The core pathology of coronavirus disease 2019 (COVID-19) is infection of airway cells by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that results in excessive inflammation and ...respiratory disease, with cytokine storm and acute respiratory distress syndrome implicated in the most severe cases. Thrombotic complications are a major cause of morbidity and mortality in patients with COVID-19. Patients with pre-existing cardiovascular disease and/or traditional cardiovascular risk factors, including obesity, diabetes mellitus, hypertension and advanced age, are at the highest risk of death from COVID-19. In this Review, we summarize new lines of evidence that point to both platelet and endothelial dysfunction as essential components of COVID-19 pathology and describe the mechanisms that might account for the contribution of cardiovascular risk factors to the most severe outcomes in COVID-19. We highlight the distinct contributions of coagulopathy, thrombocytopathy and endotheliopathy to the pathogenesis of COVID-19 and discuss potential therapeutic strategies in the management of patients with COVD-19. Harnessing the expertise of the biomedical and clinical communities is imperative to expand the available therapeutics beyond anticoagulants and to target both thrombocytopathy and endotheliopathy. Only with such collaborative efforts can we better prepare for further waves and for future coronavirus-related pandemics.
Platelets are abundant, small, anucleate circulating cells, serving many emerging pathophysiological roles beyond hemostasis; including active critical roles in thrombosis, injury response, and ...immunoregulation. In the absence of genomic DNA transcriptional regulation (no nucleus), platelets require strategic prepackaging of all the needed RNA and organelles from megakaryocytes, to sense stress (e.g., hyperglycemia), to protect themselves from stress (e.g., mitophagy), and to communicate a stress response to other cells (e.g., granule and microparticle release). Distinct from avian thrombocytes that have a nucleus, the absence of a nucleus allows the mammalian platelet to maintain its small size, permits morphological flexibility, and may improve speed and efficiency of protein expression in response to stress. In the absence of a nucleus, platelet lifespan of 7–10 days, is largely determined by the mitochondria. The packaging of 5–8 mitochondria is critical in aerobic respiration and yielding metabolic substrates needed for function and survival. Mitochondria damage or dysfunction, as observed with several disease processes, results in greatly attenuated platelet survival and increased risk for thrombovascular events. Here we provide insights into the emerging roles of platelets despite the lack of a nucleus, and the key role played by mitochondria in platelet function and survival both in health and disease.
In the broad range of human diseases, thrombo-inflammation appears as a clinical manifestation. Clinically, it is well characterized in context of superficial thrombophlebitis that is recognized as ...thrombosis and inflammation of superficial veins. However, it is more hazardous when developed in the microvasculature of injured/inflamed/infected tissues and organs. Several diseases like sepsis and ischemia-reperfusion can cause formation of microvascular thrombosis subsequently leading to thrombo-inflammation. Thrombo-inflammation can also occur in cases of antiphospholipid syndrome, preeclampsia, sickle cell disease, bacterial and viral infection. One of the major contributors to thrombo-inflammation is the loss of normal anti-thrombotic and anti-inflammatory potential of the endothelial cells of vasculature. This manifest itself in the form of dysregulation of the coagulation pathway and complement system, pathologic platelet activation, and increased recruitment of leukocyte within the microvasculature. The role of platelets in hemostasis and formation of thrombi under pathologic and non-pathologic conditions is well established. Platelets are anucleate cells known for their essential role in primary hemostasis and the coagulation pathway. In recent years, studies provide strong evidence for the critical involvement of platelets in inflammatory processes like acute ischemic stroke, and viral infections like Coronavirus disease 2019 (COVID-19). This has encouraged the researchers to investigate the contribution of platelets in the pathology of various thrombo-inflammatory diseases. The inhibition of platelet surface receptors or their intracellular signaling which mediate initial platelet activation and adhesion might prove to be suitable targets in thrombo-inflammatory disorders. Thus, the present review summarizes the concept and mechanism of platelet signaling and briefly discuss their role in sterile and non-sterile thrombo-inflammation, with the emphasis on role of platelets in COVID-19 induced thrombo-inflammation. The aim of this review is to summarize the recent developments in deciphering the role of the platelets in thrombo-inflammation and discuss their potential as pharmaceutical targets.
Venous thromboembolism (VTE), caused by altered hemostasis, remains the third most common cause of mortality among all cardiovascular conditions. In addition to established genetic and acquired risk ...factors, low-oxygen environments also predispose otherwise healthy individuals to VTE. Although disease etiology appears to entail perturbation of hemostasis pathways, the key molecular determinants during immediate early response remain elusive. Using an established model of venous thrombosis, we here show that systemic hypoxia accelerates thromboembolic events, functionally stimulated by the activation of nucleotide binding domain, leucine-rich-containing family, pyrin domain containing 3 (NLRP3) inflammasome complex and increased IL-1β secretion. Interestingly, we also show that the expression of NLRP3 is mediated by hypoxia-inducible factor 1-alpha (HIF-1α) during these conditions. The pharmacological inhibition of caspase-1, in vivo knockdown of NLRP3, or HIF-1α other than IL-1β-neutralizing antibodies attenuated inflammasome activation and curtailed thrombosis under hypoxic conditions. We extend the significance of these preclinical findings by studying modulation of this pathway in patients with altitude-induced venous thrombosis. Our results demonstrate distinctive, increased expression of NLRP3, caspase-1, and IL-1β in individuals with clinically established venous thrombosis. We therefore propose that an early proinflammatory state in the venous milieu, orchestrated by the HIF-induced NLRP3 inflammasome complex, is a key determinant of acute thrombotic events during hypoxic conditions.
Oxygen-compromised environments, such as high altitude, air travel, and sports, and pathological conditions, such as solid tumors, have been suggested to be prothrombotic. Despite the indispensable ...role of platelets in thrombus formation, the studies linking hypoxia, platelet reactivity, and thrombus formation are limited. In the present study, platelet proteome/reactivity was analyzed to elucidate the acute hypoxia-induced prothrombotic phenotype. Rats exposed to acute simulated hypoxia (282 torr/8% oxygen) demonstrated a decreased bleeding propensity and increased platelet reactivity. Proteomic analysis of hypoxic platelets revealed 27 differentially expressed proteins, including those involved in coagulation. Among these proteins, calpain small subunit 1, a 28-kDa regulatory component for calpain function, was significantly upregulated under hypoxic conditions. Moreover, intraplatelet Ca2+ level and platelet calpain activity were also found to be in accordance with calpain small subunit 1 expression. The inhibition of calpain activity demonstrated reversal of hypoxia-induced platelet hyperreactivity. The prothrombotic role for calpain was further confirmed by an in vivo model of hypoxia-induced thrombosis. Interestingly, patients who developed thrombosis while at extreme altitude had elevated plasma calpain activities and increased soluble P-selectin level. In summary, this study suggests that augmented calpain activity is associated with increased incidence of thrombosis under hypoxic environments.
•Hypoxia induces altered platelet proteome/reactivity, which correlates with a prothrombotic phenotype.•CAPNS1-dependent calpain activity in platelet activation cascade is associated with hypoxia-induced thrombogenesis.
Mitophagy can selectively remove damaged toxic mitochondria, protecting a cell from apoptosis. The molecular spatial–temporal mechanisms governing autophagosomal selection of reactive oxygen species ...(ROS)‐damaged mitochondria, particularly in a platelet (no genomic DNA for transcriptional regulation), remain unclear. We now report that the mitochondrial matrix protein MsrB2 plays an important role in switching on mitophagy by reducing Parkin methionine oxidation (MetO), and transducing mitophagy through ubiquitination by Parkin and interacting with LC3. This biochemical signaling only occurs at damaged mitochondria where MsrB2 is released from the mitochondrial matrix. MsrB2 platelet‐specific knockout and in vivo peptide inhibition of the MsrB2/LC3 interaction lead to reduced mitophagy and increased platelet apoptosis. Pathophysiological importance is highlighted in human subjects, where increased MsrB2 expression in diabetes mellitus leads to increased platelet mitophagy, and in platelets from Parkinson's disease patients, where reduced MsrB2 expression is associated with reduced mitophagy. Moreover, Parkin mutations at Met192 are associated with Parkinson's disease, highlighting the structural sensitivity at the Met192 position. Release of the enzyme MsrB2 from damaged mitochondria, initiating autophagosome formation, represents a novel regulatory mechanism for oxidative stress‐induced mitophagy.
Synopsis
Mitophagy can be selectively switched on at sites of oxidatively damaged mitochondria: MsrB2 mediates these actions by switching on Parkin and transducing activation through LC3. This mechanism in found in diabetic platelets and may be important for Parkinson's disease.
MsrB2 removes reduces oxidized methionine back to its native state and is induced in diabetic platelets.
Parkin Met192 is oxidized in a high oxidative stress environment leading to Parkin dysfunction, aggregation and prevention of mitophagy.
MsrB2 released from damaged mitochondria reduces MetO192 restoring Parkin's function (switch), allowing ubiquitination of MsrB2 and interaction with LC3 (transducer). The process of mitophagy is restored, protecting against apoptosis.
The association of mutation of Met192 with Parkinson's disease led to studies that demonstrate a reduction in MsrB2 in patients with Parkinson's disease.
Mitophagy can be selectively switched on at sites of oxidatively damaged mitochondria: MsrB2 mediates these actions by switching on Parkin and transducing activation through LC3. This mechanism in found in diabetic platelets and may be important for Parkinson's disease.
Factors that underlie the clustering of metabolic syndrome traits are not fully known. We performed whole-exome sequence analysis in kindreds with extreme phenotypes of early-onset atherosclerosis ...and metabolic syndrome, and identified novel loss-of-function mutations in the gene encoding the pancreatic elastase chymotrypsin-like elastase family member 2A (CELA2A). We further show that CELA2A is a circulating enzyme that reduces platelet hyperactivation, triggers both insulin secretion and degradation, and increases insulin sensitivity. CELA2A plasma levels rise postprandially and parallel insulin levels in humans. Loss of these functions by the mutant proteins provides insight into disease mechanisms and suggests that CELA2A could be an attractive therapeutic target.
Venous thromboembolism (VTE), the third leading cardiovascular complication, requires more understanding at molecular levels. Here, we have identified miR-145 as a key molecule for regulating ...thrombus formation in venous thrombosis (VT) employing network based bioinformatics approach and in vivo experiments. Levels of miR-145 showed an inverse correlation with thrombus load determined by coagulation variables. MiRNA target prediction tools and in vitro study identified tissue factor (TF) as a target gene for miR-145. The restoration of miR-145 levels in thrombotic animals via in vivo miR-145 mimic delivery resulted in decreased TF level and activity, accompanied by reduced thrombogenesis. MiR-145 levels were also reduced in VT patients and correlated with increased TF levels in patients, thereby, confirming our preclinical findings. Our study identifies a previously undescribed role of miRNA in VT by regulating TF expression. Therefore, restoration of miR-145 levels may serve as a promising therapeutic strategy for management of VT.
•MiR-145 is a regulator of venous thrombus formation.•Tissue factor is a direct target of miR-145.•MiR-145 is down regulated in human venous thrombosis patients.•Restoration of miRNA-145 via in vivo miRNA mimic delivery attenuated thrombus formation.
In this study we provide an insight into the molecular mechanisms of VT regulated by miRNA. Multiple investigations conducted with animal model and VT patients showed relatively reduced miR-145 expression levels under diseased condition. MiR-145 play important role in thrombus formation by regulating TF expression which have a critical role in VT. MiR-145 overexpression in animal model of VT reduces TF levels and attenuates thrombus formation which might have important implications for miRNA based therapeutic strategies in VT. This study highlights the role of miR-145 in the etiopathology of VT and also underscores the use of miR-145 mimic as an advancement to the field.
Venous malformations are low flow endothelial malformations with aberrant and ectatic venous channels. They are defects in vascular growth which causes functional and cosmetic impairment. Gradual ...growth in size of the lesion occurs due to venous congestion or thrombosis. Venous malformations in parapharyngeal space are a rare entity and are difficult to diagnose.
Case Report.
13 year old boy presented with a history of hyposmia and progressive difficulty in breathing for a duration of 2.5 years. MRI face and neck with contrast showed a 4.5 × 4.3x3.6 cm lesion in the left parapharyngeal space. CT angiogram of brain and neck demonstrated a heterogeneously enhancing mass in the left parapharyngeal region. PET scan illustrated an ill-defined mass in the left pre styloid parapharyngeal space. Biopsy from the lesion showed features consistent with venolymphatic malformation. Flexible laryngoscopy showed a bulge over the left soft palate region with narrowing of nasopharyngeal lumen. Patient underwent transoral robotic surgery for complete excision of the mass. Post-operative period was uneventful. He has been on follow up for the past 1 year with no evidence of any residual or recurrent disease.
Venolymphatic malformation is a rare lesion in the parapharyngeal space which is difficult to diagnose pre operatively. Surgical excision is the preferred modality of treatment for deep seated lesions in the parapharyngeal space. The advent of transoral robotic surgery have reduced the morbidity and improved clearance for such cases.
PDF
