coagulation cascade
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Author(s):  
Haijiao Jing ◽  
Nan Zuo ◽  
Valerie A. Novakovic ◽  
Jialan Shi

Cancer patients have increased SARS-CoV-2 susceptibility and are prone to developing severe COVID-19 infections. The incidence of venous thrombosis is approximately 20% in COVID-19 patients with cancer. It has been suggested that thrombus formation has been suggested to correlate with severe clinical manifestations, mortality, and sequelae. In this review, we primarily elaborate on the pathophysiological mechanisms of thrombosis in COVID-19 patients with cancer, emphasize the role of microparticles (MPs) and phosphatidylserine (PS) in coagulation, and propose an antithrombotic strategy. The coagulation mechanisms of COVID-19 and cancer synergistically amplify the coagulation cascade, and collectively promotes pulmonary microvascular occlusion. During systemic coagulation, the virus activates immune cells to release abundant proinflammatory cytokines, referred to as cytokine storm, resulting in the apoptosis of tumor and blood cells and subsequent MPs release. Additionally, we highlight that tumor cells contribute to MPs and coagulation by apoptosis owing to insufficient blood supply. A positive feedback loop of cytokines storm and MPs storm promotes microvascular coagulation storm, leading to microthrombi formation and inadequate blood perfusion. Microthrombi-damaged endothelial cells (ECs), tumor, and blood cells further aggravate the apoptosis of the cells and facilitate MPs storm. PS, especially on MPs, plays a pivotal role in the blood coagulation process, contributing to clot initiation, amplification, and propagation. Since coagulation is a common pathway of COVID-19 and cancer, and associated with mortality, patients would benefit from antithrombotic therapy. The above results lead us to assert that early stage antithrombotic therapy is optimal. This strategy is likely to maintain blood flow patency contributing to viral clearance, attenuating the formation of cytokines and MPs storm, maintaining oxygen saturation, and avoiding the progress of the disease.


2022 ◽  
Vol 23 (1) ◽  
Author(s):  
Suhail Khokhar ◽  
Daniela Garcia ◽  
Rajesh Thirumaran

Abstract Background Renal infarctions as a result of recreational drug use are rare and are commonly associated with cocaine use. Although amphetamines have a similar mechanism of action as cocaine, there are few reports linking them to ischemic events, and only one to renal infarction. Similarly, few reports link heroin use with infarcts, but never in the kidney. Although uncommon, several mechanisms have been implicated in heroin and amphetamine-induced infarction, including vasculopathy, vasculitis and the activation of the coagulation cascade. Case Presentation 47-year-old female with a past medical history of non-intravenous heroin and amphetamine abuse, chronic obstructive pulmonary disease, hypertension, hyperlipidemia presented with right lower extremity swelling and rash, which was diagnosed as cellulitis and treated appropriately. Incidentally, the patient was found to have an acute kidney injury and further workup identified multiple renal infarcts in the right kidney. The patient had no past medical history of clotting disorders. Blood culture and urine cultures were sterile; autoimmune and hypercoagulable workup were negative. Urinalysis was unremarkable. Urine toxicology was only positive for opiates and amphetamines, which were thought to be the most likely cause of the renal infarct. Patient was lost to outpatient follow up due to noncompliance, but returned to the hospital for re-emergence of her cellulitis, during which no new infarcts were discovered, and the previous renal infarct had scarred over. Conclusion There are very few reports of heroin and amphetamine-induced infarctions. This case report describes a rare but important complication of heroin/amphetamine abuse that could be easily overlooked.


2022 ◽  
Vol 8 ◽  
Author(s):  
Eizo Watanabe ◽  
Osamu Takasu ◽  
Youichi Teratake ◽  
Teruo Sakamoto ◽  
Toshiaki Ikeda ◽  
...  

Objective: Disseminated intravascular coagulation plays a key role in the pathophysiology of sepsis. Thrombomodulin is essential in the protein C system of coagulation cascade, and functional polymorphisms influence the human thrombomodulin gene (THBD). Therefore, we conducted a multicenter study to evaluate the influence of such polymorphisms on the pathophysiology of sepsis.Methods: A collaborative case-control study in the intensive care unit (ICU) of each of five tertiary emergency centers. The study included 259 patients (of whom 125 displayed severe sepsis), who were admitted to the ICU of Chiba University Hospital, Chiba, Japan between October 2001 and September 2008 (discovery cohort) and 793 patients (of whom 271 patients displayed severe sepsis), who were admitted to the five ICUs between October 2008 and September 2012 (multicenter validation cohort). To assess the susceptibility to severe sepsis, we further selected 222 critically ill patients from the validation cohort matched for age, gender, morbidity, and severity with the patients with severe sepsis, but without any evidence of sepsis.Results: We examined whether the eight THBD single nucleotide polymorphisms (SNPs) were associated with susceptibility to and/or mortality of sepsis. Higher mortality on severe sepsis in the discovery and combined cohorts was significantly associated with the CC genotype in a THBD promoter SNP (−1920*C/G; rs2239562) [odds ratio [OR] 2.709 (1.067–6.877), P = 0.033 and OR 1.768 (1.060–2.949), P = 0.028]. Furthermore, rs2239562 SNP was associated with susceptibility to severe sepsis [OR 1.593 (1.086–2.338), P = 0.017].Conclusions: The data demonstrate that rs2239562, the THBD promoter SNP influences both the outcome and susceptibility to severe sepsis.


2022 ◽  
Vol 8 ◽  
Author(s):  
Xiaogao Pan ◽  
Yang Zhou ◽  
Guifang Yang ◽  
Zhibiao He ◽  
Hongliang Zhang ◽  
...  

Background: Misdiagnosis and delayed diagnosis of acute aortic dissection (AAD) significantly increase mortality. Lysophosphatidic acid (LPA) is a biomarker related to coagulation cascade and cardiovascular-injury. The extent of LPA elevation in AAD and whether it can discriminate sudden-onset of acute chest pain are currently unclear.Methods: We measured the plasma concentration of LPA in a cohort of 174 patients with suspected AAD chest pain and 30 healthy participants. Measures to discriminate AAD from other acute-onset thoracalgia were compared and calculated.Results: LPA was significantly higher in AAD than in the AMI, PE, and the healthy (344.69 ± 59.99 vs. 286.79 ± 43.01 vs. 286.61 ± 43.32 vs. 96.08 ± 11.93, P < 0.01) within 48 h of symptom onset. LPA level peaked at 12 h after symptom onset, then gradually decreased from 12 to 48 h in AAD. LPA had an AUC of 0.85 (0.80–0.90), diagnosis threshold of 298.98 mg/dl, a sensitivity of 0.81, specificity of 0.77, and the negative predictive value of 0.85. The ROC curve of LPA is better than D-dimer (P = 0.041, Delong test). The decision curve showed that LPA had excellent standardized net benefits.Conclusion: LPA showed superior overall diagnostic performance to D-dimer in early AAD diagnosis may be a potential biomarker, but additional studies are needed to determine the rapid and cost-effective diagnostic tests in the emergency department.


eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
Ethan S FitzGerald ◽  
Amanda M Jamieson

Mast et al. analyzed transcriptome data derived from RNA-sequencing (RNA-seq) of COVID-19 patient bronchoalveolar lavage fluid (BALF) samples, as compared to BALF RNA-seq samples from a study investigating microbiome and inflammatory interactions in obese and asthmatic adults (Mast et al., 2021). Based on their analysis of these data, Mast et al. concluded that mRNA expression of key regulators of the extrinsic coagulation cascade and fibrinolysis were significantly reduced in COVID-19 patients. Notably, they reported that the expression of the extrinsic coagulation cascade master regulator Tissue Factor (F3) remained unchanged, while there was an 8-fold upregulation of its cognate inhibitor Tissue Factor Pathway Inhibitor (TFPI). From this they conclude that “pulmonary fibrin deposition does not stem from enhanced local [tissue factor] production and that counterintuitively, COVID-19 may dampen [tissue factor]-dependent mechanisms in the lungs”. They also reported decreased Activated Protein C (aPC) mediated anticoagulant activity and major increases in fibrinogen expression and other key regulators of clot formation. Many of these results are contradictory to findings in most of the field, particularly the findings regarding extrinsic coagulation cascade mediated coagulopathies. Here, we present a complete re-analysis of the data sets analyzed by Mast et al. This re-analysis demonstrates that the two data sets utilized were not comparable between one another, and that the COVID-19 sample set was not suitable for the transcriptomic analysis Mast et al. performed. We also identified other significant flaws in the design of their retrospective analysis, such as poor-quality control and filtering standards. Given the issues with the datasets and analysis, their conclusions are not supported.


Viruses ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 95
Author(s):  
Santanu Biswas ◽  
Emily Chen ◽  
Yamei Gao ◽  
Sherwin Lee ◽  
Indira Hewlett ◽  
...  

The impact of steroid hormones estrogen and progesterone on human immunodeficiency virus type 1 (HIV-1) replication is well documented. However, the exact mechanism involved in the regulation of HIV-1 replication by estrogen and progesterone is still unclear. In the present study, we wanted to elucidate the molecular mechanisms underlying the modulation of HIV-1 replication by estrogen and progesterone. To achieve this goal, we used real-time quantitative PCR arrays (PCR arrays) to identify differentially expressed host genes in response to hormone treatments that are involved in antiviral responses. Our in vitro results suggest that treatment with high doses of estrogen and progesterone promotes the expression of host antiviral factors Secretory leukocyte protease inhibitor (SLPI) and Serpin family C member 1 (SERPIN C1) among others produced in response to HIV-1 infection. SLPI is an enzyme that inhibits human leukocyte elastase, human cathepsin G, human trypsin, neutrophil elastase, and mast cell chymase. SERPIN C1 is a plasma protease inhibitor that regulates the blood coagulation cascade by the inhibition of thrombin and other activated serine proteases of the coagulation system. A dose dependent downmodulation of HIV-1 replication was observed in monocyte-derived macrophages (MDMs) pre-treated with the two proteins SLPI and SERPIN C1. Further investigations suggests that the host antiviral factors, SLPI and SERPIN C1 act at the pre-integration stage, inhibiting HIV-1 viral entry and leading to the observed downmodulation of HIV-1 replication. Our studies would help identify molecular mechanisms and pathways involved in HIV-1 pathogenesis.


2021 ◽  
Vol 119 (2) ◽  
pp. e2110166119
Author(s):  
Shreya Das ◽  
Mohd Saqib ◽  
Ryan C. Meng ◽  
Sridar V. Chittur ◽  
Ziqiang Guan ◽  
...  

Hemachromatosis (iron-overload) increases host susceptibility to siderophilic bacterial infections that cause serious complications, but the underlying mechanisms remain elusive. The present study demonstrates that oral infection with hyperyersiniabactin (Ybt) producing Yersinia pseudotuberculosis Δfur mutant (termed Δfur) results in severe systemic infection and acute mortality to hemochromatotic mice due to rapid disruption of the intestinal barrier. Transcriptome analysis of Δfur-infected intestine revealed up-regulation in cytokine–cytokine receptor interactions, the complement and coagulation cascade, the NF-κB signaling pathway, and chemokine signaling pathways, and down-regulation in cell-adhesion molecules and Toll-like receptor signaling pathways. Further studies indicate that dysregulated interleukin (IL)-1β signaling triggered in hemachromatotic mice infected with Δfur damages the intestinal barrier by activation of myosin light-chain kinases (MLCK) and excessive neutrophilia. Inhibiting MLCK activity or depleting neutrophil infiltration reduces barrier disruption, largely ameliorates immunopathology, and substantially rescues hemochromatotic mice from lethal Δfur infection. Moreover, early intervention of IL-1β overproduction can completely rescue hemochromatotic mice from the lethal infection.


2021 ◽  
Author(s):  
Qianman Peng ◽  
Shenqi Qian ◽  
Saud Alqahtani ◽  
Peter Panizzi ◽  
Jianzhong Shen

Recently we reported that in human coronary artery endothelial cells, activation of the P2Y2 receptor (P2Y2R) induces up-regulation of tissue factor (TF), a vital initiator of the coagulation cascade. However, others have shown that monocyte TF is more critical than endothelial TF in provoking a pro-thrombotic state. Thus, we aimed to study whether monocytes express the P2Y2R, its role in controlling TF expression, and its relevance in vivo. RT-PCR and receptor activity assays revealed that among the eight P2Y nucleotide receptors, the P2Y2 subtype was selectively and functionally expressed in human monocytic THP-1 cells and primary monocytes. Stimulation of the cells by ATP or UTP dramatically increased TF protein expression, which was abolished by AR-C118925, a selective P2Y2R antagonist, or by siRNA silencing the P2Y2R. In addition, UTP or ATP treatment induced a rapid accumulation of TF mRNA preceded with an increased TF pre-mRNA, indicating enhanced TF gene transcription. In addition, stimulation of the monocyte P2Y2R significantly activated ERK1/2, JNK, p38, and Akt, along with their downstream transcription factors including c-Jun, c-Fos, and ATF-2, whereas blocking these pathways respectively, all significantly suppressed P2Y2R-mediated TF expression. Furthermore, we found that LPS triggered ATP release and TF expression, the latter of which was suppressed by apyrase or P2Y2R blockage. Importantly, P2Y2R-null mice were more resistant than wild-type mice in response to a lethal dose of LPS, accompanied by much less TF expression in bone marrow cells. These findings demonstrate for the first time that the P2Y2R mediates TF expression in human monocytes through mechanisms involving ERK1/2, JNK, p38, and AKT, and that P2Y2R deletion protects the mice from endotoxemia-induced TF expression and death, highlighting monocyte P2Y2R may be a new drug target for the prevention and/or treatment of relevant thrombotic disease.


2021 ◽  
Author(s):  
Majdi Dwikat ◽  
Nidal Jaradat ◽  
Johnny Amer ◽  
Ahmad Abdal Rahim ◽  
Mohammad Alqadi ◽  
...  

Abstract Background: Wild plants are amply utilized in traditional medicine and folkloric food worldwide. Arum palaestinum Boiss. (AP) is one of the wild Palestinian plants which leaves have a long history in the Middle Eastern countries as food and medicine. Herby, the current study aimed to evaluate the antimicrobial, coagulation cascade activities, and anticancer effects of (AP) flowers extract Methods: The aqueous extract of (AP) flowers was screened on its antimicrobial activity using microdilution assay against eight pathogens. While, prothrombin time, activated partial thromboplastin time, and thrombin time tests were measured utilizing standard hematological methods. And Anti cancer effect was assessed by using Parameters of cell cycles and alph feta protein level that were investigated for (AP) flowers fractionated with aqueous, DMSO, and methanol Results: The antimicrobial screening results revealed that the aqueous extract of (AP) has strong antibacterial effects against P. vulgaris and E. faecium compared with Ampicillin with MIC values of 6.25, 6.25 and 18 mg/ml, respectively. The aqueous extract of (AP) showed anticoagulant activity with significant prolonged results in aPTT and TT tests at high concentrations (50 mg/ml and 25 mg/ml) and slightly prolonged results in the PT test at a high concentration (50 mg/ml). The anticancer results indicate a delay in cell cycle through decreased the cell proliferation rate following effects of the AP fractions. The delay in the S phase was in favor of the water fraction. Water and DMSO fractions while maintained the cells in the G2-M phase similar to the DOX, the flower extract in methanol accelerated the cells in the G2-M phase suggesting that (AF) flower extracts have anti-cancer properties. At the same time Aqueous extract decreased HCC aFP to 1.55-fold (P=0.0008). While DMSO and methanolic extract had no significant effects on HCC aFP levels, compared to control untreated cells of 2519.16 ± 198.1 ng/ml. This data show that (AF) aqueous solution is potent inhibitor of alpha-fetoprotein secretion (P-value <0.05), which indicates its anti-carcinogenic effects Conclusion: These results showed that the aqueous extract of (AP) plant possesses bioactive components with antibacterial and anticoagulant properties, which may be exploited in the treatment of infectious diseases and blood coagulation disorders.


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