The Experts below are selected from a list of 1137 Experts worldwide ranked by ideXlab platform
Xinkang Wang - One of the best experts on this subject based on the ideXlab platform.
-
effects of plasma kallikrein deficiency on haemostasis and thrombosis in mice murine ortholog of the fletcher trait
Thrombosis and Haemostasis, 2012Co-Authors: J E Bird, Xinkang Wang, William A Schumacher, P L Smith, J P Revelli, F Barbera, Dietmar A SeiffertAbstract:Plasma kallikrein is a multifunctional serine protease involved in contact activation of coagulation. Deficiency in humans is characterised by prolonged activated partial thromboplastin Time (aPTT); however, the balance between thrombosis and haemostasis is not fully understood. A study of plasma kallikrein-deficient mice revealed increased aPTT, without prolonged Bleeding Time. Prekallikrein antisense oligonucleotide (ASO) treatment in mice suggested potential for a positive therapeutic index. The current goal was to further define the role of plasma kallikrein in coagulation. Blood pressure and heart rate were normal in plasma kallikrein-deficient mice, and mice were completely protected from occlusion (100 ± 1.3% control flow) in 3.5% FeCl3 -induced arterial thrombosis versus heterozygotes (20 ± 11.4%) and wild-type littermates (8 ± 0%). Vessels occluded in 8/8 wild-type, 7/8 heterozygotes, and 0/8 knockouts. Anti-thrombotic protection was less pronounced in 5% FeCl3-induced arterial injury. Integrated blood flow was 8 ± 0% control in wild-type and heterozygotes, and significantly (p<0.01) improved to 43 ± 14.2% in knockouts. The number of vessels occluded was similar in all genotypes. Thrombus weight was significantly reduced in knockouts (-47%) and heterozygotes (-23%) versus wild-type in oxidative venous thrombosis. Average Tail Bleeding Time increased modestly in knockout mice compared to wild-type. Average renal Bleeding Times were similar in all genotypes. These studies confirm and extend studies with prekallikrein ASO, and demonstrate that plasma kallikrein deletion prevents occlusive thrombus formation in mice with a minimal role in provoked Bleeding. Additional support for the significance of the intrinsic pathway in the coagulation cascade is provided, as well as for a potential new anti-thrombotic approach.
-
effects of factor xi deficiency on ferric chloride induced vena cava thrombosis in mice
Journal of Thrombosis and Haemostasis, 2006Co-Authors: Xinkang Wang, Patricia L Smith, Meiyin Hsu, David Gailani, William A Schumacher, Martin L Ogletree, Dietmar A SeiffertAbstract:Summary. Background: Increased plasma levels of coagulation factor (F) XI are a risk factor for venous thrombosis. Objective: To further explore the relationship between FXI and venous thrombosis, we evaluated FXI-deficient and wild-type mice in a ferric chloride (FeCl3)-induced vena cava thrombosis model. Methods and Results: Thrombosis was induced by 3-min topical application of filter papers containing increasing concentrations of FeCl3 and the thrombus was measured at 30 min. In contrast to wild-type mice, FXI-deficient mice failed to form a thrombus with 5% FeCl3, and were partially protected against 7.5% and 10% FeCl3, respectively. The protective effect was substantially stronger than a high dose of heparin (1000 units kg−1, i.v.), clopidogrel (30 mg kg−1, p.o.) or argatroban (30 mg kg−1, i.p.). These antithrombotic agents resulted in off-scale Bleeding in a Tail Bleeding Time assay, whereas the Bleeding Time of FXI-deficient mice was unchanged compared to wild-type mice. In addition to its known effect on the coagulation cascade, enhanced clot lysis was demonstrated in FXI-deficient mouse and human plasma compared to those supplemented with FXIa. Conclusion: Given the strong antithrombotic efficacy (possibly contributed by strong anticoagulant activity associated with increased fibrinolytic activity) and mild Bleeding diathesis associated with FXI deficiency, therapeutic inhibition of FXI may be a reasonable therapeutic strategy to treat or prevent venous thrombosis.
-
murine model of ferric chloride induced vena cava thrombosis evidence for effect of potato carboxypeptidase inhibitor
Journal of Thrombosis and Haemostasis, 2006Co-Authors: Xinkang Wang, Martin L Ogletree, P L Smith, William A SchumacherAbstract:Summary. Background/objective: Thrombin-activatable fibrinolysis inhibitor (TAFI) is a plasma carboxypeptidase that renders a fibrin-containing thrombus less sensitive to lysis. In the present study, we describe the development of a murine model of vena cava thrombosis and its use to characterize the antithrombotic activity of potato carboxypeptidase inhibitor (PCI) of TAFIa (activated TAFI) in mice. Methods/results: Vena cava thrombosis was induced by various concentrations of FeCl3 in C57BL/6 mice. A relatively mild stimulus (3.5% FeCl3) induced thrombosis that was consistent and sensitive to reference antithrombotic agents such as clopidogrel and heparin. Dose–response studies identified a PCI dose (5 mg kg−1 bolus plus 5 mg kg−1 h−1, i.v.) that produced a maximum 45% decrease in vena cava thrombus mass as assessed by protein content (n = 8, P < 0.01 compared to vehicle) in the 3.5% FeCl3-induced model without exogenous tissue plasminogen activator administration. In contrast, PCI had no effect on 3.5% FeCl3-induced carotid artery thrombosis in mice. In a Tail transection Bleeding model, the 5 mg kg−1 bolus plus 5 mg kg−1 h−1 dose of PCI increased Tail-Bleeding Time up to 3.5 Times control (n = 8, P < 0.05). The ex vivo activity of antithrombotic doses of PCI was also demonstrated by the enhanced lysis of whole blood clots formed in a thrombelastograph with the addition of a sub-threshold concentration of tPA. Conclusion: These studies provide evidence for a role of TAFIa in venous thrombosis in mice, and describe an optimized vena cava injury model appropriate for the evaluation of antithrombotic drugs and the characterization of novel therapeutic targets.
-
effects of factor ix or factor xi deficiency on ferric chloride induced carotid artery occlusion in mice
Journal of Thrombosis and Haemostasis, 2005Co-Authors: Xinkang Wang, Patricia L Smith, Meiyin Hsu, William A Schumacher, Martin L Ogletree, Dietmar A Seiffert, Qiufang Cheng, Giora Z Feuerstein, David GailaniAbstract:Summary. Factor XI (FXI) and factor IX (FIX) are zymogens of plasma serine proteases required for normal hemostasis. The purpose of this work was to evaluate FXI and FIX as potential therapeutic targets by means of a refined ferric chloride (FeCl3)-induced arterial injury model in factor-deficient mice. Various concentrations of FeCl3 were used to establish the arterial thrombosis model in C57BL/6 mice. Carotid artery blood flow was completely blocked within 10 min in C57BL/6 mice by application of 3.5% FeCl3. In contrast, FXI- and FIX-deficient mice were fully protected from occlusion induced by 5% FeCl3, and were partially protected against the effect of 7.5% FeCl3. The protective effect was comparable to very high doses of heparin (1000 units kg−1) and substantially more effective than aspirin. While FXI and FIX deficiencies were indistinguishable in the carotid artery injury model, there was a marked difference in a Tail-Bleeding-Time assay. FXI-deficient and wild-type mice have similar Bleeding Times, while FIX deficiency was associated with severely prolonged Bleeding Times (>5.8-fold increase, P < 0.01). Given the relatively mild Bleeding diathesis associated with FXI deficiency, therapeutic inhibition of FXI may be a reasonable strategy for treating or preventing thrombus formation.
-
an optimized murine model of ferric chloride induced arterial thrombosis for thrombosis research
Thrombosis Research, 2005Co-Authors: Xinkang WangAbstract:Abstract Introduction/Objectives Animal models are important tools in thrombosis research and preclinical drug development. Ferric chloride has been widely used to induce arterial thrombosis in a variety of species. However, almost all previous reports applied a very high concentration of ferric chloride (10–60%) to induce thrombus formation leading to difficulties in evaluating the efficacy of antithrombotic agents. Thus, the purpose of this study was to refine the ferric-chloride-induced thrombosis model to be better suited for thrombosis research. Methods and results Dose-dependent study was used to identify a threshold concentration of ferric chloride sufficient for consistent occlusion (as reflected by the Doppler blood flow) of the carotid artery in C57BL/6 mice. Ferric chloride concentration at or about a threshold of 2.5% was found to be sensitive to anticoagulant (e.g., heparin) and antiplatelet (e.g., clopidogrel) agents. In contrast, the vessel rapidly occluded at or above 5% ferric chloride concentration despite pretreatment with the antithrombotic agents, even at doses that exerted maximal prolongation of Tail Bleeding Time. Conclusions Our study provides a simple, sensitive and highly controlled method for limiting vessel injury in mice to better detect the efficacy of antithrombotic drugs and/or evaluate therapeutic targets.
William A Schumacher - One of the best experts on this subject based on the ideXlab platform.
-
effects of plasma kallikrein deficiency on haemostasis and thrombosis in mice murine ortholog of the fletcher trait
Thrombosis and Haemostasis, 2012Co-Authors: J E Bird, Xinkang Wang, William A Schumacher, P L Smith, J P Revelli, F Barbera, Dietmar A SeiffertAbstract:Plasma kallikrein is a multifunctional serine protease involved in contact activation of coagulation. Deficiency in humans is characterised by prolonged activated partial thromboplastin Time (aPTT); however, the balance between thrombosis and haemostasis is not fully understood. A study of plasma kallikrein-deficient mice revealed increased aPTT, without prolonged Bleeding Time. Prekallikrein antisense oligonucleotide (ASO) treatment in mice suggested potential for a positive therapeutic index. The current goal was to further define the role of plasma kallikrein in coagulation. Blood pressure and heart rate were normal in plasma kallikrein-deficient mice, and mice were completely protected from occlusion (100 ± 1.3% control flow) in 3.5% FeCl3 -induced arterial thrombosis versus heterozygotes (20 ± 11.4%) and wild-type littermates (8 ± 0%). Vessels occluded in 8/8 wild-type, 7/8 heterozygotes, and 0/8 knockouts. Anti-thrombotic protection was less pronounced in 5% FeCl3-induced arterial injury. Integrated blood flow was 8 ± 0% control in wild-type and heterozygotes, and significantly (p<0.01) improved to 43 ± 14.2% in knockouts. The number of vessels occluded was similar in all genotypes. Thrombus weight was significantly reduced in knockouts (-47%) and heterozygotes (-23%) versus wild-type in oxidative venous thrombosis. Average Tail Bleeding Time increased modestly in knockout mice compared to wild-type. Average renal Bleeding Times were similar in all genotypes. These studies confirm and extend studies with prekallikrein ASO, and demonstrate that plasma kallikrein deletion prevents occlusive thrombus formation in mice with a minimal role in provoked Bleeding. Additional support for the significance of the intrinsic pathway in the coagulation cascade is provided, as well as for a potential new anti-thrombotic approach.
-
effects of factor xi deficiency on ferric chloride induced vena cava thrombosis in mice
Journal of Thrombosis and Haemostasis, 2006Co-Authors: Xinkang Wang, Patricia L Smith, Meiyin Hsu, David Gailani, William A Schumacher, Martin L Ogletree, Dietmar A SeiffertAbstract:Summary. Background: Increased plasma levels of coagulation factor (F) XI are a risk factor for venous thrombosis. Objective: To further explore the relationship between FXI and venous thrombosis, we evaluated FXI-deficient and wild-type mice in a ferric chloride (FeCl3)-induced vena cava thrombosis model. Methods and Results: Thrombosis was induced by 3-min topical application of filter papers containing increasing concentrations of FeCl3 and the thrombus was measured at 30 min. In contrast to wild-type mice, FXI-deficient mice failed to form a thrombus with 5% FeCl3, and were partially protected against 7.5% and 10% FeCl3, respectively. The protective effect was substantially stronger than a high dose of heparin (1000 units kg−1, i.v.), clopidogrel (30 mg kg−1, p.o.) or argatroban (30 mg kg−1, i.p.). These antithrombotic agents resulted in off-scale Bleeding in a Tail Bleeding Time assay, whereas the Bleeding Time of FXI-deficient mice was unchanged compared to wild-type mice. In addition to its known effect on the coagulation cascade, enhanced clot lysis was demonstrated in FXI-deficient mouse and human plasma compared to those supplemented with FXIa. Conclusion: Given the strong antithrombotic efficacy (possibly contributed by strong anticoagulant activity associated with increased fibrinolytic activity) and mild Bleeding diathesis associated with FXI deficiency, therapeutic inhibition of FXI may be a reasonable therapeutic strategy to treat or prevent venous thrombosis.
-
murine model of ferric chloride induced vena cava thrombosis evidence for effect of potato carboxypeptidase inhibitor
Journal of Thrombosis and Haemostasis, 2006Co-Authors: Xinkang Wang, Martin L Ogletree, P L Smith, William A SchumacherAbstract:Summary. Background/objective: Thrombin-activatable fibrinolysis inhibitor (TAFI) is a plasma carboxypeptidase that renders a fibrin-containing thrombus less sensitive to lysis. In the present study, we describe the development of a murine model of vena cava thrombosis and its use to characterize the antithrombotic activity of potato carboxypeptidase inhibitor (PCI) of TAFIa (activated TAFI) in mice. Methods/results: Vena cava thrombosis was induced by various concentrations of FeCl3 in C57BL/6 mice. A relatively mild stimulus (3.5% FeCl3) induced thrombosis that was consistent and sensitive to reference antithrombotic agents such as clopidogrel and heparin. Dose–response studies identified a PCI dose (5 mg kg−1 bolus plus 5 mg kg−1 h−1, i.v.) that produced a maximum 45% decrease in vena cava thrombus mass as assessed by protein content (n = 8, P < 0.01 compared to vehicle) in the 3.5% FeCl3-induced model without exogenous tissue plasminogen activator administration. In contrast, PCI had no effect on 3.5% FeCl3-induced carotid artery thrombosis in mice. In a Tail transection Bleeding model, the 5 mg kg−1 bolus plus 5 mg kg−1 h−1 dose of PCI increased Tail-Bleeding Time up to 3.5 Times control (n = 8, P < 0.05). The ex vivo activity of antithrombotic doses of PCI was also demonstrated by the enhanced lysis of whole blood clots formed in a thrombelastograph with the addition of a sub-threshold concentration of tPA. Conclusion: These studies provide evidence for a role of TAFIa in venous thrombosis in mice, and describe an optimized vena cava injury model appropriate for the evaluation of antithrombotic drugs and the characterization of novel therapeutic targets.
-
effects of factor ix or factor xi deficiency on ferric chloride induced carotid artery occlusion in mice
Journal of Thrombosis and Haemostasis, 2005Co-Authors: Xinkang Wang, Patricia L Smith, Meiyin Hsu, William A Schumacher, Martin L Ogletree, Dietmar A Seiffert, Qiufang Cheng, Giora Z Feuerstein, David GailaniAbstract:Summary. Factor XI (FXI) and factor IX (FIX) are zymogens of plasma serine proteases required for normal hemostasis. The purpose of this work was to evaluate FXI and FIX as potential therapeutic targets by means of a refined ferric chloride (FeCl3)-induced arterial injury model in factor-deficient mice. Various concentrations of FeCl3 were used to establish the arterial thrombosis model in C57BL/6 mice. Carotid artery blood flow was completely blocked within 10 min in C57BL/6 mice by application of 3.5% FeCl3. In contrast, FXI- and FIX-deficient mice were fully protected from occlusion induced by 5% FeCl3, and were partially protected against the effect of 7.5% FeCl3. The protective effect was comparable to very high doses of heparin (1000 units kg−1) and substantially more effective than aspirin. While FXI and FIX deficiencies were indistinguishable in the carotid artery injury model, there was a marked difference in a Tail-Bleeding-Time assay. FXI-deficient and wild-type mice have similar Bleeding Times, while FIX deficiency was associated with severely prolonged Bleeding Times (>5.8-fold increase, P < 0.01). Given the relatively mild Bleeding diathesis associated with FXI deficiency, therapeutic inhibition of FXI may be a reasonable strategy for treating or preventing thrombus formation.
Marie Cecile Valera - One of the best experts on this subject based on the ideXlab platform.
-
effects of conjugated estrogen and bazedoxifene on hemostasis and thrombosis in mice
Endocrine connections, 2019Co-Authors: Emmanuelle Noirrit, Coralie Fontaine, Bernard Payrastre, Marion Dupuis, Melissa Buscato, Jeanfrancois Arnal, Marie Cecile ValeraAbstract:Estrogen-progestin therapy was previously considered as the standard of care for managing bothersome symptoms associated with menopause, but it increases risks of breast cancer and of thromboembolism. The combination of conjugated estrogen (CE) with bazedoxifene (BZA) named tissue-selective estrogen complex (TSEC) was designed to minimize or even abrogate the undesirable effects on breast, while maintaining the beneficial effects such as prevention of osteoporosis and suppression of climacteric symptoms. The risk on thromboembolism associated with TSEC is unknown, although the clinical available data are reassuring. The aim of this study was to define the impact of a chronic administration of CE, BZA or CE + BZA on hemostasis and thrombosis in ovariectomized mice. As expected, CE, but not BZA neither CE + BZA, induced uterine and vagina hypertrophy. As previously demonstrated for 17β-estradiol (E2), we found that CE (i) increased Tail-Bleeding Time, (ii) prevented occlusive thrombus formation in injured carotid artery and (iii) protected against collagen/epinephrine-induced thromboembolism. Thus, whereas BZA antagonized CE action on reproductive tissues, it had no impact on the effect of CE on hemostasis, thromboembolism and arterial thrombosis in mice. CE + BZA shared the anti-thrombotic actions of CE in these mouse models. If a similar process is at work in women, CE combined with BZA could contribute to minimize the risk of thrombosis associated with hormone replacement therapy.
-
effect of estetrol a selective nuclear estrogen receptor modulator in mouse models of arterial and venous thrombosis
Molecular and Cellular Endocrinology, 2018Co-Authors: Francoise Lenfant, Marie Cecile Valera, Cendrine Cabou, Emmanuelle Noirritesclassan, Marion Dupuis, Anne Briaux, Cedric GarciaAbstract:Abstract Estetrol (E4) is a natural estrogen synthesized exclusively during pregnancy by the human fetal liver, and the physiological role of this hormone is unknown. Interestingly, E4 was recently evaluated in preclinical and phase II-III clinical studies in combination with a progestin, with the advantage to not increase the circulating level of coagulation factors, at variance to oral estradiol or ethinylestradiol. Here, we evaluated the effect of E4 on hemostasis and thrombosis in mouse. Following chronic E4 treatment, mice exhibited a prolonged Tail-Bleeding Time and were protected from arterial and also venous thrombosis in vivo. In addition, E4 treatment decreased ex vivo thrombus growth on collagen under arterial flow conditions. We recently showed that E4 activates uterine epithelial proliferation through nuclear estrogen receptor (ER) α. To analyze the impact of nuclear ERα actions on hemostasis and thrombosis, we generated hematopoietic chimera with bone marrow cells deficient for nuclear ERα. E4-induced protection against thromboembolism was significantly reduced in the absence of hematopoietic nuclear ERα activation, while the increased Tail-Bleeding Time was not impacted by this deletion. In addition to its “liver friendly” profile described in women, our data shows that E4 has anti-thrombotic properties in various mouse models. Altogether, the natural fetal estrogen E4 could represent an attractive alternative to classic estrogens in oral contraception and treatment of menopause.
-
effect of chronic estradiol plus progesterone treatment on experimental arterial and venous thrombosis in mouse
PLOS ONE, 2017Co-Authors: Marie Cecile Valera, Maeva Guillaume, Emmanuelle Noirritesclassan, Marion Dupuis, Anne Briaux, Cedric Garcia, Melissa Buscato, Alexia Vinel, T Benoit, Olivier LairezAbstract:Postmenopausal hormone replacement therapy (HRT) with estrogen plus progestogens is the first line therapy to treat menopausal symptoms. The progestogen is added to estrogen to reduce or eliminate the excess risk of endometrial cancer due to the unopposed effect of estrogen. Whereas progestin clearly opposes the proliferative and deleterious long-term actions of estrogen on the endometrium, the interference of progestin on the other estrogen action remains unclear. We previously reported that chronic subcutaneous 17α-estradiol (E2) in mice decreases platelet responsiveness, prolongs the Tail-Bleeding Time and protects against acute thromboembolism. Here, we report the tissue-specific interference of progesterone (P4) on the action of E2 in ovariectomized mice. We first confirm that, in our experimental conditions, P4 attenuates the proliferative action of E2 on the uterus and the effects of E2 on vagina weight and lubrication. We then studied the effect of E2 combined with P4 on hemostasis and thrombosis in vivo in mice and found that P4 did not interfere with the main actions of E2 on platelets, Bleeding Time and arterial and venous thrombosis. Thus, whereas activation of progesterone receptor interferes with the action of E2 on its classic sex targets, P4 appears to have minimal effect on the hemostasis and thrombosis actions of E2, supporting the prominent role of estrogens and the accessory role of natural progestin on the extra-reproductive cells and tissues involved in thrombosis.
-
protective hematopoietic effect of estrogens in a mouse model of thrombosis respective roles of nuclear versus membrane estrogen receptor α
Endocrinology, 2015Co-Authors: Marie Cecile Valera, Francoise Lenfant, Coralie Fontaine, Cendrine Cabou, Maeva Guillaume, Natalia Smirnova, Pierre Chambon, Bernard PayrastreAbstract:We recently reported that chronic 17β-estradiol (E2) treatment in mice decreases platelet responsiveness, prolongs the Tail-Bleeding Time and protects against acute thromboembolism via the hematopoietic estrogen receptor alpha (ERα), and independently of ERβ. Here, we have explored the respective roles of membrane vs nuclear actions of ERα in this process, using: 1) the selective activator of membrane ERα: estrogen dendrimer conjugate, and 2) mouse models with mutations in ERα. The selective targeting of activation function 2 of ERα provides a model of nuclear ERα loss-of-function, whereas mutation of the ERα palmitoylation site leads to a model of membrane ERα deficiency. The combination of pharmacological and genetic approaches including hematopoietic chimera mice demonstrated that absence of either membrane or nuclear ERα activation in bone marrow does not prevent the prolongation of the Tail-Bleeding Time, suggesting a redundancy of these two functions for this E2 effect. In addition, although hematop...
-
protective hematopoietic effect of estrogens in a mouse model of thrombosis respective roles of nuclear versus membrane estrogen receptor α
Endocrinology, 2015Co-Authors: Marie Cecile Valera, Francoise Lenfant, Coralie Fontaine, Cendrine Cabou, Maeva Guillaume, Natalia Smirnova, Sung Hoon Kim, Pierre ChambonAbstract:We recently reported that chronic 17β-estradiol (E2) treatment in mice decreases platelet responsiveness, prolongs the Tail-Bleeding Time and protects against acute thromboembolism via the hematopoietic estrogen receptor alpha (ERα), and independently of ERβ. Here, we have explored the respective roles of membrane vs nuclear actions of ERα in this process, using: 1) the selective activator of membrane ERα: estrogen dendrimer conjugate, and 2) mouse models with mutations in ERα. The selective targeting of activation function 2 of ERα provides a model of nuclear ERα loss-of-function, whereas mutation of the ERα palmitoylation site leads to a model of membrane ERα deficiency. The combination of pharmacological and genetic approaches including hematopoietic chimera mice demonstrated that absence of either membrane or nuclear ERα activation in bone marrow does not prevent the prolongation of the Tail-Bleeding Time, suggesting a redundancy of these two functions for this E2 effect. In addition, although hematopoietic membrane ERα is neither sufficient nor necessary to protect E2-treated mice from collagen/epinephrine-induced thromboembolism, the protection against death-induced thromboembolism is significantly reduced in the absence of hematopoietic nuclear ERα activation. Overall, this study emphasizes that hematopoietic cells (likely megakaryocytes and possibly immune cells) constitute an important target in the antithrombotic effects of estrogens, and delineate for the first Time in vivo the respective roles of membrane vs nuclear ERα effects, with a prominent role of the latter.
Dietmar A Seiffert - One of the best experts on this subject based on the ideXlab platform.
-
effects of plasma kallikrein deficiency on haemostasis and thrombosis in mice murine ortholog of the fletcher trait
Thrombosis and Haemostasis, 2012Co-Authors: J E Bird, Xinkang Wang, William A Schumacher, P L Smith, J P Revelli, F Barbera, Dietmar A SeiffertAbstract:Plasma kallikrein is a multifunctional serine protease involved in contact activation of coagulation. Deficiency in humans is characterised by prolonged activated partial thromboplastin Time (aPTT); however, the balance between thrombosis and haemostasis is not fully understood. A study of plasma kallikrein-deficient mice revealed increased aPTT, without prolonged Bleeding Time. Prekallikrein antisense oligonucleotide (ASO) treatment in mice suggested potential for a positive therapeutic index. The current goal was to further define the role of plasma kallikrein in coagulation. Blood pressure and heart rate were normal in plasma kallikrein-deficient mice, and mice were completely protected from occlusion (100 ± 1.3% control flow) in 3.5% FeCl3 -induced arterial thrombosis versus heterozygotes (20 ± 11.4%) and wild-type littermates (8 ± 0%). Vessels occluded in 8/8 wild-type, 7/8 heterozygotes, and 0/8 knockouts. Anti-thrombotic protection was less pronounced in 5% FeCl3-induced arterial injury. Integrated blood flow was 8 ± 0% control in wild-type and heterozygotes, and significantly (p<0.01) improved to 43 ± 14.2% in knockouts. The number of vessels occluded was similar in all genotypes. Thrombus weight was significantly reduced in knockouts (-47%) and heterozygotes (-23%) versus wild-type in oxidative venous thrombosis. Average Tail Bleeding Time increased modestly in knockout mice compared to wild-type. Average renal Bleeding Times were similar in all genotypes. These studies confirm and extend studies with prekallikrein ASO, and demonstrate that plasma kallikrein deletion prevents occlusive thrombus formation in mice with a minimal role in provoked Bleeding. Additional support for the significance of the intrinsic pathway in the coagulation cascade is provided, as well as for a potential new anti-thrombotic approach.
-
effects of factor xi deficiency on ferric chloride induced vena cava thrombosis in mice
Journal of Thrombosis and Haemostasis, 2006Co-Authors: Xinkang Wang, Patricia L Smith, Meiyin Hsu, David Gailani, William A Schumacher, Martin L Ogletree, Dietmar A SeiffertAbstract:Summary. Background: Increased plasma levels of coagulation factor (F) XI are a risk factor for venous thrombosis. Objective: To further explore the relationship between FXI and venous thrombosis, we evaluated FXI-deficient and wild-type mice in a ferric chloride (FeCl3)-induced vena cava thrombosis model. Methods and Results: Thrombosis was induced by 3-min topical application of filter papers containing increasing concentrations of FeCl3 and the thrombus was measured at 30 min. In contrast to wild-type mice, FXI-deficient mice failed to form a thrombus with 5% FeCl3, and were partially protected against 7.5% and 10% FeCl3, respectively. The protective effect was substantially stronger than a high dose of heparin (1000 units kg−1, i.v.), clopidogrel (30 mg kg−1, p.o.) or argatroban (30 mg kg−1, i.p.). These antithrombotic agents resulted in off-scale Bleeding in a Tail Bleeding Time assay, whereas the Bleeding Time of FXI-deficient mice was unchanged compared to wild-type mice. In addition to its known effect on the coagulation cascade, enhanced clot lysis was demonstrated in FXI-deficient mouse and human plasma compared to those supplemented with FXIa. Conclusion: Given the strong antithrombotic efficacy (possibly contributed by strong anticoagulant activity associated with increased fibrinolytic activity) and mild Bleeding diathesis associated with FXI deficiency, therapeutic inhibition of FXI may be a reasonable therapeutic strategy to treat or prevent venous thrombosis.
-
effects of factor ix or factor xi deficiency on ferric chloride induced carotid artery occlusion in mice
Journal of Thrombosis and Haemostasis, 2005Co-Authors: Xinkang Wang, Patricia L Smith, Meiyin Hsu, William A Schumacher, Martin L Ogletree, Dietmar A Seiffert, Qiufang Cheng, Giora Z Feuerstein, David GailaniAbstract:Summary. Factor XI (FXI) and factor IX (FIX) are zymogens of plasma serine proteases required for normal hemostasis. The purpose of this work was to evaluate FXI and FIX as potential therapeutic targets by means of a refined ferric chloride (FeCl3)-induced arterial injury model in factor-deficient mice. Various concentrations of FeCl3 were used to establish the arterial thrombosis model in C57BL/6 mice. Carotid artery blood flow was completely blocked within 10 min in C57BL/6 mice by application of 3.5% FeCl3. In contrast, FXI- and FIX-deficient mice were fully protected from occlusion induced by 5% FeCl3, and were partially protected against the effect of 7.5% FeCl3. The protective effect was comparable to very high doses of heparin (1000 units kg−1) and substantially more effective than aspirin. While FXI and FIX deficiencies were indistinguishable in the carotid artery injury model, there was a marked difference in a Tail-Bleeding-Time assay. FXI-deficient and wild-type mice have similar Bleeding Times, while FIX deficiency was associated with severely prolonged Bleeding Times (>5.8-fold increase, P < 0.01). Given the relatively mild Bleeding diathesis associated with FXI deficiency, therapeutic inhibition of FXI may be a reasonable strategy for treating or preventing thrombus formation.
Bernard Lambermont - One of the best experts on this subject based on the ideXlab platform.
-
pharmacological characterization of n tert butyl n 2 4 methylphenylamino 5 nitrobenzenesulfonyl urea bm 573 a novel thromboxane a2 receptor antagonist and thromboxane synthase inhibitor in a rat model of arterial thrombosis and its effects on bleedin
Journal of Pharmacology and Experimental Therapeutics, 2004Co-Authors: Jean-michel Dogné, Julien Hanson, Laurence De Leval, Stephanie Rolin, Xavier De Leval, Philippe Kolh, Vincent Tchanasato, Alexandre Ghuysen, Patrick Segers, Bernard LambermontAbstract:The present study was undertaken to characterize the antiplatelet and antithrombotic effects of BM-573 [ N - tert -butyl- N ′-[2-(4′-methylphenylamino)-5-nitrobenzenesulfonyl]urea], an original combined thromboxane receptor antagonist and thromboxane synthase inhibitor in rats, and to determine its effects on mice Bleeding Time. Intraperitoneal injection of a single dose of 5 mg/kg BM-573 to rats inhibited U-46619 (9,11-dideoxy-9,11-methanoepoxy-prostaglandin F2)-induced washed platelet aggregation 30 min and 1, 2, and 4 h after drug administration with a maximum antiplatelet effect observed after 1 and 2 h. In a rat model of thrombosis induced by ferric chloride application on the abdominal aorta, BM-573 significantly reduced the thrombus weight by 92.53, 80.20, 64.75, and 18.21% at doses of 5, 2, 0.5, and 0.2 mg/kg, respectively. Time to occlusion of abdominal aorta in the BM-573-treated group (41.50 ± 5.21 min) was significantly prolonged compared with the vehicle-treated rats (16.16 ± 0.79 min). Like furegrelate, seratrodast, and acetylsalicylic acid, BM-573 did not affect the Tail Bleeding Time induced by Tail transection in mice compared with vehicle-treated mice. Moreover, BM-573, a close derivative of the loop diuretic torasemide, failed to induce a significant increase in diuresis in rat and did not produce a decrease in blood glucose concentration as observed with the sulfonylurea glibenclamide. In conclusion, we have demonstrated that the nitrobenzenic sulfonylurea BM-573, an original combined thromboxane receptor antagonist and thromboxane synthase inhibitor, is a potent antithrombotic agent that does not affect Bleeding Time. Moreover, BM-573 lost the diuretic property of torasemide and has no impact on glycemia.
