Effects of inflammation on thrombosis and outcomes in COVID-19: secondary analysis of the ATTACC/ACTIV-4a trial.

Background: Patients hospitalized for COVID-19 are at high risk of thrombotic complications and organ failure, and often exhibit severe inflammation, which may contribute to hypercoagulability. Objectives: To determine whether patients hospitalized for COVID-19 experience differing frequencies of thrombotic and organ failure complications and derive variable benefits from therapeutic-dose heparin dependent on the extent of systemic inflammation and whether observed benefit from therapeutic-dose anticoagulation varies depending on the degree of systemic inflammation. Methods: We analyzed data from 1346 patients hospitalized for COVID-19 enrolled in the ATTACC and ACTIV-4a platforms who were randomized to therapeutic-dose heparin or usual care for whom levels of C-reactive protein (CRP) were reported at baseline. Results: Increased CRP was associated with worse patient outcomes, including a >98% posterior probability of increased organ support requirement, hospital length of stay, risk of 28-day mortality, and incidence of major thrombotic events or death (patients with CRP 40-100 mg/L or ≥100 mg/L compared to patients with CRP <40 mg/L). Patients with CRP 40 to 100 mg/L experienced the greatest degree of benefit from treatment with therapeutic doses of unfractionated or low molecular weight heparin compared with usual-care prophylactic doses. This was most significant for an increase in organ support-free days (odds ratio: 1.63; 95% confidence interval, 1.09-2.40; 97.9% posterior probability of beneficial effect), with trends toward benefit for other evaluated outcomes. Conclusion: Moderately ill patients hospitalized for COVID-19 with CRP between 40 mg/L and 100 mg/L derived the greatest benefit from treatment with therapeutic-dose heparin.

Unplanned 30-Day Readmissions after Management of Submassive and Massive Acute Pulmonary Embolism: Catheter-Directed versus Systemic Thrombolysis.

PURPOSE: To compare 30-day readmission and in-hospital outcomes from the Nationwide Readmissions Database (NRD) for catheter-directed thrombolysis (CDT) versus systemic intravenous thrombolysis (IVT) as treatments for acute submassive or massive pulmonary embolism (PE). MATERIALS AND METHODS: The NRD was queried from 2016 to 2019 for adult patients with nonseptic acute PE who underwent IVT or CDT. Massive PE was distinguished from submassive PE if patients had concurrent International Classification of Diseases (ICD-10) codes corresponding to mechanical ventilation, vasopressors, or shock. Propensity score-matched analysis was conducted to infer the association of CDT versus IVT in unplanned 30-day readmissions, nonroutine discharge, gastrointestinal bleeding (GIB), and intracranial hemorrhage (ICH). These results are demonstrated as average treatment effects (ATEs) of IVT compared with those of CDT. RESULTS: A total of 37,116 patients with acute PE were studied; 18,702 (50.3%) underwent CDT, and 18,414 (49.7%) underwent IVT. A total of 2,083 (11.1%) and 3,423 (18.6%) were massive PEs in the 2 groups, respectively (P < .001). The ATE of IVT was higher than that of CDT regarding unplanned 30-day readmissions (ATE, 0.019; P < .001), GIB (ATE, 0.012; P < .001), ICH (ATE, 0.003; P = .017), and nonroutine discharge (ATE, 0.022; P = .006). The subgroup analysis of patients with submassive PE demonstrated that IVT had a higher ATE regarding unplanned 30-day readmission (ATE, 0.028; P < .001), GIB (ATE, 0.008; P = .003), ICH (ATE, 0.002; P = .035), and nonroutine discharge (ATE, 0.019; P = .022) than CDT. CONCLUSIONS: CDT had a lower likelihood of unplanned 30-day readmissions, including when stratified by a submassive PE subtype. Additionally, adverse events, including ICH and GIB, were more likely among patients who received IVT than among those who received CDT.

(More than) doubling down: Effective fibrinolysis at a reduced rt-PA dose for catheter-directed thrombolysis combined with histotripsy.

Deep vein thrombosis is a major source of morbidity and mortality worldwide. For acute proximal deep vein thrombosis, catheter-directed thrombolytic therapy is an accepted method for vessel recanalization. Thrombolytic therapy is not without risk, including the potential for hemorrhagic bleeding that increases with lytic dose. Histotripsy is a focused ultrasound therapy that generates bubble clouds spontaneously in tissue at depth. The mechanical activity of histotripsy increases the efficacy of thrombolytic therapy at doses consistent with current pharmacomechanical treatments for venous thrombosis. The objective of this study was to determine the influence of lytic dose on histotripsy-enhanced fibrinolysis. Human whole blood clots formed in vitro were exposed to histotripsy and a thrombolytic agent (recombinant tissue plasminogen activator, rt-PA) in a venous flow model perfused with plasma. Lytic was administered into the clot via an infusion catheter at concentrations ranging from 0 (control) to 4.54 µg/mL (a common clinical dose for catheter-directed thrombolysis). Following treatment, perfusate samples were assayed for markers of fibrinolysis, hemolysis, and intact red blood cells and platelets. Fibrinolysis was equivalent between the common clinical dose of rt-PA (4.54 µg/mL) and rt-PA at a reduction to one-twentieth of the common clinical dose (0.23 µg/mL) when combined with histotripsy. Minimal changes were observed in hemolysis for treatment arms with or without histotripsy, potentially due to clot damage from insertion of the infusion catheter. Likewise, histotripsy did not increase the concentration of red blood cells or platelets in the perfusate following treatment compared to rt-PA alone. At the highest lytic dose, a refined histotripsy exposure scheme was implemented to cover larger areas of the clot. The updated exposure scheme improved clot mass loss and fibrinolysis relative to administration of lytic alone. Overall, the data collected in this study indicate the rt-PA dose can be reduced by more than a factor of ten and still promote fibrinolysis when combined with histotripsy.

Assessment of histological characteristics, imaging markers, and rt-PA susceptibility of ex vivo venous thrombi.

Venous thromboembolism is a significant source of morbidity and mortality worldwide. Catheter-directed thrombolytics is the primary treatment used to relieve critical obstructions, though its efficacy varies based on the thrombus composition. Non-responsive portions of the specimen often remain in situ, which prohibits mechanistic investigation of lytic resistance or the development of diagnostic indicators for treatment outcomes. In this study, thrombus samples extracted from venous thromboembolism patients were analyzed ex vivo to determine their histological properties, susceptibility to lytic therapy, and imaging characteristics. A wide range of thrombus morphologies were observed, with a dependence on age and etymology of the specimen. Fibrinolytic inhibitors including PAI-1, alpha 2-antiplasmin, and TAFI were present in samples, which may contribute to the response venous thrombi to catheter-directed thrombolytics. Finally, a weak but significant correlation was observed between the response of the sample to lytic drug and its magnetic microstructure assessed with a quantitative MRI sequence. These findings highlight the myriad of changes in venous thrombi that may promote lytic resistance, and imaging metrics that correlate with treatment outcomes.

Clot Degradation Under the Action of Histotripsy Bubble Activity and a Lytic Drug.

Deep vein thrombosis is a major source of morbidity worldwide. For critical obstructions, catheter-directed thrombolytics are the frontline therapy to achieve vessel recanalization. Techniques that aid lytic therapy are under development to improve treatment efficacy and reduce procedure-related complications. Histotripsy is one such adjuvant under development that relies on focused ultrasound for in situ nucleation of bubble clouds. Prior studies have demonstrated synergistic effects for clot dissolution when histotripsy is combined with lytic therapy. The success of this combination approach is hypothesized to promote thrombolytic efficacy via two mechanisms: erythrocyte fractionation (hemolysis) and increased lytic activity (fibrinolysis). In this study, the contributions of hemolysis and fibrinolysis to clot degradation under histotripsy and a lytic were quantified with measurements of hemoglobin and D-dimer, respectively. A linear regression analysis was used to determine the relationship between hemoglobin, D-dimer, and the overall treatment efficacy (clot mass loss). A similar analysis was conducted to gauge the role of bubble activity, which was assessed with passive cavitation imaging, on hemolysis and fibrinolysis. Tabulation of these data demonstrated hemolysis and fibrinolysis contributed equally to clot mass loss. Furthermore, bubble cloud activity promoted the generation of hemoglobin and D-dimer in equal proportion. These studies indicate a multifactorial process for clot degradation under the action of histotripsy and a lytic therapy.

In Vitro Thrombolytic Efficacy of Single- and Five-Cycle Histotripsy Pulses and rt-PA.

Although primarily known as an ablative modality, histotripsy can increase the efficacy of lytic therapy in a retracted venous clot model. Bubble cloud oscillations are the primary mechanism of action for histotripsy, and the type of bubble activity is dependent on the pulse duration. A retracted human venous clot model was perfused with and without the thrombolytic recombinant tissue plasminogen activator (rt-PA). The clot was exposed to histotripsy pulses of single- or five-cycle duration and peak negative pressures of 0-30 MPa. Bubble activity within the clot was monitored via passive cavitation imaging. The combination of histotripsy and rt-PA was more efficacious than rt-PA alone for single- and five-cycle pulses with peak negative pressures of 25 and 20 MPa, respectively. For both excitation schemes, the detected acoustic emissions correlated with the degree of thrombolytic efficacy. These results indicate that rt-PA and single- or multicycle histotripsy pulses enhance thrombolytic therapy.

Monocyte and macrophage subtypes as paired cell biomarkers for coronary artery disease.

NEW FINDINGS: What is the central question of this study? Are circulating monocyte markers correlated with their derived macrophage polarization patterns and coronary artery disease severity? What is the main finding and its importance? There was an inverse relationship between circulating CD16+ monocytes (high) and M2 macrophages (low) that marked coronary disease severity, and the differences in polarization of macrophages were seen despite a week of cell culture ex vivo. This study highlights the importance, and potential prognostic implications, of circulating monocyte and descendant macrophage phenotypes in coronary artery disease. ABSTRACT: Monocytes and macrophages are central to atherosclerosis, but how they combine to mark progression of human coronary artery disease (CAD) is unclear. We tested whether patients' monocyte subtypes paired with their derived macrophage profiles were correlated with extent of CAD. Peripheral blood was collected from 40 patients undergoing cardiac catheterization, and patients were categorized as having no significant CAD, single vessel disease or multivessel disease according to the number of affected coronary arteries. Mononuclear cells were measured for the monocyte markers CD14 and CD16 by flow cytometry, and separate monocytes were cultured into macrophages over 7 days and measured for the polarization markers CD86 and CD206. At baseline, patients with a greater CAD burden were older, with higher rates of statin, ß-blocker and antiplatelet drug use, whereas other characteristics were similar across the spectrum of coronary disease. CD16+ (both intermediate and non-classical) monocytes were elevated in patients with single vessel and multivessel disease compared with those without significant CAD (P < 0.05), whereas regulatory M2 macrophages (CD206+ ) were decreased in patients with single vessel and multivessel disease (P < 0.001). An inverse relationship between paired CD16+ monocytes and M2 macrophages marked CAD severity. On multivariable linear regression, CAD severity was associated, along with age and traditional cardiovascular risk factors, with CD16+ monocytes (directly) and M2 macrophages (inversely). Circulating monocytes may influence downstream polarization of lesional macrophages, and these measures of monocyte and macrophage subtypes hold potential as biomarkers in CAD.

In vitro assessment of stiffness-dependent histotripsy bubble cloud activity in gel phantoms and blood clots.

As a bubble-based ablative therapy, the efficacy of histotripsy has been demonstrated in healthy or acutely diseased models. Chronic conditions associated with stiff tissues may require additional bubble activity prior to histotripsy liquefaction. In this study, histotripsy pulses were generated in agarose phantoms of Young's moduli ranging from 12.3 to 142 kPa, and in vitro clot models with mild and strong platelet-activated retraction. Bubble cloud emissions were tracked with passive cavitation imaging, and the threshold acoustic power associated with phantom liquefaction was extracted with receiver operator characteristic analysis. The power of histotripsy-generated emissions and the degree of liquefaction were tabulated for both clot models. For the agarose phantoms, the acoustic power associated with liquefaction increased with Young's modulus. When grouped based on agarose concentration, only two arms displayed a significant difference in the liquefaction threshold acoustic power (22.1 kPa versus 142 kPa Young's modulus). The bubble cloud dynamics tracked with passive cavitation imaging indicated no strong changes in the bubble dynamics based on the phantom stiffness. For identical histotripsy exposure, the power of acoustic emissions and degree of clot lysis did not vary based on the clot model. Overall, these results indicate that a fixed threshold acoustic power mapped with passive cavitation imaging can be utilized for predicting histotripsy liquefaction over a wide range of tissue stiffness.

Cost-utility of extracorporeal cardiopulmonary resuscitation in patients with cardiac arrest.

BACKGROUND: Extracorporeal cardiopulmonary resuscitation (ECPR) is a resource-intensive tool that provides haemodynamic and respiratory support in patients who have suffered cardiac arrest. In this study, we investigated the cost-utility of ECPR (cost/QALY) in cardiac arrest patients treated at our institution. METHODS: We performed a retrospective review of patients who received ECPR following cardiac arrest between 2012 and 2018. All medical care-associated charges with ECPR and subsequent hospital admission were recorded. The quality-of-life of survivors was assessed with the Health Utilities Index Mark II. The cost-utility of ECPR was calculated with cost and quality-of-life data. RESULTS: ECPR was used in 32 patients (15/32 in-hospital, 47%) with a median age of 55.0 years (IQR 46.3-63.3 years), 59% male and 66% African American. The median duration of ECPR support was 2.1 days (IQR 0.9-3.8 days). Survival to hospital discharge was 16%. The median score of the Health Utilities Index Mark II at discharge for the survivors was 0.44 (IQR 0.32-0.52). The median operating cost for patients undergoing ECMO was $125,683 per patient (IQR $49,751-$206,341 per patient). The calculated cost-utility for ECPR was $56,156/QALY gained. CONCLUSIONS: The calculated cost-utility is within the threshold considered cost-effective in the United States (<$150,000/QALY gained). These results are comparable to the cost-effectiveness of heart transplantation for end-stage heart failure. Larger studies are needed to assess the cost-utility of ECPR and to identify whether other factors, such as patient characteristics, affect the cost-utility benefit.

Diagnosis and management of rare inferior vena cava leiomyosarcoma guided by a novel minimally invasive vascular biopsy technique.

Primary vascular tumors such as vascular leiomyosarcomas are rare, but exhibit markedly different characteristics than tumors that invade the vasculature from a secondary source. Establishing a diagnosis is essential in determining the appropriate treatment plan, but obtaining a histologic specimen may prove challenging and carry significant risks. Minimally invasive endovascular biopsy techniques can be pivotal in the diagnosis-and thus in the management-of vascular tumors. We present a case of a primary inferior vena cava leiomyosarcoma, not able to be adequately assessed by noninvasive imaging and deemed too risky to be approached with traditional percutaneous biopsy techniques. Accurate diagnosis of such tumors is critical, as the success of surgical resection, although high risk, depends greatly upon the type, location, and extent of malignancy.

3D echocardiographic analysis of aortic annulus for transcatheter aortic valve replacement using novel aortic valve quantification software: Comparison with computed tomography.

BACKGROUND: With the increasing use of transcatheter aortic valve replacement (TAVR) in patients with aortic stenosis (AS), computed tomography (CT) remains the standard for annulus sizing. However, 3D transesophageal echocardiography (TEE) has been an alternative in patients with contraindications to CT. We sought to (1) test the feasibility, accuracy, and reproducibility of prototype 3DTEE analysis software (Philips) for aortic annular measurements and (2) compare the new approach to the existing echocardiographic techniques. METHODS: We prospectively studied 52 patients who underwent gated contrast CT, procedural 3DTEE, and TAVR. 3DTEE images were analyzed using novel semi-automated software designed for 3D measurements of the aortic root, which uses multiplanar reconstruction, similar to CT analysis. Aortic annulus measurements included area, perimeter, and diameter calculations from these measurements. The results were compared to CT-derived values. Additionally, 3D echocardiographic measurements (3D planimetry and mitral valve analysis software adapted for the aortic valve) were also compared to the CT reference values. RESULTS: 3DTEE image quality was sufficient in 90% of patients for aortic annulus measurements using the new software, which were in good agreement with CT (r-values: .89-.91) and small (<4%) inter-modality nonsignificant biases. Repeated measurements showed <10% measurements variability. The new 3D analysis was the more accurate and reproducible of the existing echocardiographic techniques. CONCLUSIONS: Novel semi-automated 3DTEE analysis software can accurately measure aortic annulus in patients with severe AS undergoing TAVR, in better agreement with CT than the existing methodology. Accordingly, intra-procedural TEE could potentially replace CT in patients where CT carries significant risk.

Catheter-Directed Fibrinolysis of Submassive Pulmonary Embolism After IVC Filter Migration to Renal Veins.

A 76-year-old male presented with a submassive pulmonary embolism despite having an inferior vena cava (IVC) filter. Imaging demonstrated pulmonary artery emboli and a deep vein thrombosis in the left common femoral vein. Venography revealed the IVC filter with struts extending into the left and right renal veins. A new IVC filter was deployed below the prior filter. This case demonstrates IVC filter migration complicated by a submassive pulmonary embolism.

Transcatheter Therapy for a Large Mobile Right Atrial Thrombus and Massive Pulmonary Embolism.

A variety of interventional management approaches exist for the treatment of acute pulmonary embolism (PE). However, when PE is accompanied by residual right heart thrombus, the best therapeutic options are less clear. We describe a novel combined technique of percutaneous aspiration of unstable right atrial thrombus followed by ultrasound-directed thrombolysis of massive PE.

Sequential Organ Failure Assessment Score at Presentation Predicts Survival in Patients Treated With Percutaneous Veno-Arterial Extracorporeal Membrane Oxygenation.

BACKGROUND AND PURPOSE: This study sought to investigate demographic, clinical, and procedural determinants of outcomes in patients treated with percutaneous veno-arterial (VA) extracorporeal membrane oxygenation (ECMO) initiated in the cardiac catheterization laboratory with a portable system. METHODS: We performed a retrospective review of patients treated with percutaneous VA-ECMO during the study period at our institution. A logistic regression model was applied to investigate the association between sequential organ failure assessment (SOFA) score and survivor status. Fisher's exact test was used to examine the association between survivor status and cannula size (15 Fr vs >15 Fr). RESULTS: Percutaneous VA-ECMO was initiated in 25 patients. At 30 days, 10 patients were alive (40%). Fifteen patients had cardiac arrest (CA) prior to ECMO initiation, of which 5 were alive at 30 days (33%). Survivors had a lower baseline median SOFA score (9 vs 16; P=.02; odds ratio, 0.577). Use of a smaller cannula was associated with survival (P=.01). There was an association between the size of the arterial cannula and increased blood transfusions (P<.01). CONCLUSIONS: Lower presenting SOFA score and smaller cannula size were associated with increased survival in patients with cardiogenic shock (CS) or CA who underwent percutaneous VA-ECMO placed in the cardiac catheterization laboratory using a portable system. Calculation of the SOFA score at presentation may help physicians determine which patients may derive benefit from ECMO. Smaller cannula size, while decreasing the amount of flow, may result in decreased bleeding and increased survival.

A Practical Scoring System to Select Optimally Sized Devices for Percutaneous Patent Foramen Ovale Closure.

BACKGROUND: Patent foramen ovale (PFO) has been linked to cryptogenic stroke, and closure has been reported to improve clinical outcomes. However, there are no clear guidelines to direct device sizing. This study sought to use patient characteristics and echocardiographic findings to create a prediction score for device sizing. METHODS: This was a retrospective review of patients undergoing percutaneous PFO closure at our institution between July 2010 and December 2014. Demographic and clinical characteristics were recorded, and all pre- and intraprocedural echocardiography results were evaluated. RESULTS: Thirty-six patients underwent percutaneous PFO closure during the study period. All procedures were performed using an Amplatzer Septal Occluder "Cribriform" (ASOC) device in one of three disc diameters: 25, 30, or 35 mm. Closure was indicated for cryptogenic stroke/transient ischemic attack in 75% of cases. Every case (100%) was successful with durable shunt correction at the 6-month follow-up without complications of erosion or device embolization. The presence of atrial septal aneurysm (ASA) (p = 0.027) and PFO tunnel length >10 mm (p = 0.038) were independently associated with increased device size. A scoring system of 1 point for male sex, 1 point for ASA, and 1 point for PFO tunnel >10 mm long was associated with the size of closure device implanted (p = 0.006). CONCLUSIONS: A simple scoring system may be used to select an optimally sized device for percutaneous PFO closure using the ASOC device.