Biomedical subjects
Publications and source records attributed to B Pötzsch.
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Heparin-induced thrombocytopenia is a strong risk factor for the development of arterial and venous thromboembolic events. In patients clinically suspected for HIT, immediate cessation of heparin treatment and continuation of anticoagulant treatment using alternative anticoagulants is mandatory in order to minimize the risk of thrombotic events. Alternative anticoagulants that have been successfully used in HIT include the direct acting thrombin inhibitors hirudin, bivalirudin and argatroban, and the heparinoid orgaran. In addition, there is growing evidence that the synthetic pentasaccharide fondaparinux is usable for the treatment of HIT patients. This short review summarizes the strategies of alternate anticoagulant treatment in HIT patients and also describes long-term treatment of HIT patients.
HISTORY AND ADMISSION FINDINGS: A 50-year-old patient presented with clinical symptoms of heart failure with orthopnoe and edema (NYHA IV). INVESTIGATIONS: Echocardiography revealed a dilated left ventricle with severely reduced left ventricular function and biventricular floating thrombi, due to dilatative cardiomyopathy. TREATMENT AND COURSE: With a heart failure medication clinical symptoms reduced and body weight decreased > 10 kg in 3 weeks. Due to the high-risk constellation, anticoagulation was performed with lepirudin and the biventricular thrombi were dissolved within 17 days. At this point in time, the patient suffered from petechial bleedings, hemoptysis and gross hematuria. Despite breaking anticoagulation and substitution of PPSB with not measurable fibrinogen, subarachnoid hemorrhage occurred leading to exitus letalis. CONCLUSION: Lepirudin is a highly effective anticoagulant, that can induce severe hemorrhagic side effects in individual cases. The present case report demonstrates an immunological reaction as a rare cause with activation of prothrombin and formation of fibrin.
The 48-year-old female patient was sent to our clinic for further evaluation of a spontaneous decrease of prothrombin- and prolongation of the bleeding-time. She presented in good conditions with an enlargement of cervical lymphnodes and the history of a monoclonal plasmacyte dyscrasia. The laboratory results revealed a pronounced decrease of prothrombin-time, a prolonged activated partial thromboplastin-time, a decrease of factor VII and X activity and a light chain paraprotein. The histological examination of the bone marrow led to the diagnosis of an immunocytoma and a medullar amyloidosis. For the aim of influencing the coagulopathy the patient was treated with chemotherapy. However, she developed severe bleedings. Further haemostaseological tests presented an amyloidosis-associated decrease of factor VII and X, an acquired von Willebrands disease, an acquired thrombozytopathy and a lupus-like anticoagulans. Under substitution of factor VIII-von Willebrand-factor-complex and chemotherapeutic treatment a stabilisation over several years was achieved till the patient died due to an amyloid-associated acute pancreatitis.
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OBJECTIVES: In this study the frequency of inherited thrombophilic risk factors in a population of German CVT patients and their influence on clinical outcome were evaluated. MATERIAL AND METHODS: Twenty-five patients (age 37.1 +/- 16.3 years) with CVT were screened for inherited coagulation disorders. All participants received a full clinical follow-up (mean follow-up period 4.8 +/- 6.4 years). RESULTS: Inherited thrombophilic risk factors were identified in 9 (36%) of the 25 patients studied. Four were found positive for the heterozygous factor V Leiden mutation, 2 were heterozygous carriers of the prothrombin-G20210A-polymorphism. APC resistance proved to be a reliable screening method for factor V Leiden mutation, whereas genetic evaluation for protein S and C deficiencies failed to demonstrate any mutations despite the identification of 1 patient with a protein C and protein S deficiency each. One patient suffered from a familial plasminogen deficiency. These 9 patients had a less favorable outcome (P < 0.05). CONCLUSION: Our results demonstrate that screening for inherited thrombophilia should be an integral part in the diagnostic work up of CVT patients. Patients with inherited coagulopathies tended to have a less favorable outcome, corroborating recommendations for a longer period of oral anticoagulation.
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BACKGROUND: We prospectively investigated lepirudin for further parenteral anticoagulation in patients with heparin-induced thrombocytopenia (HIT). METHODS AND RESULTS: Patients with confirmed HIT (n=112) received lepirudin according to need for 2 to 10 days (longer if necessary): A1, treatment: 0.4 mg/kg IV bolus, followed by 0.15 mg. kg(-1). h(-1) intravenous infusion, n=65; A2, treatment in conjunction with thrombolysis: 0.2 mg/kg, followed by 0.10 mg. kg(-1). h(-1), n=4; and B, prophylaxis: 0.10 mg. kg(-1). h(-1), n=43. Outcomes from 95 eligible lepirudin-treated patients were compared with those of historical control patients (n=120). Complete laboratory response (activated partial thromboplastin time ratio >1.5 with </=2 dose increases and platelet count normalization by day 10) was achieved in 65 lepirudin-treated patients (69.1%; 95% CI, 59. 3% to 78.3%). At 2 weeks after cessation of lepirudin, 11 patients died (9.8%), 10 underwent limb amputation (8.9%), and 20 suffered a new thromboembolic complication (17.9%). The average combined event rate per patient-day decreased from 5.1% in the pretreatment period to 1.5% in the treatment period. Thirty-five days after HIT confirmation, fewer lepirudin-treated patients than historical control patients had experienced >/=1 outcome (cumulative incidence 30.9% versus 52.1%; relative risk [RR] 0.71; P=0.12, log-rank test). Bleeding events were more frequent in the lepirudin group than the historical control group (cumulative incidence at 35 days, 44.6% versus 27.2%; RR 2.57; P=0.0001, log-rank test). No difference was observed in bleeding events requiring transfusion (cumulative incidence at 35 days, 12.9% versus 9.1%; RR 1.66; P=0.23, log-rank test); no intracranial bleeding was observed in the lepirudin group. CONCLUSIONS: Lepirudin effectively prevents death, limb amputations, and new thromboembolic complications and has an acceptable safety profile in HIT patients. Treatment should be initiated as soon as possible if HIT is suspected.
BACKGROUND: No data exist regarding the inter-laboratory reproducibility of the heparin-induced-platelet-activation (HIPA) test, the most widely used functional assay in Germany for the detection of heparin-induced thrombocytopenia (HIT) antibodies. METHODS: Nine laboratories used an identical protocol to test eight different sera with the HIPA test. Five laboratories also tested the sera with a platelet factor 4 (PF4)/heparin-complex ELISA. Cross-reactivity with danaparoid-sodium was assessed using 0.2 aFXa units instead of heparin in the HIPA test. RESULTS: Two of nine laboratories had no discrepant HIPA test results. Four laboratories differed in one sample, one reported two discrepant results, and two laboratories reported more than two discrepant results. Cross-reactivity with danaparoid-sodium test results differed among laboratories. PF4/heparin ELISA results were identical in all five laboratories. CONCLUSION: The HIPA test requires strict quality control measures. Using both a sensitive functional assay (HIPA test) and a PF4/heparin ELISA will allow detection of antibodies directed to antigens other than PF4/heparin complexes as well as detection of IgM and IgA antibodies with PF4/heparin specificity.
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Escherichia coli hemolysin (HlyA) and Staphylococcus aureus alpha-toxin are membrane-perturbating bacterial exotoxins that have been implicated as significant virulence factors in human diseases. We investigated the capacity of these toxins to cause cell activation and mediator release in human endothelial cells, compared with the efficacies of thrombin and the Ca2+ ionophore A23187. Concentration ranges tested were 1 to 1000 ng/ml (HlyA), 0.01 to 10 micro/ml (alpha-toxin), 0.01 to 10 U/ml (thrombin), and 0.01 to 10 microM (A23187). All stimuli caused dose-dependent generation of platelet-activating factor, nitric oxide, and prostaglandin I2. HlyA and thrombin effected time- and dose-dependent accumulation of large quantities of inositol phosphates, with maximum effects at 100 ng/ml and 1 U/ml, respectively. Corresponding time course and dose dependency were noted for HlyA-elicited diacylglycerol formation. In contrast, only the highest concentrations of alpha-toxin (10 microg/ml) and A23187 (10 microM) effected some moderate inositol phosphate accumulation, and this was suppressed in the presence of the platelet-activating factor antagonist WEB 2086. Metabolic and secretory responses elicited by alpha-toxin were dependent on the presence of extracellular Ca2+. We conclude that both HlyA and alpha-toxin are potent inductors of inflammatory and vasodilatory mediators in human endothelial cells. HlyA-elicited effects may proceed predominantly via activation of the phosphatidylinositol hydrolysis-related signal transduction pathway, whereas transmembrane Ca2+ flux appears to be the major event underlying the release of mediators in response to alpha-toxin. These toxin properties may contribute to vasoregulatory and inflammatory disturbances encountered in states of severe infection and sepsis.
Assay conditions of a plasma-based ecarin clotting time (ECT) were evaluated and the precision of the ECT in monitoring plasma levels of r-hirudin assessed. The snake venom enzyme ecarin converts prothrombin to meizothrombin possessing only weak coagulant but strong esterase activity. In r-hirudin containing plasma samples, meizo thrombin is rapidly neutralized by r-hirudin resulting in a dose-dependent prolongation of the clotting times. Among the different assay conditions tested, addition of 50 microliters of ecarin (4 U/ml) to 100 microliters of undiluted citrate-anticoagulated plasma gave optimal results with respect to precision and reproducibility. The measuring range of the ECT performed in this way is about 0.02-5.0 micrograms/ml r-hirudin. In vitro studies performed on r-hirudin-spiked plasma samples of 50 healthy individuals demonstrate remarkably low interindividual differences in r-hirudin responsiveness as indicated by CV-values below 5% and 7% at r-hirudin concentrations between 0-3 micrograms/ml and 4-5 micrograms/ml, respectively. The specificity for r-hirudin of the ECT is further demonstrated by the strong correlation (r = 0.94) between the results of a chromogenic assay and the ECT-measured r-hirudin concentrations obtained on 67 ex vivo blood samples. Depending on the concentration of r-hirudin the ECT is sensitive to plasma levels of prothrombin. In the absence of r-hirudin the critical prothrombin concentration was found to be 20% but increasing to 60% in the presence of 2.0 micrograms/ml r-hirudin. A fibrinogen concentration of 50 mg/dl was found to be the minimal concentration independent of the r-hirudin concentration. The precision of the ECT in measuring plasma levels of r-hirudin is not influenced by treatment with heparin, aprotinin or oral anticoagulants. The data demonstrate that the ECT is a rapid and easily perfor mable clotting assay which allows accurate measurement of r-hirudin plasma levels. ECT-monitored hirudin treatment will help to establish optimal dose regimens that are more efficacious but still as safe as heparin.
PURPOSE: To report a 31-year-old healthy patient with retinal venous occlusion in his left eye attributable to primary antiphospholipid antibody syndrome. METHODS: The patient was examined clinically. Multiple serologic and clinical investigations were performed to determine the causative disease. He was closely followed up for more than 3 years. RESULTS: The presence of lupus anticoagulant in our patient was indicated by a kaolin clotting time index of 27 (normal, <17) and confirmed by the demonstration of IgG antibodies against phospholipids. After long-term oral anticoagulant treatment for 2 years, lupus anticoagulant levels returned to normal, and therapy was stopped. No further thrombotic event occurred during follow-up. CONCLUSIONS: In retinal vascular occlusions of unexplained origin, antiphospholipid antibodies may play an important role in the pathogenesis. Detecting these antibodies in the serum of patients with retinal vascular occlusion helps determine the appropriate treatment with long-term oral anticoagulants.
BACKGROUND: Acute graft thrombosis is a severe complication in vascular surgery that may require limb amputation or even cause death. Because nearly all patients undergoing vascular surgery have had previous exposure to heparin, the presence of heparin-related anti-platelet antibodies typical for heparin-associated thrombocytopenia (HAT) is one underlying possible mechanism of acute graft thrombosis. Although thrombocytopenia is a typical finding of HAT, it is not clear whether the occurrence of clinically important HAT is necessarily associated with thrombocytopenia. PATIENTS AND METHODS: Ten out of 246 patients undergoing vascular surgery were diagnosed with HAT because of otherwise unexplained acute graft thrombosis that required recurrent surgical interventions. RESULTS: In all of the 10 patients, heparin-related anti-platelet antibodies were detected although the platelet counts were within the normal range. When HAT was diagnosed, heparin administration was stopped and, after autoantibody cross-reactivity with the heparinoid Danaparoid had been excluded, anticoagulation was continued using this anticoagulant. After heparin therapy was discontinued none of the 10 patients developed further thrombotic complications. CONCLUSION: The data presented demonstrate clearly that a normal platelet count does not exclude the possibility of HAT. As a consequence of this, HAT should be suspected in patients who develop thrombotic complications during heparin treatment, regardless of the actual platelet counts.
OBJECTIVE: The efficacy and safety of recombinant hirudin (r-hirudin) compared with heparin as an anticoagulant during open-heart surgery has been studied in a pig model. METHODS: A total of 18 Göttingen minipigs were randomly divided into three treatment groups and subjected to cardiopulmonary bypass for 1 h. Heparin-treated animals received a bolus of unfractionated heparin of 400 IU/kg body weight. Recombinant hirudin was given by a bolus injection of 1 mg/kg body weight, followed by a 1 h lasting infusion of 1 mg/kg body weight per h. The heparin-anticoagulated animals and one group of the hirudin-treated animals additionally received aprotinin at a dosage of 17500 KIU/kg body weight (KIU, kallikrein inhibitory units). In the second group of r-hirudin-treated animals, the aprotinin was replaced by saline. RESULTS: The extracorporeal circuit remained patent for a 1 h pump period in all of the animals studied. There was no evidence of vascular occlusion or clot formation in the r-hirudin-treated animals. The anticoagulant efficacy of the hirudin protocol used is further demonstrated by the results of electron-microscopical scans of the pump-line filters. Fibrin deposits were visible only in the heparin-treated animals and not in r-hirudin-treated pigs. Despite this strong anticoagulant effect, there was no evidence of an increased bleeding tendency in r-hirudin-treated pigs. Moreover, histological studies showed a statistically significant (P < 0.05) higher incidence of tissue bleeding in the heparin/aprotinin-treated animals compared with the r-hirudin/aprotinin-treated pigs. Studying the platelet function, a statistically significant (P < 0.01) better preserved ADP- and collagen-induced platelet aggregation was seen in the r-hirudin/aprotinin-treated animals when compared with heparin/aprotinin-treated animals. CONCLUSIONS: These data demonstrate that r-hirudin can be used successfully as an alternative anticoagulant to heparin during cardiac operations including cardiopulmonary bypass. The better preservation of platelet function suggests that r-hirudin may reduce the postoperative risk of bleeding.