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1
Jiroušková, Markéta, Igor Chereshnev, Heikki Väänänen, Jay L. Degen та 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, № 6 (15 березня 2004): 1995–2002. http://dx.doi.org/10.1182/blood-2003-10-3401.
Повний текст джерелаАнотація:
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.
2
Sugita, Chihiro, Atsushi Yamashita, Yunosuke Matsuura, Takashi Iwakiri, Nozomi Okuyama, Shuntaro Matsuda, Tomoko Matsumoto, et al. "Elevated plasma factor VIII enhances venous thrombus formation in rabbits: Contribution of factor XI, von Willebrand factor and tissue factor." Thrombosis and Haemostasis 110, no. 07 (2013): 62–75. http://dx.doi.org/10.1160/th13-01-0069.
Повний текст джерелаАнотація:
SummaryElevated plasma levels of factor VIII (FVIII) are associated with increased risk of deep venous thrombosis. The aim of this study is to elucidate how elevated FVIII levels affect venous thrombus formation and propagation in vivo. We examined rabbit plasma FVIII activity, plasma thrombin generation, whole blood coagulation, platelet aggregation and venous wall thrombogenicity before and one hour after an intravenous infusion of recombinant human FVIII (rFVIII). Venous thrombus induced by the endothelial denudation of rabbit jugular veins was histologically assessed. Thrombus propagation was evaluated as indocyanine green fluorescence intensity. Argatroban, a thrombin inhibitor, and neutralised antibodies for tissue factor (TF), factor XI (FXI), and von Willebrand factor (VWF) were infused before or after thrombus induction to investigate their effects on venous thrombus formation or propagation. Recombinant FVIII (100 IU/kg) increased rabbit plasma FVIII activity two-fold and significantly enhanced whole blood coagulation and total plasma thrombin generation, but did not affect initial thrombin generation time, platelet aggregation and venous wall thrombogenicity. The rFVIII infusion also increased the size of venous thrombus 1 hour after thrombus induction. Argatroban and the antibodies for TF, FXI or VWF inhibited such enhanced thrombus formation and all except TF suppressed thrombus propagation. In conclusion, elevated plasma FVIII levels enhance venous thrombus formation and propagation. Excess thrombin generation by FXI and VWF-mediated FVIII recruitment appear to contribute to the growth of FVIII-driven venous thrombus.
3
Yoshida, Hideo, Janice Russell, and D. Neil Granger. "Thrombin mediates the extraintestinal thrombosis associated with experimental colitis." American Journal of Physiology-Gastrointestinal and Liver Physiology 295, no. 5 (November 2008): G904—G908. http://dx.doi.org/10.1152/ajpgi.90400.2008.
Повний текст джерелаАнотація:
Recent evidence implicating tissue factor and the protein C pathway in the hypercoagulable state associated with intestinal inflammation suggests that thrombin is likely to contribute to this response. The objective of this study was to assess the role of thrombin in the extraintestinal thrombosis associated with experimental colitis. Thrombus formation was quantified in microvessels of the cremaster muscle in mice with dextran sodium sulfate (DSS)-induced colonic inflammation. The light/dye endothelial injury model was used to elicit thrombus formation in DSS colitic mice treated with either hirudin, heparin, or antithrombin III. The initiation and propagation/stabilization phases of thrombus formation were quantified using the time of onset of the thrombus and time to blood flow cessation, respectively. Thrombus formation was accelerated in arterioles of DSS colitic mice, as exhibited by significant reductions in the time of thrombus initiation and propagation/stabilization. Colitic mice treated with hirudin, heparin, or antithrombin III did not exhibit a significant change in the time of onset of the thrombus compared with untreated colitic mice. However, all three antithrombin agents largely prevented the DSS-induced reduction in the time to flow cessation following light/dye injury, with hirudin offering complete protection. These findings indicate that thrombin plays a major role in the extraintestinal thrombus formation associated with experimental colitis. Thrombin appears to contribute to the propagation/stabilization, rather than initiation, phase of the colitis-associated thrombogenesis at the distant vascular site. The results support the therapeutic use of antithrombin agents for reducing the risk of thromboembolism in patients with inflammatory bowel disease.
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Gorter, Karin A. M., Marco C. Stehouwer, Bart P. Van Putte, Eline A. Vlot, and Rolf T. Urbanus. "Acidosis induced by carbon dioxide insufflation decreases heparin potency: a risk factor for thrombus formation." Perfusion 32, no. 3 (October 27, 2016): 214–19. http://dx.doi.org/10.1177/0267659116677307.
Повний текст джерелаАнотація:
Background: Since the introduction of CO2 insufflation during open heart surgery in our hospital, we incidentally observed thrombus formation in the dissected heart, in the pericardium and in the cardiotomy reservoir of the cardiopulmonary bypass system. Furthermore, we measured very high levels of pCO2, causing severe acidosis, in stagnant blood in the pericardium and cardiotomy reservoir. Objectives: In this in vitro study, we assessed the influence of acidosis and hypothermia on heparin potency and thrombin formation. Methods: We assessed heparin potency in function of pH (pH 5.0-7.4) and temperature (24-37°C) by comparing the activated partial thromboplastin time in platelet-poor plasma between samples with and without unfractionated heparin. We measured thrombin formation in platelet-poor plasma by means of fluorescent, calibrated, automated thrombography in function of pH (pH 5.0-7.4) and temperature (24-37°C). The parameters of interest were the endogenous thrombin potential and the peak amount of thrombin generation. Results: The major finding of this study is the significant decrease in the efficiency of unfractionated heparin in delaying thrombus formation at acidotic (pH 5.0-7.0) conditions (p=0.034-0.05). Furthermore, we found that thrombin formation is significantly increased at hypothermic (24-34°C) conditions (p=<0.001-0.01). Conclusions: Based on the results of our in-vitro study, we conclude that acidosis may lead to a decreased heparin potency. Acidosis, as induced by CO2 insufflation, may predispose patients to incidental thrombus formation in stagnant blood in the open thorax and in the cardiotomy reservoir. Hypothermia might further increase this risk. Therefore, we recommend reconsidering the potential advantages and disadvantages of using CO2 insufflation during cardiopulmonary bypass.
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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.
Повний текст джерелаАнотація:
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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Irkin, O. I., and D. O. Bilyi. "Thrombosis in the cavity of the left ventricle. Part 1. Causes, diagnosis, prevention of formation." Ukrainian Journal of Cardiology 29, no. 5-6 (January 11, 2023): 52–58. http://dx.doi.org/10.31928/2664-4479-2022.5-6.5258.
Повний текст джерелаАнотація:
More than 100 years have passed since the first description of intracavitary thrombi, but the problem of diagnosis of thrombi, risk factors for development, as well as the impact of myocardial revascularization remain is a very relevant problem today, which definitely affects the prevalence of thrombi formation in the cavity of the left ventricle (LV). This review is devoted to the description and analysis of the main methods of diagnosing the presence of a thrombus in the cavity of the LV and factors affecting the formation of a thrombus. The most adequate method for diagnosing left ventricular thrombosis is a cardiac magnetic resonance imaging, but a simpler method such as transthoracic echocardiography can be used as a screening method for most patients. Determining the causes of LV thrombosis, such as reduced ventricular mobility, local myocardial damage, the presence of hyper coagulation and inflammatory phenomena, contributes to the adequate treatment of patients and the necessary prevention of thrombus formation.
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Sagan, Agnieszka, Wojciech Mrowiecki, Tomasz Mikolajczyk, Karol Urbanski, Mateusz Siedlinski, Ryszard Nosalski, Ryszard Korbut, and Tomasz Guzik. "Local inflammation is associated with aortic thrombus formation in abdominal aortic aneurysms." Thrombosis and Haemostasis 108, no. 11 (2012): 812–23. http://dx.doi.org/10.1160/th12-05-0339.
Повний текст джерелаАнотація:
SummaryIntraluminal thrombus formation in aortic abdominal aneurysms (AAA) is associated with adverse clinical prognosis. Interplay between coagulation and inflammation, characterised by leukocyte infiltration and cytokine production, has been implicated in AAA thrombus formation. We studied leukocyte (CD45+) content by flow cytometry in AAA thrombi from 27 patients undergoing surgical repair. Luminal parts of thrombi were leukocyte-rich, while abluminal segments showed low leukocyte content. CD66b+ granulocytes were the most prevalent, but their content was similar to blood. Monocytes (CD14+) and T cells (CD3+) were also abundant, while content of B lymphocytes (CD19+) and NK cells (CD56+CD16+) were low. Thrombi showed comparable content of CD14highCD16− monocytes and lower CD14highCD16+ and CD14dimCD16+, than blood. Monocytes were activated with high CD11b, CD11c and HLA-DR expression. Total T cell content was decreased in AAA thrombus compared to peripheral blood but CD8 and CD3+CD4-CD8− (double negative T cell) contents were increased in thrombi. CD4+ cells were lower but highly activated (high CD69, CD25 and HLA-DR). No differences in T regulatory (CD4+CD25+FoxP3+) cell or pro-atherogenic CD4+CD28null lymphocyte content were observed between thrombi and blood. Thrombus T cells expressed high levels of CCR5 receptor for chemokine RANTES, commonly released from activated platelets. Leukocyte or T cell content in thrombi was not correlated with aneurysm size. However, CD3+ content was significantly associated with smoking in multivariate analysis taking into account major risk factors for atherosclerosis. In conclusion, intraluminal AAA thrombi are highly inflamed, predominantly with granulocytes, CD14highCD16− monocytes and activated T lymphocytes. Smoking is associated with T cell infiltration in AAA intraluminal thrombi.
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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.
Повний текст джерелаАнотація:
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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Lindenblatt, Nicole, Michael D. Menger, Ernst Klar, and Brigitte Vollmar. "Sustained hypothermia accelerates microvascular thrombus formation in mice." American Journal of Physiology-Heart and Circulatory Physiology 289, no. 6 (December 2005): H2680—H2687. http://dx.doi.org/10.1152/ajpheart.00425.2005.
Повний текст джерелаАнотація:
Cold is supposed to be associated with alterations in blood coagulation and a pronounced risk for thrombosis. We studied the effect of clinically encountered systemic hypothermia on microvascular thrombosis in vivo and in vitro. Ferric chloride-induced microvascular thrombus formation was analyzed in cremaster muscle preparations from hypothermic mice. Additionally, flow cytometry and Western blot analysis was used to evaluate the effect of hypothermia on platelet activation. To test whether preceding hypothermia predisposes for enhanced thrombosis, experiments were repeated after hypothermia and rewarming to 37°C. Control animals revealed complete occlusion of arterioles and venules after 742 ± 150 and 824 ± 172 s, respectively. Systemic hypothermia of 34°C accelerated thrombus formation in arterioles and venules (279 ± 120 and 376 ± 121 s; P < 0.05 vs. 37°C). This was further pronounced after cooling to 31°C (163 ± 57 and 281 ± 71 s; P < 0.05 vs. 37°C). Magnitude of thrombin receptor activating peptide (TRAP)-induced platelet activation increased with decreasing temperatures, as shown by 1.8- and 3.0-fold increases in mean fluorescence after PAC-1 binding to glycoprotein (GP)IIb-IIIa and 1.6- and 2.9-fold increases of fibrinogen binding on incubation at 34°C and 31°C. Additionally, tyrosine-specific protein phosphorylation in platelets was increased at hypothermic temperatures. In rewarmed animals, kinetics of thrombus formation were comparable to those in normothermic controls. Concomitantly, spontaneous and TRAP-enhanced GPIIb-IIIa activation did not differ between rewarmed platelets and those maintained continuously at 37°C. Moderate systemic hypothermia accelerates microvascular thrombosis, which might be mediated by increased GPIIb-IIIa activation on platelets but does not cause predisposition with increased risk for microvascular thrombus formation after rewarming.
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Ding, Katharina J., Victoria L. Cammann, Konrad A. Szawan, Barbara E. Stähli, Manfred Wischnewsky, Davide Di Vece, Rodolfo Citro, et al. "Intraventricular Thrombus Formation and Embolism in Takotsubo Syndrome." Arteriosclerosis, Thrombosis, and Vascular Biology 40, no. 1 (January 2020): 279–87. http://dx.doi.org/10.1161/atvbaha.119.313491.
Повний текст джерелаАнотація:
Objective: Takotsubo syndrome (TTS) is characterized by acute left ventricular dysfunction, which can contribute to intraventricular thrombus and embolism. Still, prevalence and clinical impact of thrombus formation and embolic events on outcome of TTS patients remain unclear. This study aimed to investigate clinical features and outcomes of patients with and without intraventricular thrombus or embolism. Additionally, factors associated with thrombus formation or embolism, as well as predictors for mortality, were identified. Approach and Results: TTS patients enrolled in the International Takotsubo Registry at 28 centers in Australia, Europe, and the United States were dichotomized according to the occurrence/absence of intraventricular thrombus or embolism. Patients with intraventricular thrombus or embolism were defined as the ThrombEmb group. Of 1676 TTS patients, 56 (3.3%) patients developed intraventricular thrombus and/or embolism following TTS diagnosis (median time interval, 2.0 days [range, 0–38 days]). Patients in the ThrombEmb group had a different clinical profile including lower left ventricular ejection fraction, higher prevalence of the apical type, elevated levels of troponin and inflammatory markers, and higher prevalence of vascular disease. In a Firth bias-reduced penalized-likelihood logistic regression model apical type, left ventricular ejection fraction ≤30%, previous vascular disease, and a white blood cell count on admission >10×10 3 cells/μL emerged as independent predictors for thrombus formation or embolism. Conclusions: Intraventricular thrombus or embolism occur in 3.3% of patients in the acute phase of TTS. A simple risk score including clinical parameters associated with intraventricular thrombus formation or embolism identifies patients at increased risk. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01947621.
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Morishima, Yoshiyuki, Tomoko Shibutani, Kengo Noguchi, Yusuke Ito, and Yuko Honda. "Edoxaban, a direct oral factor Xa inhibitor, ameliorates coagulation, microvascular thrombus formation, and acute liver injury in a lipopolysaccharide-induced coagulopathy model in rats." Journal of Thrombosis and Thrombolysis 52, no. 1 (February 3, 2021): 9–17. http://dx.doi.org/10.1007/s11239-021-02381-y.
Повний текст джерелаАнотація:
AbstractInfection increases the risk of thrombosis through the activation of inflammation and coagulation. Edoxaban, a direct oral factor Xa inhibitor, is used for the prevention and treatment of thrombotic diseases. The aim of this study was to determine the effects of edoxaban on microvascular thrombus formation in a rat model of lipopolysaccharide (LPS)-induced coagulopathy. Rats were intravenously injected with 7.5 mg/kg of LPS (Escherichia coli 055:B5). Immediately after LPS injection, the rats were treated with subcutaneous injection of edoxaban. At 2 and 6 h after the injection of LPS, biomarkers of coagulation and organ damages and inflammatory cytokines were measured. Microvascular thrombus formation in organs was evaluated using 125I-fibrinogen (human) or by the pathological analysis. Mortality was examined 24 h after LPS injection. After the injection of LPS, D-dimer and thrombin-antithrombin complex increased and platelet numbers decreased, indicating the activation of coagulation. Microvascular thrombi were found in the liver. Markers of liver injury (aspartate aminotransferase and alanine aminotransferase) also increased. Treatment with edoxaban attenuated the changes in the coagulation markers and microvascular thrombus formation in the liver. Edoxaban suppressed the increase in the liver injury markers and reduced the mortality. Edoxaban did not affect the levels of inflammatory cytokines. In conclusions, edoxaban significantly inhibited the activation of coagulation, the formation of microvascular thrombus in the liver and the liver damage, and reduced mortality in rats injected with LPS. These results suggest that the FXa inhibition by edoxaban might be a beneficial therapy for the management of infection-associated thrombosis.
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Hanséus, Katarina, Gudrun Björkhem, Peeter Jögi, and Sven-Erik Sonesson. "Formation of thrombus and thromboembolism after the bidirectional Glenn anastomosis, total cavopulmonary connection and the Fontan operation." Cardiology in the Young 8, no. 2 (April 1998): 211–16. http://dx.doi.org/10.1017/s1047951100006107.
Повний текст джерелаАнотація:
AbstractAlthough patients undergoing surgery with the Fontan procedure or its modifications are increasingly recognised to be at risk for thromboembolism, further knowledge is needed to minimise this complication and its sequels. To address this issue, we reviewed 100 patients operated with the Fontan procedure, the bidirectional Glenn anastomosis and/or the total cavopulmonary connection to describe our incidence and clinical characteristics of postoperative formation of thrombus. Symptomatic thrombosis or cerebrovascular accidents were found in 5 patients. Asymptomatic thrombus were found in another 5 patients. Three patients had venous thrombi. In 6 patients the thrombosis was found on the arterial side. In all these cases, the thrombus was located in the stump of the divided pulmonary trunk. In 3 of these patients, sudden onset of hemiparesis preceded the diagnosis of the thrombus while the remaining 3 patients were asymptomatic. In 3 cases, the formation of thrombus in the stump of the divided pulmonary trunk occurred after a bidirectional Glenn anastomosis. One patient developed severe neurological symptoms 2 months after a total cavopulmonary connection. No thrombus was found, but the patient had a small right-to-left shunt and embolization could not be excluded. The incidence of thrombosis after Fontan-type surgery in this study is 10%. Although not all episodes of thrombosis are symptomatic, there is a significant risk of severe sequels due to embolization to the pulmonary or cerebral circulations. The stump of the divided pulmonary trunk is one of the main sites for intracardiac formation of thrombus, even after a bidirectional Glenn anastomosis.
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Stöllberger, Claudia, Josef Finsterer, and Birke Schneider. "Left Ventricular Thrombi and Embolic Events in Takotsubo Syndrome despite Therapeutic Anticoagulation." Cardiology 145, no. 8 (2020): 504–10. http://dx.doi.org/10.1159/000506925.
Повний текст джерелаАнотація:
Introduction: Takotsubo syndrome (TTS) may be complicated by left-ventricular (LV) thrombus formation in 1.3–5.3% of patients. Risk factors for thrombi comprise apical TTS, elevated levels of C-reactive protein and troponine, thrombocytosis, persisting ST segment elevation and right-ventricular involvement. Embolic risk appears high, and anticoagulation is recommended. Case Presentation: We present 3 females, aged 60–82 years, with TTS-associated LV thrombi and cerebral embolism despite therapeutic anticoagulation. Two patients showed apical and 1 patient midventricular ballooning. In 2 patients LV thrombi had not been present at the first echocardiographic examination. LV thrombi were multiple and highly mobile in 2 patients; 1 patient had a single immobile thrombus associated with spontaneous echocardiographic contrast (SEC). In each case, 3 of the described risk factors for LV thrombus formation were identified. The embolic stroke occurred 41–120 h after TTS symptom onset and 21–93 h after the initiation of therapeutic anticoagulation. Two patients were discharged with a neurological deficit, and 1 of them eventually died as a consequence of the stroke. LV thrombectomy to prevent embolism, which has been reported in a small number of cases, had not been considered in our patients. Conclusion: At present, the management of patients with TTS-related thrombi is still unclear, and further studies are urgently needed to assess the best methods for imaging and anticoagulation and to determine the role of thrombolysis and cardiac surgery. Until these studies are available, we suggest the following approach: patients with a TTS-related thrombus should be monitored by echocardiography while receiving anticoagulation. In case of highly mobile LV thrombi, the heart team may consider cardiac surgery to prevent systemic embolism. The role of SEC in TTS remains to be determined.
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Belgrave, Kevin, and Shaun Cardozo. "Thrombus Formation on Amplatzer Septal Occluder Device: Pinning Down the Cause." Case Reports in Cardiology 2014 (2014): 1–2. http://dx.doi.org/10.1155/2014/457850.
Повний текст джерелаАнотація:
The use of interatrial septal occluder devices is an efficacious and less invasive alternative to open heart surgery for the repair of atrial septal defects. These devices present significant risks including thrombus formation on the device and subsequent thromboembolic events. We present a case of a woman who presented with stroke-like symptoms five years after PFO closure. The patient was subsequently found to have a thrombus on the occluder device. Our case highlights the risk of such thrombolic phenomenon and the risk associated with the device structure as a nidus for such a complication.
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Adili, Reheman, Theodore R. Holman, and Michael Holinstat. "Novel 12-LOX Inhibitor ML355 Attenuates Platelet Reactivity and Impairs Thrombus Growth, Stability and Vessel Occlusion In Vivo." Blood 126, no. 23 (December 3, 2015): 3442. http://dx.doi.org/10.1182/blood.v126.23.3442.3442.
Повний текст джерелаАнотація:
Abstract Background: Adequate platelet reactivity is required for platelet adhesion and aggregation at the site of vascular injury to maintain hemostasis. However, excessive platelet reactivity can also lead to the formation of occlusive thrombi, the predominate underlying cause of myocardial infarction and stroke. While current anti-platelet treatments limit platelet function, they often result in an increased risk of bleeding. 12-lipoxygenase (12-LOX), an oxygenase highly expressed in the platelet, has been demonstrated by our lab and others to regulate PAR4 and GPVI-mediated platelet reactivity suggesting a role of 12-LOX in regulation of vivo thrombosis. However, the ability to pharmacologically target 12-LOX in vivo has not been established to date. Aims: To determine how 12-LOX regulates thrombus formation in vivo and whether platelet 12-LOX is an effective target for anti-platelet therapeutics, wild-type (WT) or 12-LOX deficient (12-LOX-/-) mice were treated with or without the 12-LOX inhibitor, ML355, and were assessed for inhibitory effects on platelet activation in vitro, ex-vivo and in vivo. Methods: The effect of the novel 12-LOX inhibitor ML355 on human platelet function was assessed in vitro by platelet aggregometry, ex vivo by perfusion chamber. In vivo thrombus formation and vessel occlusion in small and large vessels were studied in 12-LOX-/-, WT mice and mice treated with ML355 using intravital microscopy using the FeCl3 injury models. Results: Using in vitro platelet aggregation assays, ML355 dose dependently inhibited thrombin, PAR1-AP, and PAR4-AP-induced aggregation in washed human platelets. Interestingly, the negative regulatory effects of ML355 inhibition of 12-LOX can be overcome by high concentration of thrombin. Additionally, ML355 was able to attenuate ADP-induced platelet aggregation both in platelet-rich-plasma and whole blood. In ex vivo flow chamber assays, platelet adhesion and thrombus formation on collagen-coated surfaces at high shear was attenuated in both mouse and human whole blood after incubation with ML355. Further, platelet aggregation and thrombus growth in 12-LOX-/- mice was impaired in FeCl3-induced mesenteric or carotid artery thrombosis models. Thrombi in 12-LOX-/- mice were unstable and frequently form emboli, which resulted in impaired vessel occlusion or reopening. Additionally, thrombus formation and vessel occlusion was impaired in ML355 treated WT mice. Conclusions: The highly selective 12-LOX inhibitor ML355 inhibits platelets aggregation induced by various platelet agonists and ML355 inhibition of platelet function is not agonist specific. Platelet function at high shear in ex vivo conditions in both mice and human was attenuated in the presence of ML355. Thrombus growth, stability, and vessel occlusion was impaired in mice deficient for 12-LOX. Finally, the highly selective 12-LOX inhibitor ML355 attenuates thrombus formation and prevents vessel occlusion in vivo. Our data strongly indicates 12- LOX is an important determinant of platelet reactivity and inhibition of platelet 12-LOX may represent a new target for anti-platelet therapeutics. Disclosures No relevant conflicts of interest to declare.
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Mitamura, Hideo. "Thrombus formation and its embolic risk in atrial fibrillation." Rinsho Shinkeigaku 53, no. 11 (2013): 986–88. http://dx.doi.org/10.5692/clinicalneurol.53.986.
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Shida, Yasuaki, Keiji Nogami, Hiroaki Minami, Hiroaki Yaoi, Tomoko Matsumoto, Takehisa Kitazawa, Kunihiro Hattori, and Midori Shima. "Distinct Localization of Coagulation Factor VIII, Von Willebrand Factor and Factor VIIIa-Mimetic Bispecific Antibody Contributing to Thrombus Formation Under Whole Blood Flow Conditions." Blood 124, no. 21 (December 6, 2014): 1483. http://dx.doi.org/10.1182/blood.v124.21.1483.1483.
Повний текст джерелаАнотація:
Abstract Background Factor VIII (FVIII) is an essential factor for coagulation system in the intrinsic pathway. Due to the short survival of FVIII in the plasma circulation, it requires von Willebrand factor (VWF) as a carrier protein to maintain the optimal level for hemostasis. VWF also plays an important role in primary hemostasis by bridging platelets to exposed subendothelial collagens, especially under high shear flow environment. Since VWF carries FVIII, it is conceivable that VWF takes FVIII to the sites of vascular injury. However, the role of FVIII at the local sites under flow conditions is not fully understood despite of the fact that increased level of FVIII is associated with the risk of venous thrombosis and the deficiency of FVIII is the pathology of the bleeding disorder, hemophilia A. The treatment of hemophilia A largely depends on the infusion of FVIII concentrates, which is often complicated by the development of the inhibitor. Recently, bispecific antibody（ACE910）that mimics the role of FVIIIa by recognizing FIXa and FX has been developed and is currently under clinical trial. This antibody theoretically works regardless of the presence of devastating inhibitors against FVIII. Furthermore, it could also improve the clinical outcome of the other bleeding disorders, such as von Willebrand disease (VWD). Aim To analyze the role of FVIII and VWF, and impact of ACE910 at the sites of vascular injury under various shear conditions, we have developed the flow-mediated thrombosis model using flow chamber system. Method Whole blood obtained from healthy donors, hemophilia A and VWD patients were perfused into the collagen coated flow chamber under high (2,500s-1) or low shear (50s-1) flow conditions with/without FVIII concentrate, FVIII/VWF concentrate and ACE910. Formed thrombus was fixed and immunostaining was performed with phalloidin (Platelet), anti-FVIII antibody (FVIII) and anti-thrombin antibody (Thrombin). For the detection of ACE910, anti-human IgG or anti-ACE antibody (rAQ8 or rAJ540) were used. Size of thrombi and distribution of platelet, FVIII, thrombin and ACE910 were analyzed. Result 1) Under high shear flow, thrombus formation of VWD blood was significantly impaired while blood from Hemophilia A demonstrated nearly normal thrombus formation. Addition of FVIII/VWF but not FVIII concentrate to the blood of these patients rescued the impaired thrombus formation. ACE910 enhanced the thrombus formation of blood from both VWD and hemophilia A. Under low shear flow, blood from both hemophilia A and VWD demonstrated decreased thrombus formation. FVIII, FVIII/VWF concentrates and ACE910 improved the size of thrombus. 2) Localization of FVIII was evaluated with thrombin as a marker for the activation of coagulation. Platelets and thrombin demonstrated complete co-localization and intensity of thrombin staining was associated with thrombus size. VWF localized mainly outer layer of thrombus and FVIII localized in and around thrombus. At high shear condition, FVIII and VWF mostly existed with platelets. By contrast, FVIII and VWF demonstrated less co-localization with platelets under low shear condition. ACE910 demonstrated similar tendency to FVIII localization although ACE910 did not appear around thrombus. Conclusion We have developed the flow chamber system to evaluate the extent of thrombogenesis under various shear environment. VWF showed dominant role under high shear conditions while FVIII plays a key role under low shear conditions. FVIII, VWF and ACE910 demonstrated distinct localization. Interestingly, the distribution of FVIII was broader than VWF and platelet. FVIII localized to platelets presumably prior to its activation and contributed for the subsequent thrombin generation at local sites. Finally, ACE910 demonstrated consistent enhancement of thrombus formation of blood from both hemophilia A and VWD and, therefore, is prompted for the treatment of these bleeding disorders. Disclosures Shida: Chugai Pharmaceutical Co., Ltd.: Research Funding. Nogami:Chugai Pharmaceutical Co., Ltd.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Minami:Chugai Pharmaceutical Co., Ltd.: Research Funding. Yaoi:Chugai Pharmaceutical Co., Ltd.: Research Funding. Matsumoto:Chugai Pharmaceutical Co., Ltd.: Research Funding. Kitazawa:Chugai Pharmaceutical Co., Ltd.: Employment, Equity Ownership, Patents & Royalties. Hattori:Chugai Pharmaceutical Co., Ltd.: Employment, Equity Ownership, Patents & Royalties. Shima:Chugai Pharmaceutical Co., Ltd.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
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Teragawa, Hiroki, Yuichi Orita, Chikage Oshita, and Yuko Uchimura. "Intracoronary Thrombogenicity in Patients with Vasospastic Angina: An Observation Using Coronary Angioscopy." Diagnostics 11, no. 9 (September 7, 2021): 1632. http://dx.doi.org/10.3390/diagnostics11091632.
Повний текст джерелаАнотація:
Background: Despite significant interest in intracoronary thrombi in patients with vasospastic angina (VSA), the phenomenon remains unclarified. Therefore, we investigated a possible relationship using coronary angioscopy (CAS) in VSA patients. Methods: Sixty patients with VSA, for whom we could assess the spastic segment using CAS, were retrospectively studied. An intracoronary thrombus on CAS was a white thrombus and an erosion-like red thrombus. We verified the clinical characteristics and lesional characteristics as they determined the risk of intracoronary thrombus formation. Results: There were 18 (30%) patients with intracoronary thrombi. More of the patients with intracoronary thrombi were male, current smokers and had severe concomitant symptoms; however, no statistically significant difference was observed upon logistic regression analysis. There were 18 (26%) coronary arteries with intracoronary thrombi out of 70 coronary arteries recognised in the spastic segments. Furthermore, atherosclerotic changes and segmental spasms were significant factors responsible for such lesions. Conclusion: Intracoronary thrombi occurred in 30% of VSA patients and much attention should be paid to the intracoronary thrombogenicity of VSA patients.
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Cho, Jaehyung, and Deane F. Mosher. "Enhancement of thrombogenesis by plasma fibronectin cross-linked to fibrin and assembled in platelet thrombi." Blood 107, no. 9 (May 1, 2006): 3555–63. http://dx.doi.org/10.1182/blood-2005-10-4168.
Повний текст джерелаАнотація:
To learn how plasma fibronectin stabilizes platelet-rich thrombi in injured mesenteric arterioles of mice, we studied the impact of plasma fibronectin on platelet thrombus formation ex vivo in a parallel flow chamber. Thrombi were greater on surfaces coated with fibrin cross-linked to fibronectin by activated factor XIII than on surfaces coated with fibrin lacking cross-linked fibronectin or with fibronectin alone. Platelet thrombi were even greater when plasma fibronectin was perfused with platelets, resulting in deposition of the perfused fibronectin in platelet thrombi. The effect of perfused fibronectin on thrombogenesis was lost if fibronectin deposition was blocked by coperfusion with the N-terminal 70-kDa fragment of fibronectin or a peptide based on the functional upstream domain of protein F1 of Streptococcus pyogenes. Increases in thrombus formation were dependent on a platelet activator such as lysophosphatidic acid, amount of fibronectin cross-linked to fibrin, and concentration of fibronectin in the perfusate. The dependency of fibronectin concentration extended into the range of fibronectin concentrations associated with increased risk of coronary artery disease. At such concentrations, the 2 mechanisms for insolubilization of plasma fibronectin—cross-linking to fibrin and assembly by adherent and aggregating platelets—synergize to result in many-fold enhancement of platelet thrombus formation.
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Sakariassen, K. S., M. Buchmann, M. J. A. G. Hamers, and H. Stormorken. "Iohexol, platelet activation and thrombosis." Acta Radiologica 39, no. 4 (July 1998): 355–61. http://dx.doi.org/10.1080/02841859809172444.
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Background: There is a dispute about the potential effects of radiographic contrast media (CM) on thrombogenesis. The nonionic CM iohexol triggers platelet β-thromboglobulin (β-TG) secretion, and thus may activate the platelets and promote thrombosis. We addressed this topic in a study employing a human model of arterial thrombus formation in the presence of aspirin and heparin. This was a follow-up to our initial study (on thrombus formation in native blood) which did not include antithrombotic drugs. The nonionic CM iohexol (monomer) and iodixanol (dimer) and the ionic CM ioxaglate (dimer) were compared. Methods and Results: Thrombus formation was triggered by a surface rich in either collagen or tissue factor, positioned in a parallel-plate perfusion chamber device at an arterial wall shear rate of 2600 s−1. Blood from healthy volunteers, following ingestion of 1 g aspirin, was mixed with 40 vol% CM and 2.0 IU/ml heparin and passed over the surfaces. Thrombus formation in the presence of either CM showed no difference, despite the fact that iohexol triggered a pronounced platelet β-TG secretion; iodixanol or ioxaglate were virtually inert. Conclusion: There was no association between iohexol-induced β-TG secretion and thrombus formation on collagen (platelet-driven) or on tissue factor (thrombin-driven) in the presence of a standard antithrombotic regimen of aspirin and heparin as used in the clinic. The notion of a thrombotic risk due to platelet activation by iohexol was thus not substantiated by this study.
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Laridan, Elodie, Kimberly Martinod, and Simon De Meyer. "Neutrophil Extracellular Traps in Arterial and Venous Thrombosis." Seminars in Thrombosis and Hemostasis 45, no. 01 (January 11, 2019): 086–93. http://dx.doi.org/10.1055/s-0038-1677040.
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AbstractThrombotic complications are still a major health risk worldwide. Our view on the pathophysiology of thrombosis has significantly changed since the discovery of neutrophil extracellular traps (NETs) and their prothrombotic characteristics. Generated by neutrophils that release their decondensed chromatin as a network of extracellular fibers, NETs promote thrombus formation by serving as a scaffold that activates platelets and coagulation. The thrombogenic involvement of NETs has been described in various settings of thrombosis, including stroke, myocardial infarction, and deep vein thrombosis. The aim of this review is to summarize existing evidence showing the presence of NETs in human thrombus material. Following an introduction on NETs and their role in thrombus formation, the authors address studies showing the presence of NETs in arterial or venous thrombi. In addition, they focus on potential novel therapeutic opportunities to resolve or prevent thrombosis by targeting NETs.
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Fan, Lianghao, Boli Lin, Ting Xu, Nengzhi Xia, Xiaotong Shao, Xianxi Tan, Ming Zhong, Yunjun Yang, and Bing Zhao. "Predicting intraprocedural rupture and thrombus formation during coiling of ruptured anterior communicating artery aneurysms." Journal of NeuroInterventional Surgery 9, no. 4 (April 5, 2016): 370–75. http://dx.doi.org/10.1136/neurintsurg-2016-012335.
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BackgroundIntraprocedural rupture and thrombus formation are serious complications during coiling of ruptured intracranial aneurysms, and they more often occur in patients with anterior communicating artery (ACoA) aneurysms.ObjectiveTo identify independent predictors of intraprocedural rupture and thrombus formation during coiling of ruptured ACoA aneurysms.MethodsBetween January 2008 and February 2015, 254 consecutive patients with 255 ACoA aneurysms were treated with coiling. We retrospectively reviewed intraoperative angiograms and medical records to identify intraprocedural rupture and thrombus formation, and re-measured aneurysm morphologies using CT angiography images. Multivariate logistic regression models were used to determine independent predictors of intraprocedural rupture and thrombus formation.ResultsOf the 231 patients included, intraprocedural rupture occurred in 10 (4.3%) patients, and thrombus formation occurred in 15 (6.5%) patients. Patients with smaller aneurysms more often experienced intraprocedural rupture than those with larger aneurysms (3.5±1.3 mm vs 5.7±2.3 mm). Multivariate analysis showed that smaller ruptured aneurysms (p=0.003) were independently associated with intraprocedural rupture. The threshold of aneurysm size separating rupture and non-rupture groups was 3.5 mm. Multivariate analysis showed that a history of hypertension (p=0.033), aneurysm neck size (p=0.004), and parent vessel angle (p=0.023) were independent predictors of thrombus formation. The threshold of parent vessel angle separating thrombus and non-thrombus groups was 60.0°.ConclusionsRuptured aneurysms <3.5 mm were associated with an increased risk of intraprocedural rupture, and parent vessel angle <60.0°, wider-neck aneurysms, and a history of hypertension were associated with increased risk of thrombus formation during coiling of ruptured ACoA aneurysms.
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Spronk, H., T. Padro, J. Siland, J. Prochaska, J. Winters, A. van der Wal, J. Posthuma, et al. "Atherothrombosis and Thromboembolism: Position Paper from the Second Maastricht Consensus Conference on Thrombosis." Thrombosis and Haemostasis 118, no. 02 (2018): 229–50. http://dx.doi.org/10.1160/th17-07-0492.
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AbstractAtherothrombosis is a leading cause of cardiovascular mortality and long-term morbidity. Platelets and coagulation proteases, interacting with circulating cells and in different vascular beds, modify several complex pathologies including atherosclerosis. In the second Maastricht Consensus Conference on Thrombosis, this theme was addressed by diverse scientists from bench to bedside. All presentations were discussed with audience members and the results of these discussions were incorporated in the final document that presents a state-of-the-art reflection of expert opinions and consensus recommendations regarding the following five topics: 1. Risk factors, biomarkers and plaque instability: In atherothrombosis research, more focus on the contribution of specific risk factors like ectopic fat needs to be considered; definitions of atherothrombosis are important distinguishing different phases of disease, including plaque (in)stability; proteomic and metabolomics data are to be added to genetic information. 2. Circulating cells including platelets and atherothrombosis: Mechanisms of leukocyte and macrophage plasticity, migration, and transformation in murine atherosclerosis need to be considered; disease mechanism-based biomarkers need to be identified; experimental systems are needed that incorporate whole-blood flow to understand how red blood cells influence thrombus formation and stability; knowledge on platelet heterogeneity and priming conditions needs to be translated toward the in vivo situation. 3. Coagulation proteases, fibrin(ogen) and thrombus formation: The role of factor (F) XI in thrombosis including the lower margins of this factor related to safe and effective antithrombotic therapy needs to be established; FXI is a key regulator in linking platelets, thrombin generation, and inflammatory mechanisms in a renin–angiotensin dependent manner; however, the impact on thrombin-dependent PAR signaling needs further study; the fundamental mechanisms in FXIII biology and biochemistry and its impact on thrombus biophysical characteristics need to be explored; the interactions of red cells and fibrin formation and its consequences for thrombus formation and lysis need to be addressed. Platelet–fibrin interactions are pivotal determinants of clot formation and stability with potential therapeutic consequences. 4. Preventive and acute treatment of atherothrombosis and arterial embolism; novel ways and tailoring? The role of protease-activated receptor (PAR)-4 vis à vis PAR-1 as target for antithrombotic therapy merits study; ongoing trials on platelet function test-based antiplatelet therapy adjustment support development of practically feasible tests; risk scores for patients with atrial fibrillation need refinement, taking new biomarkers including coagulation into account; risk scores that consider organ system differences in bleeding may have added value; all forms of oral anticoagulant treatment require better organization, including education and emergency access; laboratory testing still needs rapidly available sensitive tests with short turnaround time. 5. Pleiotropy of coagulation proteases, thrombus resolution and ischaemia–reperfusion: Biobanks specifically for thrombus storage and analysis are needed; further studies on novel modified activated protein C–based agents are required including its cytoprotective properties; new avenues for optimizing treatment of patients with ischaemic stroke are needed, also including novel agents that modify fibrinolytic activity (aimed at plasminogen activator inhibitor-1 and thrombin activatable fibrinolysis inhibitor.
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Sasko, Benjamin, Oliver Ritter, Peter Bramlage, and Fabian Riediger. "Late left atrial appendage closure device displacement and massive thrombus formation: a case report." European Heart Journal - Case Reports 4, no. 2 (February 20, 2020): 1–5. http://dx.doi.org/10.1093/ehjcr/ytaa014.
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Abstract Background Left atrial appendage (LAA) closure with the WATCHMAN device is an alternative to anticoagulation therapy for the prevention of stroke in selected patients with atrial fibrillation (AF). Infrequently, left atrial (LA) device-related thrombus formation occurs and it is poorly understood. Thrombus formation due to incomplete covering of the LAA is even rarer and may occur within the first few months after device implantation. Case summary Here, we present a case of a 68-year-old male patient with permanent AF, drug- and hepatitis induced liver cirrhosis (CILD Score B), and prior aortic valve replacement. The patient had a history of percutaneous LAA closure using a WATCHMAN device. He developed massive peri-device leak and thrombus arising from the space between the device and appendage cleft 2 years after implantation. Because of the high bleeding risk with a HAS-BLED score of 5 points, surgery was chosen as the therapy of choice instead of long-term anticoagulation. The patient was discharged in good clinical condition and has been scheduled for a yearly follow-up. Discussion This case emphasizes the importance of choosing appropriately sized LAA occluder devices and planning for regular post-interventional follow-ups to minimize the risk of per-device leaks and thrombi.
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Raquet, Elmar, Marc Nolte, Frauke May, Jochen Müller-Cohrs, Jenny Björkqvist, Gerhard Dickneite, Daniel Schürmann, Eva Herzog, and Ingo Pragst. "C1-esterase inhibitor treatment: preclinical safety aspects on the potential prothrombotic risk." Thrombosis and Haemostasis 112, no. 11 (November 2014): 960–71. http://dx.doi.org/10.1160/th13-06-0469.
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SummaryHuman plasma-derived C1-esterase inhibitor (C1–INH) is an efficacious and safe treatment for hereditary angioedema. However, thrombotic events in subjects treated with C1–INH at recommended or offlabel, high doses have been reported. In this study, we addressed the potential prothrombotic risk of C1–INH treatment in high doses using a non-clinical rabbit model. Following intravenous infusion of C1–INH to rabbits at doses up to 800 IU/kg, the exposure and the pharmacodynamic efficacy of C1–INH in rabbits were confirmed by activity measurements of C1-esterase, and coagulation factors XIa and XIIa, respectively. Potential prothrombotic effects were assessed following induction of venous and arterial thrombosis using in vivo models of venous and arterial stasis, complemented by various in vitro assays of coagulation markers. Administration of C1–INH at doses up to 800 IU/ kg did not potentiate thrombus formation during venous stasis. In contrast, inhibition of arterial occlusion was observed upon C1–INH administration when compared with isotonic saline treatment, indicating antithrombotic rather than prothrombotic activity of high dose C1–INH treatment in vivo. This was further confirmed in vitro by decreased thrombin generation, increased activated partial thromboplastin time, clotting time and clot formation time, and inhibition of platelet aggregation. No relevant changes in fibrinolysis or in the levels of thrombin-antithrombin complexes, and prothrombin fragment 1+2 were observed upon high dose C1–INH treatment. The data suggest that treatment of healthy rabbits with high doses of C1–INH could potentially inhibit coagulation and thrombus formation rather than induce a prothrombotic risk.
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Saldanha, Lisa J., Anthony KC Chan, and Peter L. Gross. "Exploring the Impact of Clinical Anticoagulants on Venous Thrombosis Stability Using a Novel Intravital Murine Model." Blood 118, no. 21 (November 18, 2011): 1246. http://dx.doi.org/10.1182/blood.v118.21.1246.1246.
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Abstract Abstract 1246 Background: Thrombus stability influences the progression of deep vein thrombosis to a potentially fatal pulmonary embolism (PE) event. Anticoagulants are clinically administered to treat venous thrombosis. However, the effect of anticoagulants on thrombus stability remains unknown. Objective: We developed a novel intravital mouse model to explore the hypothesis that administration of clinical anticoagulants would decrease early thrombus stability, thereby potentially increasing PE risk. Methods: The trachea and jugular vein were cannulated, and the femoral vein isolated, in wild type C57/Bl6 female mice. Platelets were labeled in vivo using anti-mouse CD41 Fab fragments conjugated to Alexa Fluor-488. A 1 × 2 mm filter paper strip, saturated in 4% ferric chloride, was applied to the femoral vein for 5 minutes to induce thrombus formation. Wide-field fluorescent microscopy was used to quantify thrombus stability. Stability was related to the number of embolic events and loss of platelet intensity captured downstream of the thrombus at 5, 15, 30, 45, and 60 minutes post thrombus formation. Results: The mean number of embolic events and loss of platelet intensity decreased over time in wild type mice (n = 12). This suggested that thrombus stability increases over time. Anticoagulants were administered via a jugular vein catheter, at 12 minutes post thrombus formation, to assess impact on embolization. The anticoagulants examined were hirudin (8U/g mouse body weight), unfractionated heparin (UFH) (0.1U/g), a covalent antithrombin-heparin complex (ATH) (0.08U/g), and fondaparinux (0.1μg/g). We observed an overall a) increase in the number of embolic events and b) increase in platelet intensity lost over time in mice injected with hirudin (n = 12) and UFH (n = 12) when compared to untreated wild type control mice. The total number of embolic events occurring over one hour substantially increased in the hirudin-treated group (p = 0.09), which was also associated with an overall increase in total platelet intensity (p = 0.08), compared to untreated control mice. In addition, there was an increase in the total number of embolic events compared to the UFH-treated group (p = 0.09). Administration of hirudin, a direct thrombin inhibitor (DTI), and UFH, an indirect thrombin inhibitor, could result in decreased venous thrombus stability. However, it appears that the DTI is associated with greater thrombus instability. In the ATH-treated group (n = 12), an increase in embolic events at 15 minutes was observed, followed by a decrease in embolization. ATH could initially disrupt thrombus stability through inhibition of fibrin-bound thrombin, before acting in a stabilizing manner. Administration of fondaparinux (n = 6), an indirect factor-Xa inhibitor, demonstrated an overall decrease in embolic events and platelet intensity lost over time. When compared to control groups, there was a significant decrease in total number of embolic events and total amount of platelet intensity lost in the fondaparinux group (p < 0.05). Use of a factor-Xa inhibitor appears to enhance thrombus stability more effectively in comparison to direct and indirect thrombin inhibitors. Conclusion: Use of anticoagulants that inhibit thrombin predominantly could decrease early thrombus stability and potentially increase the likelihood of a PE event. Disclosures: No relevant conflicts of interest to declare.
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Kamphuisen, Pieter W., and Hugo ten Cate. "Cardiovascular risk in patients with hemophilia." Blood 123, no. 9 (February 27, 2014): 1297–301. http://dx.doi.org/10.1182/blood-2013-11-453159.
Повний текст джерелаАнотація:
Abstract Patients with hemophilia, who have a lifelong hypocoagulability, seem to have a lower cardiovascular mortality than the general population. Nevertheless, the prevalence of cardiovascular risk factors in patients with hemophilia is as prevalent as in the general population, and hypertension is even more common. Furthermore, hemophiliacs have the same degree of atherosclerosis as the general population. The reduced cardiovascular mortality may be explained by reduced thrombus formation resulting from hypocoagulability. On the other hand, hemophilia, which is associated with reduced thrombin generation, may also increase atherosclerotic plaque stability, as has been shown in mice. Because treatment of these events is extremely challenging in patients with increased bleeding tendency, detection and aggressive treatment of risk factors is mandatory.
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Lawani, Osayi, and Edward Baptista. "Large Device-Related Thrombus Detected following Symptoms of Transient Ischemic Attack." Case Reports in Cardiology 2021 (November 23, 2021): 1–6. http://dx.doi.org/10.1155/2021/9195984.
Повний текст джерелаАнотація:
As an independent risk factor for stroke, atrial fibrillation has been shown to be associated with a fivefold increase in the cause of embolic stroke in comparison to healthy individuals without atrial fibrillation. This risk may be compounded by other factors; however, the main probable cause of stroke leading from atrial fibrillation is thrombus formation in the left atrial appendage. In patients for whom anticoagulation is contraindicated, left atrial appendage occlusion has become a leading alternative option for therapeutic prevention of thromboembolism and stroke in patients with this condition. Unfortunately, these devices (particularly the WATCHMAN) have been associated with a 3-6% incidence of intracardiac thrombus development postimplantation. Some risk factors for the development of device-related thrombus are high platelet count, permanent atrial fibrillation, resistance to clopidogrel, and prior transient ischemic attack or stroke. Despite following an anticoagulant regimen, thrombus formation was reported in 5.6% of participants of a randomized clinical trial, and further analysis showed that some of these patients continued to develop either ischemic stroke or thromboembolism five years later as compared to patients without initial thrombus development. We present a case of an elderly male with prior history of stroke and transient ischemic attack who developed a large device-related thrombus five months following WATCHMAN FLX™ implantation. Currently, there are no specific recommendations on the management of this rare complication; however, we discuss possible consideration of initially prolonging anticoagulation therapy following implantation for high-risk individuals, as there is an increased possibility for thrombus formation in this population. Management options should continue to be studied for therapeutic benefit in streamlining postprocedural therapy and improve future outcomes in the use of left atrial appendage occlusion devices, as well as continual thrombus prevention.
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Asbach, Stefan, Jürgen Biermann, Christoph Bode, and Thomas S. Faber. "Early Heparin Administration Reduces Risk for Left Atrial Thrombus Formation during Atrial Fibrillation Ablation Procedures." Cardiology Research and Practice 2011 (2011): 1–5. http://dx.doi.org/10.4061/2011/615087.
Повний текст джерелаАнотація:
Objective. Despite the use of anticoagulation during left atrial (LA) ablation procedures, ischemic cerebrovascular accidents (CVAs) are recognized as a serious complication. Heparin is usually given after safe transseptal access has been obtained, resulting in a short unprotected dwell time of catheters within the LA, which may account for CVAs. We investigated the frequency of CVAs and LA thrombus formation as detected by intracardiac ultrasound (ICE) depending on the timing of heparin administration.Methods and Results. Sixty LA ablation procedures with the use of ICE were performed in 55 patients. Patients were grouped by heparin administration after (Group I, ) and before (Group II, ) transseptal access. Group I patients were younger ( versus years, ); other clinical and echocardiographic characteristics did not differ between groups. Early thrombus formation was observed in 2 (15.4%) of group I patients as compared to 0% of group II patients (). One CVA (2.1%) occurred in one group II patient without prior thrombus detection, and none occurred in group I patients ().Conclusion. Early administration of heparin reduces the risk of early intracardiac thrombus formation during LA ablation procedures. This did not result in reduced rate of CVAs.
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Wolberg, Alisa S. "Factor XIII and Red Blood Cells in Venous Thrombosis." Blood 126, no. 23 (December 3, 2015): SCI—14—SCI—14. http://dx.doi.org/10.1182/blood.v126.23.sci-14.sci-14.
Повний текст джерелаАнотація:
Blood coagulation culminates in the thrombin-mediated conversion of fibrinogen to fibrin and production of a fibrin network that stabilizes the clot. The transglutaminase factor XIII(a) [FXIII(a)] crosslinks fibrin and increases the clot's resistance to fibrinolysis and mechanical disruption. Consequently, fibrin formation and crosslinking are essential for hemostasis. However, the formation of clots with abnormal fibrin network structure and/or stability (resistance to mechanical disruption or pharmacological dissolution) is a risk factor for both arterial and venous thrombosis. Improved understanding of fibrin formation and crosslinking during coagulation is essential for understanding the pathophysiologic mechanisms that promote thrombotic disease. We have shown that elevated levels of fibrinogen accelerate vessel occlusion and enhance thrombus stability in mice, demonstrating etiologic contributions of fibrin(ogen) to thrombosis. Recently, we discovered that FXIIIa transglutaminase activity also mediates venous thrombosis via its ability to promote red blood cell retention during clot contraction in whole blood. Genetic deletion of FXIII or pharmacologic inhibition of FXIIIa activity reduces red blood cell retention in clots and consequently, reduces thrombus size in vitro and in vivo. Furthermore, FXIII zymogen binding to soluble, circulating fibrinogen is necessary for normal FXIII activation and activity. The fibrinogen motif that mediates FXIII binding involves C-terminal residues in the fibrinogen gamma chain (gamma 390-396); mice that express a variant fibrinogen that has mutations within these residues show reduced binding of FXIII zymogen to fibrinogen, and delayed activation of FXIII. In venous thrombosis models, these mice phenocopy FXIII-deficient mice, producing smaller venous thrombi with reduced red blood cell content compared to thrombi from wild-type mice. Intriguingly, these mice do not exhibit bleeding or poor wound healing normally associated with FXIII deficiency. Collectively, these findings provide new insight into the pathophysiology of venous thrombosis, and expose the fibrin(ogen)-FXIII axis as a central determinant of venous thrombus formation and composition. Disclosures No relevant conflicts of interest to declare.
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Manasrah, Nouraldeen, Anas Abdel-Qader, Ali Al Sbihi, Sarah Alqasem, Lama Tareq Saif, Ahmed J. Chaudhary, Rana Ismail, and Ramegowda Rajagopal. "Left Ventricular Thrombus Formation in a Structurally and Functionally Normal Heart: A Case Report and Literature Review." Journal of Investigative Medicine High Impact Case Reports 10 (January 2022): 232470962211018. http://dx.doi.org/10.1177/23247096221101852.
Повний текст джерелаАнотація:
Left ventricular (LV) thrombosis usually occurs as a complication of acute anterior myocardial infarction (MI) and dilated cardiomyopathy. It also occurs in patients with a hypercoagulable state. However, in the setting of normal systolic function, LV thrombi are extremely rare. We present a case of a healthy woman who had LV thrombus despite normal LV systolic function that presented as an acute aortoiliac embolism.
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Ebelt, Henning, Alexandra Offhaus, Matthias Wiora, Peter Roehl, Andreas Schwenzky, Anja Weida, Matthias Hoyme, Juliane Bindemann-Koecher, and Jelena Anacker. "Impact of ultrasound contrast agent on the detection of thrombi during transoesophageal echocardiography." Open Heart 6, no. 2 (September 2019): e001024. http://dx.doi.org/10.1136/openhrt-2019-001024.
Повний текст джерелаАнотація:
BackgroundAtrial fibrillation (AF) carries the risk of thrombus formation in the left atrium and especially in the left atrial appendage (LAA). A transoesophageal echocardiography (TOE) is routinely performed in these patients to rule out thrombi before cardioversion or structural interventions like LAA closure or pulmonary vein isolation. However, in a certain number of cases, inconclusive results of the TOE may result. This study was performed to analyse whether the routine use of ultrasound contrast agent (UCA) has an influence on the frequency of thrombus detection.MethodsIn patients with AF who were scheduled for a subsequent interventional procedure, a TOE was initially performed without contrast agent. Then, the TOE was repeated with the use of UCA. The percentage of diagnostic findings regarding the prevalence of thrombus in the LAA with and without UCA were compared (thrombus present (T+), no thrombus (T−) and inconclusive result (T+/−)).Results223 patients were prospectively included into the trial. The numbers of thrombus detection were as follows: without UCA: 17 T+ (7.6%), 154 T− (69.1%), 52 T+/− (23,3%); with UCA: 16 T+ (7.2%), 179 T− (80.3%), 28 T+/− (12.6%; χ2: p<0.01). In 29 examinations (13.0%), the use of UCA had an impact on the subsequent treatment strategy.ConclusionsThe use of UCA during TOE in patients with AF has a significant impact on the subsequent patient management especially due to an improved rule out of LAA thrombi.
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Kawasaki, Tomihisa, Takehiro Kaida, Jef Arnout, Jos Vermylen, and Marc Hoylaerts. "A New Animal Model of Thrombophilia Confirms that High Plasma Factor VIII Levels Are Thrombogenic." Thrombosis and Haemostasis 81, no. 02 (1999): 306–11. http://dx.doi.org/10.1055/s-0037-1614471.
Повний текст джерелаАнотація:
SummaryThe thrombotic risk associated with elevated plasma levels of clotting factor VIII (FVIII) was investigated in a mouse model of thrombophilia. After the intravenous injection of recombinant human FVIII and/or of purified FVIII-free human von Willebrand factor (vWF), a controlled mild injury was inflicted on the carotid artery of FVB mice by irradiation with filtered green light in combination with intravenous injection of the dye rose bengal. Formation of a platelet-rich thrombus was continuously monitored for 40 min via transillumination and the thrombus size was measured via image analysis. Administration of recombinant human FVIII at 40 g/kg led to initial FVIII plasma activities equivalent to 250% of normal human plasma FVIII activity and significantly enhanced thrombus size. Immunohistochemical staining illustrated the accumulation of FVIII within the thrombi. Human vWF, even at 10 mg/kg, had no effect on thrombus formation. The thrombotic tendency induced by FVIII was significantly inhibited by the administration of human vWF in a dose-dependent manner. Separate plasma measurements revealed that human FVIII has comparable affinities for human and murine vWF but that human vWF does not effectively bind murine platelets. The inhibition by human vWF of the thrombotic tendency induced by human FVIII could therefore be explained by a lack of accumulation of FVIII within the developing thrombus because of the reduced affinity of human vWF for murine platelets and the reduced occupancy of murine von Willebrand factor by human FVIII after injection of human vWF. These results show that vWF actively participates in FVIII accumulation in the arterial thrombus and provide experimental evidence for epidemiological findings that elevated plasma FVIII levels are associated with an increased thrombotic risk, also in arteries.
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Dobie, Gasim, Daniel Man-yuen Sze, Constantine Tam, and Denise Jackson. "The Effect of Btk Inhibitors on Haemostasis and Thrombosis." Blood 132, Supplement 1 (November 29, 2018): 1126. http://dx.doi.org/10.1182/blood-2018-99-109803.
Повний текст джерелаАнотація:
Abstract Introduction The Btk inhibitor, Ibrutinib (Imbruvica) which has proven to be efficacious in achieving remission of lymphocytosis and lymph node enlargement in B-CLL, it does have adverse side effects of bleeding, including major haemorrhages. The bleeding associated with Ibrutinib use is thought to be due to a combination of on-target Btk inhibition (as Btk is a key component of platelet GPVI signalling) as well as off targeted inhibition of other kinases including EGFR, ITK, JAK3 and Tec kinase. The major next generation Btk inhibitors in clinical development include Zanubrutinib (BGB-3111). Zanubrutinib shows improved selectivity for Btk compared with Ibrutinib, and thus may have reduced bleeding effects. Our study aims to determine in detail differential platelet effects between Ibrutinib and Zanubrutinib in human and mouse models using in vitro, exvivo and in vivo approaches. Methods Intravital microscopy was used to determine thrombus formation and growth after Btk inhibitors treatment in vitro and ex vivo using micro-slides or inside the mesenteric arterioles after injury by ferric chloride (FeCl3). Z-stack digital Axiocam mRm camera (Carl Zeiss) and Zeiss Axiovision software was used to capture images. Three dimensional (3D) deconvolved reconstructions of thrombi formed were analysed for surface coverage of platelet aggregates (μm2), thrombus height (μm) and thrombus volume (μm3). Flow cytometry analysis was also used to determine the release of agonist-induced platelet P-selectin exposure and dense granule after treatment with Btk inhibitors. Results In vitro experiments demonstrated that Btk inhibitors did not affect alpha or dense granule secretion mediated by GPCRs agonists, thrombin, PAR1 or PAR4. However, they inhibited alpha granule secretion mediated by GPVI selective agonists, CRP-XL or Rhodocytin. Ibrutinib inhibited human thrombus formation on type I collagen, fibrinogen or von Willebrand factor under arterial shear with 3 fold reduction whereas Zanubrutinib had no effect over a dose dependent range of concentrations. Ibrutinib treated PRP significantly delayed the kinetics of clot retraction at all-time points over the 2 hour time frame compared to Zanubrutinib treated and vehicle control. The studies also showed that Ibrutinib but not Zanubrutinib inhibited ex vivo human thrombus formation on type I collagen under arterial shear using B-CLL patient samples. The data demonstrated that treatment of C57BL/6 mouse whole blood with 0.5-2.0 µM of ibrutinib significantly inhibited thrombus growth on type I collagen under in vitro flow conditions whereas Zanubrutinib was comparable to the vehicle control. Consequently, pre-treatment of C57BL/6 mice with ibrutinib (10 mg/kg), but not Zanubrutinib (10 mg/kg) markedly inhibited platelet thrombus growth and formation on type I collagen under ex vivo arterial flow conditions. Intravital microscopy of vascular injury of mesenteric arterioles induced by ferric chloride (FeCl3) demonstrated that Ibrutinib (10 mg/kg), but not Zanubrutinib (10 mg/kg) inhibited in vivo murine thrombus formation and growth over time. Conclusion Btk inhibitors used in the treatment of B-cell malignancies have differential effects on platelet function and thrombosis. Zanubrutinib is superior to ibrutinib as it showed no effect on platelet thrombus formation, thus reduces risk of bleeding. Disclosures Tam: AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Beigene: Honoraria.
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Ngoepe, Malebogo N., Etheresia Pretorius, Ilunga J. Tshimanga, Zahra Shaikh, Yiannis Ventikos, and Wei Hua Ho. "Thrombin–Fibrinogen In Vitro Flow Model of Thrombus Growth in Cerebral Aneurysms." TH Open 05, no. 02 (April 2021): e155-e162. http://dx.doi.org/10.1055/s-0041-1728790.
Повний текст джерелаАнотація:
AbstractCerebral aneurysms are balloon-like structures that develop on weakened areas of cerebral artery walls, with a significant risk of rupture. Thrombi formation is closely associated with cerebral aneurysms and has been observed both before and after intervention, leading to a wide variability of outcomes in patients with the condition. The attempt to manage the outcomes has led to the development of various computational models of cerebral aneurysm thrombosis. In the current study, we developed a simplified thrombin–fibrinogen flow system, based on commercially available purified human-derived plasma proteins, which enables thrombus growth and tracking in an idealized cerebral aneurysm geometry. A three-dimensional printed geometry of an idealized cerebral aneurysm and parent vessel configuration was developed. An unexpected outcome was that this phantom-based flow model allowed us to track clot growth over a period of time, by using optical imaging to record the progression of the growing clot into the flow field. Image processing techniques were subsequently used to extract important quantitative metrics from the imaging dataset, such as end point intracranial thrombus volume. The model clearly demonstrates that clot formation, in cerebral aneurysms, is a complex interplay between mechanics and biochemistry. This system is beneficial for verifying computational models of cerebral aneurysm thrombosis, particularly those focusing on initial angiographic occlusion outcomes, and will also assist manufacturers in optimizing interventional device designs.
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Swieringa, Frauke, Marijke J. E. Kuijpers, Johan W. M. Heemskerk, and Paola E. J. van der Meijden. "Targeting platelet receptor function in thrombus formation: The risk of bleeding." Blood Reviews 28, no. 1 (January 2014): 9–21. http://dx.doi.org/10.1016/j.blre.2013.12.001.
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Tekin Tak, Bahar, Firdevs Aysenur Ekizler, Serkan Cay, Habibe Kafes, Elif Hande Ozcan Cetin, Ozcan Ozeke, Firat Ozcan, Serkan Topaloglu, and Dursun Aras. "Relationship between apical thrombus formation and blood viscosity in acute anterior myocardial infarction patients." Biomarkers in Medicine 14, no. 3 (February 2020): 201–10. http://dx.doi.org/10.2217/bmm-2019-0483.
Повний текст джерелаАнотація:
Aim: This study sought to investigate the predictive value of whole blood viscosity (WBV) to identify high-risk patients who will develop an apical thrombus during the acute phase of anterior transmural infarction. Materials & methods: Consecutive 1726 patients with first acute anterior myocardial infarction were evaluated. WBV was calculated according to the Simone’s formula. Results: Patients with an apical thrombus had prolonged pain to balloon time, higher rate of post-PCI thrombolysis in myocardial infarction flow ≤1 and significantly higher mean WBV values at both shear rates than those without an apical thrombus. Conclusion: WBV values at both shear rates were found to be significant and independent predictors for early LV apical thrombus formation complicating a first-ever anterior wall myocardial infarction.
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Bye, Alexander P., Amanda J. Unsworth, Michael J. Desborough, Catherine A. T. Hildyard, Niamh Appleby, David Bruce, Neline Kriek, et al. "Severe platelet dysfunction in NHL patients receiving ibrutinib is absent in patients receiving acalabrutinib." Blood Advances 1, no. 26 (December 12, 2017): 2610–23. http://dx.doi.org/10.1182/bloodadvances.2017011999.
Повний текст джерелаАнотація:
Abstract The Bruton tyrosine kinase (Btk) inhibitor ibrutinib induces platelet dysfunction and causes increased risk of bleeding. Off-target inhibition of Tec is believed to contribute to platelet dysfunction and other side effects of ibrutinib. The second-generation Btk inhibitor acalabrutinib was developed with improved specificity for Btk over Tec. We investigated platelet function in patients with non-Hodgkin lymphoma (NHL) receiving ibrutinib or acalabrutinib by aggregometry and by measuring thrombus formation on collagen under arterial shear. Both patient groups had similarly dysfunctional aggregation responses to collagen and collagen-related peptide, and comparison with mechanistic experiments in which platelets from healthy donors were treated with the Btk inhibitors suggested that both drugs inhibit platelet Btk and Tec at physiological concentrations. Only ibrutinib caused dysfunctional thrombus formation, whereas size and morphology of thrombi following acalabrutinib treatment were of normal size and morphology. We found that ibrutinib but not acalabrutinib inhibited Src family kinases, which have a critical role in platelet adhesion to collagen that is likely to underpin unstable thrombus formation observed in ibrutinib patients. We found that platelet function was enhanced by increasing levels of von Willebrand factor (VWF) and factor VIII (FVIII) ex vivo by addition of intermediate purity FVIII (Haemate P) to blood from patients, resulting in consistently larger thrombi. We conclude that acalabrutinib avoids major platelet dysfunction associated with ibrutinib therapy, and platelet function may be enhanced in patients with B-cell NHL by increasing plasma VWF and FVIII.
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Demers, Melanie, Jaymie R. Voorhees, Siu Wong, Benoit Ho-Tin-Noé, Marilena Crescente, Grace M. Thomas, and Denisa D. Wagner. "ADAMTS13 exerts a thrombolytic effect in microcirculation." Thrombosis and Haemostasis 108, no. 09 (2012): 527–32. http://dx.doi.org/10.1160/th12-01-0046.
Повний текст джерелаАнотація:
SummaryRecombinant tissue plasminogen activator (r-tPA) is the drug of choice for thrombolysis, but it is associated with a significant risk of bleeding and is not always successful. By cleaving von Willebrand factor (VWF), the metalloprotease ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type I repeats-13) down-regulates thrombus formation in injured vessels. We investigated whether recombinant ADAMTS13 (r-ADAMTS13) induces thrombolysis in vivo in mice. Thrombosis was produced by ferric chloride-induced (FeCl3) injury in the venules of a dorsal skinfold chamber. Phosphate-buffered saline (PBS, vehicle), r-tPA or r-ADAMTS13, supplemented with hirudin (to stop ongoing thrombin generation), was directly applied onto the occluded vessel, and thrombus dissolution was evaluated by intravital microscopy. The incidence of blood flow restoration significantly increased 30 minutes (min) after r-ADAMTS13 vs. PBS treatment (60% vs. 0%, p<0.05) and 60 min after r-tPA treatment (75% vs. 17%, p<0.05). Both r-tPA and r-ADAMTS13 significantly reduced thrombus size 60 min after their superfusion (53.2% and 62.3% of the initial thrombus size, p<0.05 and p<0.01, respectively). Bleeding occurred in all r-tPA-treated chambers, while it was absent in mice treated with r-ADAMTS13 or PBS. We observed that, similar to r-tPA, r-ADAMTS13 can dissolve occlusive thrombi induced by FeCl3 injury in venules. In contrast to r-tPA, the in vivo thrombolytic effect of ADAMTS13 was not associated with any signs of haemorrhage. ADAMTS13 could represent a new therapeutic option for thrombolysis.
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McFadyen, James D., and Shaun P. Jackson. "Differentiating haemostasis from thrombosis for therapeutic benefit." Thrombosis and Haemostasis 110, no. 11 (2013): 859–67. http://dx.doi.org/10.1160/th13-05-0379.
Повний текст джерелаАнотація:
SummaryThe central role of platelets in the formation of the primary haemostatic plug as well as in the development of arterial thrombosis is well defined. In general, the molecular events underpinning these processes are broadly similar. Whilst it has long been known that disturbances in blood flow, changes in platelet reactivity and enhanced coagulation reactions facilitate pathological thrombus formation, the precise details underlying these events remain incompletely understood. Intravital microscopy studies have highlighted the dynamic and heterogeneous nature of thrombus development and demonstrated that there are considerable spatiotemporal differences in the activation states of platelets within a forming thrombus. In this review we will consider the factors regulating the activation state of platelets in a developing thrombus and discuss how specific prothrombotic factors may influence this process, leading to excessive thrombus propagation. We will also discuss some potentially novel therapeutic approaches that may reduce excess thrombus development whilst minimising bleeding risk.
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Jennings, Lisa. "Mechanisms of platelet activation: Need for new strategies to protect against platelet-mediated atherothrombosis." Thrombosis and Haemostasis 102, no. 08 (2009): 248–57. http://dx.doi.org/10.1160/th09-03-0192.
Повний текст джерелаАнотація:
SummaryPlatelets are central mediators of haemostasis at sites of vascular injury, but they also mediate pathologic thrombosis. Activated platelets stimulate thrombus formation in response to rupture of an atherosclerotic plaque or endothelial cell erosion, promoting atherothrombotic disease. They also interact with endothelial cells and leukocytes to promote inflammation, which contributes to atherosclerosis. Multiple pathways contribute to platelet activation, and current oral antiplatelet therapy with aspirin and a P2Y12 adenosine diphosphate (ADP) receptor antagonist target the thromboxane A2 and ADP pathways, respectively. Both can diminish activation by other factors, but the extent of their effects depends upon the agonist, agonist strength, and platelet reactivity status. Although these agents have demonstrated significant clinical benefit, residual morbidity and mortality remain high. Neither agent is effective in inhibiting thrombin, the most potent platelet activator. This lack of comprehensive inhibition of platelet function allows continued thrombus formation and exposes patients to risk for recurrent thrombotic events. Moreover, bleeding risk is a substantial limitation of antiplatelet therapy, because these agents target platelet activation pathways critical for both protective haemostasis and pathologic thrombosis. Novel antiplatelet therapies that provide more complete inhibition of platelet activation without increasing bleeding risk could considerably decrease residual risk for ischemic events. Inhibition of the protease-activated receptor (PAR)-1 platelet activation pathway stimulated by thrombin is a novel, emerging approach to achieve more comprehensive inhibition of platelet activation when used in combination with current oral antiplatelet agents. PAR-1 inhibition is not expected to increase bleeding risk, as this pathway does not interfere with haemostasis.
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Ajmal, Muhammad, and Vijendra Swarup. "Acute Device-Related Thrombus after Watchman Device Implant." Case Reports in Cardiology 2019 (September 3, 2019): 1–4. http://dx.doi.org/10.1155/2019/8397561.
Повний текст джерелаАнотація:
Atrial fibrillation is characterized by irregularly irregular heart rhythm with an increased morbidity and mortality. It is associated with an increased risk of thromboembolism due to formation of blood clot in the left atrium. Most of these blood clots are formed in the left atrial appendage. The risk of blood clot formation is reduced with the use of anticoagulants. The patients who cannot take anticoagulants due to an increased bleeding risk can undergo percutaneous left atrial appendage (LAA) closure. A Watchman device is used for this purpose. LAA closure with the Watchman device is associated with some adverse effects, and one of them is device-related thrombus. Currently, there are no specific guidelines for the management of device-related thrombus. We present a case of Watchman device-related thrombus which developed 16 hours after the device placement. We will also discuss various options for the management of acute thrombosis.
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Cerletti, Chiara, Giovanni De Gaetano, and Roberto Lorenzet. "PLATELET-LEUKOCYTE INTERACTIONS : MULTIPLE LINKS BETWEEN INFLAMMATION , BLOOD COAGULATION AND VASCULAR RISK." Mediterranean Journal of Hematology and Infectious Diseases 2, no. 3 (August 6, 2010): e2010023. http://dx.doi.org/10.4084/mjhid.2010.023.
Повний текст джерелаАнотація:
The aim of this review is to summarize the contribution of platelets and leukocytes and their interactions in inflammation and blood coagulation and its possible relevance in the pathogenesis of thrombosis. There is some evidence of an association between infection/inflammation and thrombosis. This is likely a bidirectional relationship. The presence of a thrombus may serve as a nidus of infection. Vascular injury indeed promotes platelet and leukocyte activation and thrombus formation and the thrombus and its components facilitate adherence of bacteria to the vessel wall. Alternatively, an infection and the associated inflammation can trigger platelet and leukocyte activation and thrombus formation. In either case platelets and leukocytes co-localize and interact in the area of vascular injury, at sites of inflammation and/or at sites of thrombosis. Following vascular injury, the subendothelial tissue, a thrombogenic surface, becomes available for interaction with these blood cells. Tissue factor, found not only in media and adventitia of the vascular wall, but also on activated platelets and leukocytes, triggers blood coagulation. Vascular-blood cell interactions, mediated by the release of preformed components of the endothelium, is modulated by both cell adhesion and production of soluble stimulatory or inhibitory molecules that alter cell function: adhesion molecules regulate cell-cell contact and facilitate the modulation of biochemical pathways relevant to inflammatory and/or thrombotic processes.
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Ali, Sajid, Justin Ugwu, and Yousuf Kanjwal. "A Stunning Left Atrial Appendage Thrombus." Cardiology 134, no. 4 (2016): 394–97. http://dx.doi.org/10.1159/000444166.
Повний текст джерелаАнотація:
Background: Left atrial appendage thrombus formation is a known major complication of atrial fibrillation and atrial flutter which increases the risk of embolism and stroke. This risk of thrombosis is greatly increased with a lack of anticoagulation. After conversion to a normal sinus rhythm in these arrhythmias, the risk of thrombus formation in the left atrium persists through a phenomenon termed atrial myocardial stunning. Case: We present the case of a patient who previously underwent successful pulmonary vein isolation and was found to be in typical isthmus-dependent atrial flutter with a questionable recurrence of atrial fibrillation. The decision was made to return for atrial flutter ablation and for evaluation of prior pulmonary vein isolation. Initially, a transesophageal echocardiogram showed a normal ejection fraction, biatrial enlargement and no left atrial appendage thrombus. Ablation of the cavotricuspid isthmus was successfully accomplished with documented bidirectional block. A transesophageal echocardiogram probe was still in place prior to planned transseptal puncture for the evaluation of pulmonary veins. A large thrombus was now observed filling the left atrial appendage. Conclusion and Objective: Atrial stunning is a transient atrial contractile dysfunction that occurs whether sinus rhythm is restored spontaneously, electrically, pharmacologically or by ablation. We know after conversion that there is higher propensity to increased spontaneous echogenic contrast and decreased velocities; however, we do not have documented knowledge of exactly how soon after the conversion to a sinus rhythm a thrombus may be seen. We demonstrate a case of acute left atrial appendage thrombus formation immediately following the successful ablation of isthmus-dependent atrial flutter. Our report validates the belief that strategies of not interrupting anticoagulation prior to the conversion of these arrhythmias should be implemented.
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Kim, Keunyoung, Youn-Kyeong Chang, Yiying Bian, Ok-Nam Bae, Kyung-Min Lim, and Jin-Ho Chung. "Pro-Coagulant and Pro-Thrombotic Effects of Paclitaxel Mediated by Red Blood Cells." Thrombosis and Haemostasis 118, no. 10 (September 20, 2018): 1765–75. http://dx.doi.org/10.1055/s-0038-1670659.
Повний текст джерелаАнотація:
Background Paclitaxel is one of the most widely used anti-cancer drugs, but numerous case reports of thrombotic events in the cancer patients using paclitaxel raise concern over its pro-thrombotic risk. Materials and Methods We investigated whether paclitaxel can elicit pro-thrombotic properties in red blood cells (RBCs) through phosphatidylserine (PS) exposure and microvesicle (MV) release. Results In freshly isolated human RBCs, paclitaxel induced thrombin generation through PS exposure and MV release, whereas either coagulation factors or platelets were unaffected. Paclitaxel-induced PS exposure in RBC was mediated by scramblase activation which was induced by calcium-independent protein kinase C (PKC)ζ activation. Paclitaxel also increased RBC-endothelial cell adhesion and RBC aggregate formation which can also contribute to thrombosis. Indeed, intravenous administration of paclitaxel to rats induced PS exposure and PKCζ activation in RBCs in vivo which ultimately promoted venous thrombus formation. Conclusion These results demonstrated that paclitaxel may elicit pro-thrombotic properties in RBCs through PS exposure and MV release, which can ultimately promote thrombus formation.
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Li, Yuan, Hongyu Wang, Yifeng Xi, Anqiang Sun, Xiaoyan Deng, Zengsheng Chen, and Yubo Fan. "A New Mathematical Numerical Model to Evaluate the Risk of Thrombosis in Three Clinical Ventricular Assist Devices." Bioengineering 9, no. 6 (May 27, 2022): 235. http://dx.doi.org/10.3390/bioengineering9060235.
Повний текст джерелаАнотація:
(1) Background: Thrombosis is the main complication in patients supported with ventricular assist devices (VAD). Models that accurately predict the risk of thrombus formation in VADs are still lacking. When VADs are clinically assisted, their complex geometric configuration and high rotating speed inevitably generate complex flow fields and high shear stress. These non-physiological factors can damage blood cells and proteins, release coagulant factors and trigger thrombosis. In this study, a more accurate model for thrombus assessment was constructed by integrating parameters such as shear stress, residence time and coagulant factors, so as to accurately assess the probability of thrombosis in three clinical VADs. (2) Methods: A mathematical model was constructed to assess platelet activation and thrombosis within VADs. By solving the transport equation, the influence of various factors such as shear stress, residence time and coagulation factors on platelet activation was considered. The diffusion equation was applied to determine the role of activated platelets and substance deposition on thrombus formation. The momentum equation was introduced to describe the obstruction to blood flow when thrombus is formed, and finally a more comprehensive and accurate model for thrombus assessment in patients with VAD was obtained. Numerical simulations of three clinically VADs (CH-VAD, HVAD and HMII) were performed using this model. The simulation results were compared with experimental data on platelet activation caused by the three VADs. The simulated thrombogenic potential in different regions of MHII was compared with the frequency of thrombosis occurring in the regions in clinic. The regions of high thrombotic risk for HVAD and HMII observed in experiments were compared with the regions predicted by simulation. (3) Results: It was found that the percentage of activated platelets within the VAD obtained by solving the thrombosis model developed in this study was in high agreement with the experimental data (r² = 0.984), the likelihood of thrombosis in the regions of the simulation showed excellent correlation with the clinical statistics (r² = 0.994), and the regions of high thrombotic risk predicted by the simulation were consistent with the experimental results. Further study revealed that the three clinical VADs (CH-VAD, HVAD and HMII) were prone to thrombus formation in the inner side of the secondary flow passage, the clearance between cone and impeller, and the corner region of the inlet pipe, respectively. The risk of platelet activation and thrombus formation for the three VADs was low to high for CH-VAD, HVAD, and HM II, respectively. (4) Conclusions: In this study, a more comprehensive and accurate thrombosis model was constructed by combining parameters such as shear stress, residence time, and coagulation factors. Simulation results of thrombotic risk received with this model showed excellent correlation with experimental and clinical data. It is important for determining the degree of platelet activation in VAD and identifying regions prone to thrombus formation, as well as guiding the optimal design of VAD and clinical treatment.
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Brickner, M. Elizabeth, Daniel B. Friedman, Carlos G. Cigarroa, and Paul A. Grayburn. "Relation of thrombus in the left atrial appendage by transesophageal echocardiography to clinical risk factors for thrombus formation." American Journal of Cardiology 74, no. 4 (August 1994): 391–93. http://dx.doi.org/10.1016/0002-9149(94)90409-x.
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Zsarnóczay, Emese, Lili Száraz, Anikó Ilona Nagy, Béla Merkely, Pál Maurovich-Horvat, and Judit Simon. "Left atrial appendage morphology and the risk of stroke." Romanian Journal of Cardiology 31, no. 1 (March 31, 2021): 46–51. http://dx.doi.org/10.47803/rjc.2021.31.1.46.
Повний текст джерелаАнотація:
In patients with non-valvular atrial fibrillation (AF) the risk of stroke is fi ve times higher than in patients with sinus rhythm. Moreover, stroke is likely to be more severe in the AF patient population. Left atrial appendage (LAA) is the most common source of emboli in AF-related stroke. LAA thrombus is present in 15% of AF patients. Therefore, numerous studies aimed to evaluate the role of LAA structure and function in stroke formation. Higher LAA volume and bigger LAA orifice have been reported to be associated with increased risks of stroke. Moreover, not only the size, but also the shape of the LAA influences thrombus formation. The presence of an obvious bend in the proximal part of the dominant LAA lobe, described as chicken wing LAA morphology has been reported to be protective against stroke. However, other studies are not consistent with this fi nding and there is no consensus about LAA morphology categories. LAA has reservoir, contractile, electric and endocrine functions, that can provide essential information about the risk of clot formation and embolic events. Decreased LAA flow velocity, reflecting lower LAA contractility has been described to be associated with higher stroke risk. All in all, even if the LAA plays an important role in stroke formation, there are controversial literature data, therefore further studies are needed to evaluate the underlying mechanisms.
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Springer, Adrian, Ruben Schleberger, Florian Oyen, Boris A. Hoffmann, Stephan Willems, Christian Meyer, Florian Langer, et al. "Genetic and Clinical Predictors of Left Atrial Thrombus: A Single Center Case-Control Study." Clinical and Applied Thrombosis/Hemostasis 27 (January 1, 2021): 107602962110211. http://dx.doi.org/10.1177/10760296211021171.
Повний текст джерелаАнотація:
Left atrial (LA) thrombus formation is the presumed origin of thromboembolic complications in patients with atrial fibrillation (AF). Beyond clinical risk factors, the factors causing formation of LA thrombi are not well known. In this case-control study, we analyzed clinical characteristics and genetic thrombophilia markers (factor V Leiden (FVL), prothrombin G20210A (FIIV), Tyr2561 variant of von Willebrand factor (VWF-V)) in 42 patients with AF and LA thrombus (LAT) and in 68 control patients with AF without LAT (CTR). Patients with LAT had more clinical conditions predisposing to stroke (mean CHA2DS2-VASc-score 3.4 ± 1.5 vs. 1.9 ± 1.4; P < 0.001), a higher LA volume (96 ± 32 vs. 76 ± 21 ml, P = 0.002) and lower LA appendage emptying velocity (0.21 ± 0.11vs. 0.43 ± 0.19 m/s, P < 0.001). Prevalence of FVL, FIIV and VWF-V mutations was not different, but in the subgroup of patients <65 years (y) there was a tendency for a higher incidence of VWF-V with a prevalence of 27% (LAT <65 y) vs. 7% (CTR <65 y, P = 0.066). These findings warrant further investigation of the VWF-V as a risk factor for LA thrombogenesis in younger patients.
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Bertog, Stefan, and Horst Sievert. "Left atrial appendage closure: prevalence and risk of device-associated thrombus formation." Cardiovascular Diagnosis and Therapy 9, no. 1 (February 2019): 104–9. http://dx.doi.org/10.21037/cdt.2018.10.05.
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