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Elimination of fibrin γ-chain cross-linking by FXIIIa increases pulmonary embolism arising from murine inferior vena cava thrombi.

ABSTRACT: The onset of venous thromboembolism, including pulmonary embolism, represents a significant health burden affecting more than 1 million people annually worldwide. Current treatment options are based on anticoagulation, which is suboptimal for preventing further embolic events. In order to develop better treatments for thromboembolism, we sought to understand the structural and mechanical properties of blood clots and how this influences embolism in vivo. We developed a murine model in which fibrin γ-chain cross-linking by activated Factor XIII is eliminated (FGG3X) and applied methods to study thromboembolism at whole-body and organ levels. We show that FGG3X mice have a normal phenotype, with overall coagulation parameters and platelet aggregation and function largely unaffected, except for total inhibition of fibrin γ-chain cross-linking. Elimination of fibrin γ-chain cross-linking resulted in thrombi with reduced strength that were prone to fragmentation. Analysis of embolism in vivo using Xtreme optical imaging and light sheet microscopy demonstrated that the elimination of fibrin γ-chain cross-linking resulted in increased embolization without affecting clot size or lysis. Our findings point to a central previously unrecognized role for fibrin γ-chain cross-linking in clot stability. They also indirectly indicate mechanistic targets for the prevention of thrombosis through selective modulation of fibrin α-chain but not γ-chain cross-linking by activated Factor XIII to reduce thrombus size and burden, while maintaining clot stability and preventing embolism.

SUBMITTER: Duval C

PROVIDER: S-EPMC8271579 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Previous observational studies suggest that inferior vena cava filter placement in pulmonary embolism patients complicated with congestive heart failure, mechanical ventilation, and shock may have a mortality benefit. We sought to analyze the survival benefits of inferior vena cava filter in pulmonary embolism patients complicated with acute myocardial infarction, acute respiratory failure, shock, or requiring treatment with thrombolytics. Methods: This retrospective observational study used hospital discharge data from the National Inpatient Sample Data (NIS). ICD-9-CM coding was used to identify complicated pulmonary embolism patients (N = 254,465) in NIS from 2002 to 2014, including the subgroups of acute myocardial infarction, acute respiratory failure, shock, and thrombolytics. Inferior vena cava filter recipients were 1:1 propensity score-matched on age, sex, race, deep vein thrombosis, Elixhauser comorbidities, and other pulmonary embolism comorbidities (45 covariates) to non-inferior vena cava filter recipients in complicated pulmonary embolism patients and separately in each subgroup. Clinical outcomes were compared between the inferior vena cava filter group and the non-inferior vena cava filter group. Results: Mortality rate in complicated pulmonary embolism patients with inferior vena cava filter placement was lower (20.9% vs. 33%; NNT = 8.28, 95% confidence interval (CI) 7.91-8.69, E-value = 2.53) and in the subgroups; acute myocardial infarction (17.9% vs. 30.1%; NNT = 8.19, 95% CI 7.52-8.92, E-value = 2.76), acute respiratory failure (19.5% vs. 29.7%; NNT = 9.76, 95% CI 8.67-11.16, E-value = 2.38), shock (30.7% vs. 47.1%; NNT = 6.08, 95% CI 5.73-6.47, E-value = 2.43), and with the use of thrombolytics (7% vs. 12.9 %; NNT 17.1, 95% CI 14.88-20.12, E-value = 3.01) (p < 0.001 for all). Conclusion: Inferior vena cava filter placement in pulmonary embolism complicated with acute myocardial infarction, acute respiratory failure, shock, or requiring thrombolytic therapy was associated with reduced mortality.

Project description:The Sentry inferior vena cava (IVC) filter is designed to provide temporary protection against pulmonary embolism (PE) during transient high-risk periods and then to bioconvert after 60 days after implantation. At the time of bioconversion, the device's nitinol arms retract from the filtering position into the caval wall. Subsequently, the stable stent-like nitinol frame is endothelialized. The Sentry bioconvertible IVC filter has been evaluated in a multicenter investigational-device-exemption pivotal trial (NCT01975090) of 129 patients with documented deep vein thrombosis (DVT) or PE, or at temporary risk of developing DVT or PE, and with contraindications to anticoagulation. Successful filter conversion was observed in 95.7% of patients at 6 months (110/115) and 96.4% at 12 months (106/110). Through 12 months, there were no cases of symptomatic PE. The rationale for development of the Sentry bioconvertible device includes the following considerations: (1) the period of highest risk of PE for the vast majority of patients occurs within the first 60 days after an index event, with most of the PEs occurring in the first 30 days; (2) the design of retrievable IVC filters to support their removal after a transitory high-PE-risk period has, in practice, been associated with insecure filter dynamics and time-dependent complications including tilting, fracture, embolization, migration, and IVC perforation; (3) most retrievable IVC filters are placed for temporary protection, but for a variety of reasons they are not removed in any more than half of implanted patients, and when removal is attempted, the procedure is not always successful even with advanced techniques; and (4) analysis of Medicare hospital data suggests that payment for the retrieval procedure does not routinely compensate for expense. The Sentry device is not intended for removal after bioconversion. In initial clinical use, complications have been limited. Long-term results for the Sentry bioconvertible IVC filter are anticipated soon.

Project description:Introduction Kidney and liver cysts in autosomal dominant polycystic kidney disease (ADPKD) can compress the inferior vena cava (IVC), but IVC compression prevalence and its risk factors are unknown. Methods Patients who have ADPKD (n = 216) with abdominal magnetic resonance imaging (MRI) studies and age-/sex-matched controls (n = 216) were evaluated for IVC compression as well as azygous vein diameter (a marker of collateral blood flow) and IVC aspect ratio (left-to-right dimension divided by anterior-to-posterior dimension with a value of 1 corresponding to a circular (high pressure) IVC caudal to compression. Results Severe IVC compression (?70%) was observed in 33 (15%) ADPKD subjects and mild compression (?50% to <70%) was observed in 33 (15%) subjects; whereas controls had no IVC compression (P < 0.001). Severe IVC compression was associated with larger azygous vein (4.0 ± 1.3 mm versus 2.3 ± 0.8 mm without IVC compression; P < 0.001) and a more circular IVC cross-section upstream (mean IVC aspect ratio: 1.16 ± 0.27 vs. 1.69 ± 0.67, P < 0.001), suggesting higher pressure upstream from the compression. IVC compression was associated with older age, lower estimated glomerular filtration rate (eGFR), greater height-adjusted total kidney volumes, greater height-adjusted liver volume (ht-LV), and greater liver and renal cyst fractions (P < 0.001). No subject younger than 30 years had IVC compression, but ADPKD subjects ?40 years old had 12-fold higher risk of IVC compression (95% confidence interval [CI]: 4.2–42.4), with highest predicted probability for Mayo Clinic classes 1D (59%; 95% CI: 39%–76%) and 1E (74%; 95% CI: 49%–90%) after adjustment (P < 0.001). Women with ht-LV ? 2000 ml/m had 83% (95% CI: 59%–95%) prevalence of IVC compression. Complications of IVC compression included deep vein thrombosis (DVT) and symptomatic hypotension. Conclusions IVC compression is common in ADPKD patients >40 years old, with Mayo Clinic class 1D/E, and in females with ht-LV > 2000 ml/m. Graphical abstract

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Elimination of fibrin γ-chain cross-linking by FXIIIa increases pulmonary embolism arising from murine inferior vena cava thrombi.

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