Synergistic Antithrombotic Properties of G4120, a RGD-Containing Synthetic Peptide, and Argatroban, a Synthetic Thrombin Inhibitor, in a Hamster Femoral Vein Platelet-Rich Thrombosis Model

1992 ◽  
Vol 68 (03) ◽  
pp. 336-340 ◽  
Author(s):  
Yoshimi Imura ◽  
Jean-Marie Stassen ◽  
Ingrid Vreys ◽  
Emmanuel Lesaffre ◽  
Herman K Gold ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Thrombus Formation ◽  
Femoral Vein ◽  
Arterial Occlusion ◽  
Thrombin Inhibitors ◽  
Thrombin Inhibitor ◽  
Rgd Peptides ◽  
Thrombosis Model ◽  
Dependent Inhibition ◽  
Dose Dependent

SummaryThe synergistic antithrombotic properties of G4120, a synthetic Arg-Gly-Asp (RGD) containing peptide which strongly inhibits platelet aggregation, and of Argatroban, a synthetic thrombin inhibitor, were examined in a reproducible quantitative hamster femoral vein platelet-rich mural thrombosis model. Bolus injections of G4120 and Argatroban inhibit thrombus formation in a dose-dependent way; 50% inhibition (ID50) is obtained with 11 µg/kg G4120 and with 2 mg/kg Argatroban. Combined bolus injections of 3 µg/kg G4120 with 0.5, 0.75 or 1 mg/kg Argatroban and of 1 mg/kg Argatroban with 1.5 or 3 µg/kg G4120 caused linear dose-dependent inhibition of thrombus formation, whereas 3 µg/kg G4120 or 1 mg/kg Argatroban alone had very little effect (<20% inhibition). ID50 was obtained with the combination of 3 µg/kg G4120 and 0.5 mg/kg Argatroban, corresponding to an equi-effective fractional combination of 0.62 with a 95% confidence interval of 0.50 to 0.74. Alternatively the ID50 was obtained with the combination of 1 mg/kg Argatroban and 1.3 µg/kg G4120, corresponding to an equi-effective fractional combination of 0.52 with a 95% confidence interval of 0.18 to 0.86. In both instances these results are indicative of a significant synergistic interaction. Bolus injection of 10 mg/kg aspirin, 100 U/kg heparin or the combination did not inhibit thrombus formation.The synergistic effect of the combination of platelet inhibiting RGD-peptides and synthetic thrombin inhibitors could be useful in the prevention of arterial occlusion with platelet-rich thrombus in patients with ischemic heart disease following thrombolytic therapy or angioplasty, although this combination is not expected to reverse platelet thrombus formation.

scholarly journals A novel nucleotide-based thrombin inhibitor inhibits clot-bound thrombin and reduces arterial platelet thrombus formation

Blood ◽  
1994 ◽  
Vol 83 (3) ◽  
pp. 677-682 ◽  
Author(s):  
WX Li ◽  
AV Kaplan ◽  
GW Grant ◽  
JJ Toole ◽  
LL Leung
Keyword(s):  
Ex Vivo ◽  
Platelet Rich Plasma ◽  
Thrombus Formation ◽  
Thrombin Inhibitors ◽  
Thrombin Inhibitor ◽  
Shear Rates ◽  
High Shear Rates ◽  
Dependent Inhibition ◽  
Platelet Thrombus

A novel thrombin inhibitor based on single-stranded (ss) deoxynucleotides with the sequence GGTTGGTGTGGTTGG (thrombin aptamer) has been recently discovered. In this study, we tested its efficacy in inhibiting clot-bound thrombin activity and platelet thrombus formation in an ex vivo whole artery angioplasty model. The thrombin aptamer showed a specific dose-dependent inhibition of thrombin-induced platelet aggregation (0.5 U/mL) in human platelet-rich plasma, with an IC50 of approximately 70 to 80 nmol/L. In an in vitro clot-bound thrombin assay system, heparin, used at clinically relevant concentrations of 0.2 U/mL and 0.4 U/mL, was ineffective in inhibiting clot-bound thrombin (6.5% and 34.9% inhibition at 0.2 U/mL and 0.4 U/mL, respectively). In contrast, the thrombin aptamer at an equivalent anticoagulant concentration inhibited clot-bound thrombin (79.7% inhibition). In an ex vivo whole artery angioplasty model, the thrombin aptamer markedly suppressed the generation of fibrinopeptide A (FPA), whereas heparin at 2 U/mL was ineffective. Compared with a scrambled ssDNA control, the thrombin aptamer reduced platelet deposition by 34.5% +/- 5% (mean +/- SEM, n = 4, P = .09) at low shear rates (approximately 200 s-1) and 61.3% +/- 11% (mean +/- SEM, n = 4, P = .05) at high shear rates (approximately 850 s-1). Thrombin aptamers based on ssDNA molecules represent a new class of thrombin inhibitors with potent anticoagulant and antithrombotic properties.

scholarly journals A novel nucleotide-based thrombin inhibitor inhibits clot-bound thrombin and reduces arterial platelet thrombus formation

Blood ◽  
1994 ◽  
Vol 83 (3) ◽  
pp. 677-682 ◽  
Author(s):  
WX Li ◽  
AV Kaplan ◽  
GW Grant ◽  
JJ Toole ◽  
LL Leung
Keyword(s):  
Ex Vivo ◽  
Platelet Rich Plasma ◽  
Thrombus Formation ◽  
Thrombin Inhibitors ◽  
Thrombin Inhibitor ◽  
Shear Rates ◽  
High Shear Rates ◽  
Dependent Inhibition ◽  
Platelet Thrombus

Abstract A novel thrombin inhibitor based on single-stranded (ss) deoxynucleotides with the sequence GGTTGGTGTGGTTGG (thrombin aptamer) has been recently discovered. In this study, we tested its efficacy in inhibiting clot-bound thrombin activity and platelet thrombus formation in an ex vivo whole artery angioplasty model. The thrombin aptamer showed a specific dose-dependent inhibition of thrombin-induced platelet aggregation (0.5 U/mL) in human platelet-rich plasma, with an IC50 of approximately 70 to 80 nmol/L. In an in vitro clot-bound thrombin assay system, heparin, used at clinically relevant concentrations of 0.2 U/mL and 0.4 U/mL, was ineffective in inhibiting clot-bound thrombin (6.5% and 34.9% inhibition at 0.2 U/mL and 0.4 U/mL, respectively). In contrast, the thrombin aptamer at an equivalent anticoagulant concentration inhibited clot-bound thrombin (79.7% inhibition). In an ex vivo whole artery angioplasty model, the thrombin aptamer markedly suppressed the generation of fibrinopeptide A (FPA), whereas heparin at 2 U/mL was ineffective. Compared with a scrambled ssDNA control, the thrombin aptamer reduced platelet deposition by 34.5% +/- 5% (mean +/- SEM, n = 4, P = .09) at low shear rates (approximately 200 s-1) and 61.3% +/- 11% (mean +/- SEM, n = 4, P = .05) at high shear rates (approximately 850 s-1). Thrombin aptamers based on ssDNA molecules represent a new class of thrombin inhibitors with potent anticoagulant and antithrombotic properties.

Antithrombotic Effect of Two Low Molecular Weight Thrombin Inhibitors and a Low-Molecular Weight Heparin in a Caval Vein Thrombosis Model in the Rat

1997 ◽  
Vol 78 (05) ◽  
pp. 1404-1407 ◽  
Author(s):  
B I Eriksson ◽  
S Carlsson ◽  
M Halvarsson ◽  
B Risberg ◽  
C Mattsson
Keyword(s):  
Molecular Weight ◽  
Low Molecular Weight Heparin ◽  
Clinical Situation ◽  
Thrombin Inhibitors ◽  
Thrombin Inhibitor ◽  
Low Molecular Weight ◽  
Surgical Trauma ◽  
Antithrombotic Effect ◽  
Caval Vein ◽  
Thrombosis Model

SummaryA sensitive thrombosis model with a high reproducibility was developed in the rat, utilizing stasis of the caval vein and a standardized surgical trauma as the only thrombogenic stimuli. Since no procoagulant substances were used, the results of the present study might be relevant in a clinical situation. The antithrombotic effect of two recently synthesized low-molecular-weight thrombin inhibitors have been compared to dalteparin, (Fragmin) a low-molecular-weight heparin fragment. Each compound was studied at 8 different doses with 10 rats in each group. On a gravimetric basis, the thrombin inhibitor melagatran was twice as potent as dalteparin (ED50 16 and 33 µ/kg per h, respectively). The second thrombin inhibitor, inogatran, had an intermediate effect, with an ED50 of 24 µLg/kg per h. No differences in antithrombotic effect were, however, found when the compounds were compared at anticoagulant equivalent doses (same APTT prolongation). A 50% reduction in the mean thrombus weight was obtained when APTT was prolonged to 1.2 to 1.3 times the pretreatment value.

scholarly journals Importance of platelets in experimental venous thrombosis in the rat

Blood ◽  
1992 ◽  
Vol 80 (9) ◽  
pp. 2281-2286 ◽  
Author(s):  
JM Herbert ◽  
A Bernat ◽  
JP Maffrand
Keyword(s):  
Venous Thrombosis ◽  
Thrombus Formation ◽  
Vena Cava ◽  
Progressive Increase ◽  
High Dose ◽  
Experimental Conditions ◽  
Dependent Inhibition ◽  
Dose Dependent Inhibition ◽  
Tissue Thromboplastin ◽  
Dose Dependent

Abstract Venous thrombosis was induced by ligature of the inferior vena cava in rats whose blood was made hypercoagulable by intravenous (IV) administration of tissue thromboplastin. From a dose-response showing that the administration of increasing doses of tissue thromboplastin resulted in a subsequent progressive increase of thrombus weight, two concentrations of tissue thromboplastin were chosen: a high dose (550 microL/kg, IV) where thrombus formation was optimal and a concentration (7 microL/kg, IV) where tissue thromboplastin-hypercoagulability was intermediate. In both experimental conditions, leukopenia provoked by a myelotoxic drug did not influence the development of venous thrombosis. However, after thrombocytopenia induced by an antiplatelet antiserum, a dramatic decrease in thrombus formation was observed in animals that had been pre-challenged with the lower dose of tissue thromboplastin, whereas decrease in platelet count did not affect venous thrombosis under high thrombogenic challenge. When administered orally 2 hours before thrombosis induction, the ticlopidine analogue clopidogrel showed dose-dependent inhibition of thrombus formation in animals that were pre-challenged with a low dose of tissue thromboplastin (ED50 = 7.9 +/- 1.5 mg/kg, orally) but remained ineffective against high tissue thromboplastin-induced venous thrombosis. We further determined the effect of heparin and hirudin, and showed that both of these drugs exhibited a more potent antithrombotic activity after injection of the lower dose of tissue thromboplastin than after injection of a high dose of tissue thromboplastin. Therefore, using our model of stasis and hypercoagulability, platelet activation played a major role in the development of venous thrombosis when the thrombogenitic stimulus was mild.

ACTIVATION DEPENDENT ALTERATIONS IN THE CHEMICAL CROSSLINKING OF ARGINYL-GLYCYL-ASPARTIC ACID (RGD) PEPTIDES WITH PLATELET GLYCOPROTEIN (GP) GPIIb-IIIa

1987 ◽  
Author(s):  
S E D’Souza ◽  
M H Ginaberg ◽  
S Lam ◽  
E A Plow
Keyword(s):  
Binding Sites ◽  
Human Platelets ◽  
Amino Acid Sequences ◽  
Platelet Glycoprotein ◽  
Chemical Crosslinking ◽  
Dependent Manner ◽  
Rgd Peptides ◽  
Dependent Inhibition ◽  
Adhesive Proteins ◽  
Dose Dependent

The platelet adhesive proteins, fibrinogen, fibronectin and von WillebrandFactor, contain RGD amino acid sequences; RGD-containing peptides inhibit the binding of these adhesive proteins to platelets; and a membrane receptor for these adhesive proteins binds to Arg-Gly-Asp and contains GPIIb-IIIa. The present study was undertaken to characterize the interaction of RGDpeptides with GPIIb-IIIa using a chemical crosslinking approach. A radioiodinated RGD-containing heptapeptide was bound to washed human platelets under conditions at which ≥ 85% of theinteraction was inhibited by excess nonlabeled peptide. After binding of the peptide to platelets for 45 min at22°, a homobifunctional crosslinking reagent was added, and the platelets were extracted and analyzed on polyacrylamide gels. With resting platelets,autoradiography of the gels revealedthat the peptide crosslinked tobothGPIIb and GPIIIa. This interaction wasinhibited by excess nonlabeled peptide but not by certain conservatively substituted RGD peptides. Stimulation of the platelets caused a dramatic increase in crosslinking of the peptide to only one of the two subunitsof GPIIb-IIIa. The stimulus dependentincrease in the crosslinking reactionwas specific and saturable as it was inhibited by RGD peptides in a dose dependent manner. In addition, peptides corresponding in structure to the carboxy terminus of the γ chain of fibrinogen also produced concentration dependent inhibition of the interaction. The increase in crosslinking induced by platelet stimulation was divalent ion dependent. Similar results werealso obtained with a second, larger RGD-containing peptide and with asecond chemical crosslinking reagent.Theseresults indicate that platelet stimulation in the presence of divalent ions causes a change which permitsmoreefficient crosslinking of RGD-containing peptides to only one of the two subunits of GPIIb-IIIa. The results are also compatible with a proximalrelationship of both subunits tothe RGD binding sites on the plateletmembrane.

scholarly journals Hirudin interruption of heparin-resistant arterial thrombus formation in baboons

Blood ◽  
1991 ◽  
Vol 77 (5) ◽  
pp. 1006-1012 ◽  
Author(s):  
AB Kelly ◽  
UM Marzec ◽  
W Krupski ◽  
A Bass ◽  
Y Cadroy ◽  
...  
Keyword(s):  
Bleeding Time ◽  
Thrombus Formation ◽  
Dependent Manner ◽  
Fibrin Deposition ◽  
Recombinant Hirudin ◽  
Arterial Thrombus ◽  
Dependent Inhibition ◽  
Antithrombotic Effects ◽  
Dose Dependent

Abstract To determine the role of thrombin in high blood flow, platelet- dependent thrombotic and hemostatic processes we measured the relative antithrombotic and antihemostatic effects in baboons of hirudin, a highly potent and specific antithrombin, and compared the effects of heparin, an antithrombin III-dependent inhibitor of thrombin. Thrombus formation was determined in vivo using three relevant models (homologous endarterectomized aorta, collagen-coated tubing, and Dacron vascular graft) by measuring: (1) platelet deposition, using gamma camera imaging of 111In-platelets; (2) fibrin deposition, as assessed by the incorporation of circulating 125I-fibrinogen; and (3) occlusion. The continuous intravenous infusion of 1, 5, and 20 nmol/kg per minute of recombinant hirudin (desulfatohirudin) maintained constant plasma levels of 0.16 +/- 0.03, 0.79 +/- 0.44, and 3.3 +/- 0.77 mumol/mL, respectively. Hirudin interrupted platelet and fibrin deposition in a dose-dependent manner that was profound at the highest dose for all three thrombogenic surfaces and significant at the lowest dose for thrombus formation on endarterectomized aorta. Thrombotic occlusion was prevented by all doses studied. In contrast, heparin did not inhibit either platelet or fibrin deposition when administered at a dose that maximally prolonged clotting times (100 U/kg) (P greater than .1), and only intermediate effects were produced at 10-fold that dose (1,000 U/kg). Moreover, heparin did not prevent occlusion of the test segments. Hirudin inhibited platelet hemostatic function in concert with its antithrombotic effects (bleeding times were prolonged by the intermediate and higher doses). By comparison, intravenous heparin failed to affect the bleeding time at the 100 U/kg dose (P greater than .5), and only minimally prolonged the bleeding time at the 1,000 U/kg dose (P less than .05). We conclude that platelet-dependent thrombotic and hemostatic processes are thrombin-mediated and that the biologic antithrombin hirudin produces a potent, dose-dependent inhibition of arterial thrombus formation that greatly exceeds the minimal antithrombotic effects produced by heparin.

GP-VI Disruption Confers Additional Protection against Arterial Thrombosis in PAR-4 Deficient Mice

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3932-3932
Author(s):  
Ivo Cornelissen ◽  
Erica De Candia ◽  
Shaun R Coughlin
Keyword(s):  
Thrombus Formation ◽  
Thrombin Inhibitor ◽  
Thrombosis Model ◽  
Abdominal Bleeding ◽  
Additional Protection ◽  
Platelet Signaling ◽  
Thrombin Activation ◽  
Platelet Thrombus ◽  
Activation Pathways ◽  
Adhesive Proteins

Abstract Following vascular injury, platelets are recruited and activated by adhesive proteins exposed on the subendothelium (including collagen), released agonists and locally generated thrombin. In mice, protease activated receptor 4 (PAR-4) mediates the platelet signaling response to thrombin. Previous studies showed that platelets from PAR-4 null mice do not respond to thrombin and while platelet thrombi do form at the site of injury in PAR-4 deficient animals, they do not propagate and extend into the lumen like thrombi in wild-type mice. The activation pathway responsible for this juxtamural platelet accumulation remains unknown. The collagen exposed on the subendothelium activates and recruites platelets at the site of injury by interacting with membrane glycoprotein (GP) VI. Therefore, the collagen-GP-VI pathway is a putative candidate for the platelet thrombus formation near the vessel wall. Using hirudin as a thrombin inhibitor in mice with disrupted GP-VI expression, it has been previously shown that GP-VI signaling and thrombin activation pathways may cooperate during thrombus growth. To more precisely evaluate the interplay between the thrombin/PAR-4 and collagen/GP-VI signaling pathways, we crossed mice lacking PAR-4 and GP-VI, and subsequently compared bleeding time and arterial thrombus formation in PAR-4:GP-VI double or single deficient animals. All genetic combinations were born at the expected mendelian distribution. Double deficient females carried offspring to term and no bleeding was observed during parturition. Pups lacking both receptors demonstrated transient perinatal abdominal bleeding which resolved rapidly. However, we observed prolonged tail bleeding times in double deficient animals compared to their single deficient littermates. Furthermore in a FeCl3-induced carotid thrombosis model, mice lacking both receptors were completely protected compared to their littermates. This study suggests that there is an interaction between the thrombin and collagen activating pathways in the setting of hemostasis and thrombosis. Figure Figure Figure Figure

scholarly journals Calin from Hirudo medicinalis, an inhibitor of platelet adhesion to collagen, prevents platelet-rich thrombosis in hamsters

Blood ◽  
1995 ◽  
Vol 85 (3) ◽  
pp. 712-719 ◽  
Author(s):  
H Deckmyn ◽  
JM Stassen ◽  
I Vreys ◽  
E Van Houtte ◽  
RT Sawyer ◽  
...  
Keyword(s):  
Platelet Adhesion ◽  
Bleeding Time ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Femoral Vein ◽  
Video Recording ◽  
Hirudo Medicinalis ◽  
Thrombosis Model

Interaction between exposed collagen and platelets and/or von Willebrand factor is believed to be one of the initiating events for thrombus formation at sites of damaged endothelium. Interference with this mechanism may provide an anti-thrombotic potential. Calin, a product from the saliva of the leech Hirudo medicinalis, was tested in vitro and for its in vivo activity in a thrombosis model in hamsters. Calin specifically and dose dependently (IC50:6.5 to 13 micrograms/mL) inhibited human platelet aggregation induced by collagen. In addition, specific platelet adhesion onto microtiter wells coated with collagen and detected with a monoclonal antiglycoprotein IIb/IIIa antibody- conjugated with horseradish peroxidase, could be completely prevented with Calin (IC50:22 micrograms/mL). A dose-response curve was constructed in groups of six hamsters in whom a standardized trauma was induced on the femoral vein. Thrombus formation was followed continuously using video recording and processing of the image obtained upon transillumination of the vessel. Intravenous Calin dose- dependently inhibited platelet-rich thrombus formation in this model with an ED50 of 0.07 mg/kg and complete inhibition with 0.2 mg/kg. No effects were seen on coagulation tests or bleeding times, whereas ex vivo aggregation induced by collagen was inhibited dose dependently. Local application of leech saliva, Calin, hirudin, or the combination of the latter two into the bleeding time wound of hamsters resulted in a mild prolongation of the bleeding time (twofold to threefold). A similar experiment in baboons did not cause any prolongation of the bleeding time. This is in sharp contrast with the long-lasting bleeding after a leech bite itself in both species. Calin from the leech Hirudo medicinalis is able, by binding to collagen, to effectively interfere with platelet-collagen interaction, which results in an antithrombotic effect observed in a platelet-rich thrombosis model in hamsters.

Evaluation of AR-H067637, the active metabolite of the new direct thrombin inhibitor AZD0837, in models of venous and arterial thrombosis and bleeding in anaesthetised rats

2010 ◽  
Vol 104 (12) ◽  
pp. 1242-1249 ◽  
Author(s):  
Susanne Pehrsson ◽  
Karin Johansson ◽  
Magnus Kjaer ◽  
Margareta Elg
Keyword(s):  
Blood Loss ◽  
Arterial Thrombosis ◽  
Bleeding Time ◽  
Thrombus Formation ◽  
Plasma Concentrations ◽  
Direct Thrombin Inhibitor ◽  
Thrombin Inhibitor ◽  
Coagulation Time ◽  
Dose Dependent ◽  
Anaesthetised Rats

SummaryAZD0837, currently in clinical development, is a once-daily oral anticoagulant that is bioconverted to AR-H067637, a selective, reversible direct thrombin inhibitor (DTI). When developing a new DTI, the anti-thrombotic effects are commonly investigated in in vivo animal models; this report shows the effect of AR-H067637 in venous and arterial thrombosis and bleeding models in anaesthetised rats. Thrombus formation was induced by topical application of ferric chloride to the carotid artery or to the caval vein with partial stasis. Cutaneous incision bleeding time and muscle transection blood loss were assessed, with or without acetylsalicylic acid (ASA). Activated partial thromboplastin time (APTT), ecarin coagulation time (ECT) and thrombin coagulation time (TCT) were used as plasma biomarkers of anticoagulant effect. Dalteparin was used as a reference compound. AR-H067637, given by continuous infusion, displayed a dose-dependent antithrombotic effect, with 50% inhibition (IC50) of thrombus size in venous and arterial thrombosis models obtained at plasma concentrations of 0.13 μM and 0.55 μM, respectively, without increased bleeding. Dose-dependent increased bleeding and blood loss were seen at plasma concentrations ≥1 μM AR-H067637. At the highest AR-H067637 plasma concentration tested, bleeding time and blood loss increased two and four times the vehicle group. Addition of ASA moderately potentiated bleeding time and blood loss. APTT, ECT and TCT were dose-dependently prolonged. These studies demonstrate that the DTI AR-H067637 inhibits thrombus formation in rat venous and arterial thrombosis models with no or minor increases in bleeding.

Exploring the Impact of Clinical Anticoagulants on Venous Thrombosis Stability Using a Novel Intravital Murine Model

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1246-1246
Author(s):  
Lisa J Saldanha ◽  
Anthony KC Chan ◽  
Peter L Gross
Keyword(s):  
Venous Thrombosis ◽  
Jugular Vein ◽  
Thrombus Formation ◽  
Femoral Vein ◽  
Factor Xa ◽  
Treated Group ◽  
Thrombin Inhibitor ◽  
Factor Xa Inhibitor ◽  
Wild Type ◽  
Over Time

Abstract Abstract 1246 Background: Thrombus stability influences the progression of deep vein thrombosis to a potentially fatal pulmonary embolism (PE) event. Anticoagulants are clinically administered to treat venous thrombosis. However, the effect of anticoagulants on thrombus stability remains unknown. Objective: We developed a novel intravital mouse model to explore the hypothesis that administration of clinical anticoagulants would decrease early thrombus stability, thereby potentially increasing PE risk. Methods: The trachea and jugular vein were cannulated, and the femoral vein isolated, in wild type C57/Bl6 female mice. Platelets were labeled in vivo using anti-mouse CD41 Fab fragments conjugated to Alexa Fluor-488. A 1 × 2 mm filter paper strip, saturated in 4% ferric chloride, was applied to the femoral vein for 5 minutes to induce thrombus formation. Wide-field fluorescent microscopy was used to quantify thrombus stability. Stability was related to the number of embolic events and loss of platelet intensity captured downstream of the thrombus at 5, 15, 30, 45, and 60 minutes post thrombus formation. Results: The mean number of embolic events and loss of platelet intensity decreased over time in wild type mice (n = 12). This suggested that thrombus stability increases over time. Anticoagulants were administered via a jugular vein catheter, at 12 minutes post thrombus formation, to assess impact on embolization. The anticoagulants examined were hirudin (8U/g mouse body weight), unfractionated heparin (UFH) (0.1U/g), a covalent antithrombin-heparin complex (ATH) (0.08U/g), and fondaparinux (0.1μg/g). We observed an overall a) increase in the number of embolic events and b) increase in platelet intensity lost over time in mice injected with hirudin (n = 12) and UFH (n = 12) when compared to untreated wild type control mice. The total number of embolic events occurring over one hour substantially increased in the hirudin-treated group (p = 0.09), which was also associated with an overall increase in total platelet intensity (p = 0.08), compared to untreated control mice. In addition, there was an increase in the total number of embolic events compared to the UFH-treated group (p = 0.09). Administration of hirudin, a direct thrombin inhibitor (DTI), and UFH, an indirect thrombin inhibitor, could result in decreased venous thrombus stability. However, it appears that the DTI is associated with greater thrombus instability. In the ATH-treated group (n = 12), an increase in embolic events at 15 minutes was observed, followed by a decrease in embolization. ATH could initially disrupt thrombus stability through inhibition of fibrin-bound thrombin, before acting in a stabilizing manner. Administration of fondaparinux (n = 6), an indirect factor-Xa inhibitor, demonstrated an overall decrease in embolic events and platelet intensity lost over time. When compared to control groups, there was a significant decrease in total number of embolic events and total amount of platelet intensity lost in the fondaparinux group (p < 0.05). Use of a factor-Xa inhibitor appears to enhance thrombus stability more effectively in comparison to direct and indirect thrombin inhibitors. Conclusion: Use of anticoagulants that inhibit thrombin predominantly could decrease early thrombus stability and potentially increase the likelihood of a PE event. Disclosures: No relevant conflicts of interest to declare.

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