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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.

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

Patients with severe forms of von Willebrand disease (vWD) most frequently require substitution of both factor VIII and von Willebrand factor (vWF). Immunate is a high-purity, double-virus inactivated FVIII/vWF concentrate derived from human plasma. The clinical efficacy of Immunate concerning the management of acute bleeding episodes and surgical prophylaxis in patients with von Willebrand disease (vWD) is being investigated and documented in a prospective, phase III, open-label, single-armed multicenter trial. Data on its pharmacokinetics are collected, and the product's safety with respect to adverse experiences is monitored.

Three patients with a history of chronic idiopathic thrombocytopenic purpura stretching back over 20 years are reported. Despite splenectomy and immunosuppressive therapy satisfactory control of their disease has not been achieved. They had remained refractory to all therapeutic manoeuvres with corticosteroids and immunosuppressives for years with thrombocyte counts between 5,000 and 25,000/microliters and the concommitant risk of bleeding. This report describes the treatment of bleeding complications in these patients with high dose intravenous immunoglobulin; the peripheral blood thrombocyte count increased in all three patients from subnormal towards normal, but 2 to 4 weeks later returned to its initial low value. During the therapeutically induced raised thrombocyte count a normal bleeding time and only a moderate inhibition of thrombocyte adhesion and aggregation was observed resulting in reasonable haemostasis. High dose intravenous immunoglobulin is therefore a practical method for the control of bleeding complications in patients with refractory chronic idiopathic thrombocytopenic purpura. A clear explanation for its mode of action has not been found - the lymphocyte subpopulations remained unchanged and immunoglobulin production in vitro during the course of treatment was only minimally decreased.

The clinical, immunological, and serological status of 28 patients with hemophilia A and of 13 patients with hemophilia B was investigated. Thirty-four patients were treated regularly by clotting factor concentrates and 7 patients had been substituted only 1 to 4 times. Almost all patients with severe hemophilia suffered from hepatopathy. No patient had clinical evidence of the acquired immunodeficiency syndrome (AIDS). Asymptomatic hemophiliacs showed a decreased number of T-helper (OKT 4) cells and an increased number of T-suppressor (OKT 8) cells, which resulted in an inversed OKT 4/OKT 8 cell ratio. Natural killer cell activity of all patients was decreased compared to controls. After culture there was no significant difference of NK cell activity between hemophiliacs and controls. This phenomena was interpreted as a possible maturation defect of NK-cells in vivo. No relationship between immunological alterations and hepatopathy, hepatitis markers, CMV antibodies, amount and source of required factor concentrates, and the kind of hemophilia was observed. IgG immunoglobulins were higher and the OKT 4/OKT 8 ratio lower in the eight patients with lymphadenopathy than in patients without lymphadenopathy. The prevalence of antibodies to human T-lymphotropic virus (HTLVIII) was measured in 35 hemophiliacs and in 25 polytransfused patients, most of whom were suffering from acute leukemia. In 8 of 35 hemophiliacs antibodies to HTLVIII virus were detected by an enzyme linked immunosorbent assay (ELISA) and confirmatory tests. All seropositive patients were treated by blood products from the United States. Eight hemophiliacs treated by factor concentrates from German donors only were seronegative. In comparison 2 of 25 examined non-hemophilia patients receiving multiple blood products from local donors were seropositive for HTLVIII. The results show that hemophilia patients treated by imported clotting factor concentrates have a high risk of HTLVIII positivity. Hemophiliacs substituted by blood products obtained by local donor pools have only a small risk of infection. Because non-hemophiliac polytransfused patients had HTLVIII antibodies, there must be asymptomatic virus carriers in the local donor pool. The HTLVIII antibody screening of all donors and the heat treating of factor concentrates will give better therapeutic safety.

In patients with Haemophilia A, the development of inhibitor is a life-threatening complication of treatment. These patients are at high risk for dangerous bleeding as a result of this acquired resistance to human Factor VIII concentrate. Although treatment of bleeding complications has been improved with the introduction of an activated prothrombin complex preparation, therapy remains unsatisfactory. Two patients with Haemophilia A inhibitor were treated with high dose intravenous immunoglobulin in the expectation of an immunosuppressive effect. A rise in the antibody titre at the same time as the administration of factor VIII concentrate showed that this treatment was ineffective in patients with Haemophilia A inhibitor.

Factor IX (FIX) recovery and half-life was measured in ten hemophilia B patients under standardized conditions. Each patient received a steam-treated high-purity factor IX concentrate at a dose of 19-39 U/kg body weight. FIX activity was determined using a one-stage assay, which was calibrated against the international concentrate standard (reagents from Immuno, Heidelberg). The in vivo recovery ranged from 24% to 53% (mean value 37.7%) and the half-disappearance time (HDT) from 8-30 h (mean 16.7 h). In four of the ten patients, the distribution and elimination half-lives were estimated and ranged from 0.3 h to 3.9 h (mean 1.4 h) and from 28.6 h to 39.7 h (mean 33.1 h), respectively. In six patients FIX was redetermined using a different FIX deficient plasma and a plasma standard (reagents from MerzDade, Munich, FRG). Recoveries and HDT based on the results obtained with this method were significantly higher (68.2% vs 39.7%; p less than 0.05), and longer (14.8 h vs 10.6 h; p less than 0.05), respectively. FIX activity was also measured by both assay systems in 100 healthy subjects (50 males, 50 females). The reagents from Immuno yielded a mean value of 0.77 U/ml, while the mean FIX activity utilizing standards and reagents from MerzDade was 1.11 U/ml (p less than 0.000001). The coefficient of correlation between the FIX activity measurements, as determined in 100 healthy subjects and 6 hemophilia B patients using the different test systems, was r = 0.9 (N = 159; y = 0.08 +/- 1.3* chi; p less than 0.001). Our data suggest that recovery and HDT of factor IX concentrate strongly depend on the assay and calibration conditions and that an international FIX activity plasma standard is urgently required.

Im Gegensatz zu aromatischen Sulfonsaurederivaten, die Aminale allein unter Bildung von Iminiumsalzen und Sulfonsaureamiden spalten, konnen die Sulfonylchloride (I) auch uber die Sulfene (IX) als Zwischenprodukte reagieren.