scholarly journals Rutin-Loaded Silver Nanoparticles With Antithrombotic Function

2020 ◽  
Vol 8 ◽  
Author(s):  
Haitao Wu ◽  
Manlin Su ◽  
Hui Jin ◽  
Xinyu Li ◽  
Puyu Wang ◽  
...  
Keyword(s):  
Silver Nanoparticles ◽  
Bleeding Time ◽  
Thrombus Formation ◽  
Aqueous Solubility ◽  
Bleeding Risk ◽  
Activated Partial Thromboplastin Time ◽  
Coagulation Parameter ◽  
Mice Model ◽  
Serum Stability ◽  
Hemorrhage Risk

In this paper, we fabricated rutin-loaded silver nanoparticles (Rutin@AgNPs) as the nano-anticoagulant with antithrombotic function. The serum stability, anticoagulation activity, and bleeding risk of Rutin@AgNPs were evaluated. The results showed Rutin@AgNPs had good serum stability, hemocompatibility, and cytocompatibility. The anticoagulation activity of rutin was maintained, and its stability and aqueous solubility were improved. The Rutin@AgNPs could provide a sustained release to prolong the half-life of rutin. The results of the coagulation parameter assay and thrombus formation test in mice model showed that the activated partial thromboplastin time and prothrombin time were prolonged, and Rutin@AgNPs inhibited the thrombosis in the 48 h period. Moreover, the limited bleeding time indicated that the Rutin@AgNPs significantly minimized the hemorrhage risk of rutin. This Rutin@AgNPs is a potential anticoagulant for antithrombotic therapy.

scholarly journals A Short Half-Life αIIbβ3 Antagonist ANTP266 Reduces Thrombus Formation

2018 ◽  
Vol 19 (8) ◽  
pp. 2306 ◽  
Author(s):  
Tong-Dan Liu ◽  
Shen-Hong Ren ◽  
Xue Ding ◽  
Zhou-Ling Xie ◽  
Yi Kong
Keyword(s):  
Half Life ◽  
Bleeding Time ◽  
Thrombus Formation ◽  
Bleeding Risk ◽  
Effective Dosage ◽  
Enzyme Linked Immunosorbent Assay ◽  
Severe Bleeding ◽  
Antithrombotic Agent ◽  
Integrin Αiibβ3 ◽  
Plasma Half Life

Integrin αIIbβ3 plays a pivotal role in platelet aggregation. Three αIIbβ3 antagonists have been approved by the Food and Drug Administration (FDA) for the treatment of cardiovascular diseases. Unfortunately, all of these three drugs can cause the side effect of severe bleeding. Therefore, developing a new αIIbβ3 antagonist with low bleeding was needed. In the present study, we screened compounds by using a fibrinogen/integrin αIIbβ3 enzyme-linked immunosorbent assay (ELISA), and a novel αIIbβ3 antagonist ANTP266 was attained. The antithrombotic effects of ANTP266 were estimated by using two animal models, the bleeding risk was estimated by using a mice tail cutting assay, and the plasma half-life time was tested by LC-MS/MS. The results showed that ANTP266 potently decreased thrombosis formation, while not prolonging bleeding time at its effective dosage. The bleeding of ANTP266 reduced rapidly as time went on from 5 to 60 min, but tirofiban produced high bleeding continuously. The plasma half-life of ANTP266 in rats was 10.8 min. Taken together, ANTP266 is an effective antithrombotic agent with a low bleeding risk. The shorter bleeding time benefits from its short plasma half-life. ANTP266 could be a candidate for developing the αIIbβ3 antagonist of rapid elimination for a patient undergoing percutaneous coronary intervention.

Safe Interruption of Ongoing Thrombosis by the Protein C Activator Thrombin Analog, W215A/E217A; a Comparison to Enoxaparin in Primates.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 909-909 ◽  
Author(s):  
Ulla M. Marzec ◽  
Leslie Bush ◽  
Erik Tucker ◽  
Andras Gruber ◽  
Stephen R. Hanson ◽  
...  
Keyword(s):  
Group Treatment ◽  
Protein C ◽  
Double Mutant ◽  
Bleeding Time ◽  
Thrombus Formation ◽  
Bleeding Risk ◽  
Expansion Chamber ◽  
Platelet Deposition ◽  
Type Flow ◽  
Human Thrombin

Abstract Antithrombotic agents are effective but pose significant bleeding risk, thus safer new agents are needed. Since the infused double mutant human thrombin (W215A/E217A; WE) binds endothelial thrombomodulin, activates protein C locally in the intraluminal boundary layer, and prevents thrombus formation without hemostasis impairment, we investigated whether WE could also interrupt the growth of existing thrombi. WE was compared to standard interventional doses of the low molecular weight heparin, enoxaparin (Sanofi) in awake baboons. Thrombosis was initiated by interposing a two part device consisting of a 2 cm, 4 mm ID polyethylene terephthalate vascular graft (DVG) followed by a 2 cm silicone rubber expansion chamber, 9 mmID. Upon initiation of blood flow at 100 mL/min, wall shear rate of 265 sec-1 in the 4 mm ID segment (arterial type flow) and 29 sec-1 in the expansion chamber (venous type flow), platelet thrombus was monitored by gamma camera imaging of autologous 111In-labelled platelets for 60 min or 90 min. Fibrin accumulation was quantified by homologous 125I-labelled fibrinogen. Hemostasis was assessed as template bleeding time prolongation. APTT was also monitored. Treatments started 25 min after the initiation of thrombosis by enoxaparin, 0.5 mg/kg (LD) and 1 mg/kg (HD) IV bolus or WE, 7.5 μg/kg/hr (LD) and 15 μg/kg/hr (HD) infusion (1/3 dose given as a bolus followed by IV infusion over 60min) and compared to saline infused controls. All interventions were given systemically, downstream from the device and 5–6 studies comprised each study group. Treatment with enoxaparin at 25 min after initiation of thrombus growth resulted in a reduction of platelet deposition of 19 % with the LD and 76 % with the HD after 35 min of therapy in the expanded venous type segment. WE reduced venous thrombosis by 45 % and 65 % at the two doses studied and was further reduced to 65 % and 80 % following 65 min of WE infusion as compared to controls. Arterial type thrombosis was reduced by WE by 34 % and 39 % respectively for the two doses studied. HD enoxaparin reduced arterial type thrombosis by 37 %. Fibrin accumulation paralleled the platelet deposition. APTT was prolonged 1.57- and 1.87-fold respectively for the WE doses without any bleeding time prolongation. Enoxaparin prolonged the APTT 1.4- and 1.75-fold, similar to WE but with a 1.13- and 1.75-fold prolongation of the bleeding time. In conclusion, the double mutant human thrombin, WE, effectively interrupted both venous and arterial type growing thrombi at very low doses without detectable compromise to hemostasis. Likewise, enoxaparin at the doses tested had similar efficacy but with a significantly prolonged bleeding time at the 1 mg/kg bolus dose. WE might provide a safer alternative to heparins in the treatment of acute progressive thrombosis.

Varicose vein surgery under anti-platelet therapy

Phlebologie ◽  
2008 ◽  
Vol 37 (06) ◽  
pp. 287-297 ◽  
Author(s):  
P.-M. Baier ◽  
Z. T. Miszczak
Keyword(s):  
Varicose Vein ◽  
Bleeding Time ◽  
Varicose Veins ◽  
Bleeding Risk ◽  
Bleeding Complications ◽  
Review Of The Literature ◽  
Varicose Vein Surgery ◽  
Anti Platelet Therapy ◽  
Male Patients ◽  
Acute Atherothrombosis

Summary Background: Platelet function inhibitors (PFI) are used for prophylaxis of atherothrombosis. These drugs cause a prolongation of the bleeding time and should eventually be stopped before an elective operation. However, there is a risk that a perioperative pause of PFI lead to acute atherothrombosis. Objective: Our aim was to study whether a discontinuation of PFI therapy is necessary to avoid bleeding complications in patients undergoing varicose vein surgery. Methods: Selective review of the literature and retrospective analysis of clinical data of our own patients. Results: In the years 2002 to 2007 a total of 10 827 patients have been operated on varicose veins, 673 (6.2%) of these aged 32–86 years (67 ± 7.9) receiving permanent PFI therapy: 256 male patients (38.0%) and 417 female (62.0%), 39.1% categorized as ASA III patients: male 11.6%, female 27.5%. 38 patients who continued PFI therapy did not demonstrate haemorrhagic complications and none of those pausing anti-platelet medication experienced thromboembolic complications. The literature survey confirmed our finding that it is not necessary to suspend PFI medication for varicose vein surgery as the bleeding risk can be controlled for by technical means. Conclusion: Discontinuation of PFI therapy prior to interventions on varicose veins does not seem to be necessary, further studies are essential though.

ADP Plays a Key Role in Thrombogenesis in Rats

1988 ◽  
Vol 59 (02) ◽  
pp. 225-230 ◽  
Author(s):  
J P Maffrand ◽  
A Bernat ◽  
D Delebassée ◽  
G Defreyn ◽  
J P Cazenave ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Bleeding Time ◽  
Thrombus Formation ◽  
Vascular Wall ◽  
Cyclooxygenase Inhibitors ◽  
High Dose ◽  
Silk Thread ◽  
Dense Granules ◽  
Prolonged Bleeding Time ◽  
Venous Shunt

SummaryThe relative importance of ADP, arachidonic acid metabolites and serotonin as thrombogenic factors was evaluated in rats by comparing, after oral administration, the effects of two inhibitors of ADP-induced platelet aggregation (ticlopidine and PCR 4099), three cyclo-oxygenase inhibitors (aspirin, triflusal and indobufen) and a selective serotonin 5HT2 receptor antagonist (ketanserin) on platelet aggregation, in four platelet-dependent thrombosis models and on bleeding time. Platelet aggregation induced by ADP and collagen was completely inhibited by ticlopidine and PCR 4099 whereas only the collagen aggregation was reduced by the cyclo-oxygenase inhibitors. Ketanserin or a depletion of platelet serotonin by reserpine did not affect platelet aggregation. Ticlopidine and PCR 4099 greatly prolonged rat tail transection bleeding time. This is probably related to their known ability to inhibit ADP-mediated platelet aggregation. In contrast, the cyclooxygenase inhibitors did not affect bleeding time at all. Reserpine and ketanserin prolonged bleeding time by interfering with the action of serotonin on the vascular wall. Ticlopidine and PCR4099 were very potent antithrombotics in all the models. Aspirin, only at a high dose, inhibited poorly thrombus formation on a silk thread in an arterio-venous shunt, suggesting that the inhibition of cyclo-oxygenase was not responsible. Triflusal was inactive in all models while indobufen slightly reduced thrombus formation in the silk thread and metallic coil models. Ketanserin and reserpine reduced thrombus only in the metallic coil model. Thrombus formation was greatly reduced in fawn-hooded rats, which lack ADP in their platelet dense granules because of a genetic storage pool deficiency. Taken together, the results obtained with the drugs and with the fawn-hooded rats support the concept that ADP plays a key role in thrombogenesis in rats.

Antithrombotic Effects and Bleeding Time Prolongation with Synthetic Platelet GPIIb/llla Inhibitors in Animal Models of Platelet-Mediated Thrombosis

1994 ◽  
Vol 71 (01) ◽  
pp. 095-102 ◽  
Author(s):  
Désiré Collen ◽  
Hua Rong Lu ◽  
Jean-Marie Stassen ◽  
Ingrid Vreys ◽  
Tsunehiro Yasuda ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Bleeding Time ◽  
Bolus Injection ◽  
Cell Injury ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Femoral Vein ◽  
Thrombotic Occlusion ◽  
Antithrombotic Effects

SummaryCyclic Arg-Gly-Asp (RGD) containing synthetic peptides such as L-cysteine, N-(mercaptoacetyl)-D-tyrosyl-L-arginylglycyl-L-a-aspartyl-cyclic (1→5)-sulfide, 5-oxide (G4120) and acetyl-L-cysteinyl-L-asparaginyl-L-prolyl-L-arginyl-glycyl-L-α-aspartyl-[0-methyltyrosyl]-L-arginyl-L-cysteinamide, cyclic 1→9-sulfide (TP9201) bind with high affinity to the platelet GPIIb/IIIa receptor.The relationship between antithrombotic effect, ex vivo platelet aggregation and bleeding time prolongation with both agents was studied in hamsters with a standardized femoral vein endothelial cell injury predisposing to platelet-rich mural thrombosis, and in dogs with a carotid arterial eversion graft inserted in the femoral artery. Intravenous administration of G4120 in hamsters inhibited in vivo thrombus formation with a 50% inhibitory bolus dose (ID50) of approximately 20 μg/kg, ex vivo ADP-induccd platelet aggregation with ID50 of 10 μg/kg, and bolus injection of 1 mg/kg prolonged the bleeding time from 38 ± 9 to 1,100 ± 330 s. Administration of TP9201 in hamsters inhibited in vivo thrombus formation with ID50 of 30 μg/kg, ex vivo platelet aggregation with an ID50 of 50 μg/kg and bolus injection of 1 mg/kg did not prolong the template bleeding time. In the dog eversion graft model, infusion of 100 μg/kg of G4120 over 60 min did not fully inhibit platelet-mediated thrombotic occlusion but was associated with inhibition of ADP-induccd ex vivo platelet aggregation and with prolongation of the template bleeding time from 1.3 ± 0.4 to 12 ± 2 min. Infusion of 300 μg/kg of TP9201 over 60 min completely prevented thrombotic occlusion, inhibited ex vivo platelet aggregation, but was not associated with prolongation of the template bleeding time.TP9201, unlike G4120, inhibits in vivo platelet-mediated thrombus formation without associated prolongation of the template bleeding time.

The Venous Antithrombotic Profile of Naroparcil in the Rabbit

1994 ◽  
Vol 72 (06) ◽  
pp. 874-879 ◽  
Author(s):  
Jean Millet ◽  
Jocelyne Theveniaux ◽  
Neil L Brown
Keyword(s):  
Oral Administration ◽  
Bleeding Time ◽  
Dermatan Sulfate ◽  
Factor Xa ◽  
Bleeding Risk ◽  
Thrombin Time ◽  
Heparin Cofactor Ii ◽  
Antithrombotic Activity ◽  
Thrombin Inhibition ◽  
Maximal Reduction

SummaryThe venous antithrombotic profile of naroparcil or (4-[4-cyanoben-zoyl]-phenyl)-1.5-dithio-β-D-xylopyranoside was investigated in the rabbit following single i. v. and oral administration. Naroparcil attenuated thrombus development in a Wessler stasis model of venous thrombosis (jugular vein) employing bovine factor Xa as a thrombogenic stimulus giving ED50 values of 21.9 mg/kg and 36.0 mg/kg after respectively i. v. and oral administration. Venous antithrombotic activity was maximal 2-3 h after i. v. administration and 4-8 h after oral administration. Four hours after the oral administration of maximal antithrombotic (Wessler model, factor Xa) doses (100 and 400 mg/kg), naroparcil had no significant effect on bleeding time. In platelet poor plasma obtained from animals treated 4 h previously with various doses (25 to 400 mg/kg) of naroparcil, there was no detectable anti-factor Xa nor antithrombin activity. Similarly, naroparcil had no effect on APTT nor on thrombin time. A sensitized thrombin time (to about 35 s) was modestly but significantly increased following oral administration of the compound at 400 mg/kg. However, thrombin generation by the intrinsic pathway was reduced in a dose-related manner, maximal reduction being 65% at 400 mg/kg. The same doses of naroparcil enhanced the formation of thrombin/heparin cofactor II complexes at the expense of thrombin/antithrombin III complexes in plasma incubated with (125I)-human a-thrombin and induced the appearance of dermatan sulfate-like material in the plasma of treated rabbits, as measured by a heparin cofactor II-mediated thrombin inhibition assay. The results suggest that naroparcil could have a safe venous antithrombotic profile following oral administration (antithrombotic effect compared to bleeding risk). It is probable that part of the mechanism of action of the β-D-xyloside, naroparcil, is due to the induction of chondroitin sulfate-like glycosaminoglycan biosynthesis, this material being detectable in the plasma.

Experimental Studies on a Recombinant Hirudin, CGP 39393

1991 ◽  
Vol 65 (04) ◽  
pp. 355-359 ◽  
Author(s):  
E Gray ◽  
J Watton ◽  
S Cesmeli ◽  
T W Barrowcliffe ◽  
D P Thomas
Keyword(s):  
Thrombin Generation ◽  
Bleeding Time ◽  
Thrombus Formation ◽  
Experimental Studies ◽  
Venous Stasis ◽  
Antithrombotic Agent ◽  
Recombinant Hirudin ◽  
Excessive Bleeding ◽  
Generation Test

SummaryThe in vitro anticoagulant activities of recombinant desulphatohirudin (r-hirudin) were studied in the activated partial thromboplastin time (APTT) and the thrombin generation test : systems. In the APTT at concentrations below 5 μg/ml, r-hirudin showed a dose-response curye. At concentrations above 5 μg/ml, the plasma became unclottable, but in the thrombin generation test , at least 10 μg/ml of r-hirudin was required for full inhibition of thrombin generation. The antithrombotic effect was assessed using a rabbit venous stasis model; 150 μg/ml r-hirudin completely prevented thrombus formation at 10 and 20 min stasis. At antithrombotic dose, the mean bleeding time ratio measured in a rabbit ear template model, was not prolonged over control values. At higher doses, the bleeding time ratios were higher than those observed for the same dosage of heparin. These data indicate that while r-hirudin is an effective antithrombotic agent, antithrombotic doses have to be carefully titrated to avoid excessive bleeding.

Vampire Bat Salivary Plasminogen Activator Evokes Minimal Bleeding Relative to Tissue-Type Plasminogen Activator as Assessed by a Rabbit Cuticle Bleeding Time Model

1995 ◽  
Vol 73 (03) ◽  
pp. 478-483 ◽  
Author(s):  
Michael J Mellott ◽  
Denise R Ramjit ◽  
Inez I Stabilito ◽  
Timothy R Hare ◽  
Edith T Senderak ◽  
...  
Keyword(s):  
Factor Viii ◽  
Plasminogen Activator ◽  
Intravenous Administration ◽  
Bleeding Time ◽  
Bleeding Risk ◽  
Tissue Type ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator ◽  
Plasma Factor ◽  
Vampire Bat

SummaryCuticle bleeding time (CBT) measurements in anesthetized rabbits were performed to assess the potential bleeding risks which may accompany the administration of tissue-type plasminogen activator (tPA) or vampire bat salivary plasminogen activator (BatPA). The dose of BatPA or tPA used in this study, 42 nmol/kg, was previously shown to be efficacious using a rabbit femoral artery thrombosis model (Gardell et al, Circulation 84:244, 1991). CBT was determined by severing the apex of the nail cuticle and monitoring the time to cessation of blood flow. CBT was minimally elevated (1.6-fold, p<NS) following bolus intravenous administration of BatPA; in contrast, bolus intravenous administration of tPA dramatically elevated CBT (6.2-fold, p<0.05). Rabbits treated with tPA, but not BatPA, displayed profound activation of systemic plasminogen and consequent degradation of Factor VIII and fibrinogen. Elevations in CBT after the administration of tPA were reversed by the replenishment of plasma Factor VIII activity to 40% of control, but were unaffected by complete replenishment of plasma fibrinogen. The results of this study suggest that the administration of BatPA, at a dose that promotes thrombolysis, may evoke a minimal bleeding risk, relative to an equi-efficacious dose of tPA. In addition, the tPA-provoked proteolytic consumption of Factor VIII may be a key contributor to the heightened bleeding risk.

Antiplatelet Effect of FK633, a Platelet Glycoprotein Ilb/IIIa Antagonist, on Thrombus Formation and Vascular Patency after Thrombolysis in the Injured Hamster Carotid Artery

1997 ◽  
Vol 77 (03) ◽  
pp. 562-567 ◽  
Author(s):  
Takehiro Kaida ◽  
Hiroyuki Matsuno ◽  
Masayuki Niwa ◽  
Osamu Kozawa ◽  
Hideo Miyata ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Carotid Artery ◽  
Vascular Injury ◽  
Bleeding Time ◽  
Thrombus Formation ◽  
Separate Experiment ◽  
Platelet Glycoprotein ◽  
Neointima Formation ◽  
Vascular Patency ◽  
Injured Artery

SummaryThe antithrombotic and restenosis-preventing effects of FK633, an inhibitor of platelet aggregation via binding to the glycoprotein (GP) Ilb/IIIa receptor, were studied. IC50 value of FK633 against platelet aggregation ex vivo induced by 2.5 |iM adenosine diphosphate (ADP) was 5.4 X 10"7 M as determined using hamster platelet rich plasma. The inhibitory effect was also investigated in vivo on thrombus formation at the carotid arterial wall injured by a modified catheter. As a control, the left carotid artery was injured and the time required to develop a thrombotic occlusion (3.9 ±1.1 min, mean ± S.E.M., n = 18) was determined. Then, the right carotid artery of the same animal was injured while a continuous intravenous (i.v.) infusion of FK633 was administered at doses of 0 (saline), 0.1,0.3 or 1.0 mg/kg/h. The time to occlusion was dose-dependently prolonged. In a separate experiment, 10% of the total tPA dose (0.52 mg/kg) was injected into the injured artery as a bolus and the remaining was infused i.v. at a constant rate for 30 min. When FK633 (0.3 or 1.0 mg/kg/h) was infused together with tPA, late patency of the reperfused artery was much improved as compared with that of treatment with tPA alone. Bleeding time, measured at the end of the tPA infusion, was markedly prolonged when the higher dose of FK633 (1.0 mg/kg/h) was coadministered, however coadministration of the lower dose of FK633 (0.3 mg/kg/h) was almost without prolongation on the bleeding time, despite a significant effect on the vascular patency after thrombolysis. Next, neointima formation was evaluated 2 weeks after the vascular injury. When FK633 (0.3 mg/kg/h) was continuously infused i. v. by an implanted osmotic pump for 3,7 or 14 days after the vascular injury, the neointimal area formation was significantly suppressed in the treatment groups for 7 or 14 days. These findings suggest that FK633 inhibits platelet activation in the injured artery and improves vascular patency after thrombolysis with tPA with a concomitant suppression of neointima formation.

The Anticoagulant and Hemorrhagic Effects of DHG, a New Depolymerized Holothurian Glycosaminoglycan, on Experimental Hemodialysis in Dogs

1997 ◽  
Vol 77 (06) ◽  
pp. 1148-1153 ◽  
Author(s):  
Kazuhisa G Minamiguchi ◽  
Keiko T Kitazato ◽  
Eiji Sasaki ◽  
Hideki Nagase ◽  
Kenji Kitazato
Keyword(s):  
Low Molecular Weight Heparin ◽  
Bleeding Time ◽  
Activated Partial Thromboplastin Time ◽  
Low Molecular Weight ◽  
Nafamostat Mesilate ◽  
Extracorporeal Circuit ◽  
Clotting Time ◽  
Prolonged Bleeding Time ◽  
Hemorrhagic Risk ◽  
Effective Doses

SummaryWe studied the use of depolymerized holothurian glycosaminoglycan (DHG) as an anticoagulant in experimental beagle-dog hemodialysis using a hollow-fiber dialyzer compared to that using unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and nafamostat mesilate (FUT). Effectiveness was based on 5 h hemodialysis and no marked clot deposition in the extracorporeal circuit. At effective doses, UFH and LMWH significantly prolonged template bleeding time, in sharp contrast to FUT and DHG, which scarcely prolonged bleeding time during hemodialysis. DHG prolonged activated partial thromboplastin time (APTT) about 6 times that of normal plasma and prolonged thrombin clotting time (TCT) markedly; FUT showed marked APTT prolongation but hardly prolonged TCT in the hemodialysis circuit at the effective dose. The anticoagulant profile of DHG thus differs completely from that of FUT. These results suggest that DHG may be useful as anticoagulant for hemodialysis with low hemorrhagic risk.

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