Vasculopathy in COVID-19 Flaumenhaft, Robert; Enjyoji, Keiichi; Schmaier, Alec A.
Blood,
07/2022, Letnik:
140, Številka:
3
Journal Article
Recenzirano
Odprti dostop
COVID-19 is a primary respiratory illness that is frequently complicated by systemic involvement of the vasculature. Vascular involvement leads to an array of complications ranging from thrombosis to ...pulmonary edema secondary to loss of barrier function. This review will address the vasculopathy of COVID-19 with a focus on the role of the endothelium in orchestrating the systemic response to SARS-CoV-2 infection. The endothelial receptor systems and molecular pathways activated in the setting of COVID-19 and the consequences of these inflammatory and prothrombotic changes on endothelial cell function will be discussed. The sequelae of COVID-19 vascular involvement at the level of organ systems will also be addressed, with an emphasis on the pulmonary vasculature, but with consideration of effects on other vascular beds. The dramatic changes in endothelial phenotypes associated with COVID-19 has enabled the identification of biomarkers that could help guide therapy and predict outcomes. Knowledge of vascular pathogenesis in COVID-19 has also informed therapeutic approaches that may control its systemic sequelae. Since our understanding of vascular response in COVID-19 continues to evolve, we will consider areas of controversy, such as the extent to which SARS-CoV-2 directly infects endothelium and the degree to which vascular responses to SARS-CoV-2 are unique or common to those of other viruses capable of causing severe respiratory disease. This conceptual framework describing how SARS-CoV-2 infection affects endothelial inflammation, prothrombotic transformation, and barrier dysfunction will provide a context for interpreting new information as it arises addressing the vascular complications of COVID-19.
Venous Thromboembolism and Cancer Schmaier, Alec A.; Ambesh, Paurush; Campia, Umberto
Current cardiology reports,
10/2018, Letnik:
20, Številka:
10
Journal Article
Recenzirano
Purpose of Review
This review aims to summarize the epidemiology, current pathophysiologic understanding, and state-of-the-art treatment of venous thromboembolism (VTE) in cancer patients.
Recent ...Findings
The risk of VTE varies among cancer patients. Recently introduced prediction models better identify those at high risk of VTE. New mechanisms underlying hypercoagulability in cancer have been uncovered. Initial data on the efficacy of direct oral anticoagulants (DOACs) compared with low-molecular weight heparin to treat VTE in patients with cancer are promising. However, they may be associated with higher risk of gastrointestinal bleeding.
Summary
VTE causes significant morbidity and mortality in cancer patients. Our understanding of the mechanisms of VTE, including those associated with cancer treatments, has significantly grown. The assessment of the benefit/risk balance of VTE treatment remains challenging in many patients with cancer. The introduction of DOACs has expanded treatment options, but knowledge on their efficacy and safety is incomplete.
Although platelets appear by embryonic day 10.5 in the developing mouse, an embryonic role for these cells has not been identified. The SYK–SLP-76 signaling pathway is required in blood cells to ...regulate embryonic blood-lymphatic vascular separation, but the cell type and molecular mechanism underlying this regulatory pathway are not known. In the present study we demonstrate that platelets regulate lymphatic vascular development by directly interacting with lymphatic endothelial cells through C-type lectin-like receptor 2 (CLEC-2) receptors. PODOPLANIN (PDPN), a transmembrane protein expressed on the surface of lymphatic endothelial cells, is required in nonhematopoietic cells for blood-lymphatic separation. Genetic loss of the PDPN receptor CLEC-2 ablates PDPN binding by platelets and confers embryonic lymphatic vascular defects like those seen in animals lacking PDPN or SLP-76. Platelet factor 4-Cre–mediated deletion of Slp-76 is sufficient to confer lymphatic vascular defects, identifying platelets as the cell type in which SLP-76 signaling is required to regulate lymphatic vascular development. Consistent with these genetic findings, we observe SLP-76–dependent platelet aggregate formation on the surface of lymphatic endothelial cells in vivo and ex vivo. These studies identify a nonhemostatic pathway in which platelet CLEC-2 receptors bind lymphatic endothelial PDPN and activate SLP-76 signaling to regulate embryonic vascular development.
Endothelial cells (ECs) normally form an anticoagulant surface under physiological conditions, but switch to support coagulation following pathogenic stimuli. This switch promotes thrombotic ...cardiovascular disease. To generate thrombin at physiologic rates, coagulation proteins assemble on a membrane containing anionic phospholipid, most notably phosphatidylserine (PS). PS can be rapidly externalized to the outer cell membrane leaflet by phospholipid "scramblases," such as TMEM16F. TMEM16F-dependent PS externalization is well characterized in platelets. In contrast, how ECs externalize phospholipids to support coagulation is not understood. We employed a focused genetic screen to evaluate the contribution of transmembrane phospholipid transport on EC procoagulant activity. We identified 2 TMEM16 family members, TMEM16F and its closest paralog, TMEM16E, which were both required to support coagulation on ECs via PS externalization. Applying an intravital laser-injury model of thrombosis, we observed, unexpectedly, that PS externalization was concentrated at the vessel wall, not on platelets. TMEM16E-null mice demonstrated reduced vessel-wall-dependent fibrin formation. The TMEM16 inhibitor benzbromarone prevented PS externalization and EC procoagulant activity and protected mice from thrombosis without increasing bleeding following tail transection. These findings indicate the activated endothelial surface is a source of procoagulant phospholipid contributing to thrombus formation. TMEM16 phospholipid scramblases may be a therapeutic target for thrombotic cardiovascular disease.
Bradykinin B2 receptor–deleted mice (Bdkrb2−/−) have delayed carotid artery thrombosis times and prolonged tail bleeding time resulting from elevated angiotensin II (AngII) and angiotensin receptor 2 ...(AT2R) producing increased plasma nitric oxide (NO) and prostacyclin. Bdkrb2−/− also have elevated plasma angiotensin-(1-7) and messenger RNA and protein for its receptor Mas. Blockade of Mas with its antagonist A-779 in Bdkrb2−/− shortens thrombosis times (58 ± 4 minutes to 38 ± 4 minutes) and bleeding times (170 ± 13 seconds to 88 ± 8 seconds) and lowers plasma nitrate (22 ± 4 μM to 15 ± 5 μM), and 6-keto-PGF1α (259 ± 103 pg/mL to 132 ± 58 pg/mL). Bdkrb2−/− platelets express increased NO, guanosine 3′,5′-cyclic monophosphate, and cyclic adenosine monophosphate with reduced spreading on collagen, collagen peptide GFOGER, or fibrinogen. In vivo A-779 or combined L-NAME and nimesulide treatment corrects it. Bdkrb2−/− platelets have reduced collagen-related peptide–induced integrin α2bβ3 activation and P-selectin expression that are partially corrected by in vivo A-779, nimesulide, or L-NAME. Bone marrow transplantations show that the platelet phenotype and thrombosis time depends on the host rather than donor bone marrow progenitors. Transplantation of wild-type bone marrow into Bdkrb2−/− hosts produces platelets with a spreading defect and delayed thrombosis times. In Bdkrb2−/−, combined AT2R and Mas overexpression produce elevated plasma prostacyclin and NO leading to acquired platelet function defects and thrombosis delay.
•In Bdkrb2−/− mice, compensatory Mas and AT2R overexpression elevates NO and PGI2 to prolong bleeding times and delay arterial thrombosis.•This NO and PGI2 elevation attenuates platelet integrin-dependent spreading and GPVI responses without altering thrombin or ADP activation.
The incidence and clinical impact of lead-related venous obstruction (LRVO) among patients with cardiovascular implantable electronic devices (CIEDs) is poorly defined.
The objectives of this study ...were to determine the incidence of symptomatic LRVO after CIED implant; describe patterns in CIED extraction and revascularization; and quantify LRVO-related health care utilization based on each type of intervention.
LRVO status was defined among Medicare beneficiaries after CIED implant from October 1, 2015, to December 31, 2020. Cumulative incidence functions of LRVO were estimated by Fine-Gray methods. LRVO predictors were identified using Cox regression. Incidence rates for LRVO-related health care visits were calculated with Poisson models.
Among 649,524 patients who underwent CIED implant, 28,214 developed LRVO, with 5.0% cumulative incidence at maximum follow-up of 5.2 years. Independent predictors of LRVO included CIEDs with >1 lead (HR: 1.09; 95% CI: 1.07-1.15), chronic kidney disease (HR: 1.17; 95% CI: 1.14-1.20), and malignancies (HR: 1.23; 95% CI: 1.20-1.27). Most patients with LRVO (85.2%) were managed conservatively. Among 4,186 (14.8%) patients undergoing intervention, 74.0% underwent CIED extraction and 26.0% percutaneous revascularization. Notably, 90% of the patients did not receive another CIED after extraction, with low use (2.2%) of leadless pacemakers. In adjusted models, extraction was associated with significant reductions in LRVO-related health care utilization (adjusted rate ratio: 0.58; 95% CI: 0.52-0.66) compared with conservative management.
In a large nationwide sample, the incidence of LRVO was substantial, affecting 1 of every 20 patients with CIEDs. Device extraction was the most common intervention and was associated with long-term reduction in recurrent health care utilization.
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MicroRNAs are small noncoding RNAs that regulate cellular development by interfering with mRNA stability and translation. We examined global microRNA expression during the differentiation of murine ...hematopoietic progenitors into megakaryocytes. Of 435 miRNAs analyzed, 13 were up-regulated and 81 were down-regulated. Many of these changes are consistent with miRNA profiling studies of human megakaryocytes and platelets, although new patterns also emerged. Among 7 conserved miRNAs that were up-regulated most strongly in murine megakaryocytes, 6 were also induced in the related erythroid lineage. MiR-146a was strongly up-regulated during mouse and human megakaryopoiesis but not erythropoiesis. However, overexpression of miR-146a in mouse bone marrow hematopoietic progenitor populations produced no detectable alterations in megakaryocyte development or platelet production in vivo or in colony assays. Our findings extend the repertoire of differentially regulated miRNAs during murine megakaryopoiesis and provide a useful new dataset for hematopoiesis research. In addition, we show that enforced hematopoietic expression of miR-146a has minimal effects on megakaryopoiesis. These results are compatible with prior studies indicating that miR-146a inhibits megakaryocyte production indirectly by suppressing inflammatory cytokine production from innate immune cells, but cast doubt on a different study, which suggests that this miRNA inhibits megakaryopoiesis cell-autonomously.
Endothelial dysfunction accompanies the microvascular thrombosis commonly observed in severe COVID-19. Constitutively, the endothelial surface is anticoagulant, a property maintained at least in part ...via signaling through the Tie2 receptor. During inflammation, the Tie2 antagonist angiopoietin-2 (Angpt-2) is released from endothelial cells and inhibits Tie2, promoting a prothrombotic phenotypic shift. We sought to assess whether severe COVID-19 is associated with procoagulant endothelial dysfunction and alterations in the Tie2/angiopoietin axis. Primary HUVECs treated with plasma from patients with severe COVID-19 upregulated the expression of thromboinflammatory genes, inhibited the expression of antithrombotic genes, and promoted coagulation on the endothelial surface. Pharmacologic activation of Tie2 with the small molecule AKB-9778 reversed the prothrombotic state induced by COVID-19 plasma in primary endothelial cells. Lung autopsies from patients with COVID-19 demonstrated a prothrombotic endothelial signature. Assessment of circulating endothelial markers in a cohort of 98 patients with mild, moderate, or severe COVID-19 revealed endothelial dysfunction indicative of a prothrombotic state. Angpt-2 concentrations rose with increasing disease severity, and the highest levels were associated with worse survival. These data highlight the disruption of Tie2/angiopoietin signaling and procoagulant changes in endothelial cells in severe COVID-19. Our findings provide rationale for current trials of Tie2-activating therapy with AKB-9778 in COVID-19.
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