Thrombus Resolution Research Articles

Anticoagulation in Pediatric Patients

The use of antithrombotic agents is increasing in infants, children and adolescents. The more recent routine inclusion of children in FDA-monitored clinical trials has propelled the rapid accumulation of safety and efficacy data on these agents in pediatric patients. Antithrombotic agents in current use include indirect or antithrombin-dependent anticoagulants, intravenous direct thrombin inhibitors, direct oral anticoagulants (DOACs) targeting thrombin or factor Xa, antiplatelet agents and thrombolytic therapies. Each class of antithrombotic agent has distinct mechanisms of action, clearance routes, half-lives, safety and dosing. Anticoagulant efficacy is dependent upon the specific clinical indication and stability of the pediatric patient. Duration of anticoagulant course is also dependent upon the clinical indication as well as rate of thrombus resolution. This manuscript reviews the mechanism of action, route of administration, route of clearance and plasma half-life for the antithrombotic agents in current use in children. Use of anticoagulation in the context of thrombolytic therapy is discussed.

Meta-Analysis of the Safety and Efficacy of Direct Oral Anticoagulants for the Treatment of Left Ventricular Thrombus.

Literature on the preferred anticoagulant for treating left ventricular thrombus (LVT) is lacking. Thus, our objective was to compare the efficacy of DOACs versus warfarin in treating LVT. Databases were searched for RCTs and adjusted observational studies that compared DOAC versus warfarin through March 2024. The primary efficacy outcomes of interest were LVT resolution, systemic embolism, composite of stroke, and TIA. The primary safety outcomes encompassed all-cause mortality and bleeding events. Our meta-analysis including 31 studies demonstrated that DOAC use was associated with higher odds of thrombus resolution (OR: 1.08, 95% CI: 0.86-1.31, p: 0.46). A statistically significant reduction in the risk of stroke/TIA was observed in the DOAC group versus the warfarin group (OR: 0.65, 95% CI: 0.48-0.89, p: 0.007). Furthermore, statistically significant reduced risks of all-cause mortality (OR: 0.68, 95% CI: 0.47-0.98, p: 0.04) and bleeding events (OR: 0.70, 95% CI: 0.55-0.89, p: 0.004) were observed with DOAC use as compared to warfarin use. Compared to VKAs, DOACs are noninferior as the anticoagulant of choice for LVT treatment. However, further studies are warranted to confirm these findings.

Factors predicting resolution of left ventricular thrombus in different time windows after myocardial infarction

BackgroundLeft ventricular thrombus (LVT) is a serious complication after myocardial infarction. However, due to its asymptomatic nature, early detection is challenging. We aimed to explore the differences in clinical correlates of LVT found in acute to subacute and chronic phases of myocardial infarction.MethodsWe collected data from 153 patients who were diagnosed with LVT after myocardial infarction at the Affiliated Hospital of Qingdao University from January 2013 to December 2022. Baseline information, inflammatory markers, transthoracic echocardiograph (TTE) data and other clinical correlates were collected. Patients were categorized into acute to subacute phase group (< 30 days) and chronic phase group (30 days and after) according to the time at which echocardiograph was performed. The resolution of thrombus within 90 days is regarded as the primary endpoint event. We fitted logistic regression models to relating clinical correlates with phase-specific thrombus resolution.ResultsFor acute to subacute phase thrombus patients: C-reactive protein levels (OR: 0.95, 95% CI: 0.918–0.983, p = 0.003) were significantly associated with thrombus resolution. For chronic phase thrombus patients: anticoagulant treatment was associated with 5.717-fold odds of thrombus resolution (OR: 5.717, 95% CI: 1.543–21.18, p = 0.009).ConclusionsHigher levels of CRP were associated with lower likelihood of LVT resolution in acute phase myocardial infarction; Anticoagulant therapy is still needed for thrombus in the chronic stage of myocardial infarction.

Repeated acute coronary syndrome caused by a mind-bending mural thrombus in ascending aorta: a case report and review of the literature

BackgroundAcute coronary syndrome due to coronary artery embolism in the setting of ascending aortic thrombus is an uncommon condition, even rarer when there is no aortic pathology such as aneurysm, severe atherosclerosis, aortic dissection, or thrombophilia (whether inherited or acquired).Case presentationWe report a case of a 58-year-old male presented with acute chest pain, electrocardiogram showing non-ST-elevation acute coronary syndrome. The computed tomography angiography of coronary artery revealed a mural thrombus in the proximal part of ascending aorta, located above the left coronary artery ostium, without any aortic pathologies. With the exception of hypertension and cigarette smoking, no other risk factors were identified in this patient that may increase the risk of thrombosis. Given the life-threatening risk of interventional therapy and surgery, the patient determinedly opted for anticoagulant and dual antiplatelet therapy. Then he experienced the reoccurrence of chest pain after 6-day treatment, progressed to anterior and inferior ST-segment elevation myocardial infarction. Coronary artery embolism originating from the ascending aortic thrombus was suspected. Considering the hemodynamic instability of the patient, the medical treatment was continued and bridged to warfarin and aspirin after discharge. Follow-up computed tomography angiography at 6 months showed no obstruction in coronary artery and complete resolution of the thrombus. No thromboembolic events occurred henceforward.ConclusionsAcute coronary syndrome could be a manifestation of secondary coronary embolism due to ascending aortic thrombus. Currently, there is no standardized guideline for the treatment of aortic mural thrombus, individualized treatment is recommended. When surgical therapy is not applicable for the patient, anticoagulation and dual antiplatelet treatment are alternative treatments that may successfully lead to the resolution of the aortic thrombus.

Comparative effectiveness of different management strategies for left atrial appendage thrombus in patients on optimal NOAC therapy

Abstract Background Left atrial appendage (LAA) thrombus is the primary cause of stroke and systemic embolism in atrial fibrillation (AF). Novel oral anticoagulants (NOACs) effectively reduce the prevalence of LAA thrombosis and stroke risk. Nonetheless, there is no clear advice for patients with a NOAC-resistant thrombus, necessitating individualized decision-making without strong support of the current guidelines. Aims To analyze patients diagnosed with an LAA thrombus despite adequate NOAC therapy and to compare the efficacy of various therapeutic strategies in achieving thrombus resolution. Methods We retrospectively analyzed patients scheduled for cardioversion or catheter ablation of AF between 2014 and 2023 who were diagnosed with LAA thrombus despite being on optimal NOAC therapy. These patients underwent follow-up transesophageal echocardiography (TEE) or cardiac CT angiography. Changes in treatment modalities were divided into four groups: transition to an alternative NOAC, switch to a vitamin K antagonist (VKA), the addition of an antiplatelet agent, or the deliberate maintenance of the current treatment. Results We analyzed the data of 90 patients comprising 103 cycles of treatment. The patients were either on rivaroxaban (41%), apixaban (32%), dabigatran (15%) or on edoxaban (12%) at the time of the initial TEE. A change to a different NOAC was observed in 37% of cases, transition to a VKA in 22%, supplementation with antiplatelet therapy in 16%, while deliberate absence of treatment modification in 25% of cases. Subsequent follow-up TEE (or CT angiography in a minority of cases) was performed at a median of 68 [43 – 94] days from the baseline evaluation. Successful thrombus resolution was achieved in 72% of cases. Evaluation of therapeutic strategies revealed that any modification of treatment was three times more effective than deliberate no change in treatment; thrombus resolution was observed in 60 (81%) vs. 17 (59%) cases (OR 3.03 [1.18 - 7.75], p = 0.021). Nevertheless, no particular strategy demonstrated superior efficacy over others. Conclusions Resolution of LAA thrombus in patients already on adequate NOAC treatment may require a revision of the prior anticoagulation strategy; however, none of the commonly employed strategies appears to exhibit distinct superiority over the rest.

HALF DOSE THROMBOLYSIS IN INTERMEDIATE – HIGH RISK PULMONARY EMBOLISM WITH TRICUSPID VALVE MOBILE MASS: A BAIL OUT STRATEGY

Abstract A 82–year–old previously healthy male was referred to the emergency department complaining sudden onset dyspnea and witnessed syncope complicated by head trauma. Recurrent dizziness occurred previously. No history or drug consumption noted. On admission: heart rate 90 beats/min, blood pressure 110/60 mmHg, respiratory rate 25 breaths/min, oxygen saturation 87% in room air, normal body temperature. No lower extremities tenderness or swelling reported. Consistent with peripheral blood oxygen saturation levels, arterial blood gas analysis showed hypoxemia and respiratory alkalosis. Laboratory exams were significant for thrombocytopenia (89.000 cells/L), elevated cardiac troponin T levels (222 ng/L) and natriuretic peptide (NT pro–BNP 3944 pg/mL). Head CT excluded acute cerebral hemorrhage. At the electrocardiogram, signs of RV strain were present (biphasic T–waves in V1–V3 leads, S1–Q3–T3). Transthoracic echocardiography (TTE) showed dilated RV with hypokinetic free wall, “D–shaped” LV, “60/60” sign and a mobile filiform mass crossing the tricuspid valve plan in the right atrium (fig. 1). The patient did not present structural valvular abnormalities or endocarditis–related risk factors. CT pulmonary angiography detected a “saddle” PE and extensive thrombosis in inferior vena cava. After unfractioned heparin (UFH) bolus, the patient was transferred to our intensive care unit and balancing risks and benefits the chosen treatment option consisted in half dose systemic thrombolysis (50 mg rtPA in 60’’; 10 mg as loading dose in 2’). Because of potential harmful effects in thrombocytopenia and recent head trauma, UFH was temporarily withheld and started again after 1 hour. The day after, a beside TTE showed complete tricuspid thrombus resolution, a significant decrease in RV/LV ratio and systolic pulmonary artery pressure (fig. 2). Apart from small hematomas, no bleedings were reported. The patient was shifted to the ward on the next day and following course was uneventful. On day 4 a direct oral anticoagulant (Dabigatran 110 mg) was started. Abdominal and inferior limb–deep–venous ultrasound were both negative for pathological reports. A total body CT was scheduled to exclude silent malignancies at discharge. Take home message: in intermediate–high risk PE, half dose systemic fibrinolysis strategy is controversial since its potential benefit is counterbalanced by concerns about major bleedings, but increasing data suggest its efficacy with low risk profile.

Abstract 2094: Sex Differences In Venous Thrombus Resolution In Mice With Metabolic Syndrome

Introduction: Metabolic syndrome (MS) is highly prevalent and have been shown to be associated with mitochondrial impairment and increased cardiovascular and thrombotic risk. It is less understood how MS impacts venous thrombosis and thrombus resolution and the effect of sex as a biological variable on these processes. We hypothesize that mice with MS will have impaired thrombus resolution, particularly males compared to females. Methods: We used a model of diet-independent MS where wildtype FVB mice that have been born to high fat diet fed mothers exhibit multiple organ manifestations of MS. 29 adult mice underwent surgical induction of deep vein thrombosis (DVT) via inferior vena cava ligation (stasis model) resulting in thrombi formation until day 3 and thrombus resolution until day 7. Immunohistochemistry was used to assess vascular tissue remodeling. Results: Comparing control mice to mice born to obese mothers after DVT, there were no significant differences in thrombus weights on day 3 (1.83±.62 vs 1.48±.53 g/kg, p =.186), suggesting a similar initial thrombus burden. However, mice born to obese mothers had significantly impaired thrombus resolution at day 7 (1.85±.53 vs 1.14±.42 g/kg, Student’s t-test p =.007) as compared to control mice born from mothers fed a regular diet. Importantly, thrombus weights were significantly larger in male offspring of obese mothers as compared to females (2.17±.67 vs 1.43±.26 g/kg, Student’s t test p =.013). Additionally, histology analyses showed associations with increased vein wall collagen deposition (Masson’s trichrome) (25±3 vs 13±4% area stained, Student’s t test, p =.0018) and neovascularization (smooth muscle cell actin) within the thrombi of mice with signs of MS as compared to control mice (70+/-10 vs 40+/-8% area stained, Student’s t test, p =.009). Conclusions: Wildtype mice with diet-independent MS demonstrate diminished thrombus resolution, with males having significantly larger thrombi than females. Impaired DVT resolution was associated with decreased tissue remodeling within the thrombi. These data suggest that MS may induce negative tissue remodeling decreasing thrombus involution and increasing vein wall fibrosis, factors that may increase the likelihood of post thrombotic syndrome.

Impact of left atrial appendage flow velocity on thrombus resolution and clinical outcomes in patients with atrial fibrillation and silent left atrial thrombi: insights from the LAT study.

Blood stasis is crucial in developing left atrial (LA) thrombi. LA appendage peak flow velocity (LAAFV) is a quantitative parameter for estimating thromboembolic risk. However, its impact on LA thrombus resolution and clinical outcomes remains unclear. The LAT study was a multicentre observational study investigating patients with atrial fibrillation (AF) and silent LA thrombi detected by transoesophageal echocardiography (TEE). Among 17 436 TEE procedures for patients with AF, 297 patients (1.7%) had silent LA thrombi. Excluding patients without follow-up examinations, we enrolled 169 whose baseline LAAFV was available. Oral anticoagulation use increased from 85.7% at baseline to 97.0% at the final follow-up (P < 0.001). During 1 year, LA thrombus resolution was confirmed in 130 (76.9%) patients within 76 (34-138) days. Conversely, 26 had residual LA thrombi, 8 had thromboembolisms, and 5 required surgical removal. These patients with failed thrombus resolution had lower baseline LAAFV than those with successful resolution (18.0 [15.8-22.0] vs. 22.2 [17.0-35.0], P = 0.003). Despite limited predictive power (area under the curve, 0.659; P = 0.001), LAAFV ≤ 20.0 cm/s (best cut-off) significantly predicted failed LA thrombus resolution, even after adjusting for potential confounders (odds ratio, 2.72; 95% confidence interval, 1.22-6.09; P = 0.015). The incidence of adverse outcomes including ischaemic stroke/systemic embolism, major bleeding, or all-cause death was significantly higher in patients with reduced LAAFV than in those with preserved LAAFV (28.4% vs. 11.6%, log-rank P = 0.005). Failed LA thrombus resolution was not rare in patients with AF and silent LA thrombi. Reduced LAAFV was associated with failed LA thrombus resolution and adverse clinical outcomes.

Comparing clinical outcomes of vitamin K antagonists vs non-vitamin K antagonists in anticoagulant therapy for mesenteric venous thrombosis

ObjectiveNon-vitamin K antagonist oral anticoagulants have shown similar efficacy and lower bleeding rates than vitamin K antagonists for venous thromboembolism. However, this has not been proven in mesenteric vein thrombosis. This study aimed to compare the clinical outcomes of vitamin K antagonists and non-vitamin K antagonist oral anticoagulants. MethodsBetween January 2014 and July 2022, mesenteric vein thrombosis was diagnosed on computed tomography in 225 patients in a tertiary hospital. Among them, a total of 44 patients who underwent long-term anticoagulation therapy over 3 months were enrolled in this study. Patients were divided into two groups based on the anticoagulant used: vitamin K antagonists (Group 1, n = 21) and non-vitamin K antagonist oral anticoagulants (Group 2, n = 23). The efficacy outcomes were symptom recurrence and thrombus resolution on follow-up computed tomography, and the safety outcome was bleeding complications. ResultsThe median age of the patients was 56 years (range, 46-68 years), and 52% were men. The most common risk factors were unprovoked intra-abdominal infections (30%). The median duration of anticoagulation therapy was 13 months (20 months in Group 1 vs 6 months in Group 2; P = .076). Of the 44 patients, 17 (39%) received the standard treatment. The median follow-up period was longer in Group 1 than in Group 2 (57 vs 28 months; P = .048). No recurrence of mesenteric vein thrombosis-related symptoms were observed in either group. The median duration of follow-up computed tomography was 31 months (42 months in Group 1 vs 18 months in Group 2; P = .064). Computed tomography revealed complete thrombus resolution, partial resolution, and no changes in 71%, 19%, and 10%, respectively (P = .075). Regarding bleeding complications, varix bleeding and melena developed in two patients in Group 2, and anticoagulation treatment thereafter ceased. ConclusionsDespite the short follow-up duration in the non-vitamin K antagonist oral anticoagulants group, there was no clinically significant difference in the thrombus resolution rate or bleeding complications when compared with the vitamin K antagonists group. Although research on the long-term effects of non-vitamin K antagonist oral anticoagulants in patients is limited, non-vitamin K antagonist oral anticoagulants can be considered an alternative to conventional treatments.

Abstract 1067: Floating Through The Aorta; Aortic Thrombus Takes It Course

Background: Aortic thrombus is an uncommon condition that is usually discovered as an incidental finding but in rare cases can be the cause of fatal conditions. The reported incidence of its intramural, pedunculated and floating types. The most common location is reported to be the descending aorta followed by the aortic arch. The pathophysiology remains unclear but possible predisposing factors include atherosclerosis, hypercoagulability disorders, malignancy, dissections, aneurysm, chronic inflammatory states, substance use and chronic steroid use. Treatment can vary from anticoagulation to thrombolysis and surgical removal based on the clinical presentation. Clinical presentation: 48-year-old male with a past medical history of hyperparathyroidism presented with three days of nausea, vomiting and lower abdominal pain. CT abdomen showed pancreatic inflammation and he was admitted for pancreatitis. MRCP was completed to evaluate for organic causes of pancreatitis which revealed left renal infarction. CTA C/A/P was done to evaluate infarction and was found to have large 1.5 x 1.1 x 2.1 cm mural thrombus, partially free-floating in distal thoracic aortic arch/proximal descending segment and focal narrowing at the origin left renal artery presumed to be of embolic origin. He was started on heparin drip for the rest of his hospital course and continued to improve. Hypercoagulable work up was unrevealing for any specific etiologies of the thrombus. Pancreatitis was determined as the presumed cause of thrombus as thromboembolism is a known possible complication of pancreatitis and splenic vein thrombosis may be seen in up to 12% of patients .Surgical intervention was initially considered, however repeat CT angiogram of chest/abdomen prior to discharge showed near resolution of thrombus with stable left renal infarct. He was discharged with apixaban and was recommended to follow-up outpatient. Conclusion: Aortic thrombus is rare due to the constant flow of pressure within the aorta. Early detection and management are crucial to avoid embolization which can lead to end organ dysfunction, limb ischemia, mesenteric ischemia, and stroke. DOAC anticoagulation is a viable and efficient therapy option if surgical intervention is not feasible

Abstract 2093: Quantitative Assessment Of Venous Thrombus Resolution And Macrophage Content In Mice Using Ferumoxytol-enhanced Magnetic Resonance Imaging

Objective: The objective of this study is to explore the feasibility of ferumoxytol-enhanced magnetic resonance imaging (Fe-MRI) for noninvasive assessment of deep venous thrombus (DVT) resolution and macrophage content in resolving thrombi in a surgical murine model of inferior vena cava (IVC) ligation. Background: Imaging evaluation of acute DVT or post-thrombotic syndrome (PTS) in animal or clinical models is limited to assessment of anatomy. We hypothesize that Fe-MRI, used to evaluate macrophage content in other inflammatory diseases, can be useful to evaluate thromboinflammatory features after DVT. Methods: Nineteen wild-type CD-1 mice underwent surgical IVC ligation to induce DVT. Mice received either saline or administered 5 mg/kg of 14E11, a Factor XI inhibitor, before the procedure. Fe-MRI was performed from days 6-7 after ligation to evaluate thrombus volume, perfusion and macrophage content via T2, and T2 *-weighted images. Mice were euthanized at days 3-15 after surgery. The thrombi and adjacent vein walls were excised, weighed, formalin fixed, and paraffin embedded for histological analysis. Specimens were stained with specific antibodies to evaluate macrophage activity, collagen deposition, neovascularization, and recanalization. Significance was determined using the Mann-Whitney U or Student’s t-test. Results: After IVC-ligation in control mice, thrombus weights decreased by 59% from day 3 to day 15. FXI inhibition led to reduced macrophage content in both thrombus (p = .008) and vein wall (p = .01), decreased thrombus volume (p = .03), decreased thrombus mass (p = .01) and impaired thrombus perfusion (p = .01) compared to control mice. Iba1 staining supported these findings, showing significantly reduced macrophage presence in thrombi (p = .02). Conclusions: Fe-MRI T2 and T2 * relaxation times can be used to characterize and quantify post-thrombotic changes of perfusion, macrophage activity, and volume over time in a surgical mouse model of venous thrombosis. This approach could lead to better quantification of in vivo inflammation correlating monocyte and macrophage activity within resolving thrombi and veins and may serve as a useful tool in research and clinically in the evaluation of DVT or PTS.

Endothelial receptor proteins in acute venous thrombosis and delayed thrombus resolution in cerebral sinus vein thrombosis

Background and purposeCerebral sinus venous thrombosis (CSVT) is a rare but life-threatening disease and its diagnosis remains challenging. Blood biomarkers, including D-Dimer are currently not recommended in guidelines. Soluble endothelial receptor proteins (sICAM-1, sPECAM-1 and sVCAM-1) have been shown to be promising diagnostic biomarkers in deep vein thrombosis (DVT) and pulmonary embolism (PE). Therefore, we examined endothelial receptor proteins as potential biomarkers for detecting CSVT.MethodsIn this bi-centre, prospective study, we quantified D-Dimer as well as sICAM-1, sPECAM-1 and sVCAM-1 in plasma of patients with clinically suspected CSVT managed in the neurological emergency department (ED) of a tertiary care hospital. All patients underwent cerebral magnetic resonance imaging (MRI) and were followed up after 3, 6 and 12 months to detect thrombus resolution.ResultsTwenty-four out of 75 (32%) patients with clinically suspected CSVT presenting with headache to the ED were diagnosed with acute CSVT. These patients had a mean age of 45 ± 16 years and 78% were female. In patients with CSVT, mean baseline D-dimer (p < 0.001) and sPECAM-1 (p < 0.001) were significantly higher compared to patients without CSVT. The combination of D-Dimer and sPECAM-1 yielded the best ROC-AUC (0.994; < 0.001) with a negative predictive value of 95.7% and a positive predictive value of 95.5%. In addition, higher baseline sPECAM-1 levels (> 198 ng/ml) on admission were associated with delayed venous thrombus resolution at 3 months (AUC = 0.83).ConclusionsPECAM-1 in combination with D-Dimer should be used to improve the diagnostic accuracy of acute CSVT and sPECAM-1 may predict long-term outcome of CSVT. Confirmatory results are needed in other settings in order to show their value in the management concept of CSVT patients.

Syringe-assisted test-aspiration with mechanical aspiration thrombectomy results in good safety and short-term outcomes in the treatment of patients with deep venous thrombosis.

To evaluate the short-term outcomes and safety of syringe-assisted test-aspiration with mechanical aspiration thrombectomy in the treatment of deep venous thrombosis. This was a single-center, retrospective study of hospitalized patients with iliofemoral and/or inferior vena caval deep venous thrombosis, excluding those with pulmonary embolism. We collected the following patient data from the electronic medical records: age, sex, provoked/unprovoked deep venous thrombosis, symptom duration, thrombosed segments, and the presence of a tumor, thrombophilia, diabetes, and/or iliac vein compression syndrome. Venography and computed tomographic venography were performed in all patients before the procedure. All patients underwent syringe-assisted test-aspiration with mechanical aspiration thrombectomy under local anesthesia and sedation, and all received low-molecular-weight heparin peri-operatively. All patients underwent implantation of an inferior vena caval filter. Rivaroxaban was administered post-procedure, instead of heparin, for 3-6 months, with lower extremity compression. Overall, 29 patients with deep venous thrombosis underwent syringe-assisted test-aspiration with mechanical aspiration thrombectomy from January 2022 to October 2022 in our institution. Technical success (>70% thrombus resolution) was achieved in all patients, and using a single procedure in 25/29 patients (86%). Concomitant stenting was performed in 18/29 (62%) of the patients, and 21/29 (69%) underwent angioplasty. The median (interquartile range) procedure time was 110min (100-122), the median intra-operative bleeding volume was 150mL (120-180), and the median decrease in the hemoglobin concentration from pre- to post-operative was 7g/L (4-14). The median follow-up duration was 7 months (5-9). All patients obtained symptomatic relief, and 27/29 achieved near-remission or full remission (combined total). No patients experienced peri-operative bleeding complications, or symptom recurrence or post-thrombectomy syndrome during follow-up. The short-term outcomes following syringe-assisted test-aspiration with mechanical aspiration thrombectomy in the treatment of deep venous thrombosis were excellent, and the procedure was safe.

Time-dependent ultrastructural changes during venous thrombogenesis and thrombus resolution

BackgroundDeep vein thrombosis is a common vascular event that can result in debilitating morbidity and even death due to pulmonary embolism. Clinically, patients with faster resolution of a venous thrombus have improved prognosis, but the detailed structural information regarding changes that occur in a resolving thrombus over time is lacking. ObjectivesTo define the spatial-morphologic characteristics of venous thrombus formation, propagation, and resolution at the submicron level over time. MethodsUsing a murine model of stasis-induced deep vein thrombosis along with scanning electron microscopy and immunohistology, we determine the specific structural, compositional, and morphologic characteristics of venous thrombi formed after 4 days and identify the changes that take place during resolution by day 7. Comparison is made with the structure and composition of venous thrombi formed in mice genetically deficient in plasminogen activator inhibitor type 1. ResultsAs venous thrombus resolution progresses, fibrin exists in different structural forms, and there are dynamic cellular changes in the compositions of leukocytes, platelet aggregates, and red blood cells. Intrathrombus microvesicles are present that are not evident by histology, and red blood cells in the form of polyhedrocytes are an indicator of clot contraction. Structural evidence of fibrinolysis is observed early during thrombogenesis and is accelerated by plasminogen activator inhibitor type 1 deficiency. ConclusionThe results reveal unique, detailed ultrastructural and compositional insights along with documentation of the dynamic changes that occur during accelerated resolution that are not evident by standard pathologic procedures and can be applied to inform diagnosis and effectiveness of thrombolytic treatments to improve patient outcomes.

Circulating miR-let7a levels predict future diagnosis of chronic thromboembolic pulmonary hypertension

Distinct patterns of circulating microRNAs (miRNAs) were found to be involved in misguided thrombus resolution. Thus, we aimed to investigate dysregulated miRNA signatures during the acute phase of pulmonary embolism (PE) and test their diagnostic and predictive value for future diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH). Microarray screening and subsequent validation in a large patient cohort (n = 177) identified three dysregulated miRNAs as potential biomarkers: circulating miR-29a and miR-720 were significantly upregulated and miR-let7a was significantly downregulated in plasma of patients with PE. In a second validation study equal expression patterns for miR-29a and miR-let7a regarding an acute event of recurrent venous thromboembolism (VTE) or deaths were found. MiR-let7a concentrations significantly correlated with echocardiographic and laboratory parameters indicating right ventricular (RV) dysfunction. Additionally, circulating miR-let7a levels were associated with diagnosis of CTEPH during follow-up. Regarding CTEPH diagnosis, ROC analysis illustrated an AUC of 0.767 (95% CI 0.54–0.99) for miR-let7a. Using logistic regression analysis, a calculated patient-cohort optimized miR-let7a cut-off value derived from ROC analysis of ≥ 11.92 was associated with a 12.8-fold increased risk for CTEPH. Therefore, miR-let7a might serve as a novel biomarker to identify patients with haemodynamic impairment and as a novel predictor for patients at risk for CTEPH.

Reduced Monocyte and Neutrophil Infiltration and Activation by P-Selectin/CD62P Inhibition Enhances Thrombus Resolution in Mice.

Venous thromboembolism is a major health problem. After thrombus formation, its resolution is essential to re-establish blood flow, which is crucially mediated by infiltrating neutrophils and monocytes in concert with activated platelets and endothelial cells. Thus, we aimed to modulate leukocyte function during thrombus resolution post-thrombus formation by blocking P-selectin/CD62P-mediated cell interactions. Thrombosis was induced by inferior vena cava stenosis through ligation in mice. After 1 day, a P-selectin-blocking antibody or isotype control was administered and thrombus composition and resolution were analyzed. Localizing neutrophils and macrophages in thrombotic lesions of wild-type mice revealed that these cells enter the thrombus and vessel wall from the caudal end. Neutrophils were predominantly present 1 day and monocytes/macrophages 3 days after vessel ligation. Blocking P-selectin reduced circulating platelet-neutrophil and platelet-Ly6Chigh monocyte aggregates near the thrombus, and diminished neutrophils and Ly6Chigh macrophages in the cranial thrombus part compared with isotype-treated controls. Depletion of neutrophils 1 day after thrombus initiation did not phenocopy P-selectin inhibition but led to larger thrombi compared with untreated controls. In vitro, P-selectin enhanced human leukocyte function as P-selectin-coated beads increased reactive oxygen species production by neutrophils and tissue factor expression of classical monocytes. Accordingly, P-selectin inhibition reduced oxidative burst in the thrombus and tissue factor expression in the adjacent vessel wall. Moreover, blocking P-selectin reduced thrombus density determined by scanning electron microscopy and increased urokinase-type plasminogen activator levels in the thrombus, which accelerated caudal fibrin degradation from day 3 to day 14. This accelerated thrombus resolution as thrombus volume declined more rapidly after blocking P-selectin. Inhibition of P-selectin-dependent activation of monocytes and neutrophils accelerates venous thrombosis resolution due to reduced infiltration and activation of innate immune cells at the site of thrombus formation, which prevents early thrombus stabilization and facilitates fibrinolysis.

Dabigatran for Treatment and Secondary Prevention of Venous Thromboembolism in Pediatric Congenital Heart Disease.

Congenital heart disease (CHD) is common in children and associated with greater risk of thrombotic complications. Management of these complications with standard-of-care treatment is suboptimal for these children. The effectiveness and safety of dabigatran were demonstrated in pivotal pediatric studies for the treatment of acute venous thromboembolism (VTE; NCT01895777) and secondary VTE prevention (NCT02197416). We report safety and efficacy outcomes from subgroup analyses of these studies for children with CHD (diagnosed according to local practice) and those without. In NCT01895777, 17/21 (81.0%) and 16/27 (59.3%) patients with CHD (including cyanotic) treated with dabigatran and standard of care, respectively, met the primary end point (complete thrombus resolution, freedom from recurrent VTE, and freedom from VTE-related death; odds ratio [OR], 0.34 [95% CI, 0.08-1.23]). In patients without CHD, 41.0% (n=64) versus 34.9% (n=22) achieved this end point with the respective treatments (OR, 0.77 [95% CI, 0.42-1.41]). Although numerical differences were observed, no heterogeneity in treatment effect of dabigatran on the composite primary end point was detected in patients with and without CHD (interaction P =0.2674). In NCT02197416, recurrent VTE at 12 months occurred in 0/17 patients with CHD versus 3/194 (1.5%) without. No patient with CHD experienced major or clinically relevant nonmajor bleeding events. Data on favorable anticoagulant alternatives for the unmet needs of children with CHD are emerging, and our exploratory results suggest that dabigatran could be an appropriate treatment choice, although challenging sample size limitations in pediatric studies require cautious interpretation of findings. URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01895777, NCT02197416.

Angiogenesis in Chronic Thromboembolic Pulmonary Hypertension: A Janus-Faced Player?

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare form of pulmonary hypertension characterized by the presence of organized thrombi that obstruct pulmonary arteries, ultimately leading to right heart failure and death. Among others, impaired angiogenesis and inflammatory thrombosis have been shown to contribute to the progression of CTEPH. In this review, we summarize the 2-faced nature of angiogenesis in both thrombus formation and resolution in the context of CTEPH and highlight the dual role of angiogenesis and neovascularization in resolving venous thrombi. Furthermore, we discuss relevant in vitro and in vivo models that support the benefits or drawbacks of angiogenesis in CTEPH progression. We discuss the key pathways involved in modulating angiogenesis, particularly the underexplored role of TGFβ (transforming growth factor-beta) signaling in driving fibrosis as an integral element of CTEPH pathogenesis. We finally explore innovative treatment strategies that target angiogenic pathways. These strategies have the potential to pioneer preventive, inventive, or alternative therapeutic options for patients with CTEPH who may not qualify for surgical interventions. Moreover, they could be used synergistically with established treatments such as pulmonary endarterectomy or balloon pulmonary angioplasty. In summary, this review emphasizes the crucial role of angiogenesis in the development of in fibrothrombotic tissue, a major pathological characteristic of CTEPH.

Direct oral anticoagulants compared with warfarin in patients with left ventricular thrombus: a cohort study from China.

Current guidelines recommend vitamin K antagonist (VKA) for left ventricular (LV) thrombus. This study aimed to compare the effectiveness and safety of direct oral anticoagulant (DOAC) and warfarin in Chinese patients with LV thrombus. Patients with LV thrombus admitted to Beijing Anzhen Hospital of Capital Medical University between January 2018 and January 2022, were enrolled in this cohort study. The primary endpoint was defined as thrombus resolution within 90 days. The secondary endpoints included thrombus resolution within 180 days, major bleeding events, and minor bleeding events. All patients were followed up for at least 90 days after diagnosis of LV thrombus. Patients were divided into the VKA and DOAC groups according to the anticoagulants. Differences in clinical endpoint events between the two groups were compared. This study included 129 and 111 patients in the VKA and DOAC groups, respectively. After adjusting for gender and smoking status, no significant difference was observed in thrombus resolution within 90 days between the VKA and DOAC groups. Additionally, there was no difference between the two groups in the secondary endpoints of thrombus resolution within 180 days, major bleeding, and minor bleeding. In subgroup analysis, rivaroxaban and dabigatran did not show significant differences in primary and secondary endpoints. This study showed no significant difference in thrombus resolution between DOAC and warfarin. DOAC might be an alternative to warfarin for the treatment of LV thrombus. However, further large prospective studies are required to explore the efficacy and safety of DOAC in patients with LV thrombus.

Left atrial appendage thrombus with severe mitral stenosis: Responders and non-responders to anticoagulation

Introduction and ObjectiveMitral stenosis (MS) is one of the most frequently observed valvular heart lesions in developing countries and is due to different etiologies. The effects of anticoagulation in different types of left atrial appendage (LAA) are unknown. The current study aimed to determine the resolution of LAA thrombus on transesophageal echocardiography (TEE) after three months of optimal anticoagulation in patients with different types of LAA at baseline cardiac computed tomography of patients with severe MS. MethodsThis prospective cohort study observed the frequency of LAA thrombus resolution after three months of anticoagulation therapy in patients with severe MS. The response rate in different morphologies of LAA and locations was also assessed. Thrombus resolution after three months of warfarin therapy was assessed on repeat TEE. ResultsA total of 88 patients were included, mean age 37.95±11.87 years. Repeat TEE showed thrombus resolution in only 27.3% of patients. The rate of thrombus resolution was 8/12 (66.7%), 4/28 (14.3%), 8/36 (22.2%), and 4/12 (33.3%) for patients with cactus, cauliflower, chicken wing, and windsock LAA type, respectively. The resolution rate was 0/12 (0%), 4/44 (9.1%), and 20/32 (62.5%) for patients with thrombus in the base, body, and tip of the LAA, respectively. ConclusionThe cactus type of LAA morphology and thrombus at the LAA tip responded well to three months of anticoagulation, however, patients with thrombus in the LAA base and body and cauliflower and chicken wing morphology were non-responders and could benefit from early referral for surgical management.