Dietary Alpha-Linolenic Acid Does Not Protect From Venous Thrombosis In The Vena Cava Stenosis Model

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3621-3621
Author(s):  
Martin F Reiner ◽  
Simona Stivala ◽  
Kimberly Martinod ◽  
Giovanni G Camici ◽  
Thomas F Lüscher ◽  
...  
Keyword(s):  
Platelet Count ◽  
Venous Thrombosis ◽  
Linolenic Acid ◽  
Platelet Activation ◽  
Arterial Thrombosis ◽  
Leukocyte Count ◽  
Thrombus Formation ◽  
Vena Cava ◽  
Alpha Linolenic Acid ◽  
Vena Cava Stenosis

Abstract Background Deep vein thrombosis (DVT) and pulmonary embolism (PE) are major causes of cardiovascular morbidity and mortality. Omega-3 fatty acids (n-3 FA) are well known for their beneficial effects on primary and secondary prevention of cardiovascular disease (CVD). We and others have previously reported that n-3 FA, particularly the plant-derived alpha-linolenic acid (ALA), inhibits atherosclerosis, reduces arterial thrombosis and decreases platelet activation in mice fed an n-3-enriched diet by antiinflammatory, antiplatelet and anticoagulant mechanisms. In this study we investigated the effects of ALA on the development of DVT in the vena cava stenosis model in mice. Hypothesis Because platelet activation and inflammatory processes may play a relevant role in venous thromboembolism, we hypothesized that ALA prevents the development of venous thrombosis in mice undergoing vena cava stenosis due to its antiplatelet, anticoagulant and antiinflammatory properties. Methods 12 to 14 weeks old C57/BL6 mice underwent 4 weeks of high- (7.3g%; hiALA) or low-ALA (0.03g%; loALA) treatment (n=11 per group) before they were exposed to vena cava stenosis. Rodents were anaesthetized, the inferior vena cava (IVC) was exposed and a ligature was placed proximal to the left renal vein in order to narrow the IVC and to provoke a reduction in blood flow and thereby induce thrombus formation. Mice were examined 48 hours after initial surgery; percentage of mice with thrombus formation and thrombus length were determined. Additionally, we performed blood count analysis and determined plasma glycocalicin index (ug/ml/250 000 platelets), the extramembranous portion of GPIbalpha, as a marker for platelet turnover and shedding of the platelet receptor for von Willebrand factor (vWF). Results Contrary to our hypothesis, treatment with ALA did neither significantly reduce the incidence (hiALA, 55 % vs loALA, 64 %; n=11 per group, p=ns) nor size of venous thrombosis (hiALA, 2.4 mm vs loALA, 2.3 mm; n=11 per group, p=ns). Glycocalicin index was comparable in both groups (hiALA, 15.0±8.1 ug/ml/250 000 platelets vs loALA, 11.1±4.5 ug/ml/250 000 platelets; n=8 per group, p=ns), indicating no difference in platelet consumption. Interestingly, we observed an increased leukocyte count and a reduced platelet count in hiALA-treated mice after 48 hours of venous thrombosis, a difference that was not observed in sham operated mice. Conclusions Dietary ALA did not protect from DVT in the mouse model of vena cava stenosis chosen. Despite its protective properties in arterial thrombosis, ALA seems to be ineffective in the pathogenesis of the stenosis-induced venous thrombosis, possibly because the pathways of platelet activation and inflammation, modified by ALA, are of lower penetrance. The findings of increased leukocyte count and decreased platelet count after 48 h of VT warrant further investigation. Disclosures: No relevant conflicts of interest to declare.

Dietary omega-3 alpha-linolenic acid does not prevent venous thrombosis in mice

2015 ◽  
Vol 113 (01) ◽  
pp. 177-184 ◽  
Author(s):  
Simona Stivala ◽  
Gianluigi Savarese ◽  
Giovanni G. Camici ◽  
Thomas F. Lüscher ◽  
Denisa Wagner ◽  
...  
Keyword(s):  
Mouse Model ◽  
Venous Thrombosis ◽  
Linolenic Acid ◽  
Thrombus Formation ◽  
Vena Cava ◽  
Cardiovascular Death ◽  
Endothelial Injury ◽  
Protective Effects ◽  
Omega 3 ◽  
Alpha Linolenic Acid

SummaryVenous thromboembolism (VTE) is a leading cause of cardiovascular death. Omega-3 fatty acids (n-3 FA) exhibit protective effects against cardiovascular disease. Others and our group have reported that the plant-derived n-3 FA alpha-linolenic acid (ALA) displays antiinflammatory, anticoagulant and antiplatelet effects, thereby reducing atherosclerosis and arterial thrombosis in mice fed a high ALA diet. Since procoagulant factors such as tissue factor and fibrin as well as platelets and leukocytes are crucially involved in the development of VTE, we investigated possible protective effects of dietary ALA on venous thrombus formation in a mouse model of stenosis- and furthermore, in a mouse model of endothelial injury-induced venous thrombosis. Four week old C57BL/6 mice underwent four weeks of high (7.3g%) or low ALA (0.03g%) treatment before being exposed to inferior vena cava (IVC) stenosis for 48 hours or laser injury of the endothelium of the internal jugular vein (IJV). Thrombus generation frequency, thrombus size and composition (IVC stenosis group) and time to thrombus formation (endothelial injury group) were assessed. In addition, plasma glycocalicin, a marker of platelet activation, platelet P-selectin and activated integrin expression as well as plasma thrombin generation was determined, but did not reveal any significant differences between he groups. Despite its protective properties against arterial thrombus formation, dietary ALA did not protect against venous thrombosis neither in the IVC stenosis nor the endothelial injury model, further indicating that the biological processes involved in arterial and venous thrombosis are different.

ROLE OF PLATELETS IN EXPERIMENTAL THROMBOSIS INDUCED BY VENOUS STASIS

1987 ◽  
Author(s):  
A Bernat ◽  
E Vallée ◽  
J P Maffrand ◽  
J Gordon
Keyword(s):  
Platelet Count ◽  
Venous Thrombosis ◽  
Thrombus Formation ◽  
Vena Cava ◽  
Venous Stasis ◽  
Severe Thrombocytopenia ◽  
Antiplatelet Effect ◽  
Experimental Thrombosis ◽  
Dense Granules

Venous stasis in the rat, induced by ligature of the vena cava, provokes thrombosis. This venous thrombosis was initially believed to be platelet-independent because severe thrombocytopenia (95 % reduction in platelet count), aspirin and dipyridamole had little effect. However, the model responded to other platelet anti-aggregators, such as Ticlopidine and its analogue PCR 4099, although these compounds had no effect on coagulation, fibrinolysis or leucocyte functions (Thromb. Res. 37, 279-285, 1985). Both these drugs are known to exert their main antiplatelet effect against aggregation induced by ADP.The aim of the present study was to re-evaluate the role of platelets in this model of venous thrombosis. We have been able to show that :1) complete thrombocytopenia (99 %), achieved with an antiplatelet anti-serum, dramatically inhibited thrombus formation (by 84 % ; p < 0.01).2) partial transfusion of platelets (23 %) from control animals to these thrombocytopenic rats re-established the thrombosis.3) transfusion (under identical conditions) of platelets from rats treated with PCR 4099 had no effect.4) vena cava ligature in Fawn Hooded rats (deficient in platelet dense granules) induced less thrombosis (64 % of control ; p < 0.05).We conclude that this venous stasis model is platelet-dependent. Furthermore, because thrombus formation was reduced in normal rats treated with anti-aggregants acting selectively against ADP, and in rats lacking ADP in their platelet dense granules, it appears that ADP plays a major role in this model of thrombosis.

Antithrombotic Properties of DU-176b, a Novel, Potent and Orally Active Direct Factor Xa Inhibitor in Rat Models of Arterial and Venous Thrombosis: Comparison with Fondaparinux, an Antithrombin Dependent Factor Xa Inhibitor.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1852-1852 ◽  
Author(s):  
Toshio Fukuda ◽  
Chikako Matsumoto ◽  
Yuko Honda ◽  
Nobutoshi Sugiyama ◽  
Yoshiyuki Morishima ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Arterial Thrombosis ◽  
Thrombus Formation ◽  
Dose Range ◽  
Vena Cava ◽  
Factor Xa ◽  
Coagulation Cascade ◽  
Factor Xa Inhibitor ◽  
Rat Models ◽  
Fxa Inhibitor

Abstract Factor Xa (FXa) is an attractive target for the treatment of thrombosis due to its crucial role in the blood coagulation cascade. Fondaparinux, a selective FXa inhibitor, has been approved for clinical use to prevent deep vein thrombosis after orthopedic surgery; however, it requires antithrombin (AT) to exert its antithrombotic effect. It is reported that AT dependent anticoagulants such as heparin are less effective to suppress platelet-rich arterial-type thrombus due to its inaccessibility to thrombus-bound FXa/thrombin. We have developed a potent direct (i.e. AT independent) FXa inhibitor, DU-176b. The objective of this study is to compare the antithrombotic properties of a direct selective FXa inhibitor, DU-176b, with an AT dependent selective FXa inhibitor, fondaparinux. We evaluated the antithrombotic effects of DU-176b and fondaparinux in rat models of arterial and venous thrombosis. The arterial and venous thrombosis was induced by topical application of ferric chloride to the carotid artery and by insertion of a platinum wire into the inferior vena cava, respectively. DU-176b (0.05 – 1.25 mg/kg/h) and fondaparinux (1 – 10 mg/kg/h for arterial thrombosis and 0.03 – 1 mg/kg/h for venous thrombosis) were intravenously administered as continuous infusions. DU-176b prevented both arterial and venous thrombosis in the same dose range. In contrast, the effective doses of fondaparinux markedly differed between these models. A higher dose of fondaparinux more than 100 times was required to inhibit arterial thrombosis compared with venous thrombosis. These results suggest that direct inhibition of FXa is a preferable strategy to AT dependent inhibition for the prevention of thrombus formation in the arteries.

scholarly journals Dietary α-Linolenic Acid Inhibits Arterial Thrombus Formation, Tissue Factor Expression, and Platelet Activation

2011 ◽  
Vol 31 (8) ◽  
pp. 1772-1780 ◽  
Author(s):  
Erik W. Holy ◽  
Marc Forestier ◽  
Eva K. Richter ◽  
Alexander Akhmedov ◽  
Florian Leiber ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Linolenic Acid ◽  
Platelet Activation ◽  
Thrombus Formation ◽  
Tissue Factor Expression ◽  
Arterial Thrombus ◽  
Factor Expression

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.

scholarly journals Noncanonical Effects of Oral Thrombin and Factor Xa Inhibitors in Platelet Activation and Arterial Thrombosis

2020 ◽  
Author(s):  
Amin Polzin ◽  
Lisa Dannenberg ◽  
Manuela Thienel ◽  
Martin Orban ◽  
Georg Wolff ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Arterial Thrombosis ◽  
Thrombus Formation ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Factor Xa ◽  
Coagulation Cascade ◽  
Platelet Activity ◽  
Vein Thrombosis

AbstractNonvitamin K oral anticoagulants (NOACs) or direct oral anticoagulants comprise inhibitors of factor Xa (rivaroxaban, apixaban, edoxaban) or factor IIa (dabigatran). Both classes efficiently interfere with the final or penultimate step of the coagulation cascade and showed superior net clinical benefit compared with vitamin K antagonists for prevention of thromboembolic events in patients with AF and for prevention and therapy of deep vein thrombosis and pulmonary embolism. None the less, accumulating data suggested, that there may be differences regarding the frequency of atherothrombotic cardiovascular events between NOACs. Thus, the optimal individualized NOAC for each patient remains a matter of debate. Against this background, some basic and translational analyses emphasized NOAC effects that impact on platelet activity and arterial thrombus formation beyond inhibition of plasmatic coagulation. In this review, we will provide an overview of the available clinical and translational evidence for so-called noncanonical NOAC effects on platelet activation and arterial thrombosis.

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.

The Role of gas6 in Venous Thrombosis In Vivo.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3057-3057
Author(s):  
Richard Robins ◽  
Peter Carmeliet ◽  
Mark Blostein
Keyword(s):  
Bone Marrow ◽  
Venous Thrombosis ◽  
Bone Marrow Cells ◽  
Conflicts Of Interest ◽  
Thrombus Formation ◽  
Recovery Period ◽  
Vena Cava ◽  
Specific Gene ◽  
Combined Genotypes

Abstract Abstract 3057 Poster Board II-1033 Gas6 is the vitamin-K dependent protein product of growth arrest specific gene 6. A genetic deficiency of this protein protects mice against experimentally induced thrombosis without causing a bleeding diathesis. Protection from thrombosis results from a deficiency in platelet aggregation and secretion. In addition to being expressed by platelets, Gas6 and its receptors are also expressed by vascular cells including the endothelium, an organ known to play a role in the hemostatic balance. While endothelial Gas6 has been shown to promote inflammation and cell survival, it remains unknown if it contributes to the pathophysiology of venous thrombosis. To answer this question, we employed a bone marrow transplantation (BMT) strategy using wild type and Gas6 null mice to create chimeric mice with combined genotypes in the vascular and platelet compartments. Mice were exposed to a dose of radiation optimized to maximize both survival and ablation of recipient marrow. Irradiated mice were then infused with bone marrow cells isolated from the femurs and tibias of donor mice and were allowed a one month recovery period for hematologic reconstitution. Success of marrow uptake was confirmed by PCR. They were then subjected to the Ferric Chloride model of venous thrombosis in the Inferior Vena Cava (IVC). Four groups of transplanted mice were studied. Results from these BMT experiment show a contributing effect by both endothelial as well as platelet Gas6 to thrombus formation (n=8, p<0.01). Mice with combined genotypes (Gas6-/- into WT and WT into Gas6 -/-) show an intermediate thrombus weight suggesting that both vascular and platelet derived Gas6 are both responsible for thrombosis pathology. Therefore, Gas6 at both sites could be potential targets in treating venous thrombosis. Disclosures No relevant conflicts of interest to declare.

The impact of leukocytosis on survival, leukemic transformation, and thrombosis in polycythemia vera

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7029-7029
Author(s):  
N. Gangat ◽  
J. Strand ◽  
C. Y. Li ◽  
A. Pardanani ◽  
R. Mesa ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Polycythemia Vera ◽  
Tobacco Use ◽  
Arterial Thrombosis ◽  
Leukocyte Count ◽  
Multivariable Analysis ◽  
Advanced Age ◽  
Leukemic Transformation ◽  
The Impact

7029 Background: A leukocyte count of > 15 ×109/L has recently been associated with myocardial infarction in polycythemia vera (PV). In the current study, we examine the impact of such degree of leukocytosis on survival, leukemic transformation (LT), and thrombosis in a large cohort of PV patients from a single institution Methods: Data was abstracted from the medical records of a consecutive cohort of patients with PV defined by the World Health Organization criteria. Results: i. Patient characteristics The study cohort included 459 patients (median age, 60 years). Median follow-up was 64 months. ii. Survival In a multivariable analysis, advanced age, leukocyte count of = 15 × 109/L, and arterial thrombosis at diagnosis were significantly associated with inferior survival. A prognostic model based on age = 60 years and leukocyte count = 15 × 109/L separated low-risk, intermediate-risk, and high-risk patient groups with respective median survivals of 272, 162, and 108 months (p<0.0001). iii. Leukemic transformation In a multivariable analysis, only leukocyte count was significantly associated with LT; median leukemia-free survival for patients with leukocyte count = 15 × 109/L was 273 months vs. not reached for those with lower leukocyte count (p<0.0001). iv. Thrombosis at diagnosis In multivariable analysis, arterial thrombosis at diagnosis was significantly associated with previous history of arterial thrombosis, hypertension, and tobacco use; venous thrombosis at diagnosis was significantly associated with previous venous event and splenomegaly. v. Thrombosis during follow- up In multivariable analysis, arterial thrombosis during follow-up was significantly associated with previous arterial event, hypertension, and tobacco use; venous thrombosis during follow-up was significantly associated with previous venous event, diabetes mellitus, advanced age, and leukocyte count = 1,500 × 109/L. Conclusions: The current study for the first time identifies leukocytosis as a risk factor for inferior survival, LT risk, and venous thrombosis in PV. No significant financial relationships to disclose.

scholarly journals Protective Effects of Kininogen-1 Gene Deficiency in Mouse Models of Venous Thrombosis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 289-289
Author(s):  
Aatira Vijay ◽  
Mohamad B Kassab ◽  
Young Jun Shim ◽  
Shadi Swaidani ◽  
Adam Mauskapf ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Thrombus Formation ◽  
Vena Cava ◽  
Continuous Light ◽  
Light Irradiation ◽  
Fluorescence Angiography ◽  
Contact Activation ◽  
Tail Vein ◽  
Platelet Accumulation

Abstract Background- High molecular weight Kininogen (HK) is a nonenzymatic co-factor of the contact activation system. HK binds prekallikrein (PK) and FXI to surfaces in proximity to FXII, amplifying PK activation by FXIIa and the reciprocal activation of FXII by activated PK (PKa), as well as FXI activation of FXIIa. PKa cleavage of HK also liberates bradykinin-a proinflammatory and vasoactive nanopeptide. The aim of this study was to define the pro-thrombotic role of kininogen in venous thrombosis (VT) and to use in vivo serial analysis of thrombus development to understand the recruitment and retention of platelets in the growing thrombus in the absence and presence of kininogen. Methods- The development of VT in mice deficient in kininogen (mKng1-/-) was compared to that in their wild-type littermates. A femoral-saphenous stasis VT model was prepared by ligating both saphenous and femoral veins. Next VT formation, growth, and dissolution (n=3 for each group) was monitored using intravital microscopy (IVM) via a multichannel epifluorescence microscope (Nikon Eclipse 90i). To induce stasis VT, FITC-dextran (10 mg/kg, ex/em 488/520 nm) was injected retro-orbitally, and then continuous light irradiation (20x objective, 475nm/35nm) of the saphenous vein was applied for 5 minutes. FITC-dextran fluorescence angiography monitored thrombus formation and dissolution. Immediately after VT formation, platelet accumulation at the thrombus site was monitored in the Cy5 channel (630/38 nm) via injection of a GPIbβ antibody conjugated with Dylight-649 (150nmol/kg), over time. All images were identically windowed in each channel, and thrombus area was measured using NIH ImageJ software. To corroborate IVM studies, we also evaluated a complete stasis model of inferior vena cava (IVC) ligation (n=7-8 per group). Thrombi were harvested after 48 hours and thrombus weight and length were measured to estimate thrombus mass. FXI circulates in blood as a homodimer along with HK. We determined the effect of kininogen deficiency on FXI activity. FXI activity assay used a combination of inhibitors, serially, to monitor the cleavage of substrate specific to activated FXI and release of chromogen, as a function of FXI activity. Finally, to determine the effects of Kng1 deficiency on bleeding, tail vein bleeding times were also determined (n=8 per group). Results- In femoral-saphenous stasis VT, thrombus developed in both groups immediately following FITC-channel light irradiation. However, thrombus size was smaller in Kng1-/- as compared to WT (Figure 1). Results from serial IVM of VT indicated faster thrombus dissolution in the Kng1-/- group. Lower platelet signals, as shown at 2 and 6 hours in the Kng1-/- mice may be consistent with this hypothesis. Thrombus area analysis suggested decreased thrombus formation in the Kng1-/- animals, and temporal analysis indicated faster dissolution by 6 hours (Figure 2). IVC ligation results corroborated the findings of femoral-saphenous DVT model, demonstrating that thrombus weight was significantly lower in Kng1-/- mice as compared to WT (p&lt;0.001, Figure 3). FXI activity was also decreased in the Kng1-/- group (p&lt;0.10). Tail vein bleeding times, however, showed no increased bleeding in Kng1-/- mice. Conclusion- These initial results suggest a pro-thrombotic role of kininogen and a protective role of kininogen deficiency in two murine venous thrombosis models, without incurring a bleeding penalty. Thrombus dissolution was faster and platelet accumulation was inhibited in Kng1-/- mice. These findings suggest that targeting kininogen may provide a new approach to prevent and treat venous thrombosis. Figure 1 Figure 1. Disclosures McCrae: Dova, Novartis, Rigel, and Sanofi Genzyme: Consultancy; Sanofi, Novartis, Alexion, and Johnson & Johnson: Consultancy, Honoraria. Jaffer: Mercator, Inc.: Other: Sponsred research.

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