Numerical study of ultra-large von Willebrand factor multimers in coagulopathy.

An excessive von Willebrand factor (VWF) secretion, coupled with a moderate to severe deficiency of ADAMTS13 activity, serves as a linking mechanism between inflammation to thrombosis. The former facilitates platelet adhesion to the vessel wall and the latter is required to cleave VWF multimers. As a result, the ultra-large VWF (UL-VWF) multimers released by Weibel-Palade bodies remain uncleaved. In this study, using a computational model based on first principles, we quantitatively show how the uncleaved UL-VWF multimers interact with the blood cells to initiate microthrombosis. We observed that platelets first adhere to unfolded and stretched uncleaved UL-VWF multimers anchored to the microvessel wall. By the end of this initial adhesion phase, the UL-VWF multimers and platelets make a mesh-like trap in which the red blood cells increasingly accumulate to initiate a gradually growing microthrombosis. Although high-shear rate and blood flow velocity are required to activate platelets and unfold the UL-VWFs, during the initial adhesion phase, the blood velocity drastically drops after thrombosis, and as a result, the wall shear stress is elevated near UL-VWF roots, and the pressure drops up to 6 times of the healthy condition. As the time passes, these trends progressively continue until the microthrombosis fully develops and the effective size of the microthrombosis and these flow quantities remain almost constant. Our findings quantitatively demonstrate the potential role of UL-VWF in coagulopathy.

Shear Stress and Endothelial Mechanotransduction in Trauma Patients with Hemorrhagic Shock: Hidden Coagulopathy Pathways and Novel Therapeutic Strategies.

Massive trauma remains a leading cause of death and a global public health burden. Post-traumatic coagulopathy may be present even before the onset of resuscitation, and correlates with severity of trauma. Several mechanisms have been proposed to explain the development of abnormal coagulation processes, but the heterogeneity in injuries and patient profiles makes it difficult to define a dominant mechanism. Regardless of the pattern of death, a significant role in the pathophysiology and pathogenesis of coagulopathy may be attributed to the exposure of endothelial cells to abnormal physical forces and mechanical stimuli in their local environment. In these conditions, the cellular responses are translated into biochemical signals that induce/aggravate oxidative stress, inflammation, and coagulopathy. Microvascular shear stress-induced alterations could be treated or prevented by the development and use of innovative pharmacologic strategies that effectively target shear-mediated endothelial dysfunction, including shear-responsive drug delivery systems and novel antioxidants, and by targeting the venous side of the circulation to exploit the beneficial antithrombogenic profile of venous endothelial cells.

A novel melanocortin fusion protein inhibits fibrinogen oxidation and degradation during trauma-induced coagulopathy.

Immune cell inflammation is implicated in the pathophysiology of acute trauma-induced coagulopathy (TIC). We hypothesized that leukocyte inflammation contributes to TIC through the oxidation and proteolysis of fibrinogen. To test this hypothesis, antioxidants and a novel anti-inflammatory melanocortin fusion protein (AQB-565) were used to study the effects of interleukin-6 (IL-6)-stimulated human leukocytes on fibrinogen using single-cell imaging flow cytometry and multiplex fluorescent western blotting. We also studied the effects of AQB-565 on fibrinogen using an in vivo rat trauma model of native TIC. IL-6 induced cellular inflammation and mitochondrial superoxide production in human monocytes, causing fibrinogen oxidation and degradation in vitro. Antioxidants suppressing mitochondrial superoxide reduced oxidative stress and inflammation and protected fibrinogen. AQB-565 decreased inflammation, inhibited mitochondrial superoxide, and protected fibrinogen in vitro. Trauma with hemorrhagic shock increased IL-6 and other proinflammatory cytokines and chemokines, selectively oxidized and degraded fibrinogen, and induced TIC in rats in vivo. AQB-565, given at the onset of hemorrhage, blocked inflammation, protected fibrinogen from oxidation and degradation, and prevented TIC. Leukocyte activation contributes to TIC through the oxidation and degradation of fibrinogen, which involves mitochondrial superoxide and cellular inflammation. Suppression of inflammation by activation of melanocortin pathways may be a novel approach for the prevention and treatment of TIC.

Change in cytokine profiles released by mast cells mediated by lung cancer-derived exosome activation may contribute to cancer-associated coagulation disorders.

BACKGROUND: Coagulation disorders are a significant cause of lung cancer mortality. Although mast cells are known to play a role in coagulation abnormalities, their specific role in this process has not yet been elucidated. METHOD: We detected mast cells in the tumor microenvironment using single-cell sequencing data and examined their correlation with thrombosis-related genes, neutrophil-related genes, neutrophil extracellular trap-related signature genes, and immune infiltration levels in lung cancer patients through bioinformatics analysis. Bone marrow mast cell uptake of exosomes isolated from the lung adenocarcinoma cell line A549, which were labeled using PKH67, was observed using confocal microscopy. Mast cell degranulation was detected by measuring the ß-hexosaminidase release rate. Additionally, cytokine array analysis was performed to identify altered mediators released by bone marrow mast cells after uptake of the exosomes. RESULTS: In our study, we found a close correlation between the proportion of mast cells in lung cancer patients and the expression levels of thrombosis-related genes and neutrophil extracellular trap signature genes, both of which play a key role in thrombophilic disorder. Moreover, we discovered that lung cancer cell-derived exosomes can be taken up by mast cells, which in turn become activated to release procoagulant mediators. CONCLUSION: Our study shows that exosomes derived from lung cancer cells can activate mast cells to release procoagulants that may contribute to abnormal blood clotting in lung cancer patients. Video Abstract.

Robust coagulation activation and coagulopathy in mice with experimental acetaminophen-induced liver failure.

BACKGROUND: Patients with acetaminophen (APAP)-induced acute liver failure (ALF) display both hyper- and hypocoagulable changes not necessarily recapitulated by standard hepatotoxic doses of APAP used in mice (eg, 300 mg/kg). OBJECTIVES: We sought to examine coagulation activation in vivo and plasma coagulation potential ex vivo in experimental settings of APAP-induced hepatotoxicity and repair (300-450 mg/kg) and APAP-induced ALF (600 mg/kg) in mice. RESULTS: APAP-induced ALF was associated with increased plasma thrombin-antithrombin complexes, decreased plasma prothrombin, and a dramatic reduction in plasma fibrinogen compared with lower APAP doses. Hepatic fibrin(ogen) deposits increased independent of APAP dose, whereas plasma fibrin(ogen) degradation products markedly increased in mice with experimental ALF. Early pharmacologic anticoagulation (+2 hours after 600 mg/kg APAP) limited coagulation activation and reduced hepatic necrosis. The marked coagulation activation evident in mice with APAP-induced ALF was associated with a coagulopathy detectable ex vivo in plasma. Specifically, prolongation of the prothrombin time and inhibition of tissue factor-initiated clot formation were evident even after restoration of physiological fibrinogen concentrations. Plasma endogenous thrombin potential was similarly reduced at all APAP doses. Interestingly, in the presence of ample fibrinogen, ∼10 times more thrombin was required to clot plasma from mice with APAP-induced ALF compared with plasma from mice with simple hepatotoxicity. CONCLUSION: The results indicate that robust pathologic coagulation cascade activation in vivo and suppressed coagulation ex vivo are evident in mice with APAP-induced ALF. This unique experimental setting may fill an unmet need as a model to uncover mechanistic aspects of the complex coagulopathy of ALF.

Neutrophil-to-lymphocyte ratio (NLR) as a predictive index for liver and coagulation dysfunction in preeclampsia patients.

BACKGROUND: Pre-eclampsia (PE) is a pregnancy disorder that is related to an enhanced immune response. Immune cell characteristics such as neutrophil or monocyte to lymphocyte ratios (NLR, MLR) are known to be related to kidney and liver dysfunction in hypertensive patients. Here, we aimed to analyze the correlations between NLR, MLR and platelet to lymphocyte ratio (PLR) and liver, renal and coagulation functional parameters and the impacts of these immune cell profiles to the prognostic significance in PE patients. METHODS: Pre-delivery hematological and biochemical parameters of 320 first-time pregnant women registered at the Obstetrics Department of Yanbian University Hospital from 2016 to 2019 were analyzed retrospectively. Patients were divided into normal pregnancy (normal, n = 161), mild PE (mPE, n = 28) and severe PE (sPE, n = 131) groups according to diagnostic criteria. Pearson correlation analysis were performed and area under the curve (AUC) were conducted for the diagnostic values of NLR, MLR and PLR. Results were validated with data from the Department of Obstetrics and Gynecology of Seoul National University Hospital (SNUH). RESULTS: Kidney functional indexes were adversative in mPE and sPE and liver and coagulation indexes were worse in sPE compared to normal groups. Among immune cells, lymphocytes were increased in mPE and sPE patients, resulted in reduced NLR, MLR and PLR in PE groups, more significant difference were shown in sPE. NLR and PLR were associated with CREA and/or BUN negatively and positive associations were observed with total protein (TP) and albumin (ALB) in sPE. Only NLR showed positive associations with coagulation indexes (PT and APTT) in sPE. AUC analysis for NLR, MLR and PLR were 0.700, 0.656, 0.643, respectively, and NLR < 3.7 predicted hypertension (95% CI in all participants: 0.647-0.749, p < 0.001). Blood pressure, liver, kidney and coagulation indexes were worse at cut off value (NLR < 3.7), and this was validated with the data from SNUH. CONCLUSION: NLR could be used as an independent predictor of liver and coagulation dysfunction in PE patients. Our results may provide non-invasive and efficient way of the risk assessment among PE patients.

Brain-Derived Neurotrophic Factor (BDNF) Is Associated with Platelet Activity and Bleeding Tendency in Patients with Gaucher Disease.

Bleeding tendency, a prominent feature of patients with Gaucher disease (GD), is associated with abnormal platelet function. Brain-derived neurotrophic factor (BDNF) is a protein with neuroprotective potential stored in alpha granules of circulating platelets. Here we studied BDNF levels in 50 patients with type I GD (GD1) and their correlation with platelet activity and bleeding tendency. Flow cytometry was used to test unstimulated and stimulated measurement of platelet surface-activated expression of αIIbß3 integrin, P-selectin and lysosomal-associated membrane protein (LAMP3/CD63). Serum and plasma BDNF levels were quantified using ELISA. The bleeding history was recorded by a bleeding questionnaire. Serum BDNF levels were positively correlated with platelet count and moderately correlated with unstimulated and stimulated platelet P-selectin expression. Patients with more than one bleeding manifestation were shown to have lower serum BDNF levels, albeit similar platelet count. Plasma BDNF levels were significantly elevated in splenectomized patients and showed a moderate positive correlation with stimulated platelet CD63 expression. These observations demonstrate the first association between BDNF levels in the peripheral blood with platelet dysfunction and increased bleeding manifestation. The role of measuring serum BDNF for assessing platelet alpha degranulation defects and bleeding risk in patients with GD and the general population needs further study.

The probable role and therapeutic potential of the PI3K/AKT signaling pathway in SARS-CoV-2 induced coagulopathy.

Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is associated with a high mortality rate. The majority of deaths in this disease are caused by ARDS (acute respiratory distress syndrome) followed by cytokine storm and coagulation complications. Although alterations in the level of the number of coagulation factors have been detected in samples from COVID-19 patients, the direct molecular mechanism which has been involved in this pathologic process has not been explored yet. The PI3K/AKT signaling pathway is an intracellular pathway which plays a central role in cell survival. Also, in recent years the association between this pathway and coagulopathies has been well clarified. Therefore, based on the evidence on over-activity of the PI3K/AKT signaling pathway in SARS-CoV-2 infection, in the current review, the probable role of this cellular pathway as a therapeutic target for the prevention of coagulation complications in patients with COVID-19 is discussed.

Endothelial thrombomodulin downregulation caused by hypoxia contributes to severe infiltration and coagulopathy in COVID-19 patient lungs.

BACKGROUND: Thromboembolism is a life-threatening manifestation of coronavirus disease 2019 (COVID-19). We investigated a dysfunctional phenotype of vascular endothelial cells in the lungs during COVID-19. METHODS: We obtained the lung specimens from the patients who died of COVID-19. The phenotype of endothelial cells and immune cells was examined by flow cytometry and immunohistochemistry (IHC) analysis. We tested the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the endothelium using IHC and electron microscopy. FINDINGS: The autopsy lungs of COVID-19 patients exhibited severe coagulation abnormalities, immune cell infiltration, and platelet activation. Pulmonary endothelial cells of COVID-19 patients showed increased expression of procoagulant von Willebrand factor (VWF) and decreased expression of anticoagulants thrombomodulin and endothelial protein C receptor (EPCR). In the autopsy lungs of COVID-19 patients, the number of macrophages, monocytes, and T cells was increased, showing an activated phenotype. Despite increased immune cells, adhesion molecules such as ICAM-1, VCAM-1, E-selectin, and P-selectin were downregulated in pulmonary endothelial cells of COVID-19 patients. Notably, decreased thrombomodulin expression in endothelial cells was associated with increased immune cell infiltration in the COVID-19 patient lungs. There were no SARS-CoV-2 particles detected in the lung endothelium of COVID-19 patients despite their dysfunctional phenotype. Meanwhile, the autopsy lungs of COVID-19 patients showed SARS-CoV-2 virions in damaged alveolar epithelium and evidence of hypoxic injury. INTERPRETATION: Pulmonary endothelial cells become dysfunctional during COVID-19, showing a loss of thrombomodulin expression related to severe thrombosis and infiltration, and endothelial cell dysfunction might be caused by a pathologic condition in COVID-19 patient lungs rather than a direct infection with SARS-CoV-2. FUNDING: This work was supported by the Johns Hopkins University, the American Heart Association, and the National Institutes of Health.

Contribution of the von Willebrand factor/ADAMTS13 imbalance to COVID-19 coagulopathy.

The 2019 coronavirus disease (COVID-19) is the disease caused by SARS-CoV-2 infection. Although this infection has been shown to affect the respiratory system, a high incidence of thrombotic events has been observed in severe cases of COVID-19 and in a significant portion of COVID-19 nonsurvivors. Although prior literature has reported on both the coagulopathy and hypercoagulability of COVID-19, the specifics of coagulation have not been fully investigated. Observations of microthrombosis in patients with COVID-19 have brought attention to potential inflammatory endothelial injury. Von Willebrand factor (VWF) and its protease, A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), play an important homeostatic role in responding to endothelial injury. This report provides an overview of the literature investigating the role the VWF/ADAMTS13 axis may have in COVID-19 thrombotic events and suggests potential therapeutic strategies to prevent the progression of coagulopathy in patients with COVID-19.

Platelet-Mediated NET Release Amplifies Coagulopathy and Drives Lung Pathology During Severe Influenza Infection.

The influenza A virus (IAV) causes a respiratory tract infection with approximately 10% of the population infected by the virus each year. Severe IAV infection is characterized by excessive inflammation and tissue pathology in the lungs. Platelet and neutrophil recruitment to the lung are involved in the pathogenesis of IAV, but the specific mechanisms involved have not been clarified. Using confocal intravital microscopy in a mouse model of IAV infection, we observed profound neutrophil recruitment, platelet aggregation, neutrophil extracellular trap (NET) production and thrombin activation within the lung microvasculature in vivo. Importantly, deficiency or antagonism of the protease-activated receptor 4 (PAR4) reduced platelet aggregation, NET production, and neutrophil recruitment. Critically, inhibition of thrombin or PAR4 protected mice from virus-induced lung tissue damage and edema. Together, these data imply thrombin-stimulated platelets play a critical role in the activation/recruitment of neutrophils, NET release and directly contribute to IAV pathogenesis in the lung.

Inflammation/coagulopathy/fibrinolysis: Dynamic indicators of COVID-19 progression in patients with moderate COVID-19 in Wenzhou, China.

BACKGROUND: The majority of the coronavirus disease 2019 (COVID-19) non-survivors meet the criteria for disseminated intravascular coagulation (DIC). Although timely monitoring of clotting hemorrhagic development during the natural course of COVID-19 is critical for understanding pathogenesis, diagnosis, and treatment of the disease, however, limited data are available on the dynamic processes of inflammation/coagulopathy/fibrinolysis (ICF). METHODS: We monitored the dynamic progression of ICF in patients with moderate COVID-19. Out of 694 COVID-19 inpatients from 10 hospitals in Wenzhou, China, we selected 293 adult patients without comorbidities. These patients were divided into different daily cohorts according to the COVID-19 onset-time. Furthermore, data of 223 COVID-19 patients with comorbidities and 22 critical cases were analyzed. Retrospective data were extracted from electronic medical records. RESULTS: The virus-induced damages to pre-hospitalization patients triggered two ICF fluctuations during the 14-day course of the disease. C-reactive protein (CRP), fibrinogen, and D-dimer levels increased and peaked at day 5 (D) 5 and D9 during the 1st and 2nd fluctuations, respectively. The ICF activities were higher during the 2nd fluctuation. Although 12-day medication returned high CRP concentrations to normal and blocked fibrinogen increase, the D-dimer levels remained high on days 17 ±â€¯2 and 23 ±â€¯2 days of the COVID-19 course. Notably, although the oxygenation index, prothrombin time and activated partial thromboplastin time were within the normal range in critical COVID-19 patients at administration, 86% of these patients had a D-dimer level > 500 µg/L. CONCLUSION: COVID-19 is linked with chronic DIC, which could be responsible for the progression of the disease. Understanding and monitoring ICF progression during COVID-19 can help clinicians in identifying the stage of the disease quickly and accurately and administering suitable treatment.

Bleeding Disorders in Primary Fibrinolysis.

Fibrinolysis is a complex enzymatic process aimed at dissolving blood clots to prevent vascular occlusions. The fibrinolytic system is composed of a number of cofactors that, by regulating fibrin degradation, maintain the hemostatic balance. A dysregulation of fibrinolysis is associated with various pathological processes that result, depending on the type of abnormality, in prothrombotic or hemorrhagic states. This narrative review is focused on the congenital and acquired disorders of primary fibrinolysis in both adults and children characterized by a hyperfibrinolytic state with a bleeding phenotype.

Heparanase as a potential player in SARS-CoV-2 infection and induced coagulopathy.

During the current formidable COVID-19 pandemic, it is appealing to address ideas that may invoke therapeutic interventions. Clotting disorders are well recognized in patients infected with severe acute respiratory syndrome (SARS) caused by a novel coronavirus (SARS-CoV-2), which lead to severe complications that worsen the prognosis in these subjects. Increasing evidence implicate Heparan sulfate proteoglycans (HSPGs) and Heparanase in various diseases and pathologies, including hypercoagulability states. Moreover, HSPGs and Heparanase are involved in several viral infections, in which they enhance cell entry and release of the viruses. Herein we discuss the molecular involvement of HSPGs and heparanase in SARS-CoV-2 infection, namely cell entry and release, and the accompanied coagulopathy complications, which assumedly could be blocked by heparanase inhibitors such as Heparin and Pixatimod.

Thromboplasminflammation in COVID-19 Coagulopathy: Three Viewpoints for Diagnostic and Therapeutic Strategies.

Thromboplasminflammation in coronavirus disease 2019 (COVID-19) coagulopathy consists of angiotensin II (Ang II)-induced coagulopathy, activated factor XII (FXIIa)- and kallikrein, kinin system-enhanced fibrinolysis, and disseminated intravascular coagulation (DIC). All three conditions induce systemic inflammation via each pathomechanism-developed production of inflammatory cytokines. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) downregulates angiotensin-converting enzyme 2, leading to an increase in Ang II levels. Ang II-induced coagulopathy comprising platelet activation, thrombin generation, plasminogen activator inhibitor-1 expression and endothelial injury causes thrombosis via the angiotensin II type 1 receptor. SARS-CoV-2 RNA and neutrophil extracellular trap (NET) DNA activate FXII, resulting in plasmin generation through FXIIa- and kallikrein-mediated plasminogen conversion to plasmin and bradykinin-induced tissue-type plasminogen activator release from the endothelium via the kinin B2 receptor. NETs induce immunothrombosis at the site of infection (lungs), through histone- and DNA-mediated thrombin generation, insufficient anticoagulation control, and inhibition of fibrinolysis. However, if the infection is sufficiently severe, immunothrombosis disseminates into the systemic circulation, and DIC, which is associated with the endothelial injury, occurs. Inflammation, and serine protease networks of coagulation and fibrinolysis, militate each other through complement pathways, which exacerbates three pathologies of COVID-19 coagulopathy. COVID-19 coagulopathy causes microvascular thrombosis and bleeding, resulting in multiple organ dysfunction and death in critically ill patients. Treatment targets for improving the prognosis of COVID-19 coagulopathy include thrombin, plasmin, and inflammation, and SARS-CoV-2 infection. Several drugs are candidates for controlling these conditions; however, further advances are required to establish robust treatments based on a clear understanding of molecular mechanisms of COVID-19 coagulopathy.

Validation of the relationship between coagulopathy and localization of hydroxyethyl starch on the vascular endothelium in a rat hemodilution model.

Various anticoagulant properties have been associated with hydroxyethyl starch (HES). However, the mechanism remains unclear and it has not been fully considered whether these properties are beyond the dilutional effect itself. The aim of this study was to reproduce the coagulopathy induced by HES and to test the hypothesis that the coagulopathy is caused by endothelial or glycocalyx damage due to localization of HES on the endothelium, which is caused by the high shear viscosity of dilutional blood. Using a rat model, we compared blood coagulability measured by Sonoclot, levels of endothelial and glycocalyx damage markers and coagulation factors, and blood shear viscosity when hemodilution was performed with physiological saline (PS), 6% HES 130/0.4 in PS, and 10% HES 200/0.5 in PS. We also evaluated the localization rates of fluorescently labeled HES on endothelium in the isolated aorta. HES decreased the fibrin gel formation rate more than did PS. HES was shown to cover the endothelium, possibly due to its high shear viscosity, and this mechanism potentially acted to protect, rather than damage, the endothelium and glycocalyx. However, this covering effect may be the cause of coagulopathy due to inhibition of von Willebrand factor secretion from the endothelium.

COVID-19-associated coagulopathy: a concise review on pathogenesis and clinical implications.

In this review, we summarize the possible mechanisms of COVID-19-associated coagulopathy and compare its features to other similar conditions. The recent COVID-19 pandemic has caused enormous mortality and morbidity worldwide. It is important to note that COVID-19-associated thrombotic events play a huge role in the morbidity of this disease. Interestingly, it has been observed that this complication may occur despite prophylactic anticoagulant therapy. Recent studies on COVID-19-associated coagulopathy revealed that the COVID-19-associated hypercoagulability is more frequently observed among those with a severe course of the disease. Various mechanisms have been suggested as explanations for this condition and possible underlying etiologies.

Lung Epithelial Cell Transcriptional Regulation as a Factor in COVID-19-associated Coagulopathies.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly become a global pandemic. In addition to the acute pulmonary symptoms of coronavirus disease (COVID-19) (the disease associated with SARS-CoV-2 infection), pulmonary and distal coagulopathies have caused morbidity and mortality in many patients. Currently, the molecular pathogenesis underlying COVID-19-associated coagulopathies are unknown. Identifying the molecular basis of how SARS-CoV-2 drives coagulation is essential to mitigating short- and long-term thrombotic risks of sick and recovered patients with COVID-19. We aimed to perform coagulation-focused transcriptome analysis of in vitro infected primary respiratory epithelial cells, patient-derived bronchial alveolar lavage cells, and circulating immune cells during SARS-CoV-2 infection. Our objective was to identify transcription-mediated signaling networks driving coagulopathies associated with COVID-19. We analyzed recently published experimentally and clinically derived bulk or single-cell RNA sequencing datasets of SARS-CoV-2 infection to identify changes in transcriptional regulation of blood coagulation. We also confirmed that the transcriptional expression of a key coagulation regulator was recapitulated at the protein level. We specifically focused our analysis on lung tissue-expressed genes regulating the extrinsic coagulation cascade and the plasminogen activation system. Analyzing transcriptomic data of in vitro infected normal human bronchial epithelial cells and patient-derived bronchial alveolar lavage samples revealed that SARS-CoV-2 infection induces the extrinsic blood coagulation cascade and suppresses the plasminogen activation system. We also performed in vitro SARS-CoV-2 infection experiments on primary human lung epithelial cells to confirm that transcriptional upregulation of tissue factor, the extrinsic coagulation cascade master regulator, manifested at the protein level. Furthermore, infection of normal human bronchial epithelial cells with influenza A virus did not drive key regulators of blood coagulation in a similar manner as SARS-CoV-2. In addition, peripheral blood mononuclear cells did not differentially express genes regulating the extrinsic coagulation cascade or plasminogen activation system during SARS-CoV-2 infection, suggesting that they are not directly inducing coagulopathy through these pathways. The hyperactivation of the extrinsic blood coagulation cascade and the suppression of the plasminogen activation system in SARS-CoV-2-infected epithelial cells may drive diverse coagulopathies in the lung and distal organ systems. Understanding how hosts drive such transcriptional changes with SARS-CoV-2 infection may enable the design of host-directed therapeutic strategies to treat COVID-19 and other coronaviruses inducing hypercoagulation.

Unrecognized blood clotting factors.

Most clotting factors were initially discovered as agents functionally deficient in the plasmas of rare patients with hereditary coagulation disorders. During 1940s to 1960s, many factors were named by different investigators after the name of the patient who lacked a new factor. Consequently, there were the same factors with different names. To avoid confusion, the International Committee on the nomenclature of clotting factors was founded and discussed the identity or non-identity of clotting factors by specialists. There remain, however, several factors that were not officially authorized. We attempt to review some of these factors that seem to be not identical with any known clotting factors.

Effect Of Justicia Adhatoda (Malabar Nut) Leaf Extract On Drug-Induced Coagulopathy In Mice And In-Vitro Platelet Aggregation Of Human Blood.

BACKGROUND: Justicia adhatoda is widely used in traditional medicine for treatment of menorrhagia, piles and bleeding disorders. Oral antiplatelet and anticoagulant drugs are routinely prescribed to patients with cardiovascular diseases. These drugs have one major adverse effect that they can cause spontaneous haemorrhage, which can be fatal. Development of a haemostatic agent can help in effective management of drug-induced haemorrhages. This study was devised to observe the effect of leaf extract of Justicia adhatoda on coagulation profile in mice and to evaluate its effect on in-vitro platelet aggregation. METHODS: The study was divided into two parts. First part was designed to evaluate the effect of J. adhatoda leaf extract on coagulation parameters. Three drugs were used to induce coagulopathy viz., warfarin, aspirin and dabigatran. Bleeding time, platelet count, PT and APTT were estimated. Second part of this study was devised to observe the effect of J. adhatoda leaf extract on in vitro platelet aggregation of human. Percent aggregation was recorded by light transmission aggregometer for three minutes. RESULTS: Leaf extract of Justicia adhatoda decreased bleeding time from 6.1±2.36 minutes in normal control to 1.9±1.03 minutes in extract treated mice. There was no effect on the coagulation parameters. Platelet count increased significantly only in the aspirin treated group that received the extract to 540±46.8x103 /µl from 436.9±37.9x103 /µl of aspirin treated group. Platelet aggregation in vitro increased in a dose dependent manner. CONCLUSION: Justicia adhatoda leaf extract is effective in controlling excessive bleeding in vivo, in mice with acquired platelet defect produced by aspirin. This haemostatic effect is probably due to increased platelet aggregation as indicated by the in vitro results.