Treatment of a woman with lupus and thromboembolism and cutaneous intolerance to heparins using fondaparinux during pregnancy.
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Anticoagulants↗
Biomedical subjects
Job Harenberg
Publications and source records attributed to Job Harenberg.
Incidence of recurrent venous thromboembolism of patients after termination of treatment with ximelagatran.
OBJECTIVE: Recurrent thromboembolic events may occur after termination of anticoagulant therapy for acute venous thromboembolism (VTE) using oral direct thrombin inhibitor ximelagatran. METHODS: Patients with VTE recruited at the German study centres were followed-up for an additional 18 months, treated initially with 2x36 mg ximelagatran daily or with enoxaparin/warfarin over 6 months (THRIVE Treatment study) and 2x24 mg ximelagatran daily or placebo over 18 months (THRIVE III study). Recurrent VTE and the combined outcome events consisting of recurrent VTE, other thrombotic complication, major bleeding and mortality were analysed. RESULTS: In the THRIVE Treatment study, no patient suffered from a recurrent VTE, but 1 patient randomised to enoxaparin/warfarin experienced major bleeding. During follow-up, 4/32 and 3/32 patients initially randomised to ximelagatran and enoxaparin/warfarin developed recurrent VTE (p=0.7024). No major bleed occurred. One patient in each group died. The incidences of the combined outcome events were not different (p=0.9326). In the THRIVE III study, 0/9 versus 5/14 patients randomised to ximelagatran and placebo developed recurrent VTE including 1 fatal pulmonary embolism (p=0.0501). During follow-up, 3/9 and no patients initially randomised to ximelagatran and placebo developed recurrent VTE. One and 3 other outcome events occurred in patients initially randomised to ximelagatran or placebo. During follow-up, recurrent VTE (p=0.6893) and combined outcome events (p=0.3642) were not different between the groups. CONCLUSION: The results of the follow-up studies suggest that thromboembolic events may re-occur in patients with acute VTE after termination of treatment with both vitamin K-antagonists and ximelagatran.
Administration, Oral↗
Prophylaxis of thrombotic and embolic events in acute ischemic stroke with the low-molecular-weight heparin certoparin: results of the PROTECT Trial.
BACKGROUND AND PURPOSE: Patients with stroke are at substantial risk of thromboembolic complications and therefore require antithrombotic prophylaxis. To show the noninferiority of the low-molecular-weight heparin certoparin to unfractionated heparin (UFH) for the prevention of thromboembolic complications, we performed a randomized, double-blind, active-controlled multicenter trial in patients with acute ischemic stroke. METHODS: Overall, 545 patients were randomized within 24 hours of stroke onset to treatment with certoparin (3000 U anti-Xa OD; n=272) or UFH (5000 U TID; n=273) for 12 to 16 days. Patients with paresis of a leg and an National Institutes of Health Stroke Scale score of 4 to 30 points were included. The primary end point was a composite outcome of proximal deep vein thrombosis, pulmonary embolism, or death related to venous thromboembolism during treatment. Computed tomography was performed at trial entry, after 7 days, and when clinical deterioration occurred. RESULTS: The per-protocol analysis revealed 17 (7.0%) primary events in the certoparin group compared with 24 (9.7%) in the UFH group, thereby demonstrating noninferiority (P=0.0011), confirmed by intention-to-treat analysis (6.6% versus 8.8%; P=0.008). Major bleeding occurred during treatment in 3 patients allocated to certoparin (1.1%) and 5 patients allocated to UFH (1.8%). CONCLUSIONS: Certoparin (3000 U anti-Xa OD) is at least as effective and safe as UFH (TID) for the prevention of thromboembolic complications in patients with acute ischemic stroke.
Adolescent↗
Treatment of patients with a history of heparin-induced thrombocytopenia and anti-lepirudin antibodies with argatroban.
Patients with heparin-induced thrombocytopenia (HIT) type II require anticoagulation with non-heparin immediate acting anticoagulants. Danaparoid may cross react with HIT-antibodies and lepirudin may generate anti-lepirudin antibodies influencing anticoagulation. We hypothesised, that the synthetic small molecular thrombin inhibitor argatroban does not induce immunoglobulins reacting towards lepirudin in patients with anti-lepirudin antibodies in the history and that titration of the anticoagulation may be easier with argatroban. We report on the treatment of four patients of a study, which was terminated prematurely due to official warnings for a repeated use of lepirudin. Two patients each received argatroban and lepirudin intravenously. A blinded assessor adjusted the doses of the anticoagulants to 1.5-3.0 fold prolongation of the aPTT. Ecarin clotting time (ECT), concentrations of lepirudin (ELISA) and of argatroban (gas-chromatography with mass spectrometry), and the generation of lepirudin antibodies (ELISA) were measured. APTT-adjusted dosages for argatroban was 2.0-2.6 microg/kg.min and for lepirudin 48-149 microg/kg.h. ECT was prolonged 2.1 to 4.5-fold with lepirudin and 4 to 7-fold with argatroban. The concentration of lepirudin ranged between 750 and 1500 ng/ml and of argatroban between 400 and 1100 ng/ml. Patients on argatroban did not generate immunoglobulin IgG reacting towards lepirudin in contrast to both patients on lepirudin who developed anti-lepirudin antibodies. Both treatments were well tolerated. Despite the low number of patients argatroban seems to lead to a more stable anticoagulant response than lepirudin resulting in a lower variability of the dosage for prophylaxis or treatment of thromboembolism of patients with a history of HIT and lepirudin antibodies.
Aged↗
Comparison of two different ecarin clotting time methods.
BACKGROUND: Ecarin Clotting Time (ECT) assay specifically determines the inhibition of meizothrombin by direct thrombin inhibitors (DTI). Blood coagulation factor levels lowered by vitamin K antagonists (VKA) may prolong ECT. Concomitant treatment of VKA with DTI may influence differently the two published ECT methods. METHODS: Lepirudin (100-3,000 ng/ml), argatroban (300--3,000 ng/ml) and melagatran (30--1000 ng/ml) were added to normal plasma (NP; n=12) samples and to plasma of patients on stable vitamin K antagonist therapy with warfarin (VKAP; n=12). ECT assays were performed according to [5] (method 1) and according to [6] (method 2). Data were subjected to multifactorial variance analysis. RESULTS: Normal ranges were 35.5+/-2.8 s in NP versus 31.8+/-1.2 s in VKAP with method 1 (p< 0.001) and 44.3+/-3.9 s in NP vs. 51.4+/-8.3 s in VKAP with method 2 (p< 0.004). Besides the inhibitors (p<0.0001), the method used (p<0.0001) and the group (NP vs. VKAP, p=0.003) had an influence on the ECT. Inhibitors (p< 0.02) or method used (p< 0.03) and the group (NP vs. VKAP, p=0.0001) influenced also the ECT ratio. DISCUSSION: Both ECT methods are suitable for monitoring different DTIs over a large linear range with both methods during concomitant treatments with vitamin K antagonists. The ECT ratio improves but not abolishes the differences between the methods. Additive effects of vitamin K antagonists on ECT methods have to be taken into consideration in clinical routine.
Antithrombins↗
Argatroban treatment for patients with intolerance to heparin and hirudin.
Argatroban is a synthetic thrombin inhibitor that acts independently of any cofactor. It inhibits free as well as fibrin- and clot-bound thrombin. The clinical history of two patients is presented, both with previous allergic reactions toward heparin and hirudin. In both patients, antibodies against hirudin were documented. Argatroban was successfully used in both patients without any side effects. We conclude argatroban to be the drug of choice in patients with intolerance to heparin and hirudin. Moreover, genetic variations affecting the hepatic catabolism of argatroban might exist, because very different dosages of argatroban were needed in the two patients.
Adolescent↗
Effects of vitamin K antagonist phenprocoumon on activated partial thromboplastin time measurement of direct thrombin inhibitors.
The activated partial thromboplastin time (aPTT) is currently the most common test used to measure the anticoagulation intensity of heparins and direct thrombin inhibitors (DTIs). Vitamin K antagonists variably affect aPTT reagents. Interactions between heparin and DTIs occur during concurrent therapy. Three DTIs (lepirudin, argatroban, melagatran) and one unfractionated heparin (liquemin) were added to normal plasma (NP) samples (n = 23) and to vitamin K antagonist plasma (VKAP) samples (n = 23) of patients treated with phenprocoumon. Lepirudin and argatroban were added at concentrations from 300 to 3000 ng/ml, melagatran from 30 to 1000 ng/ml, and unfractionated heparin from 0.016 to 0.48 IU/ml. Wave parameters of clotting time and aPTT ratio curves were evaluated by multivariate analysis for inhibitors, aPTT reagents and NP and VKAP samples. Normal ranges resulting from NP samples were 34.5 +/- 1.0 s with Pathromtin SL and 33.9 +/- 0.8 s with Platelin LS. Normal ranges using VKAP were 52.8 +/- 2.6 s (Pathromtin SL) and 44.2 +/- 1.1 s (Platelin LS) (P < 0.0001). Variance analysis showed that inhibitors, plasmas (NP versus VKAP) and reagents influenced the wave characteristics of aPTT (s) (P < 0.0001) and aPTT ratios (P < 0.0001). Distinct statistical differences between aPTT reagents on one hand and normal versus vitamin K antagonist plasma on the other hand make a comparison of reported aPTT results difficult, especially during overlapping therapy with vitamin K antagonists.
Anticoagulants↗
Treatment of heparin-induced thrombocytopenia with fondaparinux.
Anticoagulation of patients with heparin-induced thrombocytopenia (HIT) may be limited by cross-reaction of HIT antibodies with danaparoid and generation of antibodies during therapy with lepirudin. We used fondaparinux to treat 6 patients with a history of HIT with thromboembolism and 2 patients with thrombocytopenia during low-molecular-weight heparin administration.
Adult↗
[Treatment of thrombosis with low-molecular-weight heparin. Comparison of body weight-adjusted and fixed dosage].
BACKGROUND: The treatment of deep vein thrombosis (DVT) has been simplified and become safer after introduction of low-molecular-weight heparin (LMWH). The dosage of LMWH was performed by body weight adjustment without dose-finding studies. DATA: In three large clinical trials, the improved efficacy and safety of body weight-independent fixed-dose LMWH Certoparin were demonstrated using 2 x 8,000 IU subcutaneously per day for the initial treatment of symptomatic acute DVT. The reduction of thrombus size after 14 days, determined with the Marder score, and the combined endpoint, consisting of recurrent thromboembolism, major bleeding and mortality, was lower over the initial treatment with LMWH compared to intravenous APTT-adjusted unfractionated heparin (UFH). The benefit of the clinical endpoints over 6 months was demonstrated in two clinical trials. CONCLUSION: Treatment of acute DVT is more effective and safer using fixeddose 2 x 8,000 IU Certoparin for the initial treatment compared to UFH.
Adult↗
Effects of lepirudin, argatroban and melagatran and additional influence of phenprocoumon on ecarin clotting time.
INTRODUCTION: Direct thrombin inhibitors (DTI) prolong the ecarin clotting time (ECT). Oral anticoagulants (OA) decrease prothrombin levels and thus interact with actions of DTIs on the ECT method during concomitant therapy. MATERIALS AND METHODS: Actions of lepirudin, argatroban and melagatran on ECT were investigated in normal plasma (NP) and in plasma of patients (n=23 each) on stable therapy with phenprocoumon (OACP). Individual line characteristics were tested statistically. RESULTS: Control ECT in OACP was prolonged compared to NP (50.1+/-0.9 vs. 45.7+/-0.8 s; p<0.001). Lepirudin prolonged the ECT linearly. Argatroban and melagatran delivered biphasic dose-response curves. OA showed additive effects on the ECT of lepirudin but not of argatroban and melagatran. Both in NP and OACP, the first and second slopes of melagatran were steeper compared to argatroban (primary analysis; p<0.001). When using the same drug, slopes in OACP were steeper than in NP (secondary analysis; p<0.001). At similar molar concentrations, the crossing points of both slopes were significantly higher with melagatran (323.1+/-11.0 s in NP and 333.2+/-8.2 s in OACP) than with argatroban (219.6+/-14.7 and 248.4+/-15.2 s) corresponding to ratios of 7.1+/-0.2 and 6.7+/-0.2 (melagatran) vs. 4.8+/-0.3 and 4.9+/-03 with argatroban (p<0.0001). DISCUSSION: The patterns of interactions between vitamin K antagonists and DTI effects are different for bivalent (increase of slope without affecting linearity) and monovalent inhibitors (slight increase or alteration of nonlinear slopes), but there are also differences between the two monovalent inhibitors on thrombin inhibition as determined by ECT.
Anticoagulants↗
Fixed-dose, body weight-independent subcutaneous low molecular weight heparin Certoparin compared with adjusted-dose intravenous unfractionated heparin in patients with proximal deep venous thrombosis.
Subcutaneous body weight-adjusted low molecular weight heparin (LMWH) has been proven as effective and safe as intravenous aPTT-adjusted unfractionated heparin (UFH) for the treatment of patients with acute deep venous thrombosis (DVT). In this study we evaluate the efficacy of the initial treatment of proximal DVT with a fixed-dose, body weight-independent application of the LMWH Certoparin with a six month follow-up. In a prospective, multicentre, randomized, active-controlled study 1220 patients with objectively diagnosed proximal DVT were randomly assigned to subcutaneous 8000 U anti-factor Xa of Certoparin twice daily for 10 to 14 days or intravenous aPTT-adjusted UFH for 5 to 8 days. Both regimen were followed by oral anticoagulation for 6 months. The primary end point was the rate of symptomatic and objectively confirmed thromboembolic events within 6 months. The aim of the study was to demonstrate the non-inferiority of the Certoparin regimen as compared to UFH. The per-protocol analysis revealed 22 (3.8%) thromboembolic events in the Certoparin group and 24 (4.3%) in patients assigned to UFH within 6 months, thereby proving the non-inferiority (p<0.01), confirmed by intent-to-treat analysis (p<0.001). Major bleeding occurred in 6 and 7 patients started on Certoparin or UFH during the treatment period. Thromboembolic events were equally distributed in body weight categories with < 50, 50-80 and >80 kg as followed: 0, 3.6% and 4.1% of patients for the Certoparin group and 0, 4.6% and 4.2% of patients for the UFH group. The same was true for major bleeding complications with 0, 2.9% and 1.5% for Certoparin and 0, 3.5% and 4.2% for UFH. Overall mortality was 1.9% in the Certoparin group and 2.7% in the UFH group. Fixed-dose body weight-independent subcutaneous LMWH Certoparin is at least as efficacious and safe as intravenous aPTT-adjusted UFH for the initial treatment of acute proximal DVT. This effect is maintained during a 6-months follow-up of treatment with oral anticoagulation.
Aged↗
Comparison of six-month outcome of patients initially treated for acute deep vein thrombosis with a low molecular weight heparin Certoparin at a fixed, body-weight-independent dosage or unfractionated heparin.
BACKGROUND AND OBJECTIVES: Body weight-adjusted subcutaneous low molecular weight heparin (LMWH) has been proven to be more effective and safer than aPTT-adjusted intravenous unfractionated heparin (UFH) for the initial treatment of patients with acute symptomatic deep venous thrombosis (DVT) based on analyses pooling the results of studies with different LMWHs. We investigated whether these findings hold for a particular LMWH by pooling the results of two independent studies. DESIGN AND METHODS: Patients with acute symptomatic proximal DVT (n=1758), proven by ascending phlebography or compression ultrasound, received either a fixed, body weight independent dose of 8,000 IU Certoparin b.i.d. (n=893) for 8.6 days or intravenous UFH (n=865) adjusted to an 1.5 to 3.0-fold prolongation of the aPTT for 12.0 days both followed by vitamin K-antagonists for 6 months. RESULTS: Venous thromboembolism (VTE) re-occurred in 5.1% and 3.1% (RRR 0.62, CI 0.39-0.98, 2p=0.04), major bleeding in 3.5% and 1.9% (RRR 0.55, CI 0.31-0.99, 2p=0.05), mortality in 3.6% and 2.1% (RRR 0.59, CI 0.34-1.04, 2p=0.08), and the composite outcome of all three events in 10.3% and 6.3% (RRR 0.61, CI 0.44 to 0.84, 2p=0.002) of patients at 6 months initially randomised to UFH and LMWH, respectively. INTERPRETATION AND CONCLUSIONS: The initial treatment of acute DVT with a fixed dose of the LMWH, certoparin, is more effective in reducing, over 6 months, the re-occurrence of VTE and the composite outcome of recurrent VTE, major bleeding, and mortality without any relation of the bodyweight of the patients to recurrent venous thromboembolism or major bleeding complications.
Anticoagulants↗
Association of changes in D-dimer and other coagulation markers with changes in Marder score after treatment of acute venous thrombosis.
AIM: Coagulation markers are sensitive tools to assess ongoing thrombus formation. An association between changes in these markers and changes in venographic Marder scores in patients with acute deep vein-thrombosis treated with low-molecular-weight (LMWH) or unfractionated heparin (UFH) has not been reported. METHODS: We investigated differences in coagulation parameters before and at the end of a twelve days the treatment of patients with an improvement versus no improvement of the venographic findings at the end of the treatment with LMWH (n = 48) and UFH (n = 41). RESULTS: Patients with lower values in the Marder score had lower D-dimer levels at day 12 compared to entry treated with UFH and LMWH (p < 0.001). Not improved Marder scores paralleled unchanged D-dimer levels at end of both treatments. Higher values of factor-Xa inhibition and Heptest assay (p < 0.001) were measured at the end of treatment in LMWH- in contrast to UFH-patients. Thrombin inhibition was lower and unchanged at day 12 in patients treated with LMWH and UFH, respectively. Thrombin generation inhibition and release of tissue-factor pathway inhibitor remained unchanged in both groups. CONCLUSION: An improved Marder score is associated with a decrease of D-dimer during UFH and LMWH treatment of deep vein-thrombosis.
Acute Disease↗
Low-molecular-weight heparin and dermatan sulfate end group-labeled with tyramine and fluorescein. Biochemical and biological characterization of the fluorescent-labeled heparin derivative.
To improve the understanding of the biological functions and pharmacology of heparin and dermatan sulfate, low-molecular-weight heparin (LMWH) and low-molecular-weight dermatan sulfate (LMWDS) were labeled with tyramine (T) by covalently linking T to the terminal residue of 2,5-anhydromannose (or 2,5-anhydrotalose for dermatan sulfate). The covalent labeling was demonstrated by nuclear magnetic resonance spectroscopy. The tyramine-labeled LMWH (LMWH-T) was also labeled with fluorescein (F) by further reacting it with fluorescein isothiocyanate. The fluoresceinated LMWH-T (LMWH-T,F ) was used to analyze biological functions on blood coagulation and binding to leukocytes. The biological activities on factor Xa and thrombin inhibition remained unchanged compared with the parent compound. Flow cytometric analysis of leukocytes demonstrated binding of the modified heparin to granulocytes, monocytes, and lymphocytes, the half-live being twice as long as the antifactor Xa activity. F-labeled heparin was displaced by unlabeled heparin from all three populations of leukocytes. Binding of heparin to leukocytes may play an important role in inflammation and atherosclerosis.
Animals↗
Monitoring of anticoagulant effects of direct thrombin inhibitors.
Monitoring of direct thrombin inhibitors with the activated partial thromboplastin time (aPTT) is limited by poor linearity and reproducibility. Recently, direct prothrombin activation methods have been developed for coagulation analysis: ecarin clotting time (ECT) and prothrombinase-induced clotting time (PiCT). Laboratory monitoring of the direct thrombin inhibitors lepirudin, argatroban, and melagatran was analyzed and compared with monitoring unfractionated heparin (UFH). Plasma samples of six healthy donors were spiked with lepirudin and argatroban extending to 3000 ng/mL, melagatran extending to 1000 ng/mL, and UFH up to 0.48 IU/mL. Clotting times of aPTT (two reagents), ECT, PiCT, and prothrombin time were determined in a KC 10, a micro instrument. At 3000 ng/mL ECT values were 339.1 +/- 25.0 seconds with lepirudin and 457.5 +/- 29.5 seconds with argatroban. ECT was 586.0 +/- 38.2 seconds with 1000 ng/mL melagatran. The PiCT method provided clotting times of 137.0 +/- 8.4 seconds with UFH, 128.0 +/- 23.4 seconds with lepirudin, and 151 +/- 23.9 seconds with argatroban, and 153.5 +/- 9.9 seconds with melagatran, with the concentrations mentioned. ECT is more sensitive to therapeutic drug concentration ranges than aPTT (prolongations of 3-7 versus 2-3). PiCT yields comparable results with direct thrombin inhibitors and UFH. This method could therefore be suitable for monitoring both drug groups.
Anticoagulants↗
Comparative antithrombotic potencies of direct thrombin inhibitors and low-molecular-weight heparins in an ex vivo human experimental thrombosis model.
Direct thrombin inhibitors (DTIs) such as hirudins and melagatran are currently developed for antithrombotic therapy. They should possess some advantages over the currently used low-molecular-weight heparins (LMWHs). They may also act through an inhibition of thrombin-induced platelet activation. The antithrombotic effects of DTIs and of LMWHs were investigated in an ex vivo thrombosis model with human blood in order to analyze the inhibition of thrombin-antithrombin as well as the platelet factor 4 formation. The data show that DTIs inhibit both fibrin formation and platelet activation, which is of clinical relevance especially for melagatran.
Antithrombin III↗
Fixed-dose versus adjusted-dose low molecular weight heparin for the initial treatment of patients with deep venous thrombosis.
Patients with acute deep vein thrombosis (DVT) were treated with a body-weight independent dosage of 2 x 8000 aXa IU low-molecular-weight heparin (LMWH) Certoparin. After the subcutaneous administration of 8000 IU Certoparin, pharmacodynamic parameters did not differ between patients and healthy volunteers, and the AUC of the anticoagulant effects were not related to body weight. Two clinical trials demonstrated a greater regression of thrombi and a lower occurrence of recurrent venous thromboembolism (VTE), major bleeding, and mortality within 14 days of initial therapy compared with intravenous heparin. D-dimer decreased, and anti-Xa activity increased in those patients with a regression of thrombosis. The benefit of the reduced occurrence of recurrent VTE, major bleeding, and mortality was maintained up to 6 months. Major bleeding was not related to the body weight in either treatment group. Treatment of acute DVT in adults with fixed dose of 2 x 8000 aXa IU LMWH Certoparin is more effective and safer than heparin.
Anticoagulants↗
Development of a high-pressure liquid chromatography method for diagnosis of heparin-induced thrombocytopenia.
Owing to the disadvantage of radioactivity of the carbon 14 serotonin release assay and the time-consuming procedure of the enzyme immunoassay, we developed a high-pressure liquid chromatography (HPLC) method to detect serotonin released from donor platelets in the presence of heparins and serum samples from patients with heparin-induced thrombocytopenia (HIT). Samples were analyzed from 60 healthy control subjects, 19 patients with HIT, and 20 patients without HIT after incubation with heparin, low-molecular-weight heparin (LMWH), and danaparoid. Serotonin release was measured from platelets, 300 x 10(3)/microL, by HPLC. Serotonin eluted as a single peak from the HPLC column. Serum samples from patients with HIT released 5.5 to 352.5 and 6.6 to 1,533.3 ng/mL of serotonin from platelets in the presence of 0.2 IU/mL of heparin and LMWH, respectively. In the presence of 0 IU/mL of heparin, LMWH, danaparoid, and control samples, less than 2.5 ng/mL of serotonin were released. The HPLC method permits a rapid, sensitive, and quantitative determination of serotonin released from donor platelets for laboratory confirmation of HIT.
Anticoagulants↗