Novel E-Selectin Antagonist GMI-1271 Decreases Venous Thrombosis without Increased Bleeding Potential in a Mouse Model

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3422-3422 ◽  
Author(s):  
Daniel Durant Myers ◽  
Dorian L Culmer ◽  
Jose A. Diaz ◽  
Angela E. Hawley ◽  
Peter K. Henke ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Small Molecule ◽  
Inflammatory Cell ◽  
Bleeding Time ◽  
Thrombus Formation ◽  
Vein Wall ◽  
Treatment Groups ◽  
Venous Thrombus ◽  
Cell Counts ◽  
Vascular Channels

Abstract Abstract 3422 Introduction: Selectins function in venous thrombosis presumably by binding and activating immune cells to initiate the coagulation cascade. E-selectin (CD62E) is known to bind and activate both monocytes and neutrophils. GMI-1271 is a small molecule antagonist that specifically inhibits E-selectin and is rationally designed to mimic the bioactive conformation of the sialyl-Lex carbohydrate ligand. Here we determine whether specific inhibition of E-selectin is sufficient to inhibit acute venous thrombosis and associated inflammatory events in both prophylactic and treatment protocols without causing the broader effects of increased bleeding time. Methods: Male C57BL/6J mice underwent our electrolytic inferior vena cava (IVC) model to produce a non-occlusive thrombosis via electrical stimulation (250 μAmp). Animals were divided into prophylactic or treatment groups. Both groups included the following: non-thrombosed animals (TC, no surgery or drug), 2 Day sham (needle inside the IVC and no current or drug), 2 Day CTR (current and no drug), 2 Day GMI-1271 (10mg/kg IP BID), and LMWH (Lovenox®, 6mg/kg SQ QD). Animals were divided into prophylactic or treatment groups. Mice in the prophylactic group were dosed one day pre-thrombus induction through day 1. Animals in the treatment groups received the first dose of the drug following thrombus induction on day 1. Mice were euthanized 2 days post-thrombosis for tissue harvest and blood collection for the following evaluations: thrombus weight; vein wall inflammatory cell counts per high power field; vein wall-thrombus histology; and intra-thrombus polymorphonuclear cell (PMN) counts. A separate group of mice received IV administration of compounds for tail bleeding time evaluation (seconds). Results: GMI-1271 Significantly Decreases Venous Thrombus Weight (Figure 1). Treatment with GMI-1271 decreased venous thrombus formation in a dose-dependent manner with significant inhibition at 10mg/kg (P=0.0271). Treatment with LMWH significantly decreased thrombus formation 2 day post induction at 6mg/kg (P=0.0203). All mice pre-treated prophylactically with GMI-1271 or LMWH followed the same pattern of decreasing thrombus weight 2 days post injury (P<0.05). E-selectin Inhibition with GMI-1271 Does Not Increase Bleeding Potential (Figure 2) LMWH at 6 mg/kg dose significantly elevated tail bleeding times in mice versus controls (341±27, 491±60 vs. 82±6 seconds, P<0.01). GMI-1271 (10mg/kg, IV) had significantly lower tail bleeding times compared to an IV dose of LMWH (6mg/kg, P<0.01). Vein Wall Morphometrics and Histology Treatment: Only treatment with GMI-1271 significantly decreased vein wall monocyte extravasation compared to controls (P<0.05). Prophylaxis: GMI-1271 and LMWH prophylaxis significantly decreased vein wall PMN extravasation 2 days post thrombosis (P=0.027 and P=0.007 respectively). The same pattern held true for prophylaxis with GMI-1271 and LMWH on vein wall monocyte extravasation at the same time point (P<0.01). Intra-Thrombus PMN Counts: GMI-1271 prophylactic therapy significantly decreases intra-thrombus cell counts versus control animal (14.5±3.7 vs. 37.4±4.7 PMNs/HPF, P=0.009), and these animals had decreased venous thrombus burden. Of interest, only mice receiving GMI-1271 therapy visually have more intra-thrombus vascular channels compared to control animals and mice receiving LMWH therapy. Conclusion: GMI 1271 inhibits venous thrombosis and significantly decreases thrombus weight. GMI 1271 proposes a much lower risk of patients having bleeding complications. Vascular channels exclusively present in thrombi from mice receiving GMI-1271 therapy may aide in thrombus resolution which is currently under investigation. Delayed inflammatory cell recruitment of all cell types into the vein wall post thrombus induction indicates a possible decrease in leukocyte activation. This data suggest that inhibition of E-selectin is sufficient to inhibit venous thrombosis without an increased bleeding risk and the small molecule E-selectin specific antagonist GMI-1271 is a viable therapeutic candidate for venous thrombosis treatment and prophylaxis. Disclosures: Patton: GlycoMimetics: Employment. Magnani:GlycoMimetics: Employment, Equity Ownership.

E-selectin inhibition with GMI-1271 decreases venous thrombosis without profoundly affecting tail vein bleeding in a mouse model

2017 ◽  
Vol 117 (06) ◽  
pp. 1171-1181 ◽  
Author(s):  
Dorian L. Culmer ◽  
Misha L. Dunbar ◽  
Angela E. Hawley ◽  
Suman Sood ◽  
Robert E. Sigler ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Thrombus Formation ◽  
Coagulation Cascade ◽  
Thrombosis Prophylaxis ◽  
Dependent Manner ◽  
Vein Wall ◽  
Treatment Protocols ◽  
Treatment Groups ◽  
Cell Counts ◽  
Dose Dependent

SummarySelectins, such as E-selectin (CD62E), function in venous thrombosis by binding and activating immune cells to initiate the coagulation cascade. GMI-1271 is a small molecule antagonist that inhibits E-selectin activity. Here we determine whether inhibition of E-selectin is sufficient to decrease acute venous thrombosis and associated inflammatory events in both prophylactic and treatment protocols without significantly affecting haemostasis. Male C57BL/6 mice underwent surgery for experimental thrombosis induction and were harvested at peak thrombus formation in our animal model, two days post induction. Groups included non-thrombosed true controls, shams, controls, and prophylactic or treatment groups of GMI-1271 (10 mg/kg intraperitoneal BID (twice a day) and low-molecular-weight heparin (LMWH, Lovenox 6 mg/kg subcutaneously (SC), once a day (SID). Compared with control animals, prophylaxis or treatment with LMWH and GMI-1271 in a dose-dependent manner significantly decreased thrombosis. GMI-1271 significantly lowered tail bleeding times when compared to LMWH. GMI-1271 and LMWH prophylactically administered significantly decreased vein wall neutrophil cell extravasation. However, all treatment and prophylactic therapies significantly decreased vein wall monocyte extravasation versus controls. GMI-1271 prophylactic therapy significantly decreased intra-thrombus cell counts versus control animals and other treatment groups. Immunohistochemistry confirmed that both treatments with GMI-1271 and LMWH significantly decreased activated leukocyte migration. GMI-1271 therapy significantly decreased thrombus weight and resulted in significantly lower bleeding times than LMWH. GMI-1271 treated mice showed decreased local and systemic inflammatory effects while modulating neutrophil activation, suggesting that GMI-1271 is a viable therapeutic candidate for venous thrombosis prophylaxis and treatment.

Pan-Selectin Antagonist, GMI-1070 Decreases Venous Thrombosis in a Mouse Model,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3273-3273 ◽  
Author(s):  
Daniel Durant Myers ◽  
Peter K. Henke ◽  
Jose A. Diaz ◽  
Shirley K. Wrobleski ◽  
Angela E. Hawley ◽  
...  
Keyword(s):  
Mouse Model ◽  
Venous Thrombosis ◽  
Total Protein ◽  
Inflammatory Cell ◽  
Phase I Clinical Trials ◽  
Employment Equity ◽  
Vein Wall ◽  
Venous Thrombus ◽  
Cell Counts ◽  
Equity Ownership

Abstract Abstract 3273 Introduction: E- and P-selectin have structural similarities and both facilitate white blood cell tethering on vascular endothelium. The beneficial effect of combined E- and P-selectin inhibition in decreasing venous thrombosis (VT) by gene deletion in a mouse model of VT has been demonstrated. GMI-1070 is a pan-selectin inhibitor designed to mimic the bioactive conformation of the sialyl-Lex carbohydrate binding domain of E-selectin and the sulfate interactions of P- and L-selectins. GMI-1070 has primary activity against E-selectin, with second and tertiary activity against P- and L-selectin. It has passed Phase I clinical trials showing no serious adverse events, and has a serum half-life in humans of 7 to 8 hours. In this study, the effect of pan-selectin inhibition by GMI-1070 on reducing VT was evaluated. Methods: Male C57BL/6J mice (20-25grams) underwent our electrolytic IVC model (EIM) to produce a non-occlusive thrombosis via electrical free radical stimulation (250 μAmp) for 15 minutes. Experimental groups included the following: GMI-1070 delivered continuously by mini osmotic pump (300 mg/ml), and mice administered saline via the same protocol served as controls (SAL CTR). Continuous delivery of GMI-1070, or saline, began one day pre-thrombus induction. Mice were euthanized 2 and 6 days post-thrombosis for tissue harvest and blood collection for the following evaluations: thrombus weight (grams); plasma soluble E- and P-selectin (ng/mg total protein); vein wall E- and P-selectin protein by ELISA (pg/mg total protein); and vein wall inflammatory cell counts per high powered field. Results: Continuous GMI-1070 administration significantly decreased venous thrombus weight (WT) two days post thrombosis (78±8 vs. 216±97 ×10−4 grams, P<0.01), and also significantly decreased TW six days post thrombosis versus saline controls (85±8 vs. 170±48 ×10−4grams, P≤0.05) [Figure 1]. Circulating E-selectin protein was decreased significantly at both day 2 (21700±2014 vs. 56360±4284 pg/mg total protein, P<0.01), and day 6 (33070±3586 vs. 67310±2833 pg/mg total protein, P<0.01) post VT compared to respective saline controls. GMI-1070 significantly decreased vein wall E-selectin protein versus saline controls 6 days post thrombosis (281±36 vs. 676±102 pg/mg total protein, P<0.02). No effect on vein wall P-selectin protein was noted. Vein wall inflammatory cell evaluation showed neutrophils peaking at day 2, then significantly decreasing by day 6 in these mice (23±5 vs. 7±1 Cells/5HPFs, P<0.01). Conversely, vein wall monocytes were found in significant numbers 6 days post thrombosis in mice receiving GMI-1070 versus saline controls (P<0.01). Both neutrophils and monocytes showed trends of increased vein wall extravasation versus saline groups. Conclusions: GMI-1070 therapy significantly decreased venous thrombus formation. This pan-selectin inhibitor modulated circulating E- and P-selectin and vein wall E- selectin levels thus decreasing systemic and local inflammatory effects of both adhesion molecules. GMI-1070 therapy significantly increased vein wall monocytes and these mice had the greatest VT resolution. GMI-1070 has a high therapeutic potential for decreasing thrombosis and selectin related events. Disclosures: Patton: GlycoMimetics, Inc.: Employment, Equity Ownership. Magnani:GlycoMimetics, Inc.: Employment, Equity Ownership.

The Antithrombotic Efficacy of AT-1459, a Novel, Direct Thrombin Inhibitor, in Rat Models of Venous and Arterial Thrombosis

2001 ◽  
Vol 86 (12) ◽  
pp. 1512-1520 ◽  
Author(s):  
Chi-ho Yun ◽  
Hyoung-sik Seo ◽  
Takaki Koga ◽  
Takashi Dan ◽  
Hak-yeop Kim ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Arterial Thrombosis ◽  
Bleeding Time ◽  
Thrombus Formation ◽  
Direct Thrombin Inhibitor ◽  
Vehicle Group ◽  
Thrombin Inhibitor ◽  
Rat Models ◽  
Vessel Patency ◽  
Antithrombotic Efficacy

SummaryThe antithrombotic efficacy of AT-1459, a novel, direct thrombin inhibitor (Ki = 4.9 nM) was evaluated in rat models of venous thrombosis combined with a bleeding time test and arterial thrombosis.After drugs were given by i. v. bolus injection plus a continuous infusion, the ID50 (a dose that exhibits 50% inhibition of thrombus formation over each vehicle group) values of AT-1459, argatroban, and dalteparin were 0.04 mg/kg plus 0.04 mg/kg/h, 0.1 mg/kg plus 0.4 mg/ kg/h, and 13.0 IU/kg plus 26.0 IU/kg/h, respectively, in the venous thrombosis study. The BT2 (a dose that causes 2-fold prolongation of bleeding time over each vehicle group) values of AT-1459, argatroban, and dalteparin were 0.9 mg/kg plus 0.9 mg/kg/h, 1.0 mg/kg plus 0.6 mg/kg/h, and 345.5 IU/kg plus 691.0 IU/kg/h in the rat tail transection model. The ratios of BT2/ID50 of AT-1459, argatroban, and dalteparin were 22.5, 10.0, and 26.6, respectively.In a rat model of arterial thrombosis induced by topical FeCl2 application, intravenous administration of AT-1459, argatroban, and dalteparin improved the vessel patency significantly (P <0.01) at 0.6 mg/kg plus 0.6 mg/kg/h, 0.6 mg/kg plus 2.4 mg/kg/h, and 300 IU/kg plus 600 IU/kg/h, respectively.The oral antithrombotic effect of AT-1459 lasted for 6 after administering 30 mg/kg and improved the vessel patency significantly 1 h after administering the same dose in venous and arterial thrombosis models, respectively, with a rapid onset of action. Warfarin also inhibited thrombus weight and improved the vessel patency significantly after oral administration of 0.3 mg/kg for three consecutive days in the same study. The antithrombotic and hemorrhagic effects of all drugs studied were correlated with plasma concentration or clotting times.These results suggest that AT-1459 may be clinically useful as an orally available antithrombotic agent for the prevention of venous and arterial thrombosis.

Re-modelling of venous thrombosis

2013 ◽  
Vol 28 (1_suppl) ◽  
pp. 25-28 ◽  
Author(s):  
R D Malgor ◽  
N Labropoulos
Keyword(s):  
Venous Thromboembolism ◽  
Venous Thrombosis ◽  
Thrombus Formation ◽  
Temporal Relation ◽  
Morbidity And Mortality ◽  
Basic Knowledge ◽  
Venous Thrombus ◽  
Prompt Treatment ◽  
Common Causes

Venous thromboembolism is one of the most common causes of morbidity and mortality in modern societies. The entirety of events involved in venous thrombus formation and resolution remains to be elucidated. Temporal relation between the initial cellular insult, thrombus formation and resolution is critical for instituting a prompt treatment. This paper analyses the current basic knowledge and the events involved in venous remodelling after an episode of venous thrombosis.

Reversal of anticoagulant effects of edoxaban, an oral, direct factor Xa inhibitor, with haemostatic agents

2012 ◽  
Vol 107 (02) ◽  
pp. 253-259 ◽  
Author(s):  
Toshio Fukuda ◽  
Yuko Honda ◽  
Chikako Kamisato ◽  
Toshiro Shibano ◽  
Yoshiyuki Morishima
Keyword(s):  
Venous Thrombosis ◽  
Prothrombin Complex Concentrate ◽  
Bleeding Time ◽  
Factor Viia ◽  
Thrombus Formation ◽  
Factor Xa ◽  
Factor Xa Inhibitor ◽  
Direct Factor ◽  
Thrombosis Model ◽  
Haemostatic Agents

SummaryEdoxaban, an oral, direct factor Xa inhibitor, has a similar or low incidence of bleeding events compared with other anticoagulants in clinical trials. Therefore, agents to reverse the anticoagulant effects of edoxaban could be desirable in emergency situations. In this study, the reversal effects of haemostatic agents were determined on prothrombin time (PT) prolongation in vitro and bleeding time prolongation in vivo by edoxaban. PT using human plasma was measured in the presence of edoxaban at therapeutic and excess concentrations with the haemostatic agents, prothrombin complex concentrate (PPSB-HT), activated prothrombin complex concentrate (Feiba), and recombinant factor VIIa (rFVIIa). In rats, rFVIIa and Feiba was given during intensive anticoagulation with edoxaban. The haemostatic effect was evaluated in a model of planta template bleeding and a potential prothrombotic effect was evaluated in a venous thrombosis model. PPSB-HT, Feiba, and rFVIIa concentration-dependently shortened PT prolonged by edoxaban. Among these, rFVIIa and Feiba showed potent activities in reversing the PT prolongation by edoxaban. rFVIIa (1 and 3 mg/kg, i.v.) and Feiba (100 U/kg, i.v.) significantly reversed edoxaban (1 mg/kg/h)-induced prolongation of bleeding time in rats. In a rat venous thrombosis model, no potentiation of thrombus formation was observed when the highest dose (3 mg/kg) of rFVIIa was added to edoxaban (0.3 and 1 mg/kg/h) compared with the control. The present study indicated that rFVIIa, Feiba, and PPSB-HT have the potential to be reversal agents for edoxaban.

scholarly journals Treatment with an oral small molecule inhibitor of P selectin (PSI-697) decreases vein wall injury in a rat stenosis model of venous thrombosis

2006 ◽  
Vol 44 (3) ◽  
pp. 625-632 ◽  
Author(s):  
Daniel D. Myers ◽  
Peter K. Henke ◽  
Patricia W. Bedard ◽  
Shirley K. Wrobleski ◽  
Neelu Kaila ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Vein Wall ◽  
Molecule Inhibitor ◽  
Wall Injury

Subcutaneous Dosing of CRA-027483, a Small Molecule FVIIa Inhibitor, Prevents Arterial Thrombosis in a Baboon Model.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1867-1867
Author(s):  
Ulla M. Marzec ◽  
Juthamas Sukbuntherng ◽  
Stacie A. Dalrymple ◽  
Wendy B. Young ◽  
Dange Vijaykumar ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Small Molecule ◽  
Bleeding Time ◽  
Thrombus Formation ◽  
Reversible Inhibitor ◽  
Thrombosis Model ◽  
Shunt Thrombosis ◽  
Venous Shunt ◽  
Fixed Concentration ◽  
Indium 111

Abstract Vessel injury may expose tissue factor leading to the activation of FVII, initiation of coagulation, and thrombosis. A small reversible inhibitor of FVIIa (CRA-027483), dosed by subcutaneous (SC) injection, was investigated in an arterio-venous shunt thrombosis model in non-anticoagulated awake baboons. Drug pharmacokinetics (PK) and pharmacodynamics (PD) were studied in non-shunted baboons; PK and PD results were closely correlated with ~ 100% bioavailability following SC drug administration. Thrombosis was initiated by interposing within the shunt a segment of porous expanded (poly)tetrafluoroethylene vascular graft (ePTFE, 4mm ID), filled with relipidated tissue factor. Upon initiation of blood flow at 100mL/min (wall shear rate =256/sec) thrombus growth was monitored by gamma camera imaging of autologous Indium-111 labeled platelets for 1 hour. Fibrin accumulation was quantified using trace amounts of homologous fibrinogen labeled with I-125. Both bleeding time and prothrombin time (PT), the PD marker, were monitored throughout. Animals were dosed SC 90min prior to the initiation of thrombus formation, a regimen that was predicted from PK/PD to result in a fixed concentration of CRA-027483 during the thrombosis phase. Dosing of baboons with CRA 027483 at 1mg/kg, 2mg/kg and 4mg/kg SC (4–5 animals in each study group) inhibited total platelet deposition on the tissue factor surface by 13±4%, 43±30% and 67±26% respectively, vs. control results. Fibrin accumulation was reduced by 22±9%, 50±34%, and 76±19% respectively for these doses. PT values remained stable throughout the thrombosis phase and increased 1.3-, 1.6- and 2.1-fold over baseline with the escalating doses. Bleeding time measurements were slightly prolonged at the higher doses (7.3±1.6min and 7.1±2.5min for the 2mg/kg and 4mg/kg doses, respectively) as compared to the pre-drug measurement of 3.8±0.7min. We conclude that SC administration of CRA-027483, a reversible small molecule inhibitor of FVIIa, effectively reduces tissue factor-initiated thrombus formation in baboons with minimal hemostatic impairment.

A Comparison Between Low Molecular Weight Heparin (KABI 2165) and Standard Heparin in the Intravenous Treatment of Deep Venous Thrombosis

1985 ◽  
Vol 54 (04) ◽  
pp. 813-817 ◽  
Author(s):  
Göran Bratt ◽  
Eva Törnebohm ◽  
Staffan Granqvist ◽  
Wiveca Åberg ◽  
Dieter Lockner
Keyword(s):  
Molecular Weight ◽  
Venous Thrombosis ◽  
Deep Venous Thrombosis ◽  
Low Molecular Weight Heparin ◽  
Bleeding Time ◽  
Low Molecular Weight ◽  
Treatment Groups ◽  
Intravenous Treatment ◽  
Heparin Activity ◽  
The Mean

SummaryIn order to study whether a low molecular weight heparin (LMWH) of mw 4000 D is effective in the treatment of deep venous thrombosis (DVT), patients with DVT verified by phlebography were randomized to treatment by continuous intravenous infusion of either unfractionated heparin (UFH) or LMWH. The initial dose was 240 U (anti F Xa)/kg/12 h. TTiis study (study I) was stopped because of major bleeding in 2 newly operated patients in the LMWH group after 27 patients had been treated. The heparin activity measured as F Xa inhibition assayed in retrospect, was found to be much higher in the LMWH group (mean 1.6-2.0 anti F Xa U/ml) than in the UFH group (mean 0.5-0.8 anti F Xa U/ml).A second study was therefore initiated in which the DVT patients were randomly given UFH (240 U/kg/12 h) or LMWH only 120 U (anti F Xa)/kg/12 h, as initial doses (study II). In this study 27 patients could be evaluated, the mean heparin activity still being higher in the LMWH group (0.9-1.2 anti F Xa U/ml) than in the UFH group (0.5-0.7 anti F Xa U/ml).A second phlebographic investigation showed progression of thrombus size in 3 (11%) of the UFH patients of studies I and II (n = 29) and improvement in 14 (48%). There was no progression in any LMWH patient, 6 (50%) had improved in study I and 10 (77%) in study II. The mean decrease of thrombus size score (according to Marder) during treatment did not differ between the 3 groups.Antithrombin III decreased significantly in the UFH group but not in the LMWH groups. Aminotransferases increased in all 3 groups. There was no difference in mean capillary bleeding time between the 3 treatment groups.Although this material is relatively small, our findings suggest that LMWH seems to be of similar effectivity as UFH.

Plasmin Generation Plays different Roles in the Formation and Removal of Arterial and Venous Thrombus in Mice

2002 ◽  
Vol 87 (01) ◽  
pp. 98-104 ◽  
Author(s):  
Osamu Kozawa ◽  
Kiyotaka Okada ◽  
Shigeru Ueshima ◽  
Osamu Matsuo ◽  
Toshihiko Uematsu ◽  
...  
Keyword(s):  
Carotid Artery ◽  
Bleeding Time ◽  
Jugular Vein ◽  
Thrombus Formation ◽  
Endothelial Injury ◽  
Wild Type ◽  
Venous Thrombus ◽  
Vascular Patency ◽  
The Times

SummaryThe role of plasminogen (Plg) and α2-antiplasmin (α2-AP) in vascular thrombolysis in vivo was investigated in mice deficient in plasminogen (Plg−/−) or α2-AP (α2-AP−/−) or their wild type (PAI-1+/+, α2AP+/+). A thrombus was induced in the murine carotid artery or the internal jugular vein by endothelial injury. Blood flow was continuously monitored for 90 min and for 6 h 30 min after the initiation of endothelial injury. The times to occlusion by the developing thrombus in the carotid artery and the jugular vein of wild type mice were 12 ± 1.8 and 7.2 ± 1.9 min, respectively. The arterial thrombus formation in α2AP−/− mice was indistinguishable from the one in wild type mice, whereas the time to occlusion in Plg−/− was significantly shortened to 5.9 ± 1.7 min. Vascular patency after spontaneous reperfusion was markedly improved in α2-AP−/− mice. On the contrary, arterial patency in Plg−/− mice was aggravated. In venous thrombus formation, the time to occlusion in α2-AP−/− mice was significantly prolonged (27.1 ± 5.2 min), whereas in Plg−/− it was slightly shortened to 6.5 ± 2.5 min. Vascular patency after spontaneous reperfusion was also improved in α2-AP−/− mice, but not in Plg−/− mice. Histological observations using SEM indicated that fibrin nets were firmly fixed on the injured area in Plg−/− mice, but not in α2-AP−/− mice. The tail bleeding time was not different in any type of mice. However, re-bleeding time using a template bleeding device was significantly prolonged in α2-AP−/− as compared with that of wild type mice. In conclusion, lack of plasminogen markedly reduces the antithrombotic activities in vivo, whereas α2-AP plays a more important role in the formation and removal of venous thrombus in mice. Consequently, the inhibition of α2-AP could be a useful tool for the therapy of venous thrombosis and the prevention of re-thrombus formation.

Sign in / Sign up

Export Citation Format

Share Document