Lipoprotein(a)—The Crossroads of Atherosclerosis, Atherothrombosis and Inflammation

Increased lipoprotein(a) (Lp(a)) levels are an independent predictor of coronary artery disease (CAD), degenerative aortic stenosis (DAS), and heart failure independent of CAD and DAS. Lp(a) levels are genetically determinated in an autosomal dominant mode, with great intra- and inter-ethnic diversity. Most variations in Lp(a) levels arise from genetic variations of the gene that encodes the apolipoprotein(a) component of Lp(a), the LPA gene. LPA is located on the long arm of chromosome 6, within region 6q2.6–2.7. Lp(a) levels increase cardiovascular risk through several unrelated mechanisms. Lp(a) quantitatively carries all of the atherogenic risk of low-density lipoprotein cholesterol, although it is even more prone to oxidation and penetration through endothelia to promote the production of foam cells. The thrombogenic properties of Lp(a) result from the homology between apolipoprotein(a) and plasminogen, which compete for the same binding sites on endothelial cells to inhibit fibrinolysis and promote intravascular thrombosis. LPA has up to 70% homology with the human plasminogen gene. Oxidized phospholipids promote differentiation of pro-inflammatory macrophages that secrete pro-inflammatory cytokines (e. g., interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor-α). The aim of this review is to define which of these mechanisms of Lp(a) is predominant in different groups of patients.

SARS-CoV-2 infection of olfactory epithelial cells and neurons drives acute lung injury and lethal COVID-19 in mice

Lethal COVID-19 is associated with respiratory failure that is thought to be caused by acute respiratory distress syndrome (ARDS) secondary to pulmonary infection. To date, the cellular pathogenesis has been inferred from studies describing the expression of ACE2, a transmembrane protein required for SARS-CoV-2 infection, and detection of viral RNA or protein in infected humans, model animals, and cultured cells. To functionally test the cellular mechanisms of COVID-19, we generated hACE2fl animals in which human ACE2 (hACE2) is expressed from the mouse Ace2 locus in a manner that permits cell-specific, Cre-mediated loss of function. hACE2fl animals developed lethal weight loss and hypoxemia within 7 days of exposure to SARS-CoV-2 that was associated with pulmonary infiltrates, intravascular thrombosis and patchy viral infection of lung epithelial cells. Deletion of hACE2 in lung epithelial cells prevented viral infection of the lung, but not weight loss, hypoxemia or death. Inhalation of SARS-CoV-2 by hACE2fl animals resulted in early infection of sustentacular cells with subsequent infection of neurons in the neighboring olfactory bulb and cerebral cortex— events that did not require lung epithelial cell infection. Pharmacologic ablation of the olfactory epithelium or Foxg1Cre mediated deletion of hACE2 in olfactory epithelial cells and neurons prevented lethality and neuronal infection following SARS-CoV-2 infection. Conversely, transgenic expression of hACE2 specifically in olfactory epithelial cells and neurons in Foxg1Cre; LSL-hACE2 mice was sufficient to confer neuronal infection associated with respiratory failure and death. These studies establish mouse loss and gain of function genetic models with which to genetically dissect viral-host interactions and demonstrate that lethal disease due to respiratory failure may arise from extrapulmonary infection of the olfactory epithelium and brain. Future therapeutic efforts focused on preventing olfactory epithelial infection may be an effective means of protecting against severe COVID-19.

COT-9 Prognostic impact of hypercoagulation in glioblastoma and molecular mechanism thereof

Introduction: Pathological features of glioblastoma include intravascular thrombosis, suggesting that the thrombus formation in tumor microenvironment contributes to progression of gliomas. Meanwhile, glioblastoma has been known to be high risk malignant tumor for venous thromboembolism, however, it remains unclear how the coagulation-fibrinolysis system is disrupted, which essentially grow within the cranium in a localized manner, and how the disruption contributes to the malignant transformation. Methods: Total 64 patients with glioblastoma between January 2014 and April 2021 who underwent a D-dimer test before the therapeutic intervention were divided into two groups: the high D-dimer group (D-dimer level >3.0μg/ml) and the low D-dimer group (D-dimer level <3.0μg/ml). We compared the two groups in the maximum gadolinium-enhanced MRI lesions, MIB-1 index, and gene abnormalities (IDH mutation, TERT promoter mutation, and MGMT promotor methylation). The progression-free survival (PFS) and overall survival were analyzed using the Kaplan-Meier method. Furthermore, in 23 patients who underwent a D-dimer test at recurrence, the time to death after recurrence was analyzed. Results: The PFS in high D-dimer group was significantly shorter than that in the low D-dimer group (log-rank p = 0.0075). The D-dimer increase at the time of recurrence significantly correlated with the decrease in post-recurrence survival duration (log-rank p = 0.0226). Moreover, the gadolinium-enhanced lesions in the high D-dimer group were significantly larger. Conclusion: The Pre-intervention D-dimer levels and PFS suggest that glioblastoma-induced systemic enhancement of the coagulation-fibrinolysis system plays a role in the malignant transformation. The D-dimer increase during the treatment was found to be a predictor of poor prognosis after recurrence. Furthermore, the MRI findings revealed a correlation between the D-dimer increase and the size of intratumoral necrosis. Meanwhile, no correlation with the MIB-1 index was found, suggesting that the mechanism of malignant transformation by hypercoagulation differ from enhanced cell proliferation.

Anti-thrombotic action of sulfated polysaccharides on thrombosis caused by thromboplastin

The antithrombotic effect of modified sulfated polysaccharides on a model of thromboplastin-induced thrombosis was investigated, which made it possible to evaluate the effectiveness of sulfated polysaccharides as a direct anticoagulant that increases the tolerance of animals to effects causing intravascular thrombosis.

Parent artery stenting as a rescue management for stretched coils during cerebral aneurysms embolization: Report of three cases and review of literature

Background Displacement of a stretched coil into the parent artery during intracranial aneurysm coiling is a challenging situation where the risk of acute intravascular thrombosis might be a life-threatening condition. The usual way of management is coil snaring, yet in some cases, it might not be feasible to retrieve the coil. Parent artery rescue stenting had already been described as a way of management in acutely thrombosed parent arteries during aneurysm coiling. Case reports We present three cases with an inadvertent displacement of the unraveled coils into the parent artery for which rescue stenting was carried out to crush the coil against the vessel wall aiming to eliminate its thrombogenic effect. Our preliminary experience is that rescue stenting of the parent artery for stretched coil could be a convenient effective option particularly in case of failed/risky snaring with no notable immediate or long-term complications. Review and discussion We review the reported cases of stretched coils with or without further unraveling and fracture and discuss the possible consequences, salvage methods, and clinical outcomes. Neurointerventionists should be aware of this complication and get acquainted with bailout strategies.

Diagnosis and Treatment for Pediatric Supracondylar Humerus Fractures with Brachial Artery Injuries

(1) Background: This study aims to describe the clinical and paraclinical characteristics of and the diagnostic approach to brachial artery injuries in pediatric supracondylar humerus fractures, as well as to evaluate intraoperative vascular anatomical lesions and early postoperative results. (2) Methods: A retrospective, hospital-based analysis of medical records at Viet Duc University Hospital (Vietnam), using a sample of children under 16 years who met the diagnostic criteria for supracondylar humerus fractures with brachial artery injuries between January 2016 and December 2020, was performed. A total of 50 patients were included in the analysis. (3) Results: Out of 50 pediatric patients, 36 patients were male (72%) and the mean age was 5.85 years (range, 1.5–14 years). Before treatment, there were 46 patients with severely displaced fractures which were classified as Gartland type III (92%). Following casting, the percentage of those with severely displaced fractures was reduced significantly to 12%, while there were no patients with Gartland type III fractures after percutaneous pinning. Doppler sonography failed to assess vascular lesions at the fracture site before and after casting in most patients. Two-thirds of surgical cases had only vasospasm, without physical damage to the vessel wall or intravascular thrombosis. Preoperative Doppler spectrum analysis was not consistent with the severity of intraoperative brachial artery injury. Out of 24 patients with vasospasm, we performed vascular blockade using papaverin in 11 cases and intraoperative balloon angioplasty of the brachial artery using the Fogarty catheter in 13 cases. Brachial artery graft was performed with 12 patients who had anatomical damage to the vascular wall. A complication of embolism occurred in one patient immediately after surgery, and two patients had superficial infections. One month following surgery, 2 out of 36 patients had a temporary loss of sensation in the area of incision. (4) Conclusions: Most pediatric patients did not present with symptoms of critical limb ischemia similar to those associated with lower extremity vascular injuries. The diagnosis and treatment of pediatric supracondylar humerus fractures with vascular injury is difficult and time-consuming, especially in cases of transverse fractures.

Pathological Features in 100 Deceased Patients With COVID-19 in Correlation With Clinical and Laboratory Data

Background: Autopsies on COVID-19 deceased patients have many limitations due to necessary epidemiologic and preventative measures. The ongoing pandemic has caused a significant strain on healthcare systems and is being extensively studied around the world. Clinical data does not always corelate with post-mortem findings. The goal of our study was to find pathognomonic factors associated with COVID-19 mortality in 100 post-mortem full body autopsies.Materials and Methods: Following necessary safety protocol, we performed 100 autopsies on patients who were diagnosed with COVID-19 related death. The macroscopic and microscopic pathologies were evaluated along with clinical and laboratory findings.Results: Extensive coagulopathic changes are seen throughout the bodies of diseased patients. Diffuse alveolar damage is pathognomonic of COVID-19 viral pneumonia, and is the leading cause of lethal outcome in younger patients. Extrapulmonary pathology is predominantly seen in the liver and spleen. Intravascular thrombosis is often widespread and signs of septic shock are often present.Conclusion: The described pathological manifestations of COVID-19 in deceased patients are an insight into the main mechanisms of SARS-CoV-2 associated lethal outcome. The disease bears no obvious bias in severity, but seems to be more severe in some patients, hinting at genetic or epigenetic factors at play.

Critical role of oxidized LDL receptor-1 in intravascular thrombosis in a severe influenza mouse model

Although coagulation abnormalities, including microvascular thrombosis, are thought to contribute to tissue injury and single- or multiple-organ dysfunction in severe influenza, the detailed mechanisms have yet been clarified. This study evaluated influenza-associated abnormal blood coagulation utilizing a severe influenza mouse model. After infecting C57BL/6 male mice with intranasal applications of 500 plaque-forming units of influenza virus A/Puerto Rico/8/34 (H1N1; PR8), an elevated serum level of prothrombin fragment 1 + 2, an indicator for activated thrombin generation, was observed. Also, an increased gene expression of oxidized low-density lipoprotein (LDL) receptor-1 (Olr1), a key molecule in endothelial dysfunction in the progression of atherosclerosis, was detected in the aorta of infected mice. Body weight decrease, serum levels of cytokines and chemokines, viral load, and inflammation in the lungs of infected animals were similar between wild-type and Olr1 knockout (KO) mice. In contrast, the elevation of prothrombin fragment 1 + 2 levels in the sera and intravascular thrombosis in the lungs by PR8 virus infection were not induced in KO mice. Collectively, the results indicated that OLR1 is a critical host factor in intravascular thrombosis as a pathogeny of severe influenza. Thus, OLR1 is a promising novel therapeutic target for thrombosis during severe influenza.

The skeletal consequences of meningococcal septicaemia

Meningococcal septicaemia and its complication of purpura fulminans has a significant impact upon the extremities as the ischaemic insult caused by the intravascular thrombosis typical of the fulminant infection can lead to gangrene and tissue loss in the acute phase of illness and the late sequelae of growth arrest and deformity. The initial management and long-term assessment and intervention are described in this chapter.

Surgical thrombectomy versus conservative treatment in cases of acute limb ischemia with COVID-19 pneumonia

COVID-19 infection is a major cause for acute respiratory distress syndrome, multi-organ dysfunction, coagulopathy, and intravascular thrombosis; therefore, it is the main causative factor for acute limb ischemia.Aim. To compare the treatment outcome of two limb ischemic groups post COVID-19 infection in a single center and detect at least which is better for the patients in the period of COVID-19 pandemic.Material and methods. Here, in this study, we collect 26 patients and divided them into two groups, G1 (14) patients treated conservatively and G2 (12) patients treated with surgical thrombectomy. Data were analyzed to look for the outcome of groups after 24 hours and 30 days.Results. The successful rate of conservative treatment was 85,72% in G1, while it was 75% in G2. There were two amputations below the knee joint in each group. Three patients died in both groups.Conclusion. In conclusion, both conservative treatment and surgical thrombectomy have a comparable successful rate in the selected group of COVID-19 patients.