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A proposed mechanism for the observed coagulation factor changes in acute liver injury secondary to paracetamol overdose. (i) Paracetamol overdose causes cytokine release from Kupffer cells and monocytes. (ii) This results in hepatic necrosis and increased tissue factor expression. (iii) Tissue factor initiates coagulation on the platelet phospholipid surface with consumption of coagulation FVII, FX, FII and FV. Activation of FV by Xa is as efficient as by thrombin (IIa). (iv) Antithrombin inactivates both thrombin and Xa. Antithrombin levels fall in acute liver injury. (v) Markedly elevated levels of thrombin-antithrombin (TAT) complexes are seen in acute liver injury and this may explain the reduced levels of functional antithrombin, as well as reducing the activation/consumption of FXI (and subsequently FIX) and FVIII by thrombin. Much lower concentrations of thrombin are required to activate FV. This may lead to the preservation of levels of FVIII, FIX and FXI in acute liver injury. Additional mechanisms also contribute to elevate FVIII levels – see text for details.
Source publication
The mechanisms leading to the hemostatic changes of acute liver injury are poorly understood. To study these further we have assessed coagulation and immune changes in patients with acute paracetamol overdose and compared the results to patients with chronic cirrhosis and normal healthy controls. The results demonstrate that in paracetamol overdose...
Contexts in source publication
Context 1
... is of note that all of the coagulation factors which fall to lower levels in acute liver injury are those which are directly activated following tissue factor generation, whereas FIX, FXI and FVIII are activated during the ampli®cation phase of blood coagulation which is mediated by thrombin (IIa) feedback (Fig. 3). Although FV is also activated by thrombin, a much lower concentration of thrombin is required than is necessary for the activation of FXI (and subsequently FIX) and FVIII [13]. Also, FV can be activated just as ef®ciently by Xa as by thrombin [14,15]. In addition to being activated by FXI, FIX is also directly activated by the tissue ...
Context 2
... is of note that all of the coagulation factors which fall to lower levels in acute liver injury are those which are directly activated following tissue factor generation, whereas FIX, FXI and FVIII are activated during the ampli®cation phase of blood coagulation which is mediated by thrombin (IIa) feedback (Fig. 3). Although FV is also activated by thrombin, a much lower concentration of thrombin is required than is necessary for the activation of FXI (and subsequently FIX) and FVIII [13]. Also, FV can be activated just as ef®ciently by Xa as by thrombin [14,15]. In addition to being activated by FXI, FIX is also directly activated by the tissue factor-FVIIa complex. This may explain why FIX levels were found to be slightly lower than the FXI levels (mean 0.51 vs. 0.72 IU mL À1 ...
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Background
The coagulopathy of COVID-19 still awaits more clarification, and one approach that has not been investigated is to compare the hemostatic changes between COVID-19 and non-COVID-19 infected patients.
Objective
This study aims to study COVID-19 coagulopathy by measuring markers of endothelial injury and coagulation, including anticoagula...
Citations
... 13 Several studies in patients suffering from ALF have reported elevated levels of inflammatory cytokines, such as interleukin (IL)-6, IL-8, IL-10, and tumor necrosis factor alpha (TNF-α). [14][15][16] Objectives The aim of this study was to analyze cytokine levels and ALF-related laboratory parameters before and over the course of acetaminophen-induced ALF in a porcine model in order to identify biomarkers for early prediction of the clinical outcome of acute acetaminophen poisoning. ...
Background:
Acetaminophen intoxication has become the leading cause of acute liver failure (ALF) in Europe and the USA.
Objectives:
To identify early biomarkers in order to predict the development of ALF in a porcine model of acetaminophen intoxication.
Material and methods:
Six German Landrace pigs received a single acetaminophen bolus of 1 g/kg body weight via a jejunal catheter. Cytokines and laboratory parameters were analyzed at 8-hour intervals for a total of 40 h.
Results:
Three of the 6 animals survived the intoxication. The nonsurviving animals had an increase in serum lactate and interleukin (IL)-6, with a simultaneous decrease in prothrombin time (PT) and albumin concentration 8 h after intoxication. In all nonsurviving animals, elevated levels of tumor necrosis factor alpha (TNF-α) at baseline before intoxication and during the course of ALF were observed. The acetaminophen serum concentrations and toxicokinetics did not differ between the nonsurviving and surviving animals. Methemoglobinemia was proportional to the administered doses and acetaminophen blood levels, but methemoglobinemia did not affect survival.
Conclusions:
Tumor necrosis factor alpha, IL-6, lactate, prothrombin time, and albumin blood concentration were identified as early predictors of outcome after acetaminophen intoxication. An elevated TNF-α level before acetaminophen exposure was the earliest prognostic marker for a lethal outcome. Therefore, it could serve as a very early indicator of prognosis.
... Various pharmacological actions of nicotine additives and their wide use in many countries and regions stated that the chronic consumption of SLT may influence the status of haematological profiles [1,18]. The effects of tobacco on the coagulation profile showed inhibition of production clotting factors, resulting in prolonged bleeding, which is attributable to coagulation factor inhibitors [19,20]. However, previous reports described the long-term harmful effects of SLT nicotine on various body parameters, but few studies examine the effect of consumption of SLT and little is known about the effect of Tombak on haematological parameters and coagulation profiles. ...
The goal of this paper is to investigate the influence of oral dipping of Tombak Smokeless Tobacco (SLT) on prothrombin time (PT), activated partial thromboplastin time (APTT), international normalized ratio(INR) values, and platelet counts (PLTs), in Sudanese Tombak users. An analytical cross-sectional study was conducted at Kosti health insurance hospital, Sudan, in 2019. According to the inclusion and exclusion criteria, 100 adult users of oral Tombak for three or more years were chosen randomly as a study group. Another 100 matched healthy individuals who never used Tombak were randomly selected as a comparative group. Venous blood specimens were collected in ethylene diamine tetra-acetic acid (EDTA) containers for the PLT counts using the automated haematology analyser (Sysmex, Tokyo, Japan XK-21SYSMEX) and in trisodium citrate anti-coagulant containers for coagulation tests using a co-agulometer machine analyser. Our findings show a significant decrease in PLT count mean values in the Tombak users group (212.1 × 103/mm3 ± 74.3 × 103/mm3) compared with the non-taking Tombak group mean values (243.2 × 103/mm3 ± 83.0 × 103/mm3), (p < 0.006). Both PT and APTT were significantly prolonged in Tombak users (16.03 ± 1.22 s vs. 14.44 ± 0.557 s),
p < 0.001 for PT, and (41.62 ± 7.28 s vs. 34.99 ± 4.02 s), (p < 0.001) for APTT. INR mean values were significantly longer in Tombak users (1.11 ± 0.096) vs. (1.07 ± 0.66; p < 0.001). Multiple linear regression analysis findings show a significant impact of the four investigated variables, including duration of taking Tombak, age, and frequency of taking Tombak per day (p < 0.001). In conclusion, using Tombak a Smokeless Tobacco (SLT) for a long period significantly affects Platelet counts and coagulation profile.
... The extent of hypercoagulability in cirrhotic patients with Child-Pugh class C was similar to that observed in the plasma of patients with congenital protein C deficiency or factor V Leiden mutation [9]. On the other hand, several studies have demonstrated drivers of hypocoagulability in cirrhotic patients secondary to decrease the production of factors II, V, VII, IX, X, and XI produced in the liver [18]. Additionally, cirrhotic patients have thrombocytopenia secondary to splenic sequestration that contribute to a higher tendency to bleed. ...
Background
Patients with liver cirrhosis were previously considered as anticoagulated; thus, their risk of developing venous thromboembolism (VTE) is lower. Recently, several studies showed contradicting results regarding deep venous thrombosis (DVT) occurrence in cirrhotic patients. The aim of this study is to evaluate the prevalence and risk associated with developing DVT in hospitalized cirrhotic patients in a large US population.
Methods
We queried the commercial database Explorys (IMB Inc., Armonk, New York), an aggregate of electronic health record data from 26 US healthcare systems. After excluding patients under 20 years old, a cohort of patients with a Systematized Nomenclature of Medicine - Clinical Terms of "cirrhosis of the liver" and "inpatient care" between 2015-2019 were identified, and prevalence of DVT was calculated in the exposure and the control groups. Statistical analysis for a multivariable model was performed. Factors adjusted for include gender, race, obesity, hypoalbuminemia, diabetes mellitus, viral hepatitis, and liver malignancy.
Results
Among 9,990,290 patients who were hospitalized between 2015 and 2019, 157,400 patients had a diagnosis of liver cirrhosis. The prevalence of DVT in hospitalized patients with liver cirrhosis was 3.29% compared to 3.18% in non-cirrhotic patients. Using the multivariate analysis model, DVT was inversely associated with cirrhosis in hospitalized patients [OR: 0.921; p<0.0001] compared to patients without liver cirrhosis. Predictors of developing DVT among patients with cirrhosis were non-Caucasian race, obesity (BMI>30), liver malignancy, hypoalbuminemia, and diabetes mellitus. Cirrhotic patients due to viral hepatitis were less likely to develop DVT [OR: 0.775; p<0.001] compared to non-cirrhotic patients.
Conclusion
In this database, although the prevalence of DVT in cirrhotic hospitalized patients was slightly higher than in non-cirrhotic patients (3.29% vs. 3.18%, respectively), cirrhosis as an independent factor was associated with less risk of DVT during hospitalization. This poses a question regarding DVT prophylaxis necessity in this group of patients. Further studies are needed to clarify the benefit and risks of DVT prophylaxis in cirrhotic patients.
... 19,20 Previous studies (in both humans and animal experimental models) have also revealed a link between changes in the hemostatic system and the progression of APAP-induced liver damage. [21][22][23][24][25][26][27][28][29][30][31][32] Thus, there is a need for a safer and more effective alternative to classical APAP. ...
Background
Acetaminophen (APAP) is a widely self-prescribed analgesic for mild to moderate pain, but overdose or repeat doses can lead to liver injury and death. Kalyra Pharmaceuticals has developed a novel APAP analog, KP-1199, currently in Phase 1 clinical studies, which lacks hepatotoxicity. In this study, the authors evaluated the antinociceptive effect of KP-1199 on thermal injury-induced nociceptive behaviors as well as hemostatic parameters using human blood samples.
Methods
Full-thickness thermal injury was induced in anesthetized adult male Sprague–Dawley rats. On day 7 post-injury, KP-1199 (30 and 60 mg/kg) or APAP (60 mg/kg) was administered orally. Antinociception of KP-1199 and APAP were assessed at multiple time points using Hargreaves' test. In separate experiments, human whole blood was collected and treated with either KP-1199, APAP, or Vehicle (citrate buffer) at 1× (214 μg/ml) and 10× (2140 μg/ml) concentrations. The treated blood samples were assessed for: clotting function, thrombin generation, and platelet activation.
Results
APAP did not produce antinociceptive activity. KP-1199 treatment significantly increased the nociceptive threshold, and the antinociceptive activity persisted up to 3 h post-treatment. In human samples, 10× APAP caused significantly prolonged clotting times and increased platelet activation, whereas KP-1199 had caused no negative effects on either parameter tested.
Conclusion
These results suggest that KP-1199 possesses antinociceptive activity in a rat model of thermal injury. Since KP-1199 does not induce platelet activation or inhibit coagulation, it presents an attractive alternative to APAP for analgesia, especially for battlefield or surgical scenarios where blood loss and blood clotting are of concern.
... A previous study has already reported liver enzyme abnormalities, elevated serum alanine aminotransferase (ALT), and aspartate aminotransferase (AST) in 43.4% of surveyed COVID-19 patients [3], an effect also reported in a systematic review and a meta-analysis of severe and fatal COVID-19 cases where elevated serum AST levels were found. This association implies that severe COVID-19 patients are at risk of liver injury, which may accelerate the risk of developing vascular thrombosis [98], coagulopathy, and subsequent clotting issues in multiple organ systems. Patients with comorbid fatty liver or other hepatic diseases may thus be at risk of developing severe or fatal COVID-19 infections and should be monitored closely for signs of liver damage. ...
Since December 2019, the SARS-CoV-2 (COVID-19) pandemic has transfixed the medical world. COVID-19 symptoms vary from mild to severe and underlying chronic conditions such as pulmonary/cardiovascular disease and diabetes induce excessive inflammatory responses to COVID-19 and these underlying chronic diseases are mediated by endothelial dysfunction. Acute respiratory distress syndrome (ARDS) is the most common cause of death in COVID-19 patients, but coagulation induced by excessive inflammation, thrombosis, and disseminated intravascular coagulation (DIC) also induce death by multiple-organ dysfunction syndrome. These associations imply that maintaining endothelial integrity is crucial for favorable prognoses with COVID-19 and therapeutic intervention to support this may be beneficial. Here, we summarize the extent of heart injuries, ischemic stroke and hemorrhage, acute kidney injury, and liver injury caused by immune-mediated endothelial dysfunction that result in the phenomenon of multi-organ dysfunction seen in COVID-19 patients. Moreover, the potential therapeutic effect of angiotensin receptor blockers and angiotensin-converting enzyme inhibitors that improve endothelial dysfunction as well as the bradykinin storm are discussed.
... TF-initiated blood coagulation occurs in two phases: the first phase is the initiation phase, the second is the amplification phase. 2,3 The initiation phase begins from the moment when naked TF binds to factor VIIa, which is found in the circulating blood in picomolar concentrations. The formed TF-VIIa complex catalyzes the conversion of a small amount of factor X to Xa, which in turn produces an equally small amount of thrombin. ...
... This leads, in the end, to the coagulation system to bleeding or thrombosis. In viral hepatitis, there is also a decrease in the synthesis of coagulation factors, vitamin K deficiency, thrombocytopenia, etc.3 It should be noted that in chronic liver diseases of viral aetiology, the concentration of procoagulant factors, as a rule, is reduced, however, the level of endogenous anticoagulants (antithrombin, proteins C and S) is also reduced, all this taken together maintain the hemostatic balance, which can be disrupted by structural damage to endothelial cells, which is often combined with infection with dysbacteriosis.2,3 ...
... This leads, in the end, to the coagulation system to bleeding or thrombosis. In viral hepatitis, there is also a decrease in the synthesis of coagulation factors, vitamin K deficiency, thrombocytopenia, etc.3 It should be noted that in chronic liver diseases of viral aetiology, the concentration of procoagulant factors, as a rule, is reduced, however, the level of endogenous anticoagulants (antithrombin, proteins C and S) is also reduced, all this taken together maintain the hemostatic balance, which can be disrupted by structural damage to endothelial cells, which is often combined with infection with dysbacteriosis.2,3 Based on the foregoing, the purpose of this research was to assess dysfunctional endothelial disorders in patients with viral hepatitis before tooth extraction. ...
... In another study, 31 patients with acute paracetamol overdose showed reduced coagulation factors II, V, VII, and X but increased levels of factor VIII, an acute phase reactant synthesized in endothelial cells. 19,25,27,28 Coagulation factors also have a short half-life, 23 which augments the effect of reduced production of coagulation factors in ALF. These changes in coagulant factors are offset by decreased anticoagulant proteins in ALF. ...
Acute liver failure (ALF) is the rapid onset of severe liver dysfunction, defined by the presence of hepatic encephalopathy and impaired synthetic function (international normalized ratio of ≥1.5) in the absence of underlying liver disease. The elevated international normalized ratio value in ALF is often misinterpreted as an increased hemorrhagic tendency, which can lead to inappropriate, prophylactic transfusions of blood products. However, global assessments of coagulopathy via viscoelastic tests or thrombin generation assay suggest a reestablished hemostatic, or even hypercoagulable, status in patients with ALF. Although the current versions of global assays are not perfect, they can provide more nuanced insights into the hemostatic system in ALF than the conventional measures of coagulopathy.
... Owing to low expression of ACE2 in hepatocytes, it is not clear if liver cell injury is mediated through this molecule; howbeit, high expression of ACE2 (and TMPRSS2) is known in common bile duct and gallbladder epithelium [4]. Literature suggests that acute liver injury should be considered as an independent risk factor for developing vascular thrombosis [33]. ...
Several studies have described unusually high incidence of vascular thrombosis in coronavirus disease-2019 (COVID-19) patients. Pathogenesis of the vascular thrombosis in COVID-19 is least understood for now and presents a challenge to the treating physicians. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative pathogen for COVID-19, has been shown to bind to angiotensin converting enzyme 2 (ACE2) protein in human epithelial cells which facilitates its entry in the organ and mediate tissue specific pathogenesis. For ACE2 mediated cell entry of the SARS-CoV-2, co-expression of one more protein—Transmembrane protease serine 2 (TMPRSS2) is essential. Existing studies suggested significant expression of ACE2 and TMPRSS2 in human vascular endothelium. Vascular endothelial dysfunction can potentially activate coagulation cascade eventually resulting in thrombosis. ACE2 has proven role in the maintenance of endothelial integrity inside the vessels. Existing in situ evidence for SARS-CoV-1 (the causative agent for SARS pandemic of 2002, which shared ACE2 as cell entry receptor) suggested that virus binding can downregulate ACE2, thus can induce endothelial dysfunction. Recently, in situ evidence has been presented that SARS-CoV-2 can infect cells in engineered human vascular endothelium, which can be effectively blocked by using clinical-grade recombinant human ACE2. Based on the circumstantial evidence present in the literature, we propose a SARS-CoV-2 cell entry receptor ACE2 based mechanism for vascular thrombosis in COVID-19 patients.
... In this regard, some hypotheses can be done, such as the highly increased factor VIII activity [117] correcting an otherwise prolonged aPTT [118]. However, considering the hepatic origin of clotting factors and the short half-life of factor VII [119], we can also hypothesize that a prolonged PT with normal aPTT may be due to acute liver dysfunction. This is in line with the observed association between altered liver markers and COVID-19 severity [120]. ...
Background:
Complications of coronavirus disease 2019 (COVID-19) include coagulopathy. We performed a meta-analysis on the association of COVID-19 severity with changes in hemostatic parameters.
Methods:
Data on prothrombin time (PT), activated partial thromboplastin time (aPTT), D-Dimer, platelets (PLT), or fibrinogen in severe versus mild COVID-19 patients, and/or in non-survivors to COVID-19 versus survivors were systematically searched. The standardized mean difference (SMD) was calculated.
Results:
Sixty studies comparing 5487 subjects with severe and 9670 subjects with mild COVID-19 documented higher PT (SMD: 0.41; 95%CI: 0.21, 0.60), D-Dimer (SMD: 0.67; 95%CI: 0.52, 0.82), and fibrinogen values (SMD: 1.84; 95%CI: 1.21, 2.47), with lower PLT count (SMD: -0.74; 95%CI: -1.01, -0.47) among severe patients. Twenty-five studies on 1511 COVID-19 non-survivors and 6287 survivors showed higher PT (SMD: 0.67; 95%CI: 0.39, 0.96) and D-Dimer values (SMD: 3.88; 95%CI: 2.70, 5.07), with lower PLT count (SMD: -0.60, 95%CI: -0.82, -0.38) among non-survivors. Regression models showed that C-reactive protein values were directly correlated with the difference in PT and fibrinogen.
Conclusions:
Significant hemostatic changes are associated with COVID-19 severity. Considering the risk of fatal complications with residual chronic disability and poor long-term outcomes, further studies should investigate the prognostic role of hemostatic parameters in COVID-19 patients.
... Owing to low expression of ACE2 in hepatocytes, it is not clear if liver cell injury is mediated through this molecule; howbeit, high expression of ACE2 (and TMPRSS2) is known in common bile duct and gallbladder epithelium [5]. Literature suggests that acute liver injury should be considered as an independent risk factor for developing vascular thrombosis [33]. ...
