Short-term ethinylestradiol treatment suppresses inferior caval vein thrombosis in obese mice

2009 ◽  
Vol 102 (11) ◽  
pp. 993-1000 ◽  
Author(s):  
Audrey Cleuren ◽  
Berthe van Hoef ◽  
Marc Hoylaerts ◽  
Bart van Vlijmen ◽  
H. Lijnen
Keyword(s):  
Coagulation Factor ◽  
Plasminogen Activator Inhibitor ◽  
Obese Mice ◽  
Plasminogen Activator Inhibitor 1 ◽  
Short Term ◽  
Caval Vein ◽  
Thrombotic Risk ◽  
Coagulation Profile ◽  
Thrombosis Model ◽  
Inferior Caval Vein

SummaryObesity and oral estrogens are independent risk factors for venous thrombosis, and their combined effect is stronger than the sum of the isolated factors. It was the objective of this study to investigate the interaction between obesity and estrogens at the level of venous thrombotic tendency, coagulation and inflammation in a mouse model.Female C57Bl/6J mice were fed a standard fat diet (SFD) or a high fat diet (HFD) to induce nutritional obesity.After 14 weeks, while maintaining their diet, mice were orally treated eight days with 1 µg ethinylestradiol or vehicle (n=25 per group), and subsequently subjected to an inferior caval vein (ICV) thrombosis model.The ICV thrombosis model resulted in an increased thrombus weight in vehicle-treated HFD mice (3.0 ± 0.7 mg) compared to vehicle-treated SFD mice (1.4 ± 0.4 mg; p=0.064). Surprisingly, estrogens reduced thrombus weight, which was significant for the HFD group (0.8 ± 0.5 mg; p=0.013).As compared to SFD feeding, HFD feeding significantly increased plasma levels of coagulation factor VIII, combined factor II/VII/X (p<0.001), and plasminogen activator inhibitor-1 (p=0.009), causing a prothrombotic shift of the coagulation profile. Estrogens had no significant effects on this profile with either diet,whereas serum amyloidA and hepatic inflammatory cytokines were minimally affected.The synergistic effect of obesity and estrogens on the venous thrombotic risk in women could not be translated into the mouse context. Short-term ethinylestradiol administration in a mouse ICV thrombosis model counteracts the prothrombotic phenotype associated with nutritionally induced obesity, despite a comparable activated plasma coagulation profile in estrogen-treated and untreated obese mice.

scholarly journals Dissemination of extreme levels of extracellular vesicles: tissue factor activity in patients with severe COVID-19

2021 ◽  
Vol 5 (3) ◽  
pp. 628-634
Author(s):  
Christophe Guervilly ◽  
Amandine Bonifay ◽  
Stephane Burtey ◽  
Florence Sabatier ◽  
Raphaël Cauchois ◽  
...  
Keyword(s):  
Septic Shock ◽  
Tissue Factor ◽  
Extracellular Vesicles ◽  
Severe Disease ◽  
Plasminogen Activator Inhibitor ◽  
Hospitalized Patients ◽  
Plasminogen Activator Inhibitor 1 ◽  
Thrombotic Risk ◽  
Public Health Challenges ◽  
Inflammatory State

Abstract Coronavirus disease 2019 (COVID-19) has become one of the biggest public health challenges of this century. Severe forms of the disease are associated with a thrombo-inflammatory state that can turn into thrombosis. Because tissue factor (TF) conveyed by extracellular vesicles (EVs) has been implicated in thrombosis, we quantified the EV-TF activity in a cohort of hospitalized patients with COVID-19 (n = 111) and evaluated its link with inflammation, disease severity, and thrombotic events. Patients with severe disease were compared with those who had moderate disease and with patients who had septic shock not related to COVID-19 (n = 218). The EV-TF activity was notably increased in patients with severe COVID-19 compared with that observed in patients with moderate COVID-19 (median, 231 [25th to 75th percentile, 39-761] vs median, 25 [25th to 75th percentile, 12-59] fM; P &lt; .0001); EV-TF was correlated with leukocytes, D-dimer, and inflammation parameters. High EV-TF values were associated with an increased thrombotic risk in multivariable models. Compared with patients who had septic shock, those with COVID-19 were characterized by a distinct coagulopathy profile with significantly higher EV-TF and EV-fibrinolytic activities that were not counterbalanced by an increase in plasminogen activator inhibitor-1 (PAI-1). Thus, this article is the first to describe the dissemination of extreme levels of EV-TF in patients with severe COVID-19, which supports the international recommendations of systematic preventive anticoagulation in hospitalized patients and potential intensification of anticoagulation in patients with severe disease.

Inactivation of Plasminogen Activator Inhibitor-1 Accelerates Thrombolysis of a Platelet-rich Thrombus in Rat Mesenteric Arterioles

2001 ◽  
Vol 86 (12) ◽  
pp. 1528-1531 ◽  
Author(s):  
Alain Rupin ◽  
Frédéric Martin ◽  
Marie-Odile Vallez ◽  
Edith Bonhomme ◽  
Tony Verbeuren
Keyword(s):  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Tissue Type ◽  
Cerebral Stroke ◽  
Plasminogen Activator Inhibitor 1 ◽  
Thrombosis Model ◽  
Rat Mesentery ◽  
Student’S T ◽  
Activator Inhibitor ◽  
Pai 1

SummaryTo investigate the role of active plasminogen activator inhibitor 1 (PAI-1) in the evolution of a microthrombus generated in the arteriolar microcirculation, the monoclonal antibody, 33H1F7, which transforms active PAI-1 to a tissue type plasminogen activator (t-PA) substrate, was evaluated in an arteriolar thrombosis model in the rat mesentery. Arterioles (200-300 μm) were stimulated electrically to create an endothelial lesion; ADP was then perfused for 2 min to induce the formation of a platelet-rich thrombus which lysed spontaneously in 140 ± 24 s. Two successive ADP superfusions produced comparable thrombi which lysed in comparable times. Different doses of 33H1F7 were infused to rats for 30 min and the dose which inactivates rapidly and totally active rat PAI-1 (300 μg/kg/min) was selected to be tested on the thrombosis model. Infusion of 33H1F7 beginning 10 min before the ADP application significantly reduced the lysis time in comparison to the control (123 ± 30 s versus 169 ± 33 s, P < 0.05, paired Student’s t-test) and the cumulative thrombus area during the lysis period was decreased by 56 ± 7%. These results demonstrate that inactivation of PAI-1 is able to accelerate lysis of a platelet-rich clot in a mesenteric arteriole of the rat. Thus active PAI-1 most likely participates to the resistance to thrombolysis in the arteriolar microcirculation and its inactivation may shorten ischemic periods after microvascular obstruction such as e.g. during cerebral stroke.

scholarly journals Deficiency of plasma plasminogen activator inhibitor 1 results in hyperfibrinolytic bleeding

Blood ◽  
1993 ◽  
Vol 81 (9) ◽  
pp. 2357-2362 ◽  
Author(s):  
MH Lee ◽  
E Vosburgh ◽  
K Anderson ◽  
J McDonagh
Keyword(s):  
Coagulation Factor ◽  
Plasminogen Activator Inhibitor ◽  
Normal Activity ◽  
Clear Correlation ◽  
Plasminogen Activator Inhibitor 1 ◽  
Unique Role ◽  
Delayed Bleeding ◽  
History Of ◽  
Pai 1

A 63-year-old man was evaluated for a lifelong history of bleeding commencing with frequent epistaxis as a child; all previous routine coagulation parameters were within the normal range. The patient's hemorrhagic disorder is characterized predominantly by delayed bleeding at surgical sites. In the resting state, there was no clinical or laboratory evidence of excessive fibrin(ogen)olysis. Bleeding was not caused by disseminated intravascular coagulation, factor XIII deficiency, alpha 2-antiplasmin deficiency, or dysfibrinogenemia. It was found that the patient was deficient in plasma PAI-1 antigen and activity but with approximately half normal antigen and normal activity of platelet PAI-1. The low concentration of plasma PAI-1 was insufficient to neutralize circulating t-PA, resulting in high t-PA activity with normal antigen and causing the hyperfibrinolytic activity observed. Studies on seven family members of the proband indicated autosomal inheritance of plasma PAI-1 deficiency. Studies on this patient emphasize a clear correlation between decreased plasma PAI-1 activity and hyperfibrinolytic bleeding and also emphasize the unique role of plasma PAI-1 in the balance between the coagulation and fibrinolytic mechanisms.

Short-Term Infusions of Insulin, Triacylglycerol and Glucose do not Cause Acute Increases in Plasminogen Activator Inhibitor-1 Concentrations in Man

1990 ◽  
Vol 79 (5) ◽  
pp. 513-516 ◽  
Author(s):  
P. J. Grant ◽  
E. K. O. Kruithof ◽  
C. P. Felley ◽  
J. P. Felber ◽  
F. Bachmann
Keyword(s):  
Plasminogen Activator ◽  
Glucose Concentration ◽  
Plasma Insulin ◽  
Insulin Infusion ◽  
Plasma Concentrations ◽  
Plasminogen Activator Inhibitor ◽  
Plasminogen Activator Inhibitor 1 ◽  
Short Term ◽  
Mean Glucose ◽  
Activator Inhibitor

1. To investigate the acute effects of insulin and triacylglycerol (‘triglyceride’) on circulating plasminogen activator inhibitor-1 concentrations, seven healthy volunteers were studied during hyperinsulinaemic clamps in the presence of euglycaemia (mean glucose concentration 5 mmol/l) and hyperglycaemia (mean glucose concentration 9 mmol/l) with and without triacylglycerol infusions. 2. During euglycaemia, plasma insulin levels rose from baseline values [median (range)] of 13 (6.6–20.6) m-units/l to 89 (74–105) m-units/l and 99 (74–109) m-units/l after 1 and 2 h of insulin infusion, respectively. Concentrations of plasminogen activator inhibitor-1 fell from 27.5 (10–47) ng/ml to 25.0 (14.5–55) ng/ml and 15.5 (11.5–28.5) ng/ml (P < 0.02) over the same time. 3. During hyperglycaemia, plasma insulin concentrations were 12.1 (9.3–17.1) m-units/l at the run-in period and rose to 87 (73–112) m-units/l and 91 (84–97) m-units/l after 1 and 2 h of insulin infusion, respectively. Concentrations of plasminogen activator inhibitor-1 again showed a gradual fall from 24.7 (22–50) ng/ml to 14 (8.3–25.5) ng/ml and 13 (6.0–35.0) ng/ml (P < 0.02) over the same period. 4. Infusion of Intralipid in the presence of hyperinsulinaemia with either euglycaemia or hyperglycaemia was associated with a similar fall in concentrations of plasminogen activator inhibitor-1 over the study period. 5. The results from this study indicate that short-term increases in insulin, glucose or triacylglycerol do not cause acute increases in plasma concentrations of plasminogen activator inhibitor-1.

scholarly journals A Novel Inhibitor of Plasminogen Activator Inhibitor-1 Provides Antithrombotic Benefits Devoid of Bleeding Effect in Nonhuman Primates

2010 ◽  
Vol 30 (5) ◽  
pp. 904-912 ◽  
Author(s):  
Yuko Izuhara ◽  
Nagahisa Yamaoka ◽  
Hidehiko Kodama ◽  
Takashi Dan ◽  
Shunya Takizawa ◽  
...  
Keyword(s):  
Adverse Effect ◽  
Plasminogen Activator ◽  
Nonhuman Primates ◽  
Bleeding Time ◽  
Plasminogen Activator Inhibitor ◽  
Antithrombotic Effect ◽  
Plasminogen Activator Inhibitor 1 ◽  
Thrombosis Model ◽  
Activator Inhibitor ◽  
Pai 1

Inhibition of plasminogen activator inhibitor (PAI)-1 is useful to treat several disorders including thrombosis. An inhibitor of PAI-1 (TM5275) was newly identified by an extensive study of structure-activity relationship based on a lead compound (TM5007) which was obtained through virtual screening by docking simulations. Its antithrombotic efficacy and adverse effects were tested in vivo in rats and nonhuman primates (cynomolgus monkey). TM5275, administered orally in rats (1 to 10 mg/kg), has an antithrombotic effect equivalent to that of ticlopidine (500 mg/kg) in an arterialvenous shunt thrombosis model and to that of clopidogrel (3 mg/kg) in a ferric chloride-treated carotid artery thrombosis model. TM5275 does not modify activated partial thromboplastin time and prothrombin time or platelet activity and does not prolong bleeding time. Combined with tissue plasminogen activator, TM5275 improves the latter's therapeutic efficacy and reduces its adverse effect. Administered to a monkey model of photochemical induced arterial thrombosis, TM5275 (10 mg/kg) has the same antithrombotic effect as clopidogrel (10 mg/kg), without enhanced bleeding. This study documents the antithrombotic benefits of a novel, more powerful, PAI-1 inhibitor in rats and, for the first time, in nonhuman primates. These effects are obtained without adverse effect on bleeding time.

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