Magnesium Inhibits Arterial Thrombi after Vascular Injury in Rat: In Vivo Impairment of Coagulation

2001 ◽  
Vol 86 (11) ◽  
pp. 1292-1295 ◽  
Author(s):  
Luigi Sironi ◽  
Luca Tedeschi ◽  
Anna Maria Calvio ◽  
Susanna Colli ◽  
Elena Tremoli ◽  
...  
Keyword(s):  
High Frequency ◽  
Blood Clotting ◽  
Magnesium Deficiency ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Clotting Time ◽  
Chemically Induced ◽  
In Vivo Effects ◽  
Blood Clotting Time

SummaryMagnesium deficiency is associated with a high frequency of cardiac arrhythmia, hypertension and sudden ischemic death. We investigated the in vivo effects of intravenous magnesium administration in a rat model of chemically induced (FeCl3) carotid thrombosis. The infusion of magnesium sulfate (MgSO4) before the topical application of FeCl3 prevented thrombus formation at concentrations of 0.3 M and 0.6 M, and delayed it even at 0.15 M. Similar results were obtained with MgCl2. The infusion of MgSO4 0.6 M seven minutes after FeCl3 application delayed but did not prevent thrombus formation. MgSO4 slightly reduced platelet aggregation ex vivo without affecting plasma clotting tests, but in vivo blood clotting time was markedly prolonged (tail transection method), thus indicating profoundly impaired coagulation. These data provide a rationale for the use of magnesium as an anti-thrombotic agent, but its pharmacological effect critically depends on the timing of administration.

Abstract WP1: High-Frequency Optical Coherence Tomography for Cerebrovascular Disease

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Ajit S Puri ◽  
Giovanni Ughi ◽  
Robert M King ◽  
Matthew Gounis
Keyword(s):  
Optical Coherence Tomography ◽  
Cerebrovascular Disease ◽  
High Frequency ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Image Resolution ◽  
Patient Specific ◽  
Optical Coherence

Introduction: Optical coherence tomography (OCT) has played an important role in the diagnosis and treatment guidance in coronary artery disease. However, existing OCT systems are not suitable for routine neurovascular applications due to the size and tortuosity of the arteries. Hypothesis: We seek to demonstrate a prototype high-frequency OCT (HF-OCT) capable of high-resolution imaging in simulated cerebrovascular anatomy. Methods: A low-profile HF-OCT system was constructed with an image resolution approaching 10μm. Using an in vitro, patient-specific model of the circle of Willis with circulating porcine blood, we characterized the delivery of the device and ability to image in a tortuous path. Also, human cadaver intracranial atherosclerosis plaques were imaged with HF-OCT and assessed by an expert imager. Finally, neurovascular devices were implanted in 8 pigs (Fig 1) and HF-OCT imaging was compared with gold-standard DSA and CT. Results: In the phantom, optimal blood clearance was achieved through an intermediate catheter (5 Fr Navien) with infusion of contrast at 5 ml/s in the internal carotid and basilar artery, and 3 ml/sec in the MCA. The in vivo study demonstrated that both malapposition of devices or thrombus formation along the device surface could be reliably diagnosed among 3 reviewers (Fleiss’s kappa of 0.87 and 0.9, respectively). This agreement was superior to DSA and CT. Imaging in tortuous swine brachial showed in all cases imaging free of artifacts, uniform illumination and ability to visualize vessel wall layers. Plaque types including ‘lipid pools’, fibrotic, and calcific tissue from cadaver specimens of ICAD could be adequately depicted by HF-OCT. Conclusion: In vitro, in vivo and ex vivo characterization of a novel HF-OCT device has shown it is capable of imaging in the tortuous intracranial vascular anatomy. This technology has to potential to aid in the diagnosis of cerebrovascular disease and guide optimal endovascular treatment.

Effective Reversal of Edoxaban-associated Bleeding with Four-factor Prothrombin Complex Concentrate in a Rabbit Model of Acute Hemorrhage

2015 ◽  
Vol 122 (2) ◽  
pp. 387-398 ◽  
Author(s):  
Eva Herzog ◽  
Franz Kaspereit ◽  
Wilfried Krege ◽  
Baerbel Doerr ◽  
Jochen Mueller-Cohrs ◽  
...  
Keyword(s):  
Blood Loss ◽  
Prothrombin Time ◽  
Whole Blood ◽  
Thrombin Generation ◽  
Blood Clotting ◽  
Prothrombin Complex Concentrate ◽  
Rabbit Model ◽  
Clotting Time ◽  
Blood Clotting Time

Abstract Background: Edoxaban is an oral, selective direct factor Xa inhibitor approved in Japan for venous thromboembolism prevention after orthopedic surgery. Data are lacking regarding reversal strategies for edoxaban; this study assessed whether four-factor prothrombin complex concentrate (Beriplex®/Kcentra®; CSL Behring GmbH, Marburg, Germany) can effectively reverse its effects on hemostasis using a previously described rabbit model. Methods: The study comprised assessments of thrombin generation in vitro, pharmacokinetic parameters, and edoxaban reversal in vivo. In a blinded in vivo stage, a standardized kidney incision was performed in animals (n = 11 per group) randomized to receive vehicle + saline, edoxaban (1,200 μg/kg) + saline, or edoxaban (1,200 μg/kg) + four-factor prothrombin complex concentrate (50 IU/kg). Animals were monitored for treatment impact on hemostasis and coagulation parameters. Data are median (range). Statistical tests were adjusted for multiple testing. Results: Edoxaban administration increased blood loss (30 [2 to 44] ml) and time to hemostasis (23 [8.5 to 30.0] min) compared with the control group (3 [1 to 8] ml and 3 [2.0 to 5.0] min, respectively). Biomarkers of coagulation (prothrombin time, activated partial thromboplastin time, whole blood clotting time) and thrombin generation parameters (e.g., peak thrombin, endogenous thrombin potential, lag time) were also affected by edoxaban. Administration of four-factor prothrombin complex concentrate significantly reduced time to hemostasis (to 8 [6.5 to 14.0] min, observed P < 0.0001) and total blood loss (to 9 [4 to 22] ml, observed P = 0.0050) compared with the edoxaban + saline group. Of the biomarkers tested, prothrombin time, whole blood clotting time, and endogenous thrombin potential correlated best with clinical parameters. Conclusion: In a rabbit model of hemostasis, four-factor prothrombin complex concentrate administration significantly decreased edoxaban-associated hemorrhage.

Comparative Effects of ADP and Thrombin in Producing Stasis Thrombosis

1967 ◽  
Vol 18 (03/04) ◽  
pp. 537-543 ◽  
Author(s):  
R. K Stuart ◽  
D. P Thomas
Keyword(s):  
Platelet Count ◽  
Whole Blood ◽  
Marked Reduction ◽  
Blood Clotting ◽  
Thrombus Formation ◽  
Clotting Time ◽  
High Doses ◽  
Blood Clotting Time

Summary1. The effect of intravenous ADP on the platelet count, whole blood clotting time and stasis thrombosis formation was investigated in rabbits.2. 20 μ/kg and 10 mg/kg of ADP produced, respectively, a moderate and marked reduction in the circulating platelet count.3. Both the low and high doses of ADP resulted in only a relatively slight shortening of the whole blood clotting time.4. Neither dose of ADP resulted in thrombus formation in isolated venous segments after 30 min of stasis.5. It is concluded that ADP alone is unlikely to be an initiating factor in the pathogenesis of stasis thrombosis.

Anticoagulant Kinetics Following Bolus Injection of Heparin

1979 ◽  
Vol 42 (04) ◽  
pp. 1248-1260 ◽  
Author(s):  
Lyle F Mockros ◽  
Samuel D Hirsch ◽  
Leon Zuckerman ◽  
Joseph A Caprini ◽  
William P Robinson ◽  
...  
Keyword(s):  
Whole Blood ◽  
Blood Clotting ◽  
Anticoagulant Effect ◽  
Post Injection ◽  
Clotting Time ◽  
Sequential Samples ◽  
Dose Dependent ◽  
Blood Clotting Time

SummaryBolus injections of beef-lung heparin at doses of 50, 100 and 200 u/kg body weight were administered to mongrel dogs. Neutralization of the anticoagulant effect was evaluated using sequential samples withdrawn from the animals (in vivo samples) and aliquots from a 100 ml sample withdrawn from the dog at 30 minutes post-injection (in vitro samples). Tests of the activated partial thromboplastin time (APTT) and prothrombin time (PT) did not indicate the degree of anticoagulation. Tests of the whole blood clotting time (WBCT), celite- activated whole blood clotting time (ACT), and celite-activated thromboelastography (ATEG) indicated pronounced hypocoagulability immediately after the injection, followed by a fairly rapid decay in anticoagulability, and a slight Ziype/coagulability at three to four hours post injection. The results from the in vitro ATEG samples were essentially identical to those on the in vivo samples, whereas the in vitro WBCT and ACT generally indicated higher degrees of anticoagulation. Calculated half-lives of the anticoagulant effect are significantly shorter than previously reported, being 18 to 36 minutes, and slightly dose dependent. The decay of the effects, however, does not appear to follow a single exponential curve, dropping very rapidly immediately post-injection and at a somewhat slower rate 60 or more minutes post-injection.

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.

RPR120844, a Novel, Specific Inhibitor of Coagulation Factor Xa Inhibits Venous Thrombosis in the Rabbit

1999 ◽  
Vol 81 (01) ◽  
pp. 157-160 ◽  
Author(s):  
Ross Bentley ◽  
Suzanne Morgan ◽  
Karen Brown ◽  
Valeria Chu ◽  
Richard Ewing ◽  
...  
Keyword(s):  
Jugular Vein ◽  
Drug Effect ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Specific Inhibitor ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Antithrombotic Activity ◽  
Fxa Inhibitor

SummaryThe in vivo antithrombotic activity of RPR120844, a novel synthetic coagulation factor Xa (fXa) inhibitor (Ki = 7 nM), was assessed by its ability to inhibit thrombus formation in a damaged segment of the rabbit jugular vein. Intravenous dose-response studies were performed and thrombus mass (TM), activated partial thromboplastin time (APTT), prothrombin time (PT), inhibition of ex vivo fXa activity and plasma drug levels (PDL) were determined. TM, measured at the end of a 50 min infusion, was significantly reduced (p <0.05 vs saline-treated animals) by RPR120844 at 30 and 100 μg/kg/min. At doses of 10, 30 and 100 μg/kg/min, APTT was prolonged by 2.1, 4.2 and 6.1-fold, and PT was prolonged by 1.4, 2.2 and 3.5-fold, respectively. PDL were determined by measuring anti-fXa activity using an amidolytic assay. Peak PDL were 0.8 ± 0.3, 1.5 ± 0.9 and 2.4 ± 0.6 μM, respectively. The drug effect was reversible with APTT, PT and PDL returning toward pretreatment values 30 min after termination of treatment. The results suggest that RPR120844, or similar compounds, may provide an efficacious, yet easily reversible, means of inhibiting thrombus formation.

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