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1
Vandendries, Erik R., Justin R. Hamilton, Shaun R. Coughlin, Barbara C. Furie, and Bruce Furie. "Protease-Activator Receptor 4 Is Required for Maximal Thrombus Growth, but Not for Fibrin Generation in Thrombi after Laser Injury." Blood 104, no. 11 (November 16, 2004): 624. http://dx.doi.org/10.1182/blood.v104.11.624.624.
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Abstract The serine protease, thrombin, is necessary for the conversion of fibrinogen to fibrin and is a potent activator of platelets. Thrombin-induced platelet activation, as measured by shape change, calcium mobilization, and ATP secretion, requires the protease-activator receptor 4 (PAR4). Platelets isolated from PAR4 knock-out mice are unresponsive to thrombin, and PAR4 null mice appear to be protected from thrombosis in a ferric chloride-induced injury model of thrombosis and a thromboplastin model of pulmonary embolism. To examine further the role of thrombin-induced platelet activation in developing thrombi, we have examined the in vivo kinetics of thrombus formation in living mice lacking PAR4 using high-speed widefield digital microscopy. In this study, platelets were labeled using anti-CD41 Fab fragments conjugated to Alexa-488. Thrombi were generated by laser-induced injury of the cremaster arteriolar vessel wall, and the total fluorescent antibody accumulation was monitored and quantitated for 5 minutes after injury. In PAR4 null mice, the thrombi generated were significantly smaller with an early arrest of thrombus growth when compared to thrombi generated in wild-type mice. The maximum thrombus platelet accumulation in PAR4 null mice (median of 30 thrombi in 3 mice) was 75% less than that seen in wild-type mice (median of 33 thrombi in 4 mice)(P<0.001). The time to half-maximal and the time to maximal thrombus formation in PAR4 null mice is approximately 5.5 seconds and 16 seconds, respectively, compared to 45 seconds and 74 seconds in wild-type mice (P<0.001). The shortened time to maximal platelet accumulation appears to be secondary to an early termination of thrombus growth. Fibrin generation was monitored using Alexa-647 conjugated to an anti-fibrin antibody that does not recognize fibrinogen in mice simultaneously infused with anti-CD41 Fab conjugated to Alexa-488. No difference in total fibrin accumulation was seen during the first 4 minutes of thrombus formation in PAR4 null mice (median of 23 thrombi in 3 mice) compared to thrombi generated in wild-type mice (median of 26 thrombi in 4 mice) despite a significant decrease in platelet accumulation in PAR4 null thrombi. Most of the fibrin deposition in both wild-type and PAR4 null thrombi was observed at the vascular wall/thrombus interface. In summary, thrombin-induced platelet activation via PAR4 is required for normal thrombus growth. However, in this model of thrombosis, neither PAR4 nor maximal thrombus growth appears to be necessary for fibrin deposition. This suggests that a platelet-independent mechanism of thrombin generation may exist. Alternatively, the amount of platelet accumulation and activation in PAR4 null mice may be sufficient for normal thrombin generation and subsequent fibrin deposition.
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Mutch, N. J., L. A. Robbie, and N. A. Booth. "Human Thrombi Contain an Abundance of Active Thrombin." Thrombosis and Haemostasis 86, no. 10 (2001): 1028–34. http://dx.doi.org/10.1055/s-0037-1616529.
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SummaryThis study assessed the abundance and activity of thrombin in human thrombi, removed at autopsy or during surgery. Arterial and venous thrombus sections showed thrombin activity by in situ zymography, based on conversion of fibrinogen to fibrin. Hirudin or antibodies to thrombin abolished the activity. Thrombin activity in extracts of 40 thrombi was quantified by cleavage of fibrinogen or small peptide substrates; the results correlated well (r = 0.87, p<0.0001) with a median activity of about 4.5 IU/g of thrombus (wet weight). Activity correlated poorly with total prothrombin (median 27 μg/g) and was inversely related to antithrombin, but not to PAI-1. Zymography showed two major active bands, thrombin at 37 kDa, and a 50 kDa form that probably corresponds to meizothrombin desF1. The abundant local thrombin demonstrated here has implications for thrombus lysis and extension; incomplete lysis and exposure of active thrombin may lead to re-occlusion of vessels.
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Tucker, Erik I., Ulla M. Marzec, Andras Gruber, and Stephen R. Hanson. "Inhibition of Factor XI Decreases Thrombin Production and Prevents Vascular Occlusion in Experimental Thrombosis in Primates." Blood 110, no. 11 (November 16, 2007): 763. http://dx.doi.org/10.1182/blood.v110.11.763.763.
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Abstract Animal studies suggest that factor XI (FXI) substantially contributes to thrombus growth and stability, presumably by promoting thrombin generation upon the flow surface of thrombi. To further elucidate the role of FXI in thrombus development, we investigated the effect of FXI inhibition in baboons on the time course of thrombogenic marker generation and platelet activation, as measured in samples taken locally from the peripheral blood intraluminal boundary layer (IBL) that superfused forming experimental thrombi. We also tested whether FXI inhibition would reduce thrombus stability under flow and/or prevent thrombotic vessel occlusion. Thrombogenesis was initiated by placement of collagen coated clinical vascular grafts (polytetrafluoroethylene, 4 mm i.d. and 2 mm i.d.) as extension segments within a chronic arteriovenous shunt. Blood flow was controlled at 100 mL/min, producing wall shear rates of 265 sec−1 and 2120 sec−1 within the 4 mm and 2 mm devices, respectively. Deposition of 111In-labelled platelets onto collagen was measured by gamma camera imaging for 60 min. Fibrin accumulation was measured using 125I-labelled fibrinogen. Template bleeding times were used to assess hemostatic impairment. FXI was blocked by a single bolus i.v. injection of an anti-human FXI monoclonal antibody (aXIMab, 2 mg/kg), which neutralized more than 95% of circulating FXI-related procoagulant activity for at least 7 days. aXIMab administration reduced platelet and fibrin deposition by 39–59% and 83–89%, respectively (N=3), in the 4 mm grafts vs. untreated controls (N=8). IBL thrombin/antithrombin III (TAT) and β-thromboglobulin (βTG) levels were reduced by aXIMab treatment at all time points after initiation of thrombus, up to 38-fold and 7-fold respectively. In control experiments, local TAT and βTG levels peaked at about 30 min and then decreased, correlating with the time course of platelet deposition. Inhibition of FXI significantly reduced thrombus stability under high shear, enhancing distal thrombo-embolization with large reductions in thrombus volume. In contrast, significant thromboembolization was not seen in control experiments. While 2 mm grafts consistently occluded within 30 min in control studies, thrombo-occlusion was prevented by aXIMab treatment over the 1 hour study interval. Local D-dimer levels were not affected by FXI blockade, nor were bleeding times prolonged by the antibody. These findings demonstrate that inhibition of FXI can dramatically attenuate thrombin production at sites of forming thrombus, thereby reducing platelet activation, fibrin formation and vascular occlusion without compromising primary hemostasis as assessed by measurements of bleeding time. The lack of D-dimer elevation over the study interval did not, however, support a mechanism of enhanced thrombolysis during FXI inhibition in primates. Since inhibition of FXI with aXIMab prevented graft occlusion without apparent compromise of hemostasis in primates, this strategy may prove an attractive one for antithrombotic applications in man.
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Dubois, Christophe, Laurence Panicot-Dubois, Glenn Merrill-Skoloff, Bruce Furie, and Barbara C. Furie. "Glycoprotein VI–dependent and –independent pathways of thrombus formation in vivo." Blood 107, no. 10 (May 15, 2006): 3902–6. http://dx.doi.org/10.1182/blood-2005-09-3687.
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The role of the collagen receptor glycoprotein VI (GPVI) in arteriolar thrombus formation was studied in FcRγ-null mice (FcRγ–/–) lacking platelet surface GPVI. Thrombi were induced with severe or mild FeCl3 injury. Collagen exposure was significantly delayed and diminished in mild compared with severe FeCl3 injury. Times to initial thrombus formation and vessel occlusion were delayed in FcRγ–/– compared with wild-type mice after severe injury. Platelet accumulation in wild-type mice was decreased after mild compared with severe injury. However, there was little difference between platelet accumulation after severe or mild injury in FcRγ–/–. These data indicate a significant role for GPVI in FeCl3-induced thrombus formation. Pretreatment of wild-type mice with lepirudin further impaired mild FeCl3-induced thrombus formation, demonstrating a role for thrombin. Laser-induced thrombus formation in wild-type and FcRγ–/– was comparable. Collagen exposure to circulating blood was undetectable after laser injury. Normalized for thrombus size, thrombus-associated tissue factor was 5-fold higher in laser-induced thrombi than in severe FeCl3-induced thrombi. Thus, platelet activation by thrombin appears to be more important after laser injury than platelet activation by GPVI-collagen. It may thus be important when considering targets for antithrombotic therapy to use multiple animal models with diverse pathways to thrombus formation.
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Robbie, Linda, Susan Berry, Bruce Bennett, Nicola Mutch, Elaine Moir, and Nuala Booth. "Localization and Identification of Thrombin and Plasminogen Activator Activities in Model Human Thrombi by in situ Zymography." Thrombosis and Haemostasis 88, no. 12 (2002): 996–1002. http://dx.doi.org/10.1055/s-0037-1613346.
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SummaryHuman thrombi vary in their susceptibility to lysis and this is clinically important. Several potential contributory factors were examined in this study by using model thrombi, created under flow; these provide a robust, reproducible and easily-manipulated system. Here we identify the plasminogen activators (PA) active in model thrombi of known age and define the cellular and plasma contribution to activity in different areas. The cell-rich head of model thrombi had strong thrombin and PA activity, with coagulant activity also at the tail. Thrombin activity decreased as model thrombi were aged. PA activity in the thrombus head also decreased on ageing of thrombi but activity emerged around the thrombi, including the tail. Activity in the head of fresh model thrombi was primarily due to uPA, with some contribution from tPA. Experiments with thrombi prepared from platelet-rich plasma and added leucocytes showed that uPA activity at the head of fresh thrombi was derived from PMN. Older thrombi had tPA activity around the tail of the thrombus; this activity occurred in the absence of cells. This study highlights the importance of PMN-derived uPA activity in the lysis of fresh thrombi, with activity originating in the leucocyte-rich head. It also shows that thrombi are dynamic structures in which fibrin can be repeatedly laid down and lysed, observations that are relevant to therapeutic lysis and potential rethrombosis.
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Tucker, Erik I., Ulla M. Marzec, Tara C. White, Sawan Hurst, Sandra Rugonyi, Owen J. T. McCarty, David Gailani, András Gruber, and Stephen R. Hanson. "Prevention of vascular graft occlusion and thrombus-associated thrombin generation by inhibition of factor XI." Blood 113, no. 4 (January 22, 2009): 936–44. http://dx.doi.org/10.1182/blood-2008-06-163675.
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Abstract The protease thrombin is required for normal hemostasis and pathologic thrombogenesis. Since the mechanism of coagulation factor XI (FXI)–dependent thrombus growth remains unclear, we investigated the contribution of FXI to thrombus formation in a primate thrombosis model. Pretreatment of baboons with a novel anti–human FXI monoclonal antibody (aXIMab; 2 mg/kg) inhibited plasma FXI by at least 99% for 10 days, and suppressed thrombin-antithrombin (TAT) complex and β-thromboglobulin (βTG) formation measured immediately downstream from thrombi forming within collagen-coated vascular grafts. FXI inhibition with aXIMab limited platelet and fibrin deposition in 4-mm diameter grafts without an apparent increase in D-dimer release from thrombi, and prevented the occlusion of 2-mm diameter grafts without affecting template bleeding times. In comparison, pretreatment with aspirin (32 mg/kg) prolonged bleeding times but failed to prevent graft occlusion, supporting the concept that FXI blockade may offer therapeutic advantages over other antithrombotic agents in terms of bleeding complications. In whole blood, aXIMab prevented fibrin formation in a collagen-coated flow chamber, independent of factor XII and factor VII. These data suggest that endogenous FXI contributes to arterial thrombus propagation through a striking amplification of thrombin generation at the thrombus luminal surface.
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Wysokinski, Waldemar, Robert McBane, James H. Chesebro, and Whyte G. Owen. "Reversibility of Platelet Thrombosis In Vivo." Thrombosis and Haemostasis 76, no. 06 (1996): 1108–13. http://dx.doi.org/10.1055/s-0038-1650714.
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SummaryReversibility in vivo of acute platelet thrombosis in response to specific anticoagulants is analyzed with thrombi that develop in segments (1 cm) of porcine carotid arteries externally crushed with a hemostat. Most thrombi fill the lumens of the injured segments (ca. 1 cm × 3 mm, 1 × w) within 30 min and comprise masses of platelets interpenetrated with neutrophil-lined seepage channels of blood. Continuous quantitative assay of thrombus mass is provided by a gamma detector placed over the injured segments to collect counts from 111In-labeled platelets. Thrombi established 30 min after injury, otherwise stable for 6 h, clear during 30-60 min of continuous infusion of either hirudin, tick anticoagulant or activated porcine protein C, or intermittent activation of endogenous protein C with a latent thrombin reagent. Anticoagulant dose-dependence of thrombus clearance is established for hirudin between 0.01 and 1.0 mg/kg/min. Thrombi become progressively refractory to hirudin between 0.5 and 6 h after injury. Neither heparin nor low-molecular-weight heparin in full (clinical) anticoagulant doses yield significant dethrombosis. It is concluded that, within time limits, controlled thrombin generation in platelet thrombi maintains platelet cohesion without catalyzing irreversible platelet aggregation or clotting of fibrinogen.
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Dubois, Christophe, Laurence Panicot-Dubois, Justin F. Gainor, Barbara C. Furie, and Bruce Furie. "Thrombin-Dependent Platelet Activation Is VWF-Independent during Thrombus Formation In Vivo." Blood 108, no. 11 (November 16, 2006): 1510. http://dx.doi.org/10.1182/blood.v108.11.1510.1510.
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Abstract Adhesion to and activation of platelets at an injured vessel wall are critical events in the formation of a thrombus. Calcium mobilization is one marker of platelet activation. Of different agonists capable of activating platelets in vitro, thrombin, collagen and vWF have been described to induce calcium mobilization, leading to the formation of aggregates. Using high speed digital multichannel intravital microscopy, we characterized calcium mobilization during platelet activation and thrombus formation in genetically modified mice. The kinetics of platelet activation and accumulation after laser-induced injury in cremaster muscle arterioles of living mice were analyzed. In wild type mice, platelets adhered and accumulated rapidly at the site of laser-induced injury. Thrombi increased in size, reached a maximum size at 90–120 sec, decreased in size and then stabilized within 3 to 4 min post-injury. In vWF−/− mice, the kinetics of platelet accumulation followed the same pattern as in wild type mice. However, a significant albeit modest reduction in the size of each thrombus was observed in these genetically deficient mice in comparison with wild type mice. By ranking the thrombi by size, we observed that 40% of the thrombi formed in vWF−/− mice were present in the quadrant containing the smallest thrombi versus 18% for the wild type mice. Only 8% of the thrombi formed in vWF−/− mice were distributed in the quadrant containing the largest thrombi versus 32% for the wild type mice. In wild type mice treated with lepirudin, a specific inhibitor of thrombin activity, a small early accumulation of platelets was observed at about 16 sec whereas in untreated wild type mice this early accumulation is often obscured by subsequent thrombin-mediated platelet accumulation and activation. However, at the time of maximal thrombus size in wild-type mice, platelet accumulation in wild type mice was more than ten-fold greater than in wild type mice treated with lepirudin. The kinetics of platelet accumulation were similar in FcRγ−/− mice lacking GPVI, GPVI-depleted mice and wild type mice. Furthermore, depletion of GPVI from the platelet surface of vWF−/− mice or platelets of wild type mice treated with lepirudin did not alter the kinetics of platelet accumulation in those mice. By monitoring calcium mobilization per platelet engaged in the growing thrombus, we observed that elevated calcium levels in each platelet were similar in FcRγ−/−, GPVI depleted, vWF−/− and wild type mice. However in wild type mice treated with lepirudin, platelet calcium mobilization was almost completely inhibited in comparison with those observed in wild type mice. Our results indicate that thrombin is the major agonist leading to platelet activation after laser-induced injury. Collagen, as previously reported (Dubois, Blood.2006;107:3902) does not play a role in platelet thrombus formation after laser injury and, based on data reported here, does not play a role in platelet activation in this model. vWF is important for the growth of the platelet thrombus but is not required for initial platelet accumulation or platelet activation in vivo in this thrombosis model. The platelet agonist or ligand responsible for initial early platelet accumulation after laser-induced injury is unknown, and does not require GPVI, thrombin or vWF.
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Brill-Edwards, Patrick, Joanne Van Ryn-McKenna, Lu Cai, Frederick A. Ofosu, and Michael R. Buchanan. "Prevention of Thrombus Growth by Antithrombin III-Dependent and Two Direct Thrombin Inhibitors in Rabbits: Implications for Antithrombotic Therapy." Thrombosis and Haemostasis 68, no. 04 (1992): 424–27. http://dx.doi.org/10.1055/s-0038-1646290.
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SummaryWe compared the abilities of heparin and two direct thrombin inhibitors to prevent fibrin accretion onto pre-existing thrombi in rabbits. Inhibition of thrombus growth was measured as the ability of each test compound to inhibit the accretion of 125I-fibrin onto thrombi pre-formed in jugular veins of rabbits. When administered as a continuous infusion, the two direct (i. e. antithrombin III-independent) thrombin inhibitors, r-hirudin and a tripeptide, Ac(D)-Phe-Pro-bor-Arg (P-8714) inhibited fibrin accretion as effectively as heparin, but did so in doses which generated little systemic anticoagulation, as compared to the marked anticoagulation associated with the heparin effect. However, both r-hirudin and P-8714 were more effective when they were administered as a single bolus injection than as a continuous infusion. Under the former conditions, there was only a transient systemic anticoagulant effect. We conclude that direct or antithrombin III-independent thrombin inhibitors are more effective than heparin in preventing thrombus growth. The limited effect of heparin is likely due to fibrin impairing the ability of heparin/antithrombin III to inactivate thrombin.
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Chou, Janet, Nigel Mackman, Glenn Merrill-Skoloff, Brian Pedersen, Barbara C. Furie, and Bruce Furie. "Hematopoietic cell-derived microparticle tissue factor contributes to fibrin formation during thrombus propagation." Blood 104, no. 10 (November 15, 2004): 3190–97. http://dx.doi.org/10.1182/blood-2004-03-0935.
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Abstract Tissue factor (TF) is expressed on nonvascular cells and cells within the vessel wall and circulates in blood associated with microparticles. Although blood-borne TF accumulates into the developing thrombus during thrombus formation, the contribution of blood-borne TF and vessel wall TF to thrombin generation in vivo following vessel injury is unknown. To determine the source and role of blood-borne microparticle TF, we studied arterial thrombus formation in a living mouse using intravital microscopy. Platelet, TF, and fibrin accumulation in the developing thrombus was compared in wild-type and low TF mice. Compared to wild-type mice, low TF mice formed very small platelet thrombi lacking TF or fibrin. Wild-type and low TF mice received transplants of bone marrow from wild-type and low TF mice. Arterial thrombi in low TF bone marrow/wild-type chimeric mice had decreased size and decreased TF and fibrin levels. Arterial thrombi in wild-type bone marrow/low TF chimeric mice showed decreased platelet thrombus size but normal TF and fibrin levels. This demonstrates that blood-borne TF associated with hematopoietic cell-derived microparticles contributes to thrombus propagation.
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Ahmed, Muhammad Usman, Valeria Kaneva, Stéphane Loyau, Dmitry Nechipurenko, Nicolas Receveur, Marion Le Bris, Emily Janus-Bell, et al. "Pharmacological Blockade of Glycoprotein VI Promotes Thrombus Disaggregation in the Absence of Thrombin." Arteriosclerosis, Thrombosis, and Vascular Biology 40, no. 9 (September 2020): 2127–42. http://dx.doi.org/10.1161/atvbaha.120.314301.
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Objective: Atherothrombosis occurs upon rupture of an atherosclerotic plaque and leads to the formation of a mural thrombus. Computational fluid dynamics and numerical models indicated that the mechanical stress applied to a thrombus increases dramatically as a thrombus grows, and that strong inter-platelet interactions are essential to maintain its stability. We investigated whether GPVI (glycoprotein VI)-mediated platelet activation helps to maintain thrombus stability by using real-time video-microscopy. Approach and Results: We showed that GPVI blockade with 2 distinct Fab fragments promoted efficient disaggregation of human thrombi preformed on collagen or on human atherosclerotic plaque material in the absence of thrombin. ACT017-induced disaggregation was achieved under arterial blood flow conditions, and its effect increased with wall shear rate. GPVI regulated platelet activation within a growing thrombus as evidenced by the loss in thrombus contraction when GPVI was blocked, and the absence of the disaggregating effect of an anti-GPVI agent when the thrombi were fully activated with soluble agonists. The GPVI-dependent thrombus stabilizing effect was further supported by the fact that inhibition of any of the 4 key immunoreceptor tyrosine-based motif signalling molecules, src-kinases, Syk, PI3Kβ, or phospholipase C, resulted in kinetics of thrombus disaggregation similar to ACT017. The absence of ACT017-induced disaggregation of thrombi from 2 afibrinogenemic patients suggests that the role of GPVI requires interaction with fibrinogen. Finally, platelet disaggregation of fibrin-rich thrombi was also promoted by ACT017 in combination with r-tPA (recombinant tissue plasminogen activator). Conclusions: This work identifies an unrecognized role for GPVI in maintaining thrombus stability and suggests that targeting GPVI could dissolve platelet aggregates with a poor fibrin content.
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Cornelissen, Ivo, Erica De Candia, and Shaun R. Coughlin. "GP-VI Disruption Confers Additional Protection against Arterial Thrombosis in PAR-4 Deficient Mice." Blood 112, no. 11 (November 16, 2008): 3932. http://dx.doi.org/10.1182/blood.v112.11.3932.3932.
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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
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Shaya, Shana A., Dhulfiha Muzafar Gani, Jeffrey I. Weitz, Paul Y. Kim, and Peter L. Gross. "Factor XIII Prevents Pulmonary Emboli in Mice by Stabilizing Deep Vein Thrombi." Thrombosis and Haemostasis 119, no. 06 (April 20, 2019): 992–99. http://dx.doi.org/10.1055/s-0039-1685141.
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Background Deep vein thrombosis (DVT) can lead to pulmonary embolism (PE), but the mechanisms responsible for this progression are unknown. Previously, we showed that inhibition of thrombin-mediated activation of factor (F) XIII promotes venous thrombus stability in a murine model. Aim In this study, we investigate the consequence of attenuating fibrinolysis, using FXIII, α2-antiplasmin (α2-AP) or ε-aminocaproic acid (EACA) supplementation, on clot lysis and venous thrombus stability using the same mouse model. Methods In vitro plasma clot lysis assay shows that EACA and α2-AP but not FXIII, inhibit fibrinolysis. Ferric chloride induced thrombi in the femoral vein of mice. After thrombus formation, mice received saline, EACA, α2-AP or FXIII, with or without dalteparin or dabigatran. Thrombus sizes and embolization over 2 hours were visualized using intravital videomicroscopy. Lungs were sectioned to quantify emboli presence via histology. Results The change in thrombus size over time was significantly greater after EACA treatment, but not FXIII or α2-AP supplementation, compared with saline. α2-AP-supplementation did not alter thrombus stability. Thrombi were more stable following EACA treatment and FXIII supplementation as evidenced by less embolic events and PE burden, even when they were anticoagulated with either dalteparin or dabigatran. Conclusion FXIII supplementation stabilized venous thrombi, even in the presence of anticoagulants, and did not alter thrombus size. Supplemental FXIII may be useful to stabilize DVT and be an alternative adjunctive treatment to minimize PE, even when anticoagulants are used.
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Agnelli, G., C. Renga, JI Weitz, GG Nenci, and J. Hirsh. "Sustained antithrombotic activity of hirudin after its plasma clearance: comparison with heparin." Blood 80, no. 4 (August 15, 1992): 960–65. http://dx.doi.org/10.1182/blood.v80.4.960.960.
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Abstract Thrombus extension in patients with venous thromboembolism is due to the accretion of fibrin onto existing thrombi. Extension is promoted by both circulating and thrombus-bound thrombin, which convert fibrinogen to fibrin. Heparin is an effective antithrombotic agent, but it requires continuous administration to achieve persistent inhibition of thrombus extension. Heparin is highly effective in inhibiting fluid phase thrombin, but is a relatively ineffective inhibitor of thrombus- bound thrombin. Hirudin, unlike heparin, inactivates both circulating and fibrin-bound thrombin and, therefore, has the potential to prevent thrombus extension even after a short course of treatment. The aim of this study was to evaluate the time course of the accretion of new fibrin onto preexisting rabbit jugular vein thrombi after a 3-hour infusion of saline, heparin, and hirudin. Heparin and recombinant (r)- hirudin (CGP 39399) were infused at doses that doubled the activated partial thromboplastin time (aPTT). At the end of the 3-hour infusions in rabbits treated with saline, heparin (0.75 mg/kg), or r-hirudin (1.25 mg/kg), accretion of 125I-fibrinogen was 59 +/- 5 micrograms, 34 +/- 4 micrograms, and 21 +/- 2 micrograms, respectively (heparin and r- hirudin v saline, P less than .01; r-hirudin v heparin, P less than .01). Three hours after the end of the infusions, the accreted 125I- fibrinogen in the saline-, heparin-, and hirudin-treated animals was 89 +/- 6 micrograms, 51 +/- 7 micrograms, and 23 +/- 3 micrograms, respectively; 9 hours after the end of the infusions, the accreted 125I- fibrinogen was 112 +/- 9 micrograms, 82 +/- 7 micrograms, and 25 +/- 3 micrograms, respectively. aPTT and thrombin clotting time (TCT) returned to the baseline value 90 minutes after the end of heparin or r- hirudin infusion. During in vitro experiments, human fibrin clots previously incubated in human plasma containing r-hirudin did not promote fibrinopeptide A (FPA) generation when washed and then incubated in human plasma in the absence of thrombin inhibitors. This persistent inhibition of FPA production was not observed after incubation in human plasma of human plasma clots preincubated with heparin. We conclude that heparin is effective in inhibiting thrombus extension while it is present in the circulation, but that this effect is rapidly lost after its plasma clearance. In contrast, the antithrombotic activity of r-hirudin is sustained beyond its plasma clearance, presumably because of its ability to inactivate thrombus- bound thrombin. Our findings indicate that r-hirudin might be an effective antithrombotic agent even when used for short periods.
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Agnelli, G., C. Renga, JI Weitz, GG Nenci, and J. Hirsh. "Sustained antithrombotic activity of hirudin after its plasma clearance: comparison with heparin." Blood 80, no. 4 (August 15, 1992): 960–65. http://dx.doi.org/10.1182/blood.v80.4.960.bloodjournal804960.
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Thrombus extension in patients with venous thromboembolism is due to the accretion of fibrin onto existing thrombi. Extension is promoted by both circulating and thrombus-bound thrombin, which convert fibrinogen to fibrin. Heparin is an effective antithrombotic agent, but it requires continuous administration to achieve persistent inhibition of thrombus extension. Heparin is highly effective in inhibiting fluid phase thrombin, but is a relatively ineffective inhibitor of thrombus- bound thrombin. Hirudin, unlike heparin, inactivates both circulating and fibrin-bound thrombin and, therefore, has the potential to prevent thrombus extension even after a short course of treatment. The aim of this study was to evaluate the time course of the accretion of new fibrin onto preexisting rabbit jugular vein thrombi after a 3-hour infusion of saline, heparin, and hirudin. Heparin and recombinant (r)- hirudin (CGP 39399) were infused at doses that doubled the activated partial thromboplastin time (aPTT). At the end of the 3-hour infusions in rabbits treated with saline, heparin (0.75 mg/kg), or r-hirudin (1.25 mg/kg), accretion of 125I-fibrinogen was 59 +/- 5 micrograms, 34 +/- 4 micrograms, and 21 +/- 2 micrograms, respectively (heparin and r- hirudin v saline, P less than .01; r-hirudin v heparin, P less than .01). Three hours after the end of the infusions, the accreted 125I- fibrinogen in the saline-, heparin-, and hirudin-treated animals was 89 +/- 6 micrograms, 51 +/- 7 micrograms, and 23 +/- 3 micrograms, respectively; 9 hours after the end of the infusions, the accreted 125I- fibrinogen was 112 +/- 9 micrograms, 82 +/- 7 micrograms, and 25 +/- 3 micrograms, respectively. aPTT and thrombin clotting time (TCT) returned to the baseline value 90 minutes after the end of heparin or r- hirudin infusion. During in vitro experiments, human fibrin clots previously incubated in human plasma containing r-hirudin did not promote fibrinopeptide A (FPA) generation when washed and then incubated in human plasma in the absence of thrombin inhibitors. This persistent inhibition of FPA production was not observed after incubation in human plasma of human plasma clots preincubated with heparin. We conclude that heparin is effective in inhibiting thrombus extension while it is present in the circulation, but that this effect is rapidly lost after its plasma clearance. In contrast, the antithrombotic activity of r-hirudin is sustained beyond its plasma clearance, presumably because of its ability to inactivate thrombus- bound thrombin. Our findings indicate that r-hirudin might be an effective antithrombotic agent even when used for short periods.
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Rouzaud, Marie-Catherine, Stéphane Loyau, Martine Jandrot-Perrus, Marie-Christine Bouton, Yacine Boulaftali, Lamia Lamrani, and Benoît Ho-Tin-Noé. "The mouse dorsal skinfold chamber as a model for the study of thrombolysis by intravital microscopy." Thrombosis and Haemostasis 107, no. 05 (2012): 962–71. http://dx.doi.org/10.1160/th11-10-0705.
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SummaryAlthough intravital microscopy models of thrombosis in mice have contributed to dissect the mechanisms of thrombus formation and stability, they have not been well adapted to study long-term evolution of occlusive thrombi. Here, we assessed the suitability of the dorsal skinfold chamber (DSC) for the study of thrombolysis and testing of thrombolytic agents by intravital microscopy. We show that induction of FeCl3-induced occlusive thrombosis is achievable in microvessels of DSCs, and that thrombi formed in DSCs can be visualised by intravital microscopy using brightfield transmitted light, or fluorescent staining of thrombus components such as fibrinogen, platelets, leukocytes, and von Willebrand factor. Direct application of control saline or recombinant tissue-plasminogen activator (rtPA) to FeCl3-produced thrombi in DSCs did not affect thrombus size or induce recanalisation. However, in the presence of hirudin, rtPA treatment caused a rapid dose-dependent lysis of occlusive thrombi, resulting in recanalisation within 1 hour after treatment. Skin haemorrhage originating from vessels located inside and outside the FeCl3-injured area was also observed in DSCs of rtPA-treated mice. We further show that rtPA-induced thrombolysis was enhanced in plasminogen activator inhibitor-1-deficient (PAI-1−/−) mice, and dropped considerably as the time between occlusion and treatment application increased. Together, our results show that by allowing visualization and measurement of thrombus lysis and potential bleeding complications of thrombolytic treatments, the DSC provides a model for studying endogenous fibrinolysis and for first-line screening of thrombolytic agents. Furthermore, using this system, we found that thrombin and clot aging impair the thrombolytic action of rtPA towards FeCl3-produced thrombi.
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Jiroušková, Markéta, Igor Chereshnev, Heikki Väänänen, Jay L. Degen, and Barry S. Coller. "Antibody blockade or mutation of the fibrinogen γ-chain C-terminus is more effective in inhibiting murine arterial thrombus formation than complete absence of fibrinogen." Blood 103, no. 6 (March 15, 2004): 1995–2002. http://dx.doi.org/10.1182/blood-2003-10-3401.
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Abstract An elevated plasma fibrinogen level is a risk factor for thrombotic cardiovascular disease, but which of fibrinogen's functions is responsible for the increased risk is unknown. To define better the contribution of fibrinogen to large vessel thrombus formation, we studied carotid artery thrombosis in wild-type mice, mice lacking fibrinogen (fbg–/–), mice treated with 7E9 (a blocking antibody to the fibrinogen γ-chain C-terminus), and mice expressing a mutant fibrinogen (γΔ5) that lacks the γ-chain platelet-binding motif QADGV. In control mice, thrombus formation resulted in occlusion in 8 ± 2 minutes (mean ± SD). In fbg–/– mice, thrombi grew to large sizes, but then they abruptly embolized, confirming previous observations by others in an arteriolar thrombus model. In contrast, mice treated with 7E9 and γΔ5 mice developed only small, nonoclusive mural thrombi and embolization was limited. These findings reveal that a fibrinogen antibody, 7E9, or a fibrinogen mutant retaining clotting function, can limit thrombus formation more effectively than the complete absence of fibrinogen. We hypothesize that the smaller thrombi in these animals result from the ability of fibrin to bind and sequester thrombin and/or the ability of the altered fibrinogen molecules, which cannot recruit platelets, to bind to and passivate the surface.
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Vogel, Gerard M. T., Ronald G. M. van Amsterdam, Wim J. Kop, and Dirk G. Meuleman. "Pentasaccharide and Orgaran® Arrest, whereas Heparin Delays Thrombus Formation in a Rat Arteriovenous Shunt." Thrombosis and Haemostasis 69, no. 01 (1993): 029–34. http://dx.doi.org/10.1055/s-0038-1651543.
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SummaryThe mode of action of glycosaminoglycans (GAGs) towards thrombus formation in a rat arteriovenous shunt was studied by simultaneous examination of thrombus weight, platelet consumption and thrombin generation during 45 min of blood circulation. A comparison was made between the effects of heparin, the heparinoid Org 10172 (Orgaran®), and the chemically synthesized methoxy derivative of the antithrombin III binding pentasaccharide fragment of heparin (Org 31540).All three compounds inhibited thrombus growth by 30% at a dose of 80 anti-Xa U/kg i. v. when assessed after 15 min of circulation through the shunt. In addition, a systemic decrease of 27% of platelet numbers in the placebo group was inhibited by heparin and Orgaran® with 63% and by pentasaccharide with 48%. At a later stage, after 45 min of circulation, at comparable plasma anti-Xa levels, thrombi which had formed in the presence of Orgaran® or pentasaccharide, but not in the presence of heparin, became less or non thrombogenic. This non-thrombogenicity was reflected by i) an inhibition of the local deposition of [51Cr]platelets of 75% with Orgaran® and of 57% with pentasaccharide, and ii) an inhibition of ex-vivo thrombus-induced thrombin generation in pooled rat plasma of 67% with Orgaran® and of 52% with pentasaccharide (inhibition compared to placebo).Although the mechanism of inducing non-thrombogenicity of a (developing) thrombus by Orgaran® and pentasaccharide requires further investigation, the suppression of the local thrombin generation potency, measured by thrombus-induced thrombin generation in pooled plasma, is much more correlated with thrombus growth than systemic anticoagulant activity. This suppression is likely to be due to the anti-Xa activity, as reflected by the efficacy of the pure Xa inhibiting pentasaccharide. Limitation of thrombus growth adds to the prophylactic perspective of Orgaran® and pentasaccharide in preventing thrombosis.
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Kanji, Rahim, Ying X. Gue, Vassilios Memtsas, and Diana A. Gorog. "Fibrinolysis in Platelet Thrombi." International Journal of Molecular Sciences 22, no. 10 (May 12, 2021): 5135. http://dx.doi.org/10.3390/ijms22105135.
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The extent and duration of occlusive thrombus formation following an arterial atherothrombotic plaque disruption may be determined by the effectiveness of endogenous fibrinolysis. The determinants of endogenous fibrinolysis are the subject of much research, and it is now broadly accepted that clot composition as well as the environment in which the thrombus was formed play a significant role. Thrombi with a high platelet content demonstrate significant resistance to fibrinolysis, and this may be attributable to an augmented ability for thrombin generation and the release of fibrinolysis inhibitors, resulting in a fibrin-dense, stable thrombus. Additional platelet activators may augment thrombin generation further, and in the case of coronary stenosis, high shear has been shown to strengthen the attachment of the thrombus to the vessel wall. Neutrophil extracellular traps contribute to fibrinolysis resistance. Additionally, platelet-mediated clot retraction, release of Factor XIII and resultant crosslinking with fibrinolysis inhibitors impart structural stability to the thrombus against dislodgment by flow. Further work is needed in this rapidly evolving field, and efforts to mimic the pathophysiological environment in vitro are essential to further elucidate the mechanism of fibrinolysis resistance and in providing models to assess the effects of pharmacotherapy.
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Ofosu, F. A., F. Fernandez, N. Anvari, C. Caranobe, F. Dol, Y. Cadroy, M. Petitou, J. Mardiguian, P. Sié, and B. Boneu. "Further Studies on the Mechanisms for the Antithrombotic Effects of Sulfated Polysaccharides in Rabbits." Thrombosis and Haemostasis 60, no. 02 (1988): 188–92. http://dx.doi.org/10.1055/s-0038-1647027.
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SummaryA recent study (Fernandez et al., Thromb. Haemostas. 1987; 57: 286-93) demonstrated that when rabbits were injected with the minimum weight of a variety of glycosaminoglycans required to inhibit tissue factor-induced thrombus formation by —80%, exogenous thrombin was inactivated —twice as fast in the post-treatment plasmas as the pre-treatment plasmas. In this study, we investigated the relationship between inhibition of thrombus formation and the extent of thrombin inhibition ex vivo. We also investigated the relationship between inhibition of thrombus formation and inhibition of prothrombin activation ex vivo. Four sulfated polysaccharides (SPS) which influence coagulation in a variety of ways were used in this study. Unfractionated heparin and the fraction of heparin with high affinity to antithrombin III potentiate the antiproteinase activity of antithrombin III. Pentosan polysulfate potentiates the activity of heparin cofactor II. At less than 10 pg/ml of plasma, all three SPS also inhibit intrinsic prothrombin activation. The fourth agent, dermatan sulfate, potentiates the activity of heparin cofactor II but fails to inhibit intrinsic prothrombin activation even at concentrations which exceed 60 pg/ml of plasma. Inhibition of thrombus formation by each sulfated polysaccharides was linearly related to the extent of thrombin inhibition achieved ex vivo. These observations confirm the utility of catalysis of thrombin inhibition as an index for assessing antithrombotic potential of glycosaminoglycans and other sulfated polysaccharides in rabbits. With the exception of pentosan polysulfate, there was no clear relationship between inhibition of thrombus formation and inhibition of prothrombin activation ex vivo.
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Dyr, Jan E., Tomas Riedel, Jana Stikarova, Jiri Suttnar, Jaroslav Cermak, Roman Kotlin, Martin Hajsl, Petr Tousek, Viktor Kocka, and Martin Maly. "Spatially Organized Structure of Coronary Thrombus in Acute Myocardial Infarction." Blood 128, no. 22 (December 2, 2016): 716. http://dx.doi.org/10.1182/blood.v128.22.716.716.
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Abstract Introduction The use of thromboaspiration in primary percutaneous intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) has offered a unique opportunity to study thrombus composition, its dynamic formation, and architecture in vivo. There has been, however, several limitations, not least the fact that the technique has not yet allowed a precise transversal analysis from one side of the artery to the other, as is done in histological analysis. The dynamic process of intracoronary thrombus formation in STEMI patients is thus still not well understood. Ischemic time was hypothesized to be among the strongest independent correlates of thrombus architecture. In time the platelets are decreasing its proportion and fibrin proportion is increasing (J Silvain, J-P Collet, JW Weisel et al, J Am Coll Cardiol 2011; 57:1359). However, no real report on the internal structures of the in vivo formed thrombi has been shown so far. Therefore, we investigated both the surface and the composition of longitudinally freeze-fractured thrombi. Methods Thrombi were collected by PCI from 119 STEMI patients. Out of the patients there were "early comers " (˃12 h from symptom onset; 23 patients) and "late comers" (more than 720 min; 29 patients). The mean age of all patients was 64 years, 70% of patients were males, 51% were smokers, 50% had arterial hypertension, 20% were diabetics and 23% had chronic renal insufficiency. Scanning electron microscopy; collected thrombi obtained by PCI were thoroughly washed in saline solution and stored in 4% formaldehyde prior dehydration. To reveal the internal structures of the thrombi selected samples were longitudinally freeze fractured in liquid nitrogen and coated with platinum. Samples were examined in SEM Vega Plus TS 5135 (Tescan s.r.o., Brno, Czech Republic). Whole areas of the freeze-fractured thrombi were scanned. Results and discussion The thrombus composition of longitudinally freeze-fractured thrombi was compared between groups of "early-comers" and "late-comers. The distribution of the components in the "early comers" thrombi freeze-fracture seemed to be uniform. Platelets were far the main component (about 75 % in proportion) of the "early comers" thrombus, followed by fibrin and other compounds. The amount of red blood cells was negligible (about 2 - 8 %). We did not observe any significant differences between the thrombi in the group of early comers. Thrombi of the "late-comers" group were composed mainly of red blood cells; platelets and fibrin formed only minority of the thrombi. In contrast to the "early comers" the distribution of the main thrombus components in the "late comers" thrombi was dramatically different between individual parts of the thrombus. The number of platelets and red blood cells varied from 0% to almost 99% and vice versa. It was possible to estimate the initiating place of the thrombus as well as the direction of the growth. Each thrombus could be divided into parts formed mainly either by platelets or by red blood cells. It seems that thrombus develops a regional architecture defined by the extent of platelet activation and packing density. It has been reported that in contracted clots and thrombi, erythrocytes are compressed to close-packed polyhedral structures with platelets and fibrin on the surface demonstrating how contracted clots form an impermeable barrier important for hemostasis and wound healing (D Cines, T Lebedeva, J Weisel et al, Blood 2014; 123:1596). Our investigation of the composition of the in vivo formed thrombi supports these results and helps to explain how fibrinolysis is greatly retarded as clots grow and contract. We have found that on the surfaces of late-comers thrombi fibrin thick fibrils were present. It has been shown that the association of soluble fibrinogen with the fibrin clot results in the reduced adhesiveness of such fibrinogen/fibrin matrices toward leukocytes and platelets (VK Lishko, T Burke, T Ugarova, Blood 2007; 109:1541). Fibrinopeptides A are less accessible for thrombin in surface bound fibrinogen which thus provides additional level of protection of thrombi from premature dissolution (T Riedel, L Medved, JE Dyr, Blood 2011; 117:1700). These findings may have great impact on our knowledge of pathophysiology of the thrombus growth and possible therapeutic consequences related to the time of symptom onset. Disclosures No relevant conflicts of interest to declare.
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Barbera, Letterio, Dajana Muth-Werthmann, Stefan Siebers, Helmut Ermert, Stathis Philippou, Achim Mumme, and Bruno Geier. "Ultrasound elastography for the age determination of venous thrombi." Thrombosis and Haemostasis 93, no. 02 (2005): 368–74. http://dx.doi.org/10.1160/th04-07-0437.
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SummaryThe exact age determination of venous thrombi is important if thrombolytic therapy or surgical thrombectomy is considered. Clinical symptoms as well as duplex-ultrasound and phlebography are unreliable in this respect and do not allow an exact age estimation. Ultrasound elastography can provide information about the elastic properties of thrombi. Since thrombus elasticity decreases with age due to the organisation process, it should be possible to use elastography to stage the degree of organisation and thereby determine the age of venous thrombi. Experimental venous thrombi aging 1, 3, 6, 9, 12 and 15 days were created in a porcine model by laparoscopic ligation of the infrarenal Vena cava in combination with transfemoral infusion of thrombin. The thrombosed iliac veins were explanted and embedded in gelatine, after that they underwent examination by ultrasound elastography. In addition, histological evaluation of the thrombi was performed. Elastography demonstrated a decline in thrombus elasticity between days 6 and 12 with the 12-day-old thrombi being about 3 times harder then the 6-dayold thrombi. This correlated with the histological findings, which demonstrated a marked increase in fibroblast and collagen production in the clots during this time, with the 12– and 15-day thrombi showing signs of advanced organisation. In conclusion, in an experimental setting, ultrasound elastography was helpful in determining the exact age of venous thrombi. The differences in elasticity were most pronounced between days 6 and 12, which is also the most relevant time frame when considering invasive therapies in human venous thrombosis.
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Laurance, Sandrine, Francois-Rene Bertin, Talin Ebrahimian, Stephanie Lehoux, Catherine A. Lemarie, and Mark D. Blostein. "Gas6 Promotes Pro-Inflammatory (Ly6Chi) Monocyte Recruitment in Venous Thrombosis." Blood 124, no. 21 (December 6, 2014): 1533. http://dx.doi.org/10.1182/blood.v124.21.1533.1533.
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Abstract Recent studies have demonstrated that innate immune cells, i.e. neutrophils and monocytes, provide the initiating stimulus for venous thrombus development. Gas6 was found to promote inflammation by inducing interactions between the endothelium and innate immune cells. In addition, we recently showed that Gas6 was involved in venous thrombosis by inducing tissue factor expression in the endothelium. Since Gas6 is expressed in monocytes, we hypothesize that Gas6 may be involved in monocyte recruitment during venous thrombosis. Venous thrombosis was induced in the inferior vena cava of wild type (WT) and Gas6 deficient (-/-) mice using 5% FeCl3. Using ultrasonography, we found that global monocyte depletion by clodronate resulted in the formation of smaller thrombi. Selective depletion of the pro-inflammatory (Ly6Chi) monocyte subset, using an anti-CCR2 antibody, also induced the formation of smaller clots. In addition, MOMA-2 (monocyte-macrophage marker) staining showed a reduced number of monocytes in thrombi from Gas6-/- mice. More importantly, immunofluorescent staining revealed that fewer Ly6Chi monocytes were recruited to the thrombi of Gas6-/- mice compared to WT. However, Ly6Clow (patrolling) monocytes were equivalently recruited between Gas6-/- and WT mice. In vitro, mRNA expression of CCR2 was increased by thrombin in WT but not in Gas6-/- monocytes. The mRNA and protein expression of the CCR2 ligand, CCL2, was also increased by thrombin in WT but not in Gas6-/- endothelial cells. CCL2 secretion, as demonstrate by ELISA, was induced by thrombin treatment in WT but not in Gas6-/- endothelial cells. Conditioned media from WT or Gas6-/- endothelial treated by thrombin was used for monocyte migration experiments. The conditioned media from WT endothelial cells treated with thrombin increased migration of WT monocytes compared to media from untreated or Gas6-/- endothelial cells. Our results demonstrate an important role for Ly6Chi monocytes in thrombus formation and that Gas6 is specifically involved in the recruitment of these monocytes through the expression of CCL2 and CCR2. Disclosures No relevant conflicts of interest to declare.
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Larson, Douglas F., David Arzouman, Leigh Kleinert, Vangie Patula, and Stuart Williams. "Comparison of Sarns 3M heparin bonded to Duraflo II and control circuits in a porcine model: macro- and microanalysis of thrombi accumulation in circuit arterial filters." Perfusion 15, no. 1 (January 2000): 13–20. http://dx.doi.org/10.1177/026765910001500103.
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Heparin-bonded perfusion circuits have been reported to reduce the thrombus formation during various levels of systemic heparinization. The goal of this study was to compare the efficacy of thrombo-resistance of the Sarns 3M heparin-bonded circuit to Baxter Duraflo II and untreated control in a porcine model. Fifteen Yorkshire pigs (60-65 kg) were anesthetized, heparinized with 3000 IU, intravenously (i.v.) and surgically cannulated with an internal jugular outflow and a femoral vein inflow. All circuits consisted of a 22-Fr venous cannula, centrifugal pump, arterial filter, an 18-Fr cannula for return and connected with equal lengths of 3/8″ polyvinyl chloride tubing. The flows were maintained at 2.0 l/min for 4 h. Thrombus formation in filter samples were morphometrically analyzed through macro-densitometry, light microscopy, and scanning electron microscopy (SEM). Our findings revealed that the 3M circuit had significantly less gross thrombus ( p < 0.001), 66% and 84% less microscopic thrombi and fivefold less SEM-measured aggregates ( p = 0.03) compared to the Duraflo II and uncoated groups. This study demonstrated that the 3M heparin-bonded circuit had significantly reduced the formation of micro- and macro-thrombi in the minimally heparinized pig model compared to the Duraflo II and untreated control circuits.
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van der Meijden, Paola E. J., Imke C. A. Munnix, Jocelyn M. Auger, José W. P. Govers-Riemslag, Judith M. E. M. Cosemans, Marijke J. E. Kuijpers, Henri M. Spronk, Steve P. Watson, Thomas Renné, and Johan W. M. Heemskerk. "Dual role of collagen in factor XII–dependent thrombus formation." Blood 114, no. 4 (July 23, 2009): 881–90. http://dx.doi.org/10.1182/blood-2008-07-171066.
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Abstract In vivo mouse models have indicated that the intrinsic coagulation pathway, initiated by factor XII, contributes to thrombus formation in response to major vascular damage. Here, we show that fibrillar type I collagen provoked a dose-dependent shortening of the clotting time of human plasma via activation of factor XII. This activation was mediated by factor XII binding to collagen. Factor XII activation also contributed to the stimulating effect of collagen on thrombin generation in plasma, and increased the effect of platelets via glycoprotein VI activation. Furthermore, in flow-dependent thrombus formation under coagulant conditions, collagen promoted the appearance of phosphatidylserine-exposing platelets and the formation of fibrin. Defective glycoprotein VI signaling (with platelets deficient in LAT or phospholipase Cγ2) delayed and suppressed phosphatidylserine exposure and thrombus formation. Markedly, these processes were also suppressed by absence of factor XII or XI, whereas blocking of tissue factor/factor VIIa was of little effect. Together, these results point to a dual role of collagen in thrombus formation: stimulation of glycoprotein VI signaling via LAT and PLCγ2 to form procoagulant platelets; and activation of factor XII to stimulate thrombin generation and potentiate the formation of platelet-fibrin thrombi.
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Regan Baird, T., David Gailani, Bruce Furie, and Barbara C. Furie. "Factor XI Deficient Mice Have Reduced Platelet Accumulation and Fibrin Deposition after Laser Injury." Blood 104, no. 11 (November 16, 2004): 218. http://dx.doi.org/10.1182/blood.v104.11.218.218.
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Abstract Tissue factor exposure at sites of vascular injury results in the generation of factor Xa and thrombin. A current model of blood coagulation suggests that the amount of thrombin generated through this pathway is limited by the inhibition of the factor VIIa-tissue factor complex by tissue factor pathway inhibitor in the presence of factor Xa. The initial thrombin activates a number of hemostatic proteins including factor XI. Factor XIa then activates factor IX leading to generation of the tenase complex to maintain the thrombin flux. While in vitro studies support this hypothesis the importance of factor XI for thrombus formation in vivo remains unclear. We have examined thrombus formation upon laser injury to the arterioles (30–50 μm diameter) of the cremaster muscle in living mice lacking factor XI using digital multi-channel fluorescence intravital microscopy. Platelets were labeled with Alexa 488 conjugated murine CD41 Fab fragments by systemic infusion of the antibody. Maximum platelet accumulation in factor XI null mice (median of 35 thrombi in 4 mice) is only 25% of that of wild type mice (median of 40 thrombi in 4 mice) after injury (p<0.03). The time course of platelet accumulation is similar between both genotypes. Maximum platelet accumulation occurs in approximately 90 seconds (p<0.2). Fibrin deposition was observed simultaneously using an Alexa 660 conjugated anti-fibrin antibody that does not recognize fibrinogen. Maximum fibrin deposition in factor XI null mice is 50% that of wild type mice (p<0.001) and the rate of fibrin generation is slower in factor XI null mice. However, the time to achieve half maximal fibrin deposition is approximately the same in factor XI null mice (77 sec) compared to wild type mice (63.5 sec, p<0.09). These data suggest that the primary difference in response to laser induced injury between the factor XI null mice and wild type mice is the level of thrombin generated and supports the hypothesis that factor XI participates in maintaining thrombin flux after inhibition of the factor VII-tissue factor. The model above postulates a single source of tissue factor, the vessel wall, and further, that the tissue factor-factor VIIa complex formed from the exposed tissue factor is rapidly inactivated by tissue factor pathway inhibitor after the appearance of the initial factor Xa formed. In addition it has been suggested that a rapidly growing thrombus blocks access to vascular wall tissue factor. However we have recently observed that there is a P-selectin and P-selectin glycoprotein ligand 1 dependent pathway of blood coagulation that recruits blood borne tissue factor into a growing thrombus at sites of laser-induced vessel injury. Both vessel wall and blood borne tissue factor are required for normal thrombus formation. Our data suggest that although tissue factor is continuously recruited to the growing thrombus, factor XIa plays a significant role in thrombin generation.
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Schumacher, W. A., T. E. Steinbacher, C. L. Heran, J. R. Megill, and S. K. Durham. "Effects of Antithrombotic Drugs in a Rat Model of Aspirin-Insensitive Arterial Thrombosis." Thrombosis and Haemostasis 69, no. 05 (1993): 509–14. http://dx.doi.org/10.1055/s-0038-1651642.
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SummaryThese studies describe experimental conditions where aspirin is less effective than other antiplatelet and anticoagulant drugs in inhibiting acute arterial thrombosis. External electrolytic injury of the rat carotid artery was used to induce occlusive thrombi in 97% of vehicle-treated rats. Thrombi were revealed by light and electron microscopy to be comprised primarily of platelets enmeshed in a fibrin network. The thrombin inhibitor D-phenylalanyl-L-prolyl-L-arginyl chloromethy ketone (PPACK; 6 mg/kg, i. v.) decreased thrombus weight by 90%. Aspirin alone (1, 10 and 30 mg/kg, i. v.), dipyridamole alone (5 mg/kg i. v.) and aspirin (1 and 10 mg/kg, i. v.) in combination with dipyridamole (5 mg/kg, i. v.) did not inhibit thrombosis. The platelet-activating factor (PAF) antagonist, WEB 2086, (1 mg/kg i. v.) was also ineffective. Other drugs had intermediate activity. Thrombi were decreased 56% by the thromboxane receptor antagonist, BMS 180,291, either alone (5.8 mg/kg i.v.) or in combination with aspirin (10 mg/kg, i.v.). Heparin (900 U/kg, i.v.), warfarin (0.25 mg/kg, p.o. once daily for 3 days) and ticlopidine (200 mg/ kg, p.o. once daily for 3 days) reduced thrombus weight by 63, 73 and 43% respectively. Reductions in thrombus weight were always associated with improvements in either average blood flow or vessel patency.
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Bagdy, Dániel, Gabriella Szabó, Éva Barabás, and Sándor Bajusz. "Inhibition by D-MePhe-Pro-Arg-H (GYKI-14766) of Thrombus Growth in Experimental Models of Thrombosis." Thrombosis and Haemostasis 68, no. 02 (1992): 125–29. http://dx.doi.org/10.1055/s-0038-1656336.
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SummaryThe antithrombotic action of the highly effective synthetic thrombin inhibitor D-MePhe-Pro-Arg-H (GYKI-14766) was studied in various models of experimental thrombosis. The compound administered to rats and rabbits by i. v. bolus injections, continuous i. v. infusions, subcutaneously and orally, respectively, induced significant decrease in thrombus weight (i) in a quantitative venous thrombosis model with stasis based on vascular lesion in rats, (ii) in an extracorporeal arterio-venous shunt model in rabbits, and (iii) prevented the occlusion of the vessel in arterial thrombosis induced by mechanical damage in rats. By using the arterio-venous shunt model in rabbits the inhibitory effect on thrombus growth could be demonstrated as a function of dose and time in self-controlled experiments. Blood level of the inhibitor determined by a bioassay varied between 0.09-0.67 µg/ml whole blood when doses of 15 and 20 mg/kg were administered orally. A correlation was found between thrombin time, platelet aggregation induced by thrombin ex vivo and the weight of thrombi formed.
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Jasuja, Reema, Hans-Ulrich Pauer, Regan T. Baird, Bruce Furie, and Barbara Furie. "Reduction of Phosphatidylserine Exposure through Copper Chelation Leads to Reduced Fibrin Deposition After Laser Induced Vascular Injury In Vivo." Blood 114, no. 22 (November 20, 2009): 3049. http://dx.doi.org/10.1182/blood.v114.22.3049.3049.
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Abstract Abstract 3049 Poster Board II-1025 Colocalization and assembly of blood coagulation factors in the presence of negatively charged phospholipids leads to a 1,000-fold increase in the rate of thrombin generation compared to the solution reaction. We have established prothrombin fragment 1, the region of prothrombin containing the γ-carboxy-glutamic acid domain, as a probe for anionic phospholipids including phosphatidylserine. Prothrombin fragment 1 binds with high affinity to phosphatidylserine-containing membranes in vitro and identifies phosphatidylserine exposure relevant for the site of assembly of coagulation complexes in vivo. In order to determine the effect of phosphatidylserine exposure on thrombus formation during the laser injury model in vivo, we treated mice orally with the Cu2+ chelator tetrathiomolybdate for one week prior to study. This treatment has been shown to suppress phosphatidylserine exposure in rats (PNAS, 100: 6700-05, 2003). After copper chelator treatment, normal partial thromboplastin times (39 sec vs 42 sec, p=0.5) and whole blood counts in treated versus untreated mice were similar, suggesting that copper chelation did not affect the function of coagulation factors or total blood cell counts. Annexin V and Prothrombin fragment 1 were also used to measure phosphatidylserine exposure after thrombin (1 U/ml) stimulation of washed platelets using flow cytometric analysis. Platelets from untreated mice exhibited 2-fold increase in binding of both Annexin V and Prothrombin fragment 1 after thrombin stimulation; these values are similar to those previously reported. In contrast, the platelets of treated mice did not expose phosphatidylserine upon thrombin stimulation. Treatment with copper chelator did not affect platelet degranulation, as determined by surface exposure of P-selectin in flow cytometry. In addition, total phospholipid content and the ratio of outer to inner membrane phospholipids was not affected by treatment with copper chelator, suggesting that any reduction in detection of phosphatidylserine was due to reduction in exposure on the cell surface in response to an appropriate stimulus rather than reduced biosynthesis. Fluorescently conjugated Prothrombin fragment 1 or fluorescently conjugated antibody directed against phosphatidylserine were used as probes to follow the kinetics of phosphatidylserine exposure after the laser injury of cremaster muscle arterioles of a living mouse using high speed fluorescence intravital microscopy. Endogenous platelets were labeled with a fluorescently conjugated Fab fragment of an anti-CD41 antibody and fibrin deposition was measured using a fluorescently conjugated antibody that recognizes fibrin but not fibrinogen. We observed a 42% reduction (median of 18 thrombi, p=0.02) in Prothrombin fragment 1 binding and a 60% reduction (median of 27 thrombi, p=0.0002) in anti-phosphatidylserine binding after laser injury compared to untreated animals (n=58 thrombi). The accumulation of platelets during thrombus formation was not affected by the treatment when compared to untreated mice (p=0.4). On the other hand, fibrin deposition was reduced by 64% in treated mice (median of 38 thrombi, p=0.001) when compared to untreated animals (39 of thrombi). These data suggest that suppression of phosphatidylserine exposure reduces assembly of coagulation complexes resulting in a suboptimal concentration of thrombin for full fibrin generation but sufficient thrombin to activate platelets to yield a normal platelet thrombus. This emphasizes the importance of the exposure of anionic phospholipids as the surface for the colocalization of the coagulation complexes in vivo. Disclosures No relevant conflicts of interest to declare.
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Calzavarini, Sara, Raja Prince-Eladnani, François Saller, Luca Bologna, Laurent Burnier, Anne C. Brisset, Claudia Quarroz, et al. "Platelet protein S limits venous but not arterial thrombosis propensity by controlling coagulation in the thrombus." Blood 135, no. 22 (May 28, 2020): 1969–82. http://dx.doi.org/10.1182/blood.2019003630.
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Abstract Anticoagulant protein S (PS) in platelets (PSplt) resembles plasma PS and is released on platelet activation, but its role in thrombosis has not been elucidated. Here we report that inactivation of PSplt expression using the Platelet factor 4 (Pf4)-Cre transgene (Pros1lox/loxPf4-Cre+) in mice promotes thrombus propensity in the vena cava, where shear rates are low, but not in the carotid artery, where shear rates are high. At a low shear rate, PSplt functions as a cofactor for both activated protein C and tissue factor pathway inhibitor, thereby limiting factor X activation and thrombin generation within the growing thrombus and ensuring that highly activated platelets and fibrin remain localized at the injury site. In the presence of high thrombin concentrations, clots from Pros1lox/loxPf4-Cre− mice contract, but not clots from Pros1lox/loxPf4-Cre+ mice, because of highly dense fibrin networks. Thus, PSplt controls platelet activation as well as coagulation in thrombi in large veins, but not in large arteries.
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Stolla, Moritz, Lucia Stefanini, Jessica Hirsch, Claire Roden, Timothy Daniel Ouellette, Mortimer Poncz, and Wolfgang Bergmeier. "The Signaling Molecule CalDAG-GEFI Represents a Novel Target for Antithrombotic Therapy." Blood 114, no. 22 (November 20, 2009): 1077. http://dx.doi.org/10.1182/blood.v114.22.1077.1077.
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Abstract Abstract 1077 Poster Board I-99 Background/Objective: The signaling molecule Ca2+ and diacylglycerol regulated guanine nucleotide exchange factor I (CalDAG-GEFI) plays a crucial role in the immediate, Ca2+ dependent activation of Rap1 and intergrin αaIIbβ3 in stimulated platelets. Our previous studies demonstrated that signaling by protein kinase C and the Gi-coupled receptor for ADP, P2Y12, provides an alternative pathway that facilitates the delayed but prolonged activation of Rap1. P2Y12 inhibitors such as clopidogrel bisulfate (Plavix) are currently considered the gold standard for the prevention and treatment of thrombotic complications. The aims of the study were to: 1) evaluate CalDAG-GEFI signaling as a potential new target for antithrombotic therapy and 2) to compare the contribution of CalDAG-GEFI and P2Y12 signaling to thrombus formation in pre-clinical models of models of thrombotic disease. Methods/Results: Thrombus formation was compared in: wildtype (WT), CalDAG-GEFI-/-, WT treated with clopidogrel (clopidogrel was administered orally 24h and 3h prior to the experiment at a dosage of 0,075mg/g bodyweight) and CalDAG-GEFI-/- mice treated with clopidogrel. Thrombosis was studied in three different models: 1) laser-induced thrombosis in the microcirculation of the cremasteric muscle (thrombin-dependent, localized), tissue factor-induced pulmonary thromboembolism (thrombin-dependent, systemic) and FeCl3-induced thrombosis in the mesentery (collagen/thrombin-dependent, localized). As shown previously, clopidogrel treatment significantly reduced but did not abolish laser-induced thrombus formation in WT mice. Laser induced thrombosis was completely inhibited in arterioles of CalDAG-GEFI -/- mice, while significant thrombus formation was observed in venules. Clopidogrel treatment of CalDAG-GEFI-/- mice further reduced venous thrombus formation, providing in vivo confirmation that platelet aggregation in the absence of CalDAG-GEFI requires P2Y12 signaling. In line with these findings, we observed that CalDAG-GEF-/- mice were partially protected from tissue factor-induced pulmonary thromboembolism when compared to clopidogrel-treated CalDAG-GEF-/- mice. In the model of FeCl3-induced thrombosis, CalDAG-GEFI-/- platelets adhered to the damaged vascular wall but failed to form thrombi in both venules and arterioles. In contrast clopidogrel-treated WT mice were protected from FeCl3-induced vessel occlusion but continuously formed embolizing thrombi of considerable size that contained activated platelets. This phenomenon was detectable in both arterioles and venules and might be of clinical relevance. Conclusion: Our studies identify CalDAG-GEFI as a promising new target for antiplatelet therapy. CalDAG-GEFI inhibition will have a strong antithrombotic effect as it is a critical component of the near-immediate platelet response to exposed extracellular matrix and/or soluble agonists. However, backup by PKC/P2Y12 signaling should allow for the formation of small but stable mural thrombi, especially under low flow conditions as found in veins and in venules, thus limiting the risk of bleeding complications. Disclosures: Poncz: Diagnostica Stago: Patents & Royalties.
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Siljander, P., O. Carpen, and R. Lassila. "Platelet-derived microparticles associate with fibrin during thrombosis." Blood 87, no. 11 (June 1, 1996): 4651–63. http://dx.doi.org/10.1182/blood.v87.11.4651.bloodjournal87114651.
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Platelet-derived microparticles (MP) are reported to express both pro- and anticoagulant activities. Nevertheless, their functional significance has remained unresolved. The present study monitored the generation and fate of MP in an experimental model of thrombosis with costimulation of platelets by collagen and thrombin. When minimally anticoagulated (0.5 micromol/L PPACK) blood was perfused over immobilized fibrillar type I collagen in a flow chamber at a low shear rate (300 s(-1)), endogenous thrombin was generated, as evidenced by thrombin-antithrombin III complex. In contrast to full anticoagulation 150 micromol/L PPACK) and the absence of collagen, large platelet aggregates and fibrin ensued during perfusions over collagen in the presence of thrombin. In these thrombi, MP, defined as GPIIbIIIa- and P- selectin-positive vesicles (<1 micron), were found to align fibrin in immunofluorescence and scanning immunoelectron microscopy. Moreover, in sections of embolectomized thromboemboli from patients GPIIbIIIa- and P- selectin-positive material compatible with MP was detected in a fibrin strand-like pattern. In vitro binding studies showed that MP bound to fibrin and acted there as procoagulants. In summary, we show that MP generated during thrombus formation associate with local fibrin. This adhesive function fibrin could imply a sustained modulatory role for MP in evolving thrombi.
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Alkarithi, Ghadir, Cédric Duval, Yu Shi, Fraser L. Macrae, and Robert A. S. Ariëns. "Thrombus Structural Composition in Cardiovascular Disease." Arteriosclerosis, Thrombosis, and Vascular Biology 41, no. 9 (September 2021): 2370–83. http://dx.doi.org/10.1161/atvbaha.120.315754.
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Thrombosis is a major complication of cardiovascular disease, leading to myocardial infarction, acute ischemic stroke, or venous thromboembolism. Thrombosis occurs when a thrombus forms inside blood vessels disrupting blood flow. Developments in thrombectomy to remove thrombi from vessels have provided new opportunities to study thrombus composition which may help to understand mechanisms of disease and underpin improvements in treatments. We aimed to review thrombus compositions, roles of components in thrombus formation and stability, and methods to investigate thrombi. Also, we summarize studies on thrombus structure obtained from cardiovascular patients and animal models. Thrombi are composed of fibrin, red blood cells, platelets, leukocytes, and neutrophil extracellular traps. These components have been analyzed by several techniques, including scanning electron microscopy, laser scanning confocal microscopy, histochemistry, and immunohistochemistry; however, each technique has advantages and limitations. Thrombi are heterogenous in composition, but overall, thrombi obtained from myocardial infarction are composed of mainly fibrin and other components, including platelets, red blood cells, leukocytes, and cholesterol crystals. Thrombi from patients with acute ischemic stroke are characterized by red blood cell- and platelet-rich regions. Thrombi from patients with venous thromboembolism contain mainly red blood cells and fibrin with some platelets and leukocytes. Thrombus composition from patients with myocardial infarction is influenced by ischemic time. Animal thrombosis models are crucial to gain further mechanistic information about thrombosis and thrombus structure, with thrombi being similar in composition compared with those from patients. Further studies on thrombus composition and function are key to improve treatment and clinical outcome of thrombosis.
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Buchanan, MR, B. Boneu, F. Ofosu, and J. Hirsh. "The relative importance of thrombin inhibition and factor Xa inhibition to the antithrombotic effects of heparin." Blood 65, no. 1 (January 1, 1985): 198–201. http://dx.doi.org/10.1182/blood.v65.1.198.198.
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Abstract The relative importance of antithrombin and anti-factor Xa activities of heparin fractions required to achieve optimal antithrombotic effects is unknown. To study this, we measured the effects of standard heparin, an octasaccharide heparin fraction (anti-factor Xa activity only), and dermatan sulfate (antithrombin activity only) on the prevention of thrombosis and related this to their anticoagulant effects in vivo in rabbits. Thrombosis was measured as the incorporation of 125I- fibrinogen into tissue thromboplastin-induced thrombi using a Wessler- type model. Ex vivo changes in thrombin clotting time (TCT) were used as an index of antithrombin activity, and a chromogenic anti-factor Xa assay was used to measure anti-factor Xa activity. In addition, the ability of the three sulfated polysaccharides to simultaneously inhibit the generation of thrombin activity and to enhance the inactivation of the factor Xa added to initiate thrombin generation in plasma was determined. Standard heparin, in a dose of 10 anti-factor Xa U/kg, inhibited thrombus formation by 90%, prolonged the TCT by two seconds, and resulted in an anti-factor Xa level of 0.32 U/mL. The octasaccharide heparin fraction, in a dose of 10 anti-factor Xa U/kg, inhibited thrombus formation by 41%, had no effect on the TCT, and resulted in an anti-factor Xa level of 0.28 U/mL. Higher doses of the octasaccharide resulted in a further increase in the anti-factor Xa levels but had no further effect on thrombus formation. Dermatan sulfate, in a dose of 500 micrograms/kg, inhibited thrombus formation by 95%, but had no affect on the TCT. These results indicate that the antithrombotic effect achieved by inhibiting factor Xa is limited and that better antithrombotic effects are achieved by heparin or heparin- like substances capable of influencing the inactivation and/or the generation of thrombin.
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Buchanan, MR, B. Boneu, F. Ofosu, and J. Hirsh. "The relative importance of thrombin inhibition and factor Xa inhibition to the antithrombotic effects of heparin." Blood 65, no. 1 (January 1, 1985): 198–201. http://dx.doi.org/10.1182/blood.v65.1.198.bloodjournal651198.
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The relative importance of antithrombin and anti-factor Xa activities of heparin fractions required to achieve optimal antithrombotic effects is unknown. To study this, we measured the effects of standard heparin, an octasaccharide heparin fraction (anti-factor Xa activity only), and dermatan sulfate (antithrombin activity only) on the prevention of thrombosis and related this to their anticoagulant effects in vivo in rabbits. Thrombosis was measured as the incorporation of 125I- fibrinogen into tissue thromboplastin-induced thrombi using a Wessler- type model. Ex vivo changes in thrombin clotting time (TCT) were used as an index of antithrombin activity, and a chromogenic anti-factor Xa assay was used to measure anti-factor Xa activity. In addition, the ability of the three sulfated polysaccharides to simultaneously inhibit the generation of thrombin activity and to enhance the inactivation of the factor Xa added to initiate thrombin generation in plasma was determined. Standard heparin, in a dose of 10 anti-factor Xa U/kg, inhibited thrombus formation by 90%, prolonged the TCT by two seconds, and resulted in an anti-factor Xa level of 0.32 U/mL. The octasaccharide heparin fraction, in a dose of 10 anti-factor Xa U/kg, inhibited thrombus formation by 41%, had no effect on the TCT, and resulted in an anti-factor Xa level of 0.28 U/mL. Higher doses of the octasaccharide resulted in a further increase in the anti-factor Xa levels but had no further effect on thrombus formation. Dermatan sulfate, in a dose of 500 micrograms/kg, inhibited thrombus formation by 95%, but had no affect on the TCT. These results indicate that the antithrombotic effect achieved by inhibiting factor Xa is limited and that better antithrombotic effects are achieved by heparin or heparin- like substances capable of influencing the inactivation and/or the generation of thrombin.
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Tucker, Erik I., Michael Wallisch, Philberta Y. Leung, Andras Gruber, Enrico Di Cera, and Norah G. Verbout. "Rapid Interruption Of Occlusive Thrombus Formation By The Protein C Activator Enzyme EWE Thrombin (ProCase) In Primates." Blood 122, no. 21 (November 15, 2013): 202. http://dx.doi.org/10.1182/blood.v122.21.202.202.
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Abstract A hemostatically safe antithrombotic treatment with rapid onset could significantly improve the chances for survival during acute thrombotic events such as heart attack and ischemic stroke. Current thrombolytic treatment with tissue plasminogen activator (tPA) is effective at halting and reversing the progression of arterial thrombi, but bleeding side-effects significantly limit its usefulness. EWE thrombin (ProCase) is an investigational selective protein C activator thrombin analog under development for treating acute thrombotic emergencies. We therefore tested the ability of EWE thrombin to interrupt arterial-type thrombus formation in baboons compared to a standard interventional dose of tPA (1mg/kg, iv). Thrombosis was initiated by interposing 2mm or 4mm internal diameter (ID) collagen coated ePTFE vascular grafts within an arterio/venous shunt. Platelet thrombus formation was monitored by gamma camera imaging of autologous 111In-labelled platelets for a total of 90 min in the 4mm grafts, or until occlusion time in the 2mm grafts. Fibrin deposition was determined by direct measurement of 125I-labelled fibrinogen. All interventions were given systemically, starting 30 min or 15 min after thrombus initiation for the 4mm grafts and 2mm grafts, respectively. In the 4mm devices, treatment with tPA reduced graft-associated platelet accumulation by 17% and fibrin deposition by 61% compared with controls (n=6 each). A negative platelet accumulation rate, which is an indication of thrombolysis, occurred between 40-50 min after initiating tPA treatment. EWE thrombin, at doses ranging from 2-10µg/kg iv bolus rapidly interrupted thrombus development and reduced platelet deposition by 43-65% (n=4). Fibrin deposition was also reduced by 36-49% compared with controls. A negative platelet accumulation rate occurred between 10-15 min after EWE thrombin treatment, compared with continuous platelet accumulation in all control experiments. In the 2mm ID grafts, 0/6 control group devices remained patent with an average occlusion time of 25±2 min. By comparison, EWE thrombin (10µg/kg iv bolus given at 15 min) successfully interrupted occlusive thrombus formation in 40% of the devices (2/5) during the 60 min study, and significantly prolonged the occlusion time to an average of 43±8 min. These data suggest that EWE thrombin can effectively interrupt occlusive arterial-type thrombus development at very low doses, and appears to be more effective and act more rapidly than tPA at limiting experimental platelet-rich thrombus accumulation. We conclude that EWE thrombin may be a more effective and safer alternative to tPA for treating acute thrombotic emergencies. Disclosures: Tucker: Aronora, Inc: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees. Wallisch:Aronora, Inc: Employment. Leung:Aronora, Inc: Employment, Equity Ownership. Gruber:Aronora, Inc.: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees. Verbout:Aronora, Inc: Employment, Equity Ownership.
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Kraft, Peter, Michael K. Schuhmann, Melanie Dittmeier, Felix Fluri, and Christoph Kleinschnitz. "Pretreatment with rivaroxaban attenuates stroke severity in rats by a dual antithrombotic and anti-inflammatory mechanism." Thrombosis and Haemostasis 115, no. 04 (2016): 835–43. http://dx.doi.org/10.1160/th15-08-0631.
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SummaryStroke outcome is more favourable in patients receiving oral anticoagulants compared with non-anticoagulated patients. The reasons for this “stroke-attenuating” property of oral anticoagulants are largely unknown. This study examined whether prestroke anticoagulation with rivaroxaban, a novel direct factor Xa inhibitor, influences stroke severity, thrombin-mediated intracerebral thrombus formation and pro-inflammatory processes in a rat model of brain ischaemia/reperfusion injury. Male Wistar rats were anticoagulated with rivaroxaban and subjected to 90 minutes of transient middle cerebral artery occlusion. Infarct size, functional outcome and the occurrence of intracranial haemorrhage (ICH) were assessed until day 7. Thrombin generation was determined by measuring the amount of thrombin/antithrombin complex. Intracerebral thrombus formation was evaluated by histology and Western blot. CD68-immunoreactivity and the expression of cytokines and adhesion molecules were investigated to assess postischaemic inflammation. The integrity of the blood–brain barrier was analysed using fluorescein isothiocyanate-dextran. Rats pretreated with rivaroxaban developed significantly smaller strokes and less severe functional deficits compared with controls. Although rivaroxaban strongly reduced thrombin-mediated thrombus formation, this was not accompanied by an increased risk of ICH. In addition, rivaroxaban dampened the inflammatory response in the ischaemic brain by downregulating ICAM-1 expression and the activation of CD68+-immune cells. In contrast, rivaroxaban had no effect on the integrity of the blood–brain barrier after stroke. Here, we identified reduced thrombo-inflammation as a major determinant of the stroke-protective property of rivaroxaban in rats. Further studies are needed to assess the therapeutic potential of novel oral anticoagulants in the acute phase after a stroke.
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Di Meglio, Lucas, Jean-Philippe Desilles, Véronique Ollivier, Mialitiana Solo Nomenjanahary, Sara Di Meglio, Catherine Deschildre, Stéphane Loyau, et al. "Acute ischemic stroke thrombi have an outer shell that impairs fibrinolysis." Neurology 93, no. 18 (September 20, 2019): e1686-e1698. http://dx.doi.org/10.1212/wnl.0000000000008395.
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ObjectivesThrombi responsible for large vessel occlusion (LVO) in the setting of acute ischemic stroke (AIS) are characterized by a low recanalization rate after IV thrombolysis. To test whether AIS thrombi have inherent common features that limit their susceptibility to thrombolysis, we analyzed the composition and ultrastructural organization of AIS thrombi causing LVO.MethodsA total of 199 endovascular thrombectomy-retrieved thrombi were analyzed by immunohistology and scanning electron microscopy (SEM) and subjected to ex vivo thrombolysis assay. The relationship between thrombus organization and thrombolysis resistance was further investigated in vitro using thrombus produced by recalcification of citrated whole blood.ResultsSEM and immunohistology analyses revealed that, although AIS thrombus composition and organization was highly heterogeneous, AIS thrombi shared a common remarkable structural feature in the form of an outer shell made of densely compacted thrombus components including fibrin, von Willebrand factor, and aggregated platelets. In vitro thrombosis experiments using human blood indicated that platelets were essential to the formation of the thrombus outer shell. Finally, in both AIS and in vitro thrombi, the thrombus outer shell showed a decreased susceptibility to tissue plasminogen activator–mediated thrombolysis as compared to the thrombus inner core.InterpretationIrrespective of their etiology and despite their heterogeneity, intracranial thrombi causing LVO have a core shell structure that influences their susceptibility to thrombolysis.
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Heo, Ji Hoe, Hyo Suk Nam, Young Dae Kim, Jin Kyo Choi, Byung Moon Kim, Dong Joon Kim, and Il Kwon. "Pathophysiologic and Therapeutic Perspectives Based on Thrombus Histology in Stroke." Journal of Stroke 22, no. 1 (January 31, 2020): 64–75. http://dx.doi.org/10.5853/jos.2019.03440.
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Recent advances in endovascular thrombectomy have enabled the histopathologic analysis of fresh thrombi in patients with acute stroke. Histologic analysis has shown that the thrombus composition is very heterogeneous between patients. However, the distribution pattern of each thrombus component often differs between patients with cardiac thrombi and those with arterial thrombi, and the efficacy of endovascular thrombectomy is different according to the thrombus composition. Furthermore, the thrombus age is related to the efficacy of reperfusion therapy. Recent studies have shown that neutrophils and neutrophil extracellular traps contribute to thrombus formation and resistance to reperfusion therapy. Histologic features of thrombi in patients with stroke may provide some clues to stroke etiology, which is helpful for determining the strategy of stroke prevention. Research on thrombus may also be helpful for improving reperfusion therapy, including the development of new thrombolytic agents.
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Agnelli, Giancarlo, Claudia Pascucci, Benilde Cosmi, and Giuseppe G. Nenci. "The Comparative Effects of Recombinant Hirudin (CGP 39393) and Standard Heparin on Thrombus Growth in Rabbits." Thrombosis and Haemostasis 63, no. 02 (1990): 204–7. http://dx.doi.org/10.1055/s-0038-1645195.
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SummaryThe aim of this study was to compare the ability of standard heparin and recombinant (r-)hirudin, a specific inhibitor of thrombin, to inhibit thrombus growth in a rabbit jugular vein model. Doses of standard heparin and r-hirudin equivalent in prolonging the aPTT were first identified. The ability of these doses to inhibit 125I-fibrin accretion onto preexisting thrombi was then evaluated. 0.5 and 0.75 mg/kg of standard heparin and 0.8 and 1.25 mg/kg of r-hirudin infused over 3 h produced a mean prolongation of the aPTT of 1.5 and 2 times, respectively. In saline treated rabbits 62 ± 7 μg of 125I-fibrin were accreted on the pre-formed thrombi. The lower doses of standard heparin and r-hirudin produced a 125I-fibrin accretion of 44 ± 5 and 25 ± 4 μg, respectively (p <0.01). The two higher doses of standard heparin and r-hirudin produced a 125I-fibrin accretion of 34 ± 4 and 17 ± 3 μg, respectively (p <0.01). The increase in the dose of standard heparin up to 2.5 mg/kg produced a 125I-fibrin accretion of 26 ± 3 μg, a 58% reduction when compared with saline. The increase in the dose of r-hirudin up to 5 mg/kg produced a 125I-fibrin accretion of 12 ± 2 μg, an 81% reduction when compared with saline. No further inhibition was observed when the doses of both agents were further increased. We conclude that doses of standard heparin and r-hirudin equivalent in prolonging the aPTT have a different effect on thrombus growth inhibition, r-hirudin being twice as effective as standard heparin. Exclusive inhibition of thrombin without any other inhibiting effect on blood coagulation appears to be sufficient to inhibit thrombus growth. Our results seem to be promising in view of a clinical evaluation of r-hirudin
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Diquelou, A., S. Lemozy, D. Dupouy, B. Boneu, K. Sakariassen, and Y. Cadroy. "Effect of blood flow on thrombin generation is dependent on the nature of the thrombogenic surface." Blood 84, no. 7 (October 1, 1994): 2206–13. http://dx.doi.org/10.1182/blood.v84.7.2206.2206.
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Abstract We have investigated the influence of blood flow on thrombin generation, fibrin formation, and fibrin deposition on procoagulant and nonprocoagulant surfaces. Nonanticoagulated human blood was drawn for 5 minutes directly from an antecubital vein over stimulated endothelial cells expressing tissue factor and over human type III collagen fibrils, positioned in parallel-plate perfusion chambers. The shear rates at these surfaces were 50, 650, and 2,600 s-1. Deposition of platelets and fibrin was measured by morphometry. Thrombin and fibrin formation was determined by measuring prothrombin fragments 1 + 2 (F 1 + 2), thrombin-antithrombin III complexes, (T-AT) and fibrinopeptide A (FPA) in blood effluent from the perfusion chamber at the end of the 5- minute perfusion period. On procoagulant endothelial cells, the thrombi were primarily composed of fibrin. The fibrin deposition (81%, 21%, and 2% at 50, 650, and 2,600 s-1, respectively) and plasma levels of F 1 + 2, T-AT and FPA were shear rate dependent and highest at 50 s-1. There was a positive correlation between F 1 + 2 and T-AT and the fibrin deposition (P < .01). In contrast, the collagen surface triggered primarily thrombi that were composed of platelets. The platelet thrombi and plasma levels of F 1 + 2 and T-AT were also dependent on the shear rate, but highest at 650 and 2,600 s-1. F 1 + 2 and T-AT reached the same level as observed with procoagulant endothelial cells at the higher shear rates. There was a positive correlation between F 1 + 2 and T-AT and the platelet thrombus formation (P < .05), confirming the predominant role of platelets in thrombin generation. Thus, thrombin formation is strongly influenced by the blood flow, and this effect depends on the composition of the thrombogenic surface.
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Diquelou, A., S. Lemozy, D. Dupouy, B. Boneu, K. Sakariassen, and Y. Cadroy. "Effect of blood flow on thrombin generation is dependent on the nature of the thrombogenic surface." Blood 84, no. 7 (October 1, 1994): 2206–13. http://dx.doi.org/10.1182/blood.v84.7.2206.bloodjournal8472206.
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We have investigated the influence of blood flow on thrombin generation, fibrin formation, and fibrin deposition on procoagulant and nonprocoagulant surfaces. Nonanticoagulated human blood was drawn for 5 minutes directly from an antecubital vein over stimulated endothelial cells expressing tissue factor and over human type III collagen fibrils, positioned in parallel-plate perfusion chambers. The shear rates at these surfaces were 50, 650, and 2,600 s-1. Deposition of platelets and fibrin was measured by morphometry. Thrombin and fibrin formation was determined by measuring prothrombin fragments 1 + 2 (F 1 + 2), thrombin-antithrombin III complexes, (T-AT) and fibrinopeptide A (FPA) in blood effluent from the perfusion chamber at the end of the 5- minute perfusion period. On procoagulant endothelial cells, the thrombi were primarily composed of fibrin. The fibrin deposition (81%, 21%, and 2% at 50, 650, and 2,600 s-1, respectively) and plasma levels of F 1 + 2, T-AT and FPA were shear rate dependent and highest at 50 s-1. There was a positive correlation between F 1 + 2 and T-AT and the fibrin deposition (P < .01). In contrast, the collagen surface triggered primarily thrombi that were composed of platelets. The platelet thrombi and plasma levels of F 1 + 2 and T-AT were also dependent on the shear rate, but highest at 650 and 2,600 s-1. F 1 + 2 and T-AT reached the same level as observed with procoagulant endothelial cells at the higher shear rates. There was a positive correlation between F 1 + 2 and T-AT and the platelet thrombus formation (P < .05), confirming the predominant role of platelets in thrombin generation. Thus, thrombin formation is strongly influenced by the blood flow, and this effect depends on the composition of the thrombogenic surface.
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Eriksen, Erlend, Jon Herstad, Kartika Ratna Pertiwi, Vegard Tuseth, Jan Erik Nordrehaug, Øyvind Bleie, and Allard C. van der Wal. "Thrombus characteristics evaluated by acute optical coherence tomography in ST elevation myocardial Infarction." PLOS ONE 17, no. 4 (April 11, 2022): e0266634. http://dx.doi.org/10.1371/journal.pone.0266634.
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Aims ST elevation myocardial infarction (STEMI) is caused by an occlusive thrombosis of a coronary artery. We wanted to assess if the thrombus can be characterized according to erythrocyte content and age using intravascular optical coherence tomography (OCT) in a clinical setting. Methods and results We performed manual thrombus aspiration in 66 STEMI patients. OCT was done of the thrombus remnants after aspiration. A light intensity ratio was measured through the thrombus. Forty two of the aspirates had thrombus which could be analyzed histomorphologically for analysis of erythrocyte and platelet content, and to determine the age of thrombus as fresh, lytic or organized. There were 11 red, 21 white and 10 mixed thrombi. Furthermore, 36 aspirates had elements of fresh, 7 of lytic and 8 of organized thrombi. There was no correlation between colour and age. OCT appearance could not predict erythrocyte or platelet content. The light intensity ratios were not significantly different in fresh, lytic or organized thrombi. Conclusion OCT could not differentiate between red and white thrombi, nor determine thrombus age.
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Alias, Sherin, Bassam Redwan, Adelheid Panzenböck, Max P. Winter, Uwe Schubert, Robert Voswinckel, Maria K. Frey, et al. "Defective Angiogenesis Delays Thrombus Resolution." Arteriosclerosis, Thrombosis, and Vascular Biology 34, no. 4 (April 2014): 810–19. http://dx.doi.org/10.1161/atvbaha.113.302991.
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Objective— Restoration of patency is a natural target of vascular remodeling after venous thrombosis that involves vascular endothelial cells and smooth muscle cells, as well as leukocytes. Acute pulmonary emboli usually resolve <6 months. However, in some instances, thrombi transform into fibrous vascular obstructions, resulting in occlusion of the deep veins, or in chronic thromboembolic pulmonary hypertension (CTEPH). We proposed that dysregulated thrombus angiogenesis may contribute to thrombus persistence. Approach and Results— Mice with an endothelial cell–specific conditional deletion of vascular endothelial growth factor receptor 2/kinase insert domain protein receptor were used in a model of stagnant flow venous thrombosis closely resembling human deep vein thrombosis. Biochemical and functional analyses were performed on pulmonary endarterectomy specimens from patients with CTEPH, a human model of nonresolving venous thromboembolism. Endothelial cell–specific deletion of kinase insert domain protein receptor and subsequent ablation of thrombus vascularization delayed thrombus resolution. In accordance with these findings, organized human CTEPH thrombi were largely devoid of vascular structures. Several vessel-specific genes, such as kinase insert domain protein receptor, vascular endothelial cadherin, and podoplanin, were expressed at lower levels in white CTEPH thrombi than in organizing deep vein thrombi and organizing thrombi from aortic aneurysms. In addition, red CTEPH thrombi attenuated the angiogenic response induced by vascular endothelial growth factor. Conclusions— In the present work, we propose a mechanism of thrombus nonresolution demonstrating that endothelial cell–specific deletion of kinase insert domain protein receptor abates thrombus vessel formation, misguiding thrombus resolution. Medical conditions associated with the development of CTEPH may be compromising early thrombus angiogenesis.
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Akamatsu, Kanako, Takahide Ito, Kazushi Sakane, Yumiko Kanzaki, Koichi Sohmiya, and Masaaki Hoshiga. "Left Atrial Ball-Shaped Thrombus with Concomitant Biatrial Appendage Thrombi in a Patient with Prior Mitral Valve Replacement." Case Reports in Cardiology 2019 (April 16, 2019): 1–4. http://dx.doi.org/10.1155/2019/6531890.
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We reported a 67-year-old woman in whom large atrial thrombi were found by chance during discontinuation of therapeutic anticoagulation. The patient, with a history of mitral valve replacement surgery, had stopped anticoagulation for months because of intractable gastrointestinal bleeding, during which she was found to have 3 large thrombi in the atria on transesophageal echocardiography: left atrial free-floating ball-shaped thrombus, left atrial appendage thrombus, and right atrial appendage thrombus. One month following diagnosis, she still had the free-floating thrombus despite adequate anticoagulation. Free-floating ball-shaped thrombus is a rare finding observed on echocardiography in patients with mitral valve disease and an even rarer finding in case of appendage thrombi coexisting.
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Marti-Bonmati, L., E. Lonjedo, D. Mathieu, C. Coffin, C. Poyatos, and M. C. Anglade. "Tumoural portal vein thrombosis." Acta Radiologica 38, no. 5 (September 1997): 655–59. http://dx.doi.org/10.1080/02841859709172397.
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Purpose: Intrahepatic thrombus is usually associated with either cirrhosis or hepato-cellular carcinoma (HCC). Most HCCs enhance after the administration of MnDPDP (Teslascan). Our objective was to analyze the enhancement characteristics of tumour portal vein thrombi. Material and Methods: Thrombi affecting the main or segmental portal veins (17 cases) and the suprahepatic inferior vena cava (1 case) were retrospectively selected from a series of 128 patients studied with MR imaging before and after the administration of MnDPDP. Enhancement was assessed qualitatively and quantitatively. Results: All tumour thrombi enhanced after MnDPDP administration. The enhancement was more conspicuous in the GRE images. On the quantitative evaluation, the portal thrombus enhancement was greater for GRE images than SE images. Portal thrombi enhanced more than the liver and the HCCs. There was a significant difference between the enhancement of the HCCs and the thrombi with both MR imaging techniques. Conclusion: The greater enhancement of the tumour thrombus associated with the liver and HCC may suggest that other mechanisms, apart from accumulation of the contrast medium within the hepatocytes inside the thrombi, are involved in thrombus enhancement.
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Maekawa, Kota, Masunari Shibata, Hideki Nakajima, Akane Mizutani, Yotaro Kitano, Masaru Seguchi, Masayoshi Yamasaki, et al. "Erythrocyte-Rich Thrombus Is Associated with Reduced Number of Maneuvers and Procedure Time in Patients with Acute Ischemic Stroke Undergoing Mechanical Thrombectomy." Cerebrovascular Diseases Extra 8, no. 1 (January 15, 2018): 39–49. http://dx.doi.org/10.1159/000486042.
Full textAbstract:
Background: Only few studies have investigated the relationship between the histopathology of retrieved thrombi and clinical outcomes. This study aimed to evaluate thrombus composition and its association with clinical, laboratory, and neurointerventional findings in patients treated by mechanical thrombectomy due to acute large vessel occlusion. Methods: At our institution, 79 patients were treated by mechanical thrombectomy using a stent retriever and/or aspiration catheter between August 2015 and August 2016. The retrieved thrombi were quantitatively analyzed to quantify red blood cells, white blood cells, and fibrin by area. We divided the patients into two groups – a fibrin-rich group and an erythrocyte-rich group – based on the predominant composition in the thrombus. The groups were compared for imaging, clinical, and neurointerventional data. Results: The retrieved thrombi from 43 patients with acute stroke from internal carotid artery, middle cerebral artery, or basilar artery occlusion were histologically analyzed. Erythrocyte-rich thrombi were present in 18 cases, while fibrin-rich thrombi were present in 25 cases. A cardioembolic etiology was significantly more prevalent among the patients with fibrin-rich thrombi than among those with erythrocyte-rich thrombi. Attenuation of thrombus density as shown on computed tomography images was greater in patients with erythrocyte-rich thrombi than in those with fibrin-rich thrombi. All other clinical and laboratory characteristics remained the same. Patients with erythrocyte-rich thrombi had a smaller number of recanalization maneuvers, shorter procedure times, a shorter time interval between arrival and recanalization, and a higher percentage of stent retrievers in the final recanalization procedure. The occluded vessels did not differ significantly. Conclusions: In this study, erythrocyte-rich thrombus was associated with noncardioembolic etiology, higher thrombus density, and reduced procedure time.
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Matthiasson, Stefan E., Bengt Lindblad, Thomas Mätzsch, Jan Holst, and David Bergqvist. "Effect of Low Molecular Weight Heparin, Dextran and Their Combinations on Experimental Venous Thrombosis in Rabbits." Thrombosis and Haemostasis 71, no. 03 (1994): 363–65. http://dx.doi.org/10.1055/s-0038-1642444.
Full textAbstract:
SummaryAn experimental model based on the combination of endothelial damage and flow reduction was used to induce jugular vein thrombosis in rabbits. The effect on thrombosis of a low molecular weight heparin (LMWH [Fragmin]), dextran 70, placebo and their combination was studied in a double-blind fashion with actual doses used in clinical thromboprophylaxis. Saline and polygeline were used as placebo in the control group. Four groups with 120 isolated vein segments in 60 animals were studied for presence of thrombus formation, occlusive thrombi and thrombus weights. Dextran reduced the thrombus weights (p = 0.048) and the formation of occlusive thrombi (p = 0.01), but not the formation of thrombi when compared with the placebo control group. Similarily, LMWH reduced the thrombus weights (p = 0.046), the formation of thrombi (p = 0.007) and occlusive thrombi (p = 0.0001). Compared with the LMWH group the group treated with the combination of LMWH and dextran was found to reduce the frequency of occlusive thrombi (p = 0.03) and numerically, but not significantly, further reduce the overall frequency of thrombosis (p = 0.18) and thrombus weights (p = 0.11). The results are consistent with an augmentation of the antithrombotic effect of LMWH by dextran 70. The need for further evaluation of the combined efficacy of LMWH and dextran is apparent from this study.
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Kaiser, Brigitte, and Jawed Fareed. "Recombinant Full-length Tissue Factor Pathway Inhibitor (TFPI) Prevents Thrombus Formation and Rethrombosis after Lysis in a Rabbit Model of Jugular Vein Thrombosis." Thrombosis and Haemostasis 76, no. 04 (1996): 615–20. http://dx.doi.org/10.1055/s-0038-1650631.
Full textAbstract:
SummaryIn the jugular vein of rabbits thrombus formation was induced by vessel wall damage using a balloon catheter and following reduction of blood flow by 80-90% for 60 min (partial stasis). The blood flow in the vein was measured continuously and the incidence of primary thrombus formation, the time until lysis with recombinant tissue-type plasminogen activator (rt-PA) as well as the incidence of rethrombosis after lysis were determined. At the end of the experiment the wet weight of the thrombus formed inside the vessel was measured. For the determination of haemostaseological parameters blood was drawn from the cannulated femoral artery.Recombinant full-length tissue factor pathway inhibitor (TFPI) was studied with regard to its effect both on primary thrombus formation and on rethrombosis after lysis. In control animals damage of the vessel wall combined with partial stasis led to the formation of occlusive venous thrombi. In vitro bolus injection of TFPI (5,10,20 Μg/kg) at the time of thrombus induction prevented the formation of venous thrombi during the 1 h period of partial stasis. In the subsequent observation period a dose-dependent inhibition of later occurring partial or complete thrombotic occlusion was found. At the dose of 20 Μg/kg i.v. in all animals TFPI prevented a complete thrombotic occlusion of the vein up to 3 h after stasis. To study the effectiveness of TFPI on rethrombosis after lysis TFPI was injected i.v. after lysis of the thrombus with rt-PA (600 Μg/kg i.v. bolus + 600 Μg/kg i.v. infusion over 60 min). In saline treated control rabbits a reocclusion of the vessel was seen in 8 of 10 animals. TFPI (10, 20, 40 Μg/kg i.v.) injected at the end of rt-PA administration caused a dose-dependent inhibition of thrombotic reocclusion after lysis. At 40 Μg/kg i.v. the formation of occlusive thrombi was prevented up to 3 h after lysis. TFPI at the doses used caused modest anticoagulant effects in global clotting assays; activated partial thromboplastin time (APTT), prothrombin time (PT) and thrombin time (TT) were only slightly prolonged. A clear and dose-dependent prolongation of clotting times was only seen in the Heptest® assay.The results show that the physiologic coagulation inhibitor TFPI acts as a strong antithrombotic agent in an experimental model of venous thrombus formation and thrombotic reocclusion after lysis in rabbits.
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Stehbens, W. E. "Observations on the Development of Mural Thrombi in Chronic Experimental Aneurysms in Sheep." Thrombosis and Haemostasis 78, no. 02 (1997): 952–57. http://dx.doi.org/10.1055/s-0038-1657658.
Full textAbstract:
SummaryObservations were made on mural thrombi in experimental venous pouch aneurysms in sheep. Thrombi associated with mural tears and dissection consisted predominantly of laminated fibrin masking the earlier platelet deposition and infiltrating the wall to some extent. Thrombus growth was associated with platelet masses of Zahn and secondary fibrin deposition. Intervening spaces contained a variable quantity of coagulated plasma, fibrin mesh, leucocytes, disintegrating red cells and platelets rather than red thrombus as often suggested. Periodic deposition of platelet masses with surface rippling, the whorling patterns of laminated fibrin and mechanical disruption of red cells indicated the importance of haemodynamics. Coarse macroscopic lamination of mural thrombi was attributed in part to recurrent dissections between the wall and the mural thrombus and of the thrombus itself. These accounted for growth of thrombus with expansion of the wall and interference with organization of the thrombus. The model has proved suitable for the study of thrombogenesis and thrombus behaviour in aneurysms.