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Alan E Mast - One of the best experts on this subject based on the ideXlab platform.
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absence of hematopoietic tissue factor pathway inhibitor mitigates bleeding in mice with hemophilia
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Susan A Maroney, Brian C Cooley, Josephine P Ferrel, Catherine E Bonesho, Lone Nielsen, Peter B Johansen, Mette B Hermit, Lars Christian Petersen, Alan E MastAbstract:Tissue factor pathway inhibitor (TFPI) blocks thrombin generation via the extrinsic blood coagulation pathway. Because the severe bleeding in patients with hemophilia occurs from deficiency of intrinsic blood coagulation pathway factor VIII or IX, pharmacological agents that inactivate TFPI and, therefore, restore thrombin generation via the extrinsic pathway, are being developed for treatment of hemophilia. Murine models of combined TFPI and factor VIII deficiency were used to examine the impact of TFPI deficiency on bleeding and clotting in hemophilia. In breeding studies, Factor VIII null (F8−/−) did not rescue the embryonic death of TFPI null (Tfpi−/−) mice. Tfpi+/− did not alter the bleeding phenotype of F8−/− mice. However, total inhibition of intravascular TFPI through injection of anti-TFPI antibody mitigated tail vein bleeding. Interestingly, tail blood loss progressively decreased at doses greater than needed to totally inhibit plasma TFPI, suggesting that inhibition of a sequestered pool of TFPI released at the injury site mitigates bleeding. Because TFPI is sequestered within platelets and released following their activation, the function of platelet TFPI was examined in F8−/− mice lacking hematopoietic cell TFPI that was generated by fetal liver transplantation. Blood loss after tail transection significantly decreased in Tfpi+/−;F8−/− mice with hematopoietic Tfpi−/− cells compared with Tfpi+/−;F8−/− mice with Tfpi+/+ hematopoietic cells. Additionally, following femoral vein injury, Tfpi+/−;F8−/− mice with Tfpi−/− hematopoietic cells had increased fibrin deposition compared with identical-genotype mice with Tfpi+/+ hematopoietic cells. These findings implicate platelet TFPI as a primary physiological regulator of bleeding in hemophilia.
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murine hematopoietic cell tissue factor pathway inhibitor limits thrombus growth
Arteriosclerosis Thrombosis and Vascular Biology, 2011Co-Authors: Susan A Maroney, Brian C Cooley, Josephine P Ferrel, Catherine E Bonesho, Alan E MastAbstract:Objective—Tissue factor (TF)–factor VIIa initiates blood coagulation and is found on microparticles that accumulate within intravascular thrombi. Tissue factor pathway inhibitor (TFPI), a factor Xa (fXa)–dependent inhibitor of TF–factor VIIa, is produced by megakaryocytes and is present in platelets. We sought to determine the role of platelet TFPI in regulation of thrombus growth. Methods and Results—Western blot analyses demonstrated that murine platelets produce TFPIα, the most evolutionarily conserved alternatively spliced isoform of TFPI. A mouse model of hematopoietic cell TFPI deficiency was developed by transplanting irradiated TFPI+/− mice with TFPI−/− fetal liver cells. Platelets from transplanted mice totally lack TFPI inhibitory activity. An electrolytic vascular injury model was used to assess thrombus growth in the femoral vein and carotid artery. Mice lacking hematopoietic TFPI developed larger femoral vein and carotid artery thrombi than TFPI+/− mice transplanted with TFPI+/+ hematopoietic...
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combined tissue factor pathway inhibitor and thrombomodulin deficiency produces an augmented hypercoagulable state with tissue specific fibrin deposition
Journal of Thrombosis and Haemostasis, 2007Co-Authors: Susan A Maroney, Brian C Cooley, Alan E Mast, Rashmi Sood, Hartmut WeilerAbstract:Summary. Background and Objective: Tissue factor pathway inhibitor (TFPI) and thrombomodulin (TM) are endothelial-associated anticoagulant proteins thought to control hemostasis in specific vascular beds. Here, we have examined the consequences of TFPI deficiency in the presence of a compounding procoagulant state caused by reduced TM function. Methods and results: TFPI+/−/TMpro/pro mice are born at less than expected frequency in either TFPI+/−/TMpro/+ or TMpro/pro mothers but are born at near the expected frequency in TMpro/+ mothers. Adult TFPI+/−/TMpro/pro mice have elevated thrombin–antithrombin complex and increased thrombus volume in an electrical injury model of venous thrombosis. In striking contrast to mice with single deficiency of TFPI or TM, TFPI+/−/TMpro/pro mice exhibit augmented fibrin deposition not only in the liver, but also in the cerebral microvasculature. Conclusions: TFPI+/−/TMpro/pro mice exhibit partial intrauterine lethality when carried by mothers with an underlying prothrombotic state, providing the first experimental evidence in an animal model that TFPI-dependent control of hemostasis in the vascular bed of the placenta fulfills a critical role for successful pregnancy outcome. In addition to the placenta, partial TFPI deficiency interacts with decreased TM function in an organ selective manner to produce fibrin deposition in other specific vascular beds, the liver and brain.
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characterization of the association of tissue factor pathway inhibitor with human placenta
Arteriosclerosis Thrombosis and Vascular Biology, 2002Co-Authors: Alan E Mast, Nayana Acharya, Mark J Malecha, Connie L Hall, Dennis J DietzenAbstract:Objective— Tissue factor pathway inhibitor (TFPI) is an endothelial-associated inhibitor of blood coagulation. Because the mechanism for attachment of TFPI to endothelium is not clear, we investigated its association with human placenta. Methods and Results— Western blots demonstrate that treatment with phosphatidylinositol-specific phospholipase C (PIPLC) removes more placental TFPI than either PBS or heparin, a finding confirmed by immunohistochemistry. The amounts of heparin-releasable and PIPLC-releasable TFPI activity on placental endothelium were measured in placentas from 5 individuals. PIPLC removes >10-fold more TFPI activity from the placental fragments than 10 U/mL heparin and >100-fold more than 1 U/mL heparin. Pretreatment of the placental fragments with PIPLC increases the amount of heparin-releasable TFPI by ≈3-fold. An antibody specific for the C-terminal region of TFPI recognizes PIPLC-releasable TFPI in Western blots. Conclusions— GPI-anchored TFPI is the predominant form on placental endothelium. Heparin-releasable TFPI likely represents only a small portion of the total TFPI on endothelium that remains attached to cell-surface glycosaminoglycans after cleavage of the GPI anchor by endogenous enzymes. The predominance of GPI-anchored TFPI suggests that heparin infusion does not significantly redistribute TFPI within the vasculature. The intact C-terminus in GPI-anchored TFPI indicates it is not directly attached to a GPI anchor. Rather, it most likely associates with endothelium by binding to a GPI-anchored protein.
Hans-peter Piepho - One of the best experts on this subject based on the ideXlab platform.
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Percentage changes in numbers of warthog, lesser kudu, Thomson’s gazelle, eland, oryx, Topi, hartebeest, impala, Grevy’s zebra and waterbuck in each of the 21 rangeland counties between 1977–1980 and 2011–2016.
2016Co-Authors: Hans-peter Piepho, Mohamed Y. Said, Gordon O. Ojwang, Lucy W. Njino, Shem C. Kifugo, Patrick W. WarguteAbstract:Percentage changes in numbers of warthog, lesser kudu, Thomson’s gazelle, eland, oryx, Topi, hartebeest, impala, Grevy’s zebra and waterbuck in each of the 21 rangeland counties between 1977–1980 and 2011–2016.
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The distribution of the proportion of the total biomass of warthog, lesser kudu, Thomson’s gazelle, eland, oryx, Topi, hartebeest, impala, Grevy’s zebra and waterbuck among the 21 rangeland counties of Kenya during 1977–80 and 2011–2016.
2016Co-Authors: Hans-peter Piepho, Mohamed Y. Said, Gordon O. Ojwang, Lucy W. Njino, Shem C. Kifugo, Patrick W. WarguteAbstract:The distribution of the proportion of the total biomass of warthog, lesser kudu, Thomson’s gazelle, eland, oryx, Topi, hartebeest, impala, Grevy’s zebra and waterbuck among the 21 rangeland counties of Kenya during 1977–80 and 2011–2016.
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rainfall influences on ungulate population abundance in the mara serengeti ecosystem
Journal of Animal Ecology, 2008Co-Authors: Joseph O Ogutu, Hans-peter Piepho, Holly T Dublin, N Bhola, Robin S ReidAbstract:1. Rainfall is the prime climatic factor underpinning the dynamics of African savanna ungulates, but no study has analysed its influence on the abundance of these ungulates at monthly to multiannual time scales. 2. We report relationships between rainfall and changes in age- and sex-structured abundances of seven ungulate species monitored monthly for 15 years using vehicle ground counts in the Maasai Mara National Reserve, Kenya. 3. Abundance showed strong and curvilinear relationships with current and cumulative rainfall, with older Topi, Damaliscus korrigum (Ogilby); warthog, Phacochoerus aethiopicus (Pallas); waterbuck, Kobus ellipsyprimnus (Ogilby); and impala, Aepyceros melampus (Lichtenstein) responding to longer lags than younger animals, portraying carryover effects of prior habitat conditions. 4. The abundances of newborn calves were best correlated with monthly rainfall averaged over the preceding 5-6 months for Topi, waterbuck, warthog, and 2 months for the migratory zebra Equus burchelli (Gray), but with seasonal rainfall averaged over 2-5 years for giraffe, Giraffa camelopardalis (L.); impala; and kongoni, Alcelaphus busephalus (Pallas). The cumulative late wet-season rainfall was the best predictor of abundance for quarter- to full-grown animals for most species. Monthly rainfall exerted both negative and positive effects on the abundances of zebra, impala and waterbuck. Ignoring age, both sexes responded similarly to rainfall. 5. Births were strongly seasonal only for warthog and Topi, but peaked between August and December for most species. Hence abundance was strongly seasonal for young Topi and warthog and the migratory zebra. Pronounced seasonality in births for warthog and Topi obliterated otherwise strong relationships between abundance and rainfall when both month and rainfall were included in the same model. Aggregated density produced relationships with rainfall similar to those for fully grown animals, emphasizing the necessity of demographic monitoring to reliably reveal rainfall influences on ungulate abundance in the Mara. 6. Strong relationships between abundance and rainfall suggest that rainfall underpins the dynamics of African savanna ungulates, and that changes in rainfall due to global warming may markedly alter the abundance and diversity of these mammals. Ungulates respond to rainfall fluctuations through movements, reproduction or survival, and the responses appear independent of breeding phenology and synchrony, dietary guild, or degree of water dependence. Newborns and adults have contrasting responses to rainfall. Males and females respond similarly to rainfall when age is ignored.
Patrick W. Wargute - One of the best experts on this subject based on the ideXlab platform.
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Percentage changes in numbers of warthog, lesser kudu, Thomson’s gazelle, eland, oryx, Topi, hartebeest, impala, Grevy’s zebra and waterbuck in each of the 21 rangeland counties between 1977–1980 and 2011–2016.
2016Co-Authors: Hans-peter Piepho, Mohamed Y. Said, Gordon O. Ojwang, Lucy W. Njino, Shem C. Kifugo, Patrick W. WarguteAbstract:Percentage changes in numbers of warthog, lesser kudu, Thomson’s gazelle, eland, oryx, Topi, hartebeest, impala, Grevy’s zebra and waterbuck in each of the 21 rangeland counties between 1977–1980 and 2011–2016.
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The distribution of the proportion of the total biomass of warthog, lesser kudu, Thomson’s gazelle, eland, oryx, Topi, hartebeest, impala, Grevy’s zebra and waterbuck among the 21 rangeland counties of Kenya during 1977–80 and 2011–2016.
2016Co-Authors: Hans-peter Piepho, Mohamed Y. Said, Gordon O. Ojwang, Lucy W. Njino, Shem C. Kifugo, Patrick W. WarguteAbstract:The distribution of the proportion of the total biomass of warthog, lesser kudu, Thomson’s gazelle, eland, oryx, Topi, hartebeest, impala, Grevy’s zebra and waterbuck among the 21 rangeland counties of Kenya during 1977–80 and 2011–2016.
Susan A Maroney - One of the best experts on this subject based on the ideXlab platform.
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absence of hematopoietic tissue factor pathway inhibitor mitigates bleeding in mice with hemophilia
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Susan A Maroney, Brian C Cooley, Josephine P Ferrel, Catherine E Bonesho, Lone Nielsen, Peter B Johansen, Mette B Hermit, Lars Christian Petersen, Alan E MastAbstract:Tissue factor pathway inhibitor (TFPI) blocks thrombin generation via the extrinsic blood coagulation pathway. Because the severe bleeding in patients with hemophilia occurs from deficiency of intrinsic blood coagulation pathway factor VIII or IX, pharmacological agents that inactivate TFPI and, therefore, restore thrombin generation via the extrinsic pathway, are being developed for treatment of hemophilia. Murine models of combined TFPI and factor VIII deficiency were used to examine the impact of TFPI deficiency on bleeding and clotting in hemophilia. In breeding studies, Factor VIII null (F8−/−) did not rescue the embryonic death of TFPI null (Tfpi−/−) mice. Tfpi+/− did not alter the bleeding phenotype of F8−/− mice. However, total inhibition of intravascular TFPI through injection of anti-TFPI antibody mitigated tail vein bleeding. Interestingly, tail blood loss progressively decreased at doses greater than needed to totally inhibit plasma TFPI, suggesting that inhibition of a sequestered pool of TFPI released at the injury site mitigates bleeding. Because TFPI is sequestered within platelets and released following their activation, the function of platelet TFPI was examined in F8−/− mice lacking hematopoietic cell TFPI that was generated by fetal liver transplantation. Blood loss after tail transection significantly decreased in Tfpi+/−;F8−/− mice with hematopoietic Tfpi−/− cells compared with Tfpi+/−;F8−/− mice with Tfpi+/+ hematopoietic cells. Additionally, following femoral vein injury, Tfpi+/−;F8−/− mice with Tfpi−/− hematopoietic cells had increased fibrin deposition compared with identical-genotype mice with Tfpi+/+ hematopoietic cells. These findings implicate platelet TFPI as a primary physiological regulator of bleeding in hemophilia.
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murine hematopoietic cell tissue factor pathway inhibitor limits thrombus growth
Arteriosclerosis Thrombosis and Vascular Biology, 2011Co-Authors: Susan A Maroney, Brian C Cooley, Josephine P Ferrel, Catherine E Bonesho, Alan E MastAbstract:Objective—Tissue factor (TF)–factor VIIa initiates blood coagulation and is found on microparticles that accumulate within intravascular thrombi. Tissue factor pathway inhibitor (TFPI), a factor Xa (fXa)–dependent inhibitor of TF–factor VIIa, is produced by megakaryocytes and is present in platelets. We sought to determine the role of platelet TFPI in regulation of thrombus growth. Methods and Results—Western blot analyses demonstrated that murine platelets produce TFPIα, the most evolutionarily conserved alternatively spliced isoform of TFPI. A mouse model of hematopoietic cell TFPI deficiency was developed by transplanting irradiated TFPI+/− mice with TFPI−/− fetal liver cells. Platelets from transplanted mice totally lack TFPI inhibitory activity. An electrolytic vascular injury model was used to assess thrombus growth in the femoral vein and carotid artery. Mice lacking hematopoietic TFPI developed larger femoral vein and carotid artery thrombi than TFPI+/− mice transplanted with TFPI+/+ hematopoietic...
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combined tissue factor pathway inhibitor and thrombomodulin deficiency produces an augmented hypercoagulable state with tissue specific fibrin deposition
Journal of Thrombosis and Haemostasis, 2007Co-Authors: Susan A Maroney, Brian C Cooley, Alan E Mast, Rashmi Sood, Hartmut WeilerAbstract:Summary. Background and Objective: Tissue factor pathway inhibitor (TFPI) and thrombomodulin (TM) are endothelial-associated anticoagulant proteins thought to control hemostasis in specific vascular beds. Here, we have examined the consequences of TFPI deficiency in the presence of a compounding procoagulant state caused by reduced TM function. Methods and results: TFPI+/−/TMpro/pro mice are born at less than expected frequency in either TFPI+/−/TMpro/+ or TMpro/pro mothers but are born at near the expected frequency in TMpro/+ mothers. Adult TFPI+/−/TMpro/pro mice have elevated thrombin–antithrombin complex and increased thrombus volume in an electrical injury model of venous thrombosis. In striking contrast to mice with single deficiency of TFPI or TM, TFPI+/−/TMpro/pro mice exhibit augmented fibrin deposition not only in the liver, but also in the cerebral microvasculature. Conclusions: TFPI+/−/TMpro/pro mice exhibit partial intrauterine lethality when carried by mothers with an underlying prothrombotic state, providing the first experimental evidence in an animal model that TFPI-dependent control of hemostasis in the vascular bed of the placenta fulfills a critical role for successful pregnancy outcome. In addition to the placenta, partial TFPI deficiency interacts with decreased TM function in an organ selective manner to produce fibrin deposition in other specific vascular beds, the liver and brain.
George J Broze - One of the best experts on this subject based on the ideXlab platform.
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the kunitz 3 domain of tfpi α is required for protein s dependent enhancement of factor xa inhibition
Blood, 2010Co-Authors: Matthew Ndonwi, Elodee A Tuley, George J BrozeAbstract:Protein S (PS) enhances the inhibition of factor Xa (FXa) by tissue factor pathway inhibitor-α (TFPI-α) in the presence of Ca2+ and phospholipids. Altered forms of recombinant TFPI-α were used to determine the structures within TFPI-α that may be involved in this PS-dependent effect. Wild-type TFPI-α (TFPIWT), TFPI-α lacking the K3 domain (TFPI-ΔK3), and TFPI-α containing a single amino acid change at the putative P1 residue of K3 (R199L, TFPIK3P1) produced equivalent FXa inhibition in the absence of PS, whereas the response in FXa inhibition produced by PS was reduced with TFPIK3P1 (EC50 61.8 ± 13.4nM vs 8.0 ± 0.4nM for TFPIWT) and not detectable with TFPI-ΔK3. Ligand blotting and surface plasmon resonance experiments demonstrated that FXa bound TFPIWT and TFPI-ΔK3 but not the isolated K3 domain, whereas PS bound TFPIWT and the K3 domain but not TFPI-ΔK3. Addition of TFPIWT, TFPIK3P1, or TFPI-ΔK3 produced comparable prolongation of FXa-induced coagulation in PS-deficient plasma, but the anticoagulant effect of TFPIWT was substantially greater than that of TFPIK3P1 > TFPI-ΔK3 in normal plasma and PS-deficient plasma reconstituted with PS. We conclude that the PS-mediated enhancement of FXa inhibition by TFPI-α involves an interaction between PS and TFPI-α, which requires the K3 domain of TFPI-α.
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role for the kunitz 3 domain of tissue factor pathway inhibitor α in cell surface binding
Circulation, 2004Co-Authors: Orlando Piro, George J BrozeAbstract:Background— Tissue factor pathway inhibitor (TFPI)-α, a key regulator of tissue factor–induced coagulation, contains 3 tandem Kunitz-type inhibitory domains. Kunitz-1 binds and inhibits factor VIIa in the factor VIIa/tissue factor complex, and Kunitz-2 binds and inhibits factor Xa. The role of the Kunitz-3 domain of TFPI-α, however, has remained an enigma. Methods and Results— To determine the structures within TFPI-α involved in its binding to cell surface, altered forms of TFPI-α were expressed in C127 (mouse mammary) cells: C-terminal truncated forms TFPI-α (252), TFPI-α (242), and TFPI-α (181), which also lacks the third Kunitz domain (K3); TFPI-α (desK3), which lacks only the K3 domain; and TFPI-α (R199L), in which the putative P1 site in K3 is changed from arginine to leucine. By flow cytometry (fluorescence-activated cell sorting), the altered forms 252, 242, and R199L showed significantly reduced binding, whereas the forms 181 and desK3 completely failed to bind to the cell surface. Transient expr...
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the effect of leukocyte elastase on tissue factor pathway inhibitor
Blood, 1992Co-Authors: Darryl A Higuchi, K M Likert, George J BrozeAbstract:Tissue factor pathway inhibitor (TFPI) is a multivalent Kunitz-type inhibitor that directly inhibits factor Xa and, in a factor Xa- dependent fashion, also inhibits the factor VIIa/tissue factor (TF) catalytic complex. The Kunitz-2 domain in TFPI is needed for the binding and inhibition of factor Xa, while the Kunitz-1 domain appears to be responsible for binding factor VIIa in a quaternary factor Xa- TFPI-factor VIIa/TF inhibitory complex. Human leukocyte elastase (HLE) proteolytically cleaves TFPI between threonine-87 and threonine-88 within the polypeptide that links the Kunitz-1 and Kunitz-2 domains in the TFPI molecule. HLE treatment not only affects the ability of TFPI to inhibit factor VIIa/TF, but also dramatically reduces its inhibition of factor Xa. Both purified HLE and stimulated neutrophils regenerate TF activity from a preformed factor Xa-TFPI-factor VIIa/TF inhibitory complex. Kinetic analysis suggests that HLE cleavage does not effect the affinity of the initial encounter interaction between factor Xa and TFPI, whereas it markedly reduces the affinity of the final factor Xa:TFPI complex with Ki (final) values for untreated and HLE-treated TFPI of 58 pmol/L and 4.4 nmol/L, respectively. Thus, an epitope in the amino-terminal region of TFPI or a conformation of the TFPI molecule that requires the presence of this region is needed in concert with the Kunitz-2 domain to produce optimal inhibition of factor Xa by TFPI.
