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Alisa S Wolberg - One of the best experts on this subject based on the ideXlab platform.
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thrombin generating potential plasma Clot Formation and Clot lysis are impaired in patients with bleeding of unknown cause
Journal of Thrombosis and Haemostasis, 2019Co-Authors: Stefanie Hofer, Alisa S Wolberg, Silvia Koder, Ingrid Pabinger, Judit Rejto, Helmuth Haslacher, Johanna GebhartAbstract:BACKGROUND In a large proportion of patients with a mild to moderate bleeding tendency no diagnosis can be established (bleeding of unknown cause, BUC). OBJECTIVES To investigate possible dysfunctions in thrombin generation and plasma Clot Formation and lysis in patients with BUC from the Vienna Bleeding Biobank (VIBB). PATIENTS AND METHODS Thrombin generation and plasma Clot properties of 382 BUC patients were compared to those of 100 healthy controls and 16 patients with factor VIII (FVIII) activity ≤50%. RESULTS Thrombin generation was significantly impaired in BUC patients compared to healthy controls, exhibiting a prolonged lag time and time to peak and decreased maximum thrombin generation, velocity index, and area under the curve (AUC). The assessment of Clot Formation and lysis in BUC patients revealed a lower Clot Formation rate (Vmax), resulting in a longer TTP, increased absorbance (ΔAbs), and a shorter Clot lysis time (CLT) than in healthy controls. Comparing patients with FVIII activity ≤ 50% to those with BUC, parameters of thrombin generation and Clot Formation and lysis were either stronger or comparably impaired. Bleeding severity did not correlate with parameters of thrombin generation, Clot Formation, or Clot lysis. CONCLUSION Patients with BUC have an impaired hemostatic capacity reflected by a lower thrombin-generation potential, a lower Clot Formation rate, increased Clot turbidity, and shorter Clot lysis time, which might contribute to their increased bleeding tendency. Assays monitoring these parameters can alert physicians of hemostatic impairment and should be considered in situations where traditional hemostatic lab tests fail to reveal the clinical bleeding tendency.
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abnormal plasma Clot Formation and fibrinolysis reveal bleeding tendency in patients with partial factor xi deficiency
Blood Advances, 2018Co-Authors: Gillian N Gidley, Lori A Holle, John Burthem, Paula H B Boltonmaggs, Alisa S WolbergAbstract:: Individuals with factor XI (FXI) deficiency have a variable bleeding risk that cannot be predicted from plasma FXI antigen or activity. This limitation can result in under- or overtreatment of patients and risk of bleeding or thrombosis. Previously, plasma Clot fibrinolysis assays showed sensitivity to bleeding tendency in a small cohort of patients with severe FXI deficiency. Here, we determined the ability of plasma Clot Formation, structure, and fibrinolysis assays to predict bleeding tendency in a larger, independent cohort of patients with severe and partial FXI deficiency. Patients were characterized as nonbleeders or bleeders based on bleeding after tonsillectomy and/or dental extraction before diagnosis of FXI deficiency. Blood was collected in the absence or presence of the contact pathway inhibitor corn trypsin inhibitor (CTI). Clotting was triggered in platelet-poor plasma with tissue factor, CaCl2, and phospholipids in the absence and presence of thrombomodulin or tissue plasminogen activator. Clot Formation and fibrinolysis were assessed by turbidity and confocal microscopy. CTI-treated plasmas from bleeders showed significantly reduced Clot Formation and decreased resistance to fibrinolysis compared with plasmas from controls or nonbleeders. Differences were enhanced in the presence of CTI. A model that combines activated partial thromboplastin time with the rate of Clot Formation and area under the curve in fibrinolysis assays identifies most FXI-deficient bleeders. These results show assays with CTI-treated platelet-poor plasma reveal Clotting and Clot stability deficiencies that are highly associated with bleeding tendency. Turbidity-based fibrinolysis assays may have clinical utility for predicting bleeding risk in patients with severe or partial FXI deficiency.
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thrombin generation fibrin Clot Formation and hemostasis
Transfusion and Apheresis Science, 2008Co-Authors: Alisa S Wolberg, Robert A CampbellAbstract:Hemostatic Clot Formation entails thrombin-mediated cleavage of fibrinogen to fibrin. Previous in vitro studies have shown that the thrombin concentration present during Clot Formation dictates the ultimate fibrin structure. In most prior studies of fibrin structure, Clotting was initiated by adding thrombin to a solution of fibrinogen; however, Clot Formation in vivo occurs in an environment in which the concentration of free thrombin changes over the reaction course. These changes depend on local cellular properties and available concentrations of pro- and anti-coagulants. Recent studies suggest that abnormal thrombin generation patterns produce abnormally structured Clots that are associated with an increased risk of bleeding or thrombosis. Further studies of fibrin Formation during in situ thrombin generation are needed to understand fibrin Clot Formation in vivo.
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thrombin generation and fibrin Clot structure
Blood Reviews, 2007Co-Authors: Alisa S WolbergAbstract:Generation of a hemostatic Clot requires thrombin-mediated conversion of fibrinogen to fibrin. Previous in vitro studies have demonstrated that the thrombin concentration present at the time of gelation profoundly influences fibrin Clot structure. Clots formed in the presence of low thrombin concentrations are composed of thick fibrin fibers and are highly susceptible to fibrinolysis; while, Clots formed in the presence of high thrombin concentrations are composed of thin fibers and are relatively resistant to fibrinolysis. While most studies of Clot Formation have been performed by adding a fixed amount of purified thrombin to fibrinogen, Clot Formation in vivo occurs in a context of continuous, dynamic changes in thrombin concentration. These changes depend on the local concentrations of pro- and anti-coagulants and cellular activities. Recent studies suggest that patterns of abnormal thrombin generation produce Clots with altered fibrin structure and that these changes are associated with an increased risk of bleeding or thrombosis. Furthermore, it is likely that Clot structure also contributes to cellular events during wound healing. These findings suggest that studies explicitly evaluating fibrin Formation during in situ thrombin generation are warranted to explain and fully appreciate mechanisms of normal and abnormal fibrin Clot Formation in vivo.
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high dose factor viia improves Clot structure and stability in a model of haemophilia b
British Journal of Haematology, 2005Co-Authors: Alisa S Wolberg, G Allen, Dougald M Monroe, Ulla Hedner, Harold R Roberts, Maureane HoffmanAbstract:Factor IX (FIX) deficiency results in haemophilia B and high dose recombinant activated factor VII (rFVIIa) can decrease bleeding. Previously, we showed that FIX deficiency results in a reduced rate and peak of thrombin generation. We have now used plasma and an in vitro coagulation model to examine the effect of these changes in thrombin generation on fibrin Clot structure and stability. Low FIX delayed the Clot Formation onset and reduced the fibrin polymerisation rate. Clots formed without FIX were composed of thicker fibrin fibres than normal. rFVIIa shortened the Clot Formation onset time and improved the fibre structure of haemophilic Clots. We also examined Clot Formation in the presence of a fibrinolytic challenge by including tissue plasminogen activator or plasmin in the reaction milieu. In these assays, normal FIX levels supported Clot Formation; however, Clots did not form in the absence of FIX. rFVIIa partially restored haemophilic Clot Formation. These results were independent of the effects of the thrombin-activatable fibrinolysis inhibitor. Our data suggest that rFVIIa enhances haemostasis in haemophiliacs by increasing the thrombin generation rate to both promote Formation of a structurally normal Clot and improve Clot Formation and stability at sites with high endogenous fibrinolytic activities.
Maureane Hoffman - One of the best experts on this subject based on the ideXlab platform.
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high dose factor viia improves Clot structure and stability in a model of haemophilia b
British Journal of Haematology, 2005Co-Authors: Alisa S Wolberg, G Allen, Dougald M Monroe, Ulla Hedner, Harold R Roberts, Maureane HoffmanAbstract:Factor IX (FIX) deficiency results in haemophilia B and high dose recombinant activated factor VII (rFVIIa) can decrease bleeding. Previously, we showed that FIX deficiency results in a reduced rate and peak of thrombin generation. We have now used plasma and an in vitro coagulation model to examine the effect of these changes in thrombin generation on fibrin Clot structure and stability. Low FIX delayed the Clot Formation onset and reduced the fibrin polymerisation rate. Clots formed without FIX were composed of thicker fibrin fibres than normal. rFVIIa shortened the Clot Formation onset time and improved the fibre structure of haemophilic Clots. We also examined Clot Formation in the presence of a fibrinolytic challenge by including tissue plasminogen activator or plasmin in the reaction milieu. In these assays, normal FIX levels supported Clot Formation; however, Clots did not form in the absence of FIX. rFVIIa partially restored haemophilic Clot Formation. These results were independent of the effects of the thrombin-activatable fibrinolysis inhibitor. Our data suggest that rFVIIa enhances haemostasis in haemophiliacs by increasing the thrombin generation rate to both promote Formation of a structurally normal Clot and improve Clot Formation and stability at sites with high endogenous fibrinolytic activities.
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high dose factor viia improves Clot structure and stability in a model of haemophilia b
British Journal of Haematology, 2005Co-Authors: Alisa S Wolberg, Dougald M Monroe, Ulla Hedner, Harold R Roberts, Geoffrey A Allen, Maureane HoffmanAbstract:SummaryFactor IX (FIX) deficiency results in haemophilia B and high doserecombinant activated factor VII (rFVIIa) can decrease bleeding.Previously, we showed that FIX deficiency results in a reduced rate andpeak of thrombin generation. We have now used plasma and an in vitrocoagulation model to examine the effect of these changes in thrombingeneration on fibrin Clot structure and stability. Low FIX delayed the ClotFormation onset and reduced the fibrin polymerisation rate. Clots formedwithout FIX were composed of thicker fibrin fibres than normal. rFVIIashortened the Clot Formation onset time and improved the fibre structure ofhaemophilic Clots. We also examined Clot Formation in the presence of afibrinolytic challenge by including tissue plasminogen activator or plasmin inthe reaction milieu. In these assays, normal FIX levels supported ClotFormation; however, Clots did not form in the absence of FIX. rFVIIa partiallyrestored haemophilic Clot Formation. These results were independent of theeffects of the thrombin-activatable fibrinolysis inhibitor. Our data suggestthat rFVIIa enhances haemostasis in haemophiliacs by increasing thethrombin generation rate to both promote Formation of a structurallynormal Clot and improve Clot Formation and stability at sites with highendogenous fibrinolytic activities.Keywords: Clot, fibrin, fibrinolysis, haemophilia, recombinant factor VIIa,plasmin.
Verena Schroeder - One of the best experts on this subject based on the ideXlab platform.
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MASP-1 of the complement system enhances Clot Formation in a microvascular whole blood flow model
2018Co-Authors: Lorenz Jenny, József Dobó, Péter Gál, Gábor Pál, Wilbur A. Lam, Verena SchroederAbstract:The complement and coagulation systems closely interact with each other. These interactions are believed to contribute to the proinflammatory and prothrombotic environment involved in the development of thrombotic complications in many diseases. Complement MASP-1 (mannan-binding lectin-associated serine protease-1) activates coagulation factors and promotes Clot Formation. However, this was mainly shown in purified or plasma-based static systems. Here we describe the role of MASP-1 and complement activation in fibrin Clot Formation in a microvascular, whole blood flow model. This microfluidic system simulates blood flow through microvessels at physiological flow and shear rates and represents the closest model system to human physiology so far. It features parallel microchannels cultured with endothelial cells in a transparent microfluidic chip allowing real-time evaluation of Clot Formation by confocal microscopy. To test their effects on Clot Formation, we added the following activators or inhibitors (individually or in combination) to whole blood and performed perfusion experiments: rMASP-1cf (recombinant active form of MASP-1), complement activator zymosan, selective MASP-1 inhibitor SGMI-1 (based on the Schistocerca gregaria protease inhibitor scaffold), classical pathway inhibitor rSALO (recombinant salivary anti-complement from Lutzomyia longipalpis). Addition of rMASP-1cf resulted in accelerated fibrin Clot Formation while addition of SGMI-1 delayed it. Complement activation by zymosan led to increased Clot Formation and this effect was partially reversed by addition of rSALO and almost abolished in combination with SGMI-1. We show for the first time a strong influence of MASP-1, complement activation and pathway-specific inhibition on coagulation in a microvascular flow system that is closest to human physiology, further underpinning the in vivo relevance of coagulation and complement interactions.
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Effects of MASP-1 of the complement system on activation of coagulation factors and plasma Clot Formation. PLoS One 2012; 7: e35690
2016Co-Authors: Katharina Hess, Ramzi Ajjan, Fladia Phoenix, Verena SchroederAbstract:Background: Numerous interactions between the coagulation and complement systems have been shown. Recently, links between coagulation and mannan-binding lectin-associated serine protease-1 (MASP-1) of the complement lectin pathway have been proposed. Our aim was to investigate MASP-1 activation of factor XIII (FXIII), fibrinogen, prothrombin, and thrombin-activatable fibrinolysis inhibitor (TAFI) in plasma-based systems, and to analyse effects of MASP-1 on plasma Clot Formation, structure and lysis. Methodology/Principal Findings: We used a FXIII incorporation assay and specific assays to measure the activation products prothrombin fragment F1+2, fibrinopeptide A (FPA), and activated TAFI (TAFIa). Clot Formation and lysis were assessed by turbidimetric assay. Clot structure was studied by scanning electron microscopy. MASP-1 activated FXIII and, contrary to thrombin, induced FXIII activity faster in the Val34 than the Leu34 variant. MASP-1-dependent generation of F1+2, FPA and TAFIa showed a dose-dependent response in normal citrated plasma (NCP), albeit MASP-1 was much less efficient than FXa or thrombin. MASP-1 activation of prothrombin and TAFI cleavage were confirmed in purified systems. No FPA generation was observed in prothrombin-depleted plasma. MASP-1 induced Clot Formation in NCP, affected Clot structure, and prolonged Clot lysis. Conclusions/Significance: We show that MASP-1 interacts with plasma Clot Formation on different levels and influence
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effects of masp 1 of the complement system on activation of coagulation factors and plasma Clot Formation
PLOS ONE, 2012Co-Authors: Katharina Hess, József Dobó, Péter Gál, Verena Schroeder, Ramzi Ajjan, Fladia PhoenixAbstract:Background Numerous interactions between the coagulation and complement systems have been shown. Recently, links between coagulation and mannan-binding lectin-associated serine protease-1 (MASP-1) of the complement lectin pathway have been proposed. Our aim was to investigate MASP-1 activation of factor XIII (FXIII), fibrinogen, prothrombin, and thrombin-activatable fibrinolysis inhibitor (TAFI) in plasma-based systems, and to analyse effects of MASP-1 on plasma Clot Formation, structure and lysis. Methodology/Principal Findings We used a FXIII incorporation assay and specific assays to measure the activation products prothrombin fragment F1+2, fibrinopeptide A (FPA), and activated TAFI (TAFIa). Clot Formation and lysis were assessed by turbidimetric assay. Clot structure was studied by scanning electron microscopy. MASP-1 activated FXIII and, contrary to thrombin, induced FXIII activity faster in the Val34 than the Leu34 variant. MASP-1-dependent generation of F1+2, FPA and TAFIa showed a dose-dependent response in normal citrated plasma (NCP), albeit MASP-1 was much less efficient than FXa or thrombin. MASP-1 activation of prothrombin and TAFI cleavage were confirmed in purified systems. No FPA generation was observed in prothrombin-depleted plasma. MASP-1 induced Clot Formation in NCP, affected Clot structure, and prolonged Clot lysis. Conclusions/Significance We show that MASP-1 interacts with plasma Clot Formation on different levels and influences fibrin structure. Although MASP-1-induced fibrin Formation is thrombin-dependent, MASP-1 directly activates prothrombin, FXIII and TAFI. We suggest that MASP-1, in concerted action with other complement and coagulation proteins, may play a role in fibrin Clot Formation.
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influence of blood coagulation factor xiii and fxiii val34leu on plasma Clot Formation measured by thrombelastography
Thrombosis Research, 2001Co-Authors: Verena Schroeder, Tushar Chatterjee, H P KohlerAbstract:Blood coagulation factor XIII (FXIII) plays an important role in the final stage of the blood coagulation process. Thrombelastography (TEG) enables global assessment of the hemostatic function. The present study tested for the first time the specificity and sensitivity of the rotation thrombelastography (ROTEG: rotation thrombelastography) method for the influence of FXIII and the FXIIIVal34Leu polymorphism on thrombelastograms measured in citrated plasma. Three thrombelastographic parameters were determined in (a) citrated pool plasma, (b) FXIII-deficient plasma, (c) different mixtures of both, and (d) in 60 plasma samples genotyped for FXIIIVal34Leu. Thrombelastograms from FXIII-deficient plasma were significantly smaller than those from pool plasma (8 mm vs. 20.9 mm). Increasing amounts of pool plasma added to FXIII-deficient plasma led to an increase in maximum Clot firmness (MCF). FXIIIVal34Leu showed an influence on Clot Formation time (CFT) values, which decreased with increasing number of Leu alleles. The difference between the wild type and the homozygote mutant genotype was statistically significant (median 185.3 vs. 86.0 s, P=.031). ROTEG is a simple but effective method for the investigation of FXIII function in plasma. The ROTEG method has shown to be not only specific for the FXIII influence, as effects exclusively dependent on FXIII could be observed, but also sensitive, as already smallest amounts of FXIII could be detected. Additionally, the impact of a common genetic polymorphism on ROTEG could be shown for the first time.
Kenichi A Tanaka - One of the best experts on this subject based on the ideXlab platform.
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the impact of hematocrit on fibrin Clot Formation assessed by rotational thromboelastometry
Anesthesia & Analgesia, 2012Co-Authors: Satoru Ogawa, Daniel Bolliger, Fania Szlam, Takashi Nishimura, Edward P Chen, Kenichi A TanakaAbstract:BACKGROUND Rotational thromboelastometry (ROTEM®)-based FIBTEM is used perioperatively to assess the extent of fibrin polymerization in whole blood. In FIBTEM, cytochalasin D eliminates the contribution of platelets to whole blood Clotting, but changing levels in fibrin(ogen) and erythrocytes may differently affect Clot Formation. Because dynamic changes of hematocrit are not reflected in plasma fibrinogen measurements, we hypothesized that the lack of erythrocytes in isolated plasma measurements would affect the relationship between the Clauss method and whole blood-based FIBTEM during cardiac surgery. Therefore, in the current study we investigated the influence of perioperative hematocrit changes on FIBTEM and fibrinogen measurements. METHODS Blood samples were collected from 6 consenting healthy volunteers. FIBTEM tests were run before and after serial in vitro dilutions of whole blood with saline or autologous plasma (5:1, 2:1, and 1:1 v/v). We then evaluated the relationship between FIBTEM-maximal Clot firmness (MCF) and the Clauss fibrinogen method in relation to hematocrit values before and after cardiac surgery. Pearson correlation coefficients were determined between laboratory test results and ROTEM variables. RESULTS Upon in vitro hematocrit reduction, FIBTEM-MCF was progressively decreased depending on the extent of saline dilution, but it was increased by 31% after 1:1 volume replacement with autologous plasma (P 30%) (r = 0.88 and 0.67, respectively). CONCLUSIONS Perioperative changes in hematocrit affect the correlation between plasma fibrinogen levels and FIBTEM-MCF values. The higher correlation between FIBTEM-MCF and plasma fibrinogen with lower hematocrit (<25%) indicates that FIBTEM is a practical method to determine the need for fibrinogen replacement in bleeding patients who typically develop perioperative anemia.
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principles and practice of thromboelastography in clinical coagulation management and transfusion practice
Transfusion Medicine Reviews, 2012Co-Authors: Kenichi A Tanaka, Daniel Bolliger, Manfred D SeebergerAbstract:In the recent years, thromboelastography has become a popular monitoring device for hemostasis and transfusion management in major surgery, trauma, and hemophilia. Thromboelastography is performed in whole blood and assesses the viscoelastic property of Clot Formation under low shear condition. Thromboelastography can be performed with a variety of activator and inhibitors at different concentrations representing the most important factors for different intervals and Clot Formation variables reported in multiple studies and algorithms. Furthermore, fibrinogen levels and platelet counts have a major influence on thromboelastographic variables. In addition, differences in patient populations, devices, and preanalytical conditions contribute to some conflicting findings in different studies.
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improved Clot Formation by combined administration of activated factor vii novoseven and fibrinogen haemocomplettan p
Anesthesia & Analgesia, 2008Co-Authors: Kenichi A Tanaka, Fania Szlam, Taro Taketomi, Andreas Calatzis, Jerrold H LevyAbstract:BACKGROUND: Recombinant activated factor VII (rFVIIa) is increasingly used for treating refractory bleeding after cardiac surgery. However, hemostasis also depends on coagulation factors, including fibrinogen, which stabilizes platelet plugs at sites of vascular injury. We compared the hemostatic effects of rFVIIa, fibrinogen, or their combination. METHODS: Blood samples were obtained from 12 volunteers and from 7 patients after cardiopulmonary bypass (CPB). The in vitro effects of rFVIIa (1.5 μg/mL), fibrinogen (100 mg/dL), and the combination were evaluated under simulated coagulopathy in volunteer plasma using heparin (0.1 U/mL) or tissue plasminogen activator (0.1 μg/mL). Hemostatic interventions were compared using thromboelastometry, which measures Clotting time (CT, s), angle of thrombus Formation, and maximal Clot firmness (MCF, mm). The Thrombinoscope™ was used to quantitate thrombin generation after addition of fibrinogen and/or rFVIIa. RESULTS: In heparinized volunteer plasma, rFVIIa shortened CT (1st and 3rd quartiles) from 663 (522–736) to 435 (397–531) s, but it did not affect MCF. Fibrinogen increased MCF from 26.0 (24.4–26.7) to 30.5 (26.3–31.5) mm without affecting CT. The combination of rFVIIa and fibrinogen in heparinized samples was most effective in improving CT to 359 (324–522) s and MCF to 29 (27.8–31.0) mm. In tissue plasminogen activator-treated volunteer plasma, fibrinolysis increased by more than 45% by the addition of rFVIIa. After CPB, both CT and MCF were most improved with coadministration of rFVIIa and fibrinogen. Thrombinoscope evaluation demonstrated that rFVIIa decreased the lag time and increased peak thrombin generation, whereas fibrinogen had no effect. CONCLUSION: The onset of fibrin Formation and thrombin generation were shortened after rFVIIa addition, but fibrin Clot strength was only increased after fibrinogen supplementation. In vitro Clot Formation was most improved by using both rFVIIa and fibrinogen in whole blood after CPB.
Jorgen Ingerslev - One of the best experts on this subject based on the ideXlab platform.
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a direct thrombin inhibitor studied by dynamic whole blood Clot Formation haemostatic response to ex vivo addition of recombinant factor viia or activated prothrombin complex concentrate
Thrombosis and Haemostasis, 2006Co-Authors: Benny Sorensen, Jorgen IngerslevAbstract:Direct thrombin inhibitors have proven efficacious in prevention of venous thromboembolism. Bleeding complications are rare, but in case of acute serious bleeding,an effective and instant haemostatic intervention may be required. In the present study it was demonstrated that the direct thrombin inhibitor melagatran induces dose-dependent abnormalities in whole blood (WB) Clotting profiles as recorded by a recently described modified thrombelastographic model, and that rFVIIa or APCC are capable of improving the haemostatic capacity. Experiments were performed using WB from 30 healthy males. In-vitro titration experiments (n=10) with addition of melagatran to WB corresponding to plasma concentrations ranging from 0 to 5.0 μM (12 steps) showed a dose-dependent prolongation of the Clot initiation and characteristic decrease of the maximum rate of Clot propagation. In-vitro intervention studies (n=20) were completed with four different concentrations of melagatran as well as addition of four different levels of rFVIIa or APCC. At all tested concentrations of melagatran, rFVIIa significantly shortened the melagatran-induced prolonged Clot initiation but induced only minor improvements of the reduced Clot propagation. In contrast, APCC significantly and dose-dependently shortened the Clot initiation and accelerated the Clot propagation. In conclusion, our thrombelastographic model appears useful for evaluating the effect of direct thrombin inhibitors on dynamicWB Clot Formation and rFVIIa, but especially APCC significantly improved theWB Clot Formation.The pronounced stabilizing effect of APCC may be caused by its content of prothrombin and activated coagulation factors.
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melagatran and dynamic whole blood Clot Formation haemostatic response to ex vivo recombinant factor viia and activated prothrombin complex concentrate
Blood, 2004Co-Authors: Benny Sorensen, Stefan Carlsson, Margareta Elg, Jorgen IngerslevAbstract:Abstract The direct thrombin inhibitor melagatran (Exanta™, Astra Zeneca, Sweden) has proven efficient for the prevention and treatment of thromboembolism. Major bleeding complications are rare and may often be managed by discontinuation of the drug; however, in some cases of acute serious bleeding, an effective and instant haemostatic intervention may be needed. Potential haemostatic agents may include recombinant factor VIIa (rFVIIa - NovoSeven®, Novo Nordisk, Denmark) or activated prothrombin complex concentrate (APCC - Feiba®, Baxter, Austria). We hypothesized that melagatran induces abnormal whole blood (WB) Clotting profiles and rFVIIa as well as APCC may improve the deteriorated Clotting profiles. This study aimed to investigate the effect of ex vivo addition of melagatran to WB from healthy males and explore the haemostatic potential of rFVIIa and APCC. Following informed consent, 15 healthy males with an average age of 34 years were enrolled for blood sampling. Continuous WB coagulation profiles were recorded by ROTEG® thrombelastography employing activation with minute amounts of tissue factor (Innovin® final dilution 1:17,000 ~0.35pM). The initiation phase of WB Clot Formation was defined by the Clotting time (CT - sec). Coagulation raw data were processed to provide dynamic parameters that concur with the propagation of WB coagulation such as maximum velocity (MaxVel - mm*100/sec) and time to maximum velocity (t, MaxVel - sec). Titration experiments (n=10) with ex vivo addition of melagatran to WB corresponding plasma concentrations ranging from 0 to 5.0 μM (12 steps) showed a significant and dose dependent prolongation of the CT and t, MaxVel. The MaxVel of WB Clot Formation was initially reduced from average 13.8 mm*100/sec (12.2-15.4, 95 % CI) to a plateau level of average 9.6 (7.5–12.2) at concentrations of melagatran ranging from 0.125 μM to 0.50 μM. A further and progressive decline in MaxVel was observed at concentrations of melagatran exceeding 1.0μM. Intervention studies (n=10) were performed ex vivo on WB spiked with melagatran at 0.25, 0.50, 1.0, and 2.0 μM followed by ex vivo addition of rFVIIa at concentrations of 25, 50, 100, and 200 nM or APCC at concentration of 0.5, 1.0, 2.0, and 4.0 U/mL. In all tested concentrations of melagatran, rFVIIa significantly shortened the CT and t, MaxVel, while the reduced MaxVel was not accelerated. No dose-response effect of rFVIIa was detected. In contrast, at all concentration of melagatran, APCC significantly and dose dependently shortened the CT, the t, MaxVel as well as increased the MaxVel. As compared to rFVIIa, the effect of APCC was statistically more potent. At melagatran 0.25 μM, APCC at 1.0, 2.0, and 4.0 U/mL normalized the MaxVel. In all other experimental settings, rFVIIa or APCC did not normalize the dynamic WB coagulation parameters following anticoagulation with melagatran. In conclusion, melagatran induces unique changes of dynamic WB Clot Formation as illustrated by the prolonged initiation and plateau interval of MaxVel in Clot propagation. rFVIIa as well as APCC significantly improved the WB Clot Formation, although reversal of melagatran anticoagulation was not obtained. The more pronounced effect of APCC may be caused by addition of prothrombin and activated coagulation factors. However, this intervention may be less safe than use of rFVIIa.