolism and mainly biliary excretion. Renal impairment will not result in altered or delayed elimination. For many years, argatroban has been used in Japan and in the United States and is approved by the FDA for anticoagulation in patients with heparin-induced thrombocytopenia (HIT type II). The ease of monitoring with the activated partial thromboplastin time, lack of induction of antibodies and adequate safety in renal failure patients, make this drug a favourable mode therapy in comparison with other anticoagulants such as lepirudin or heparinoids. Since June 2005 argatroban has been approved in Germany for the treatment of patients with HIT type II. The main characteristics of the drug with special considerations for anaesthesiologists and intensive care physicians are presented in this review.

When patients with von Willebrand's disease were given a single injection of desmopressin (0.4 microg/kg body weight), there was a considerable increase in platelet reactivity (from 0.95 +/- 0.19 to 1.44 +/- 0.42; p = 0.0033). On flow cytometry, increased glycoprotein Ib/IX expression in the platelets was found after the desmopressin injection; when phycoerythrin-marked anti-CD62 antibodies were used, the mean fluorescence rose from 428.9 +/- 56.6 to 440.7 +/- 51.4 (p = 0.0056), and from 425.9 +/- 55.0 to 437.4 +/- 53.9 (p = 0.0018) when phycoerythrin-marked anti-thrombospondin antibodies were used. Apart from the rise in the von Willebrand factor, this could explain the increased platelet reactivity. However, the surface expression of CD62, CD63 and thrombospondin on platelets did not change following the desmopressin injection.

Melagatran is a direct inhibitor of thrombin and-like its oral prodrug ximelagatran-a newly developed dipetide with high antithrombotic efficacy. They present a linear dose-response, a short plasma half-life and the therapeutic range may be advantageous compared with classic anticoagulants such as heparins or vitamin K antagonists. The results of clinical studies for prevention and treatment of thromboembolic complications are encouraging. The use of melagatran and ximelagatran will gain significance in the perioperative management, thus being of particular importance for anaesthesiology and critical care medicine in the near future.

To investigate the influence of two non-ionic radiographic contrast media with different osmolality on thrombocytic function and the plasmatic coagulation system.The study was carried out as a randomised, prospective, comparative study with two contrast media in a heart catheter laboratory.Activating influences on platelet aggregation, procoagulatory or profibrinolytic functions or injury to the endothelium could be ruled out. Apparently, also differences in substance properties, such as the media's ionic character or osmolality had no demonstrable influence on the interaction with haemostatis and blood vessels. An adjuvant, antithrombotic therapy was carried out, which consisted of platelet aggregation inhibitors and heparins.Our findings agree with the results of recent clinical trials, which demonstrated no relevant disadvantage of non-ionic contrast media as regards thrombotic complications.

Previous studies demonstrated that naftidrofuryl increased the cutaneous and intramuscular tissue pO2 at rest. The presented open prospective pilot study is to investigate in apparently healthy subjects (n=12) whether naftidrofuryl also affects pO2 in situations of muscular stress. The pO2 is measured with a flexible probe in the anterior tibial muscle during treadmill exercise prior to and after one-week treatment with 100 mg of naftidrofuryl administered three times a day. The intake of naftidrofuryl proved to significantly affect the intramuscular partial oxygen pressure. With 38.6+/-22.9 mmHg, the pO2 is at rest already significantly (p0.05), i.e., approx. 40% higher after one week of intake than before treatment (27.3+/-12.1 mmHg). This higher pO2 level is maintained during exercise. The higher the physical load, the larger the difference in pO2. While under naftidrofuryl treatment the measured pO2 values exhibit the tendency to increase during the first exercise phase (at a load of 3 km/h and a gradient 5 degree), the differences are even significant under higher physical stress (at 5 km/h and a gradient of 10 degree). With 33.9+/-12.0 mmHg the mean minimum pO2 determined at the higher load level still ranges above the basal pO2 measured before the start of naftidrofuryl treatment.

A multicenter trial was started in Germany in September 1998 using a high-purity FVIII/vWF concentrate (IMMUNATE, Baxter Deutschland) for the treatment of patients with von Willebrand Disease (vWD).

Patients in intensive care may be at high risk of in vivo platelet activation because comorbid conditions, such as infections, septicemia, shock, disseminated intravascular coagulation, and cancer represent procoagulant states. Hyperreactivity 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, thrombocytopenia 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 monitored 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 recanalization of the lower extremity could be achieved. Three patients 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 fibrinolysis with recombinant tissue plasminogen activator (rtPA) and r-hirudin treatment. Two lethal events probably caused by the underlying multimorbidity could not be prevented. No recurrence of thrombosis occurred, and there were no severe bleeding 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/microL to 96,000 plus or minus 61,000/microL, and increased during rhirudin treatment to mean values of 224,000 plus or minus 126,000/microL. 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.

Functionally active antithrombin can be quantified by chromogenic substrate assays utilizing the heparin cofactor activity of antithrombin and the inhibition rates of thrombin or of activated factor X (FXa). Thrombin-based assays but not FXa-based assays may overestimate the antithrombin activity due to their sensitivity toward heparin cofactor II. We focused on the question whether an overestimation of antithrombin activity by thrombin-based assays involves the risk of misdiagnosing antithrombin-deficient individuals as being non-deficient. We determined antithrombin using two thrombin-based assays and one FXa-based assay in 27 plasma samples from patients with acquired antithrombin deficiency spiked with lepirudin, in antithrombin-deficient plasma and in mixtures of antithrombin-deficient plasma and normal plasma. We also measured antithrombin in healthy subjects, in patients with inherited and acquired antithrombin deficiency and in patients under high-dose heparin treatment. At therapeutic final concentrations of lepirudin, antithrombin activities were considerably overestimated by the thrombin-based assays but not by the FXa-based assay. The residual antithrombin activities in antithrombin-deficient plasma determined by the thrombin-based assays were markedly higher than the corresponding values obtained with the FXa-based assay. The thrombin-based assays also overestimated antithrombin activity in patients under high-dose heparin. However, the degree of overestimation in the range between 50 and 100 IU/dl was too low to misidentify individuals with inherited or acquired antithrombin deficiency as normal. We conclude that functionally active antithrombin can be reliably determined using FXa-based chromogenic substrate assays in all settings examined. Thrombin-based assays must not be used in patients under treatment with hirudin or other direct thrombin inhibitors.

Als Teil des inhibitorischen Systems kommt dem Protein C eine zentrale Bedeutung im hamostatischen Gleichgewicht zu. Die Inzidenz des hereditaren Protein C-Mangels betragt etwa 1:250; bei der uberwiegenden Mehrzahl dieser Patienten (heterozygoter Protein C-Mangel) tritt mindestens ein thromboembolisches Ereignis noch vor dem 4o. Lebensjahr auf. Dabei werden spontan oder postoperativ auftretende Thrombosen beobachtet, aber auch Thromboembolien an atypischer Stelle (Mesenterialvenen-/Pfortaderthrombose, intrazerebrale Venenthrombose) oder unter Einnahme hormonhaltiger Medikamente (Antikonzeptiva) beschrieben. Die Prophylaxe besteht bislang in der risikobezogenen, niedrigdosierten Heparinapplikation (Primarprophylaxe) oder einer dauerhaften Antikoagulantienbehandlung (Sekundarprophylaxe, z.B. Phenprocoumon). In vorliegender Arbeit stellen wir das perioperative Vorgehen bei einem Patienten vor, bei dem zur Rezidivprophylaxe ein Protein C-Konzentrat anlaslich einer endoskopischen Cholezystektomie perioperativ verabreicht wurde.

The oxygen partial pressure (pO2) in the anterior tibial muscle was measured in n=12 (6 physically active and 6 sedentary) apparently healthy subjects. This was the first time a flexible micro catheter with an outer diameter of 0.45 mm was used during skeletal muscular activity in men. A two level tread mill test which is used in the diagnosis of peripheral arterial occlusive disease was chosen to induce physical stress. In the healthy volunteers a pO2 increase was noted at the beginning of exercise. This was followed by a pO2 decrease because of an increased O2 demand in the working muscle. The initial pO2 increase was thought to be due to the recruitment of capillaries and not the subsequently increased heart rate. At rest and during activity pO2 values were higher in physically active subjects than in the sedentary and the exercise induced decrease of pO2 values was slower and in addition to this the compensation to baseline values quicker.

Quality of live, defined by different models, has become a major focus of research in chronic disorders. Patients with hemophilia have been found to suffer seriously from the impact of HIV infection. To compare the impact of HIV infection on HIV-positive and HIV-negative patients, we evaluated a group of 60 patients, 30 being positive and 30 negative, suffering from hemophilia, using the Karnofsky index of functioning besides more general social and clinical data. Most patients (n = 53) suffered from hemophilia A. The mean Karnofsky score decreased from 65.22 to 63.43 in the HIV-infected group between 1988 and 1991, but increased from 77.7 to 82.2 in the HIV-negative group; differences were not significant, though differences were significant between the HIV-infected and HIV-negative groups. The Karnofsky score remained constant or increased in 26 (86.6%) of the HIV-negative patients, in contrast to 50% in the infected group. Seven patients, all from the infected group, had died in 1991. The initial Karnofsky score was not a prognosticator of survival. The group as a whole was socially well integrated. Consequently, the Karnofsky score can be a useful instrument in evaluating the global quality of live in HIV-infected patients, though a careful evaluation of results is necessary and a low initial score does not predict survival.

Die May-Hegglin-Anomalie (MHA) 1st eine seltene, autosomal dominant vererbbare Form der Thrombozytopenie; sie ist gekennzeichnet durch Riesenthrombozyten und zytoplasmatische Einschluβkorperchen in Granulozyten (Dohle-Korperchen; Oski et al. 1962; Greinacher et al. 1992). Der geringere Teil der Patienten weist eine hamorrhagische Diathese auf, wohingegen der weit uberwiegende Anteil der Betroffenen asymptomatisch bleibt, so daβ die Diagnose meist zufallig gestellt wird. In vorliegender Arbeit dokumentieren wir den klinischen Verlauf eines Patienten mit MHA, bei dem nicht ein Blutungsereignis, sondern ein akuter Myokardinfarkt mit thrombotischem Verschluβ der rechten Kranzarterie zur stationaren Aufnahme fuhrte.

Systematic studies of a possible human neuropathogenicity of the Erve virus have not yet been carried out. In a randomized, blind study 166 patients with viral encephalitis, 46 patients with cerebral hemorrhage, 72 patients with "thunderclap" headache, and 205 healthy blood donors were examined by indirect immunofluorescence for Erve virus antibodies. None of the patients with encephalitis, two patients with cerebral hemorrhage (4.3%), 10 patients with thunderclap headache (13.9%; p0.0001), and two blood donors (1.0%) exhibited antibodies against the Erve virus. These results suggest a human pathogenicity of the Erve virus for the first time.

Die Sepsis ist eine systemische Reaktion auf eine Infektion, die mit multiplen immunologischen, hamostaseologischen, vaskularen und metabolischen Pathomechansimen einhergeht. Die Entwicklung einer DIC ist eine haufige Komplikation bei der Sepsis. Der erworbene Antithrombin (AT)-Mangel hat hierbei eine zentrale Bedeutung. Dies konnte in zahlreichen Studien gezeigt werden. Die Substitution mit AT zur Verbesserung der Prognose bei Sepsis bietet Vorteile und wird allgemein empfohlen. Prospektive kontrollierte Studien mit hoher Fallzahl zur definitiven Etablierung einer AT-Substitution bei Sepsis stehen jedoch noch aus.

Infusion of the large volumes of high molecular weight hydroxyethyl starch (HES) has been know to lead to coagulation disorders. Medium molecular starch is considered a safe alternative, even after repeated administration. In 10 patients with cerebrovascular diseases, a 10-day hemodilution was carried out using 10% HES 200/0.62. Initially, a loading dose of 500 ml was administered once over 45-60 min, followed by 500 ml maintenance dose per day for 10 days. Its high intravascular molecular weight (120,000 D) showed that cleavage of the starch is slowed due to the higher degree of substitution. The continuous increase of HES-serum concentration to 27.7 mg/ml gave evidence of a cumulation of poorly degradable molecules. Although this caused a prolonged volume effect, plasma viscosity and erythrocyte aggregation were influenced in an unfavourable way. The negative effects were not evident in their influence on the coagulation system. Under therapy, a significant 42.8% increase (p0.01) in activated partial thromboplastin time occurred. Factor VIII:C, von Willebrand ristocetin co-factor and von Willebrand factor antigen dropped during the therapy below the hemostasiological limit of 30% (p0.01), and in some patients below 10%. A high degree of substitution, particularly after repeated infusion, leads to a cumulation of large molecules that are difficult to break down and which unfavourably affect rheological and hemostasiological parameters.

Congenital dysfibrinogenemia is based on different alterations in the structure of the fibrinogen molecule leading to a variety of disturbances in the clotting process. Clinical manifestations of the disorder are showing a wide range from asymptomatic states to mild bleeding diathesis as well as thrombotic complications. In this study two of the 14 patients with dysfibrinogenemia showed a history of mild bleeding while the others showed no clinical symptoms. As fibrinogen is also an important factor of the blood fluidity not only haemostatic but also rheological parameters were measured. Included in the study were 14 patients with ascertained dysfibrinogenemia in comparison to 11 non-affected relatives and a control group of 297 apparently healthy subjects. Plasma viscosity (p0.0001) and erythrocyte aggregation index (p0.00001) were significantly higher in the patients than in their healthy relatives and the control group. A pathologically increased erythrocyte aggregation was found in 10 of the 14 patients but only in 1 of the 10 relatives. The dysfunction of the fibrinogen molecule thus influences the aggregation process of the red blood cells to a greater extent than normal fibrinogen. Moreover, there seems to be a stronger influence of the dysfunctional fibrinogen molecule on the aggregation process than on plasma viscosity. To date the question if the enhanced erythrocyte aggregation in dysfibrinogenemic patients may be of any diagnostic interest and if there are significant differences between patients with bleeding diathesis and thrombophilia cannot be answered and remains to be cleared in further investigations.

Im Jahr 1994 bzw. 1995 wurden die Gene fur die Gerinnungsfaktoren VIII:C und IX:C isoliert und charakterisiert (Gietschier et al. 1984; Wood et al. 1984; Toole et al. 1985; Anson et al. 1984; Yoshitake et al. 1985). Damit waren die Voraussetzungen fur die genomische Diagnostik zur Konduktorinnenbestimmung (Carrierdiagnostik) und pranatalen Diagnostik gegeben.

It is a well-known fact that plasma substitutes reduce the number of platelets after one-time administration due to a dilution effect. So far, it has not been sufficiently investigated how a long-term hemodilution therapy affects platelet number, volume distribution and function. In 20 patients with cerebrovascular diseases a 10-day hemodilution therapy was carried out. The patients were randomly and double-blind treated with either medium molecular weight (MMW) hydroxyethyl starch (HES) 200/0.5 or low molecular weight (LMW) HES 40/0.5. On the first day of therapy, both groups showed a significant reduction in the number of platelets (-13.2% and -8.4%, respectively, p0.05), which was smaller than the dilution effect. During the course of the therapy, the platelet number increased, reaching its initial value. Mean platelet volume decreased in both groups significantly (MMW HES -4.7%, p0.05, LMW HES -4.6%, p0.01). The share of large platelets decreased disproportionately (MMW HES -15.4%, p0.01, LMW HES -11.4%, p0.01). Spontaneous platelet aggregation was not affected by HES. During the course of a long-term hemodilution therapy, the initial dilution-induced drop in platelet number is quickly compensated. The decline in mean platelet volume, which increases towards the end of the therapy, is due to a great extent to a decline in the number of large platelets. This in turn is probably caused by a colloid-osmotic shrinkage of the platelets and increased degradation. There were no signs for a clinically relevant impairment of platelet function.

Salicylates increase the risk of hemorrhage. An ischemic brain infarct has not previously been described following intoxication with salicylates. Case report. A 58-year-old comatose patient was admitted with symptoms of a basilar artery thrombosis. A diagnostic angiography was impossible because laboratory results showed a prothrombin time (Quick) of 9% and a toxic salicylate level of 528 mg/l. During the next few days CCT and MRI scans revealed ischemic infarctions within the brain stem. Discussion. Salicylates can induce hemorrhage both by inhibiting platelet aggregation and - especially in higher doses - by vitamin K antagonism, leading to severe coagulopathy. The occurrence of an ischemic infarction, as presented in this case report, can be explained by a reduction of the vitamin K-dependent protein C level.

Complications concerning the blood coagulation have been observed repeatedly after administration of highly substituted, high molecular weight hydroxyethyl starch (HES), but it has not been examined as to how intravascular molecular weight and degree of substitution of HES influence platelet number and volume after repeated administration. Thirty patients with cerebrovascular diseases were treated for 10 days with hemodilution. 500 to 1500 ml of HES 200/0.62 (n = 10), HES 200/0.5 (n = 10) or HES 40/0.5 (n = 10) were infused daily. During the first days, the number of platelets was not lowered beyond the dilution effect, but at the end of the therapy the number of platelets had increased in all 3 groups beyond the initial value. Platelet volume was lowered significantly in the 3 groups. HES 200/0.62 caused the largest drop in platelet volume (-10%, p

Dextrans are known to inhibit platelet aggregation. However, conflicting results have been reported with hydroxyethyl starch (HES), usually administered as a single dose. To clarify this, we studied the effects of HES on platelet number, aggregation and volume during the course of long-term hemodilution therapy. Twelve patients with disturbances of cerebrovascular perfusion were randomized and divided into two groups of 6 patients each. One group was treated with 10% HES 200/0.62, the other with 6% HES 200/0.62. The patients in group 1 received a loading dose of 500 ml, followed by 500 ml daily for 10 days. Group 2 patients were infused a loading dose of 500 ml, followed by 1000 ml on days 1 to 4 and 500 ml on days 5 to 10. 10% HES had a larger volume effect. The hematocrit was lowered by 19.0%, whereas 6% HES caused a decrease of only 15.6%. 10% HES lowered the platelet number significantly (p0.05) by 5.8%, 6% HES did not lower the platelet number significantly. Platelet volume decreased significantly during therapy (p0.05) in both groups. 10% HES reduced the platelet volume by 13.9%, the reduction with 6% HES was 9.0%. Under therapy with 10% HES, platelet aggregation declined slightly, but significantly (p0.05), whilst no effect was seen with 6% HES. During long-term hemodilution therapy with HES, the initial decrease in platelet number, which is due to dilution, is quickly compensated. The continuous decline in mean platelet volume during therapy is probably due to colloid-osmotic shrinkage. Since there is a positive correlation between platelet size and function, the slight inhibition of platelet aggregation caused by 10% HES is possibly due to the observed decline in platelet volume.

To prevent dangers to health resulting from the application of drugs, the legislator requires the central registration and evaluation of all drug risks, especially of side effects and reciprocal effects. Since 1988 pharmaceutical enterprises have had to denominate a qualified person ('Stufenplanbeauftragter') who is responsible for the fulfilment of obligatory reporting. In case of complaints or side effects he has to take suitable measures according to a special plan ('Stufenplan').The basis of this survey are the legal requirements for drugs ('Arzneimittelgesetz') and supplementary regulations which define the duties of the 'Stufenplanbeauftragter'.Blood components are subject to the legal requirements ('Arzneimittelgesetz') without reservations. Therefore the corresponding regulations have to be applied without modification in institutes for transfusion medicine. In this article the tasks of the 'Stufenplanbeauftragter' are summarized and practical experience of a university institute for transfusion medicine is presented.In connection with the transmission of viral infectious diseases it became evident that the 'Stufenplanbeauftragter' is very important for the initiation of effective measures in case of serious side effects. The security of blood components could be improved by the realization of the corresponding legal requirements in the institutes for transfusion medicine.

Investigation of the influence of C2/C6 occupation ratio of 2 different 6% hydroxyethyl starch (HES) solutions on elimination kinetics and blood fluidity.A single-blinded, prospective randomised cross-over study.Haemostasiological-angiologic outpatient department of the university of Homburg.6 voluntary apparently healthy subjects.A 500 ml infusion of 2 different HES solutions (6% HES 200/0.5 or 6% HES 200/0.62, respectively) was given intravenously within 1 h. A wash-out phase of 3 months was kept between both infusions. The concentration and distribution of the molecular weight of the intravasal HES molecules up until 24 h after the infusion as well as the blood fluidity before and after the infusion were measured.Besides the molecular substitution (MS), which is different for the 2 employed HES solutions, the occupation ratio of the C2 respectively C6 (C2/C6 occupation ratio) of the glucose ring influences the breakdown of the HES molecules. This influences the blood fluidity. While the decrease in haematocrit 1 h after the end of the infusion is comparable, the decrease in the haematocrit in the case of high C2/C6 occupation ratio and a high MS is maintained for a longer period of time. The increase in plasma viscosity in the case of high C2/C6 occupation ratio and high MS is more marked.The infusion of HES 200/0.62 leads to a significantly longer prevalence in comparison to HES 200/0.5, in combination with clearly larger degradation products in the plasma; this fact causes a more marked dilutional effect, but also a more marked increase in the plasma viscosity up to 24 h after the end of infusion. In the discussion on haemodilution therapy in patients with arterial occlusive disease the employment of HES which induces an increase in plasma viscosity is thought to be a disadvantage.

The goal of the study is to test and control the quality of a special leap-frog technique which enables saving heterologous blood.In a randomized double-blind placebo-controlled study homologous blood was taken in 40 out of 100 patients with coronary heart disease before aortocoronary bypass operation. The leap-frog technique was used. Within 8 weeks 3-4 erythrocyte concentrates and 0.9-1.2 liters plasma were sampled. The volume (verum: HES 200/0.5 10%; placebo: 0.9% NaCl solution) substituted corresponding to the volume of blood donated. Each patient received 200 mg Fe2+/day p.o.Clinically, only patients treated with HES in stage of autologous blood sampling benefited significantly. Two patients showed adverse effects. The peri- and postoperative course was comparable. In the NaCl group one of the patients received homologous erythrocyte concentrates. None of the patients died pre-, peri- or post-operatively.40% of the cardiosurgical patients could be considered for autologous blood donation. Isovolemic hemodilution with HES 200/0.5 10% was a suitable and safe measure in preoperative blood sampling. Physical exercise should be performed before and after autologous blood donation. A reduced exercise tolerance suggests that autologous blood donation should be stopped.

Clinically, only patients treated with HES in stage of autologous blood sampling benefited significantly. Two patients showed adverse effects. The peri- and postoperative course was comparable. In the NaCl group one of the patients received homologous erythrocyte concentrates. None of the patients died pre-, peri- or postoperatively. 40% of the cardiosurgical patients could be considered for autologous blood donation. Isovolemic hemodilution with HES 200/0.5 10% was a suitable and safe measure in preoperative blood sampling. Physical exercise test should be performed before and after autologous blood donation. A reduced exercise tolerance suggests to stop autologous blood donation.

The platelet reactivity was measured before and 1 h after thrombapheresis in n = 54 donors. On average, apheresis did not significantly influence the platelet reactivity. Still in 10% of the donors a marked increase in platelet reactivity was seen.

The biological response to 4 different heparins after successive subcutaneous administration once daily for 5 days at a dose used for primary prophylaxis of deep vein thrombosis was investigated in a randomized cross-over study in 12 volunteers. Three different preparations of low molecular weight heparins (LMWH) were administered, 10,000 U unfractionated heparin (UFH) was used as a control. The anticoagulant properties in terms of anti-Xa activities, as measured by a chromogenic substrate assay or Heptest, showed high interindividual variations with peak levels 2 to 4 h following injections. There was a significantly higher increase of anti-Xa activities 3 h after administration at day 5, when compared with day 1, for two LMWH's, suggesting an accumulation of the anticoagulatory effect. The anticoagulant activity, especially when measured by Heptest, was significantly influenced by the body weight. This could be observed for all LMWH's. For the assessment of anticoagulant activity in LMWH-treated individuals, the chromogenic substrate assay and Heptest revealed maximal correlation (r = 0.51), while in UFH-treated individuals, peak correlation (r = 0.75) was observed between the partial thromboplastin time and thrombin clotting time. The chromogenic substrate method was the most sensitive anti-Xa assay, showing also the smallest interindividual variation. No significant influence of heparins neither on platelet count and function nor on fibrinolysis were recognized. Enhanced lipolytic activities were not observed. There was an increase of alanine aminotransferases induced by UFH as well as LMWH's, which, however, was most pronounced after UFH.

When no specific factor concentrate is available fresh-frozen plasma (FFP) is indicated in the treatment of clinically relevant hemorrhagic diathesis. These disorders include congenital factor V and XI deficiencies, multiple factor defects, as disseminated intravascular coagulation and severe liver disease, and patients receiving massive transfusions, when bleeding occurs and severe abnormalities on coagulation testing are evident. FFP is beneficial when used with plasma exchange in thrombotic thrombocytopenic purpura and related disorders. Various virucidal treatments including solvent-detergent (SD), photoactivated dyes (methylene blue) or pasteurization have been evolved to improve virus safety of human plasma. More extensive studies to demonstrate efficient virus inactivation in plasma have been performed with SD compared to other methods. On the other hand, the use of single-donor FFP in methylene blue treatment is possibly superior to pooled plasma which is processed according to the SD procedure. Pasteurization enables the inactivation not only of lipid-enveloped but also of non-lipid-enveloped viruses. Virucidal treatment of plasma may cause alterations in clotting factors, fibrinolysis and protease inhibitors; however, the currently achieved recovery of procoagulant activities is approximately comparable with that found in untreated FFP. The toxicity of virucidal additives is reported to be negligible since manufacturing includes a removal procedure (SD) or comparably low amounts (methylene blue) are used in inactivation treatment.

Quality controls of autologous blood collections in critically ill patients comprise the control of blood products, blood collection, and of the patients themselves. The control of products is defined in European guidelines, the AMG (law governing the manufacture and prescription of medicine) and GMP regulations. The products are described in the monograph of the Federal Health Office. The quality control of blood collection in patients with a critical vascular disease is important since vagotonic or hypertensive crises may occur frequently (in 10-15% of cardiosurgical patients). The quality control of the critically ill patients themselves is important in order to be able to balance benefits against risks. A phlebotomy of 500 ml may lead to a considerable deterioration of the clinical condition. The clinical condition can be controlled by simple exercise tests prior to and after the blood collection (bicycle ergometer, treadmill or climbing stairs). In our own investigations only about 25% of cardiosurgical patients (40% of patients with aortocoronary venous bypass) received autohemotherapy, and 20% of them showed a clinical deterioration during the phase of blood collection. Other problematic patients are those suffering from a tumor. A clear clinical benefit of autohemotherapy in these patients has not been demonstrated up to now; nevertheless, when a curative therapy is possible, they should be treated with autohemotherapy.

In a randomized placebo-controlled double-blind cross-over study it could be shown that 5 h after the administration of garlic powder (Kwai, Sapec; total dose of 900 mg garlic powder) a significant increase in capillary skin perfusion by 55% occurs in the healthy volunteers. Placebo did not cause any changes. The difference between the two study phases is also significant. The increased erythrocyte velocity results from vasodilation of precapillary arterioles which increases diameter of erythrocyte column by an average of 8.6%. Simultaneously inflow of interstitial fluidity accompanied by a significant decrease in haematocrit and plasma viscosity occurs (rheoregulation).