Use of a functional assay to diagnose protein S deficiency; inappropriate testing yields equivocal results

Inherited deficiency of protein S (PS) is a rare but accepted risk factor for venous thromboembolism. There is accumulating evidence that inherited PS deficiency may be associated with a variety of adverse obstetric events. Acquired PS deficiency may be caused by a variety of clinical states including normal pregnancy. We conducted a retrospective audit of the results of screening for PS deficiency through our reference laboratory. The majority of patients in this audit with significantly reduced (<50%) free functional PS levels had a major confounding factor likely to cause acquired PS deficiency, most frequently pregnancy. Recommendations for PS testing for the diagnosis of hereditary PS deficiency include deferring testing until at least 40 days post-partum. It appears that these recommendations are not being adhered to leading to difficulty in the interpretation of results.     

Further evidence for the presence of anti-protein S autoantibodies in patients with systemic lupus erythematosus.

Acquired protein S (PS) deficiency in systemic lupus erythematosus (SLE) has been previously reported, but its mechanism and its possible thrombotic role have not been established. The aim of our study was to provide further evidence for auto-immune PS deficiency in 27 Tunisian SLE patients, using PS-specific enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance technology (SPR). PS deficiencies for PS activity, free PS or total PS, respectively, were found in 19, 18 and 12 patients. A significant correlation (r= -0.475, P< 0.016) was found between free/total PS ratio and C4bBP levels, suggesting a role of inflammation in free PS deficiency. Immunoglobulin IgG antibodies to PS were detected in four patients by both ELISA and SPR, in six patients only by ELISA, and in two patients only by SPR. Signals for anti-PS IgG by ELISA and SPR were, however, significantly correlated (r = 0.549, P = 0.003). These results suggest that an auto-immune mechanism could account for low PS activity in patients with SLE. Auto-antibodies to PS may form immune complexes, inducing increased clearance of PS or interfering with the protein C-protein S system.     

Serum polyethylene glycol-specific IgE and IgG in patients with hypersensitivity to COVID-19 mRNA vaccines

BackgroundThe mechanism of allergic reactions to COVID-19 mRNA vaccines has not been clarified. Polyethylene glycol (PEG) is a potential antigen in the components of vaccines. However, there is little evidence that allergy after COVID-19 mRNA vaccination is related to PEG. Furthermore, the role of polysorbate (PS) as an antigen has also not been clarified. The objective of this study was to investigate whether PEG and PS allergies are reasonable causes of allergic symptoms after vaccination by detecting PEG-specific and PS-specific antibodies.MethodsFourteen patients who developed immediate allergic reactions to BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccines and nineteen healthy controls who did not present allergic symptoms were recruited. Serum PEG-specific immunoglobulin E (IgE) and immunoglobulin G (IgG) and PS-specific IgE and IgG were measured by enzyme-linked immunosorbent assay. Skin tests using PEG-2000 and PS-80 were applied to five patients and three controls.ResultsSerum levels of PEG-specific IgE and IgG in patients with immediate allergic reactions to the COVID-19 mRNA vaccine were higher than those in the control group. Serum levels of PS-specific IgE in patients with allergy to the vaccine were higher than those in patients of the control group. Intradermal tests using PEG verified the results for PEG-specific IgE and IgG.ConclusionsThe results suggest that PEG is one of the antigens in the allergy to COVID-19 mRNA vaccines. Cross-reactivity between PEG and PS might be crucial for allergy to the vaccines. PEG-specific IgE and IgG may be useful in diagnosing allergy to COVID-19 mRNA vaccines.     

Unusual thromboses associated with protein S deficiency in patients with acquired immunodeficiency syndrome: case reports and review of the literature

Recent reports indicate that patients infected with HIV are at increased risk for the development of thrombosis. Among other possibilities, an acquired deficiency of protein S (PS), one of the plasma's natural anticoagulants, might explain this tendency. PS deficiency can be classified in three types depending on the levels of total and free protein (antigenic assays) as well as anticoagulant activity (functional assay). Although the prevalence of inherited PS deficiency is not known because of its rarity, several conditions can lead to acquired forms of the disease. We report two AIDS patients with coexistent type III PS deficiency and thrombosis. Our first patient presented with bilateral chronic leg ulcers and a skin biopsy revealed dermal microthromboses. On laboratory evaluation he had PS deficiency and was started on anticoagulation, but was lost to follow-up. The second patient presented with hepatic vein thrombosis (Budd-Chiari syndrome) and was also PS deficient. On long-term anticoagulation, she experienced resolution of the thrombosis. Neither patient had prior personal or family history of venous thrombosis, nor acquired risk factors such as immobility, acute infection, recent surgery, or hormonal therapy. The literature contains a few reports of skin ulcers and Budd-Chiari syndrome associated with PS deficiency, although none in AIDS patients. While a larger number of studies describe an association between PS deficiency and HIV infection, the causal effect of this deficiency on the thrombophilic tendency in AIDS has not been established. We propose that awareness of the increased risk for thrombosis in HIV infection is important to the understanding of disease pathophysiology and management of these patients.     

Insights into disparities observed with COVID-19

The onset of human disease by infection with SARS-CoV-2 causing COVID-19 has revealed risk factors for disease severity. There are four identified factors that put one at high risk for infection and/or mortality creating a disparity: age, co-morbidities, race/ethnicity and gender. Data indicate that the older a person is, and/or the presence of obesity and diabetes, cardiovascular disease and chronic kidney disease place one at higher risk for COVID-19. In the United States, specific race/ethnicities, particularly African Americans and Native Americans, are strong COVID-19 risk components. Male gender has also emerged as a severity risk factor. For age and racial/ethnicities, the accumulation of health co-morbidities is common precipitating mechanisms. In particular, underlying socio-economic structures in the United States likely drive development of co-morbidities, putting affected populations at higher risk for severe COVID-19. Sudden cardiac death triggered by a common sodium channel variant in African Americans with COVID-19 has not been evaluated as a cause for racial disparity. There is no evidence that racial/ethnic differences for COVID-19 are caused by ABO blood groups, use of angiotensin-converting enzyme (ACE) inhibitors or from amino acid substitutions in the SARS-CoV-2 spike protein. There is growing evidence that androgen-enabled expression of ACE2 receptors and the serine protease TMPRSS2, two permissive elements engaging the SARS-CoV-2 spike protein for infection, may contribute to severe COVID-19 in men. Overall, COVID-19 has generated disparities for who is infected and the severity of that infection. Understanding the mechanisms for the disparity will help nullify the differences in risk for COVID-19.     

Liver injury induced by COVID 19 treatment – what do we know?

The severity of coronavirus disease 2019 (COVID-19) may be correlated with the risk of liver injury development. An increasing number of studies indicate that degrees of hepatotoxicity have been associated with using some medications in the management of COVID-19 patients. However, limited studies have systematically investigated the evidence of drug-induced liver injury (DILI) in COVID-19 patients. An increasing number of studies indicate that degrees of hepatotoxicity have been associated with using some of these medications in the management of COVID-19 patients. Significantly, it was relieved after the cessation of these agents. However, to our knowledge, no studies have systematically investigated the evidence of DILI in COVID-19 patients. In this review, we discussed the association between hepatotoxicity in COVID-19 patients and the drugs used in these patients and possible mechanisms of hepatotoxicity. The currently available evidence on the association of different therapeutic agents with hepatotoxicity in COVID-19 patient was systematically reviewed.     

Vitamin D deficiency in patients with diabetes and COVID- 19 infection

Background and aimsData show that vitamin D deficiency may play a role in patients with diabetes mellitus and COVID-19 infection. In this article, we review evidence of vitamin D deficiency and COVID-19 infection in context of diabetes mellitus.MethodsA literature search was carried out by using the key term ‘COVID 19’ combined with ‘Diabetes’, ‘Vitamin D’, ‘Extra skeletal effects’, ‘immunity’, ‘infection’, ‘India’ from Pub Med (National Library of Medicine, Bethesda, MD and Google Scholar from December 2019 to May 2020. A manual search of the references was also carried out.ResultsVitamin D deficiency has been linked to increased morbidity and mortality in COVID -19 infections but convincing data on diabetic subgroup of patients in particular is still awaited.ConclusionRobust studies are required to ascertain if Vitamin D supplementation could be beneficial in patients with diabetes and COVID-19.     

COVID-19 and pediatric fatty liver disease: Is there interplay?

The rapid global spread of coronavirus disease 2019 (COVID-19) infection has become a major health issue with higher morbidity and mortality rates. Besides respiratory symptoms, a growing body of evidence indicates a variety of gastrointestinal manifestations including liver involvement. In this regard, several data supported an association between COVID-19 infection and liver injury in adults, while in children there is compelling but currently limited evidence. In particular, patients with COVID-19 have shown a higher risk of liver injury (mainly expressed as increased transaminase levels or hepatic steatosis). Conversely, a greater risk of more severe forms of COVID-19 infection has been observed in subjects with pre-existing chronic liver diseases. The dramatic interplay between COVID-19 and liver damage has been related to the inflammatory pathways chronically active in patients with nonalcoholic fatty liver disease and acutely in those affected by COVID-19, but other different pathogenic mechanisms have also been supposed. Of note, patients with previous metabolic comorbidities also had a higher risk of severe COVID-19 infection. This emphasizes the pathogenic interrelation of the inflammatory pathways with a dysregulated metabolic milieu in COVID-19 patients. Taking into account the prognostic role of fatty liver in COVID-19 patients and its intrinsic relationship with metabolic abnormalities even in childhood, a strict monitoring of this condition is recommended. We aimed to summarize the most recent evidence regarding the potential interplay between pediatric fatty liver and COVID-19.     

Acquired free protein S deficiency associated with multiple myeloma: A case report

Investigation of recurrent venous thromboembolic events in a 46-year-old man with progressive IgG kappa (total serum IgG, 74.3 mg/ml) multiple myeloma revealed profound reductions in free protein S (PS) antigen (<0.1 U/ml) and PS activity (0.33 U/ml). Total PS antigen, protein C, antithrombin III, and C4b-binding protein levels were within normal limits. The patient had no family history suggestive of a congenital PS deficiency and no history of thrombosis predating the diagnosis of his plasma cell dyscrasia. Patient IgG was isolated from serum using a protein A-sepharose affinity column and characterized. PS-dependent clotting assays (Staclot Protein S, Diagnostica Stago, Asnleres sur-Seine, France) performed on normal pooled plasma mixed with dilutions of patient IgG (0.0–33.0 mg/ml) revealed a dose-dependent neutralization of PS activity by 43%. Total and free PS antigen levels were measured using Laurell rocket electroimmunodiffusion (Assera-Plate Protein S, Diagnostica Stago), which revealed a similar dose-dependent reduction in free PS antigen but preserved normal total PS antigen. Free PS antigen was reduced by 77% to 0.23 U/ml using an IgG concentration (16.5 mg/ml) less than one-fourth of that of the patient at time of serum collection. Specific binding of the patient IgG to commercially available purified human PS was demonstrated by Western Immunoblot analysis. Whereas acquired free PS deficiency has been previously reported in association with nephrotic syndrome, inflammatory bowel disease, HIV infection, and varicella infection, this is the first reported case of a hypercoagulable syndrome associated with acquired free PS deficiency and multiple myeloma. © 1996 Wiley-Liss, Inc.     

Impaired coagulation,liver dysfunction and COVID-19: Discovering an intriguing relationship

Coronavirus disease 2019 (COVID-19) is, at present, one of the most relevant global health problems. In the literature hepatic alterations have been described in COVID-19 patients, and they are mainly represented by worsening of underlying chronic liver disease leading to hepatic decompensation and liver failure with higher mortality. Several potential mechanisms used by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to cause liver damage have been hypothesized. COVID-19 primary liver injury is less common than secondary liver injury. Most of the available data demonstrate how liver damage in SARS-CoV-2 infection is likely due to systemic inflammation, and it is less likely mediated by a cytopathic effect directed on liver cells. Moreover, liver alterations could be caused by hypoxic injury and drugs (antibiotics and non-steroidal anti-inflammatory drugs, remdesivir, tocilizumab, tofacitinib and dexamethasone). SARS-CoV-2 infection can induce multiple vascular district atherothrombosis by affecting simultaneously cerebral, coronary and peripheral vascular beds. Data in the literature highlight how the virus triggers an exaggerated immune response, which added to the cytopathic effect of the virus can induce endothelial damage and a prothrombotic dysregulation of hemostasis. This leads to a higher incidence of symptomatic and confirmed venous thrombosis and of pulmonary embolisms, especially in central, lobar or segmental pulmonary arteries, in COVID-19. There are currently fewer data for arterial thrombosis, while myocardial injury was identified in 7%-17% of patients hospitalized with SARS-CoV-2 infection and 22%-31% in the intensive care unit setting. Available data also revealed a higher occurrence of stroke and more serious forms of peripheral arterial disease in COVID-19 patients. Hemostasis dysregulation is observed during the COVID-19 course. Lower platelet count, mildly increased prothrombin time and increased D-dimer are typical laboratory features of patients with severe SARS-CoV-2 infection, described as “COVID-19 associated coagulopathy.” These alterations are correlated to poor outcomes. Moreover, patients with severe SARS-CoV-2 infection are characterized by high levels of von Willebrand factor with subsequent ADAMTS13 deficiency and impaired fibrinolysis. Platelet hyperreactivity, hypercoagulability and hypofibrinolysis during SARS-CoV-2 infection induce a pathological state named as “immuno-thromboinflammation.” Finally, liver dysfunction and coagulopathy are often observed at the same time in patients with COVID-19. The hypothesis that liver dysfunction could be mediated by microvascular thrombosis has been supported by post-mortem findings and extensive vascular portal and sinusoidal thrombosis observation. Other evidence has shown a correlation between coagulation and liver damage in COVID-19, underlined by the transaminase association with coagulopathy, identified through laboratory markers such as prothrombin time, international normalized ratio, fibrinogen, D-dimer, fibrin/fibrinogen degradation products and platelet count. Other possible mechanisms like immunogenesis of COVID-19 damage or massive pericyte activation with consequent vessel wall fibrosis have been suggested.     

Acquired FXIII inhibitors: a systematic review

Coagulation factor XIII (FXIII) is a protein that promotes fibrin stabilization by forming multiple covalent cross-links between fibrin monomers. Beside congenital FXIII deficiency, due to FXIII gene mutations, severe acquired FXIII deficiency has been described in association with autoantibodies against coagulation FXIII. These inhibitors, which occurs very rarely but may cause life-threatening bleeding complications, may arise spontaneously or in association with autoimmune and lymphoproliferative disorders or medications. The management of patients with acquired FXIII inhibitors is very demanding and treatment regimens must be focused on eradication of the inhibitor and to increase the plasma FXIII levels. In this systematic review, we analyse all the published case-reports on anti-FXIII autoantibodies focusing on the clinical features and treatment modalities of this acquired hemorrhagic condition.     

Acute liver injury in COVID-19 patients hospitalized in the intensive care unit: Narrative review

In recent years, humanity has been confronted with a global pandemic due to coronavirus disease 2019 (COVID-19), which has caused an unprecedented health and economic crisis worldwide. Apart from the respiratory symptoms, which are considered the principal manifestations of COVID-19, it has been recognized that COVID-19 constitutes a systemic inflammatory process affecting multiple organ systems. Across the spectrum of organ involvement in COVID-19, acute liver injury (ALI) has been gradually gaining increasing attention by the international scientific community. COVID-19 associated liver impairment can affect a considerable proportion of COVID-19 patients and seems to correlate with the severity of the disease course. Indeed, COVID-19 patients hospitalized in the intensive care unit (ICU) run a greater risk of developing ALI due to the severity of their clinical condition and in the context of multi-organ failure. The putative pathophysiological mechanisms of COVID-19 induced ALI in ICU patients remain poorly understood and appear to be multifactorial in nature. Several theories have been proposed to explain the occurrence of ALI in the ICU setting, such as hypoperfusion and ischemia due to hemodynamic instability, passive liver congestion as a result of congestive heart failure, ischemia-reperfusion injury, hypoxia due to respiratory failure, mechanical ventilation itself, sepsis and septic shock, cytokine storm, endotheliitis with concomitant coagulopathy, drug-induced liver injury, parenteral nutrition and direct cytopathic viral effect. It should be noted that no specific therapy for COVID-19 induced ALI exists. Therefore, the therapeutic approach lies in preventive measures and is exclusively supportive once ALI ensues. The aim of the current review is to scrutinize the existing evidence on COVID-19 associated ALI in ICU patients, explore its clinical implications, shed light on the underlying pathophysiological mechanisms and propose potential therapeutic approaches. Ongoing research on the particular scientific field will further elucidate the pathophysiology behind ALI and address unresolved issues, in the hope of mitigating the tremendous health consequences imposed by COVID-19 on ICU patients.     

Evolución clínica en un receptor de trasplante de hígado con la COVID-19: ¿Un efecto benéfico del tacrolimus?

Coronavirus disease 2019 (COVID-19) is a serious respiratory illness caused by SARS-CoV-2. There is controversy about whether their immunosuppressive status is a risk factor or a protective factor for developing severe disease.We report herein the clinical outcome of three family members that had COVID-19 infection, presenting with and without different risk factors that have been described in more severe disease. Paradoxically, the patient with more risks of developing a severe disease, a 64-year-old woman, 2-years liver transplant recipient under treatment with tacrolimus, presented a similar outcome compared to the two other members of the family. She showed shorter hospitalization time, similar clinical outcome with fewer oxygen needs.The present clinical observation raises the question about the possible beneficial effect of tacrolimus in patients with COVID-19. Indeed, tacrolimus (FK-506) have an inhibitory effect on human coronaviruses by: 1) an antiviral effect by binding to the FK-506-binding proteins (FKBP) with a subsequent inhibition of their peptidyl-prolyl cis/trans isomerase (PPIase) activity, which seems to be important for the coronavirus life cycle; and 2) regulating the immune response by the inhibition of the activity of the nuclear factor of activated T-cells (NFAT) required for immunosuppression.The present observation states that liver recipients’ patients with COVID-19 may not have worse outcomes when compared with other patients that have COVID-19 risk factors and puts in evidence the two mechanisms related to tacrolimus.     

COVID-19 related biliary injury:A review of recent literature

Since its emergence in 2019, it has become apparent that coronavirus 2019(COVID-19) infection can result in multi systemic involvement. In addition to pulmonary symptoms, hepatobiliary involvement has been widely reported. Extent of hepatic involvement ranges from minor elevation in liver function tests(LFTs) to significant hepatocellular or cholestatic injury. In majority of cases, resolution of hepatic injury or improvement in LFTs is noted as patients recover from COVID-19 infection. However,...     

Effects of solvent/detergent-treated plasma and fresh-frozen plasma on haemostasis and fibrinolysis in complex coagulopathy following open-heart surgery

BACKGROUND AND OBJECTIVES: Solvent/detergent-treated plasma (SDP) contains markedly lower protein S (PS) and plasmin inhibitor (PI) activity than standard fresh-frozen plasma (FFP). It has also been reported that SDP contains no alpha(1)-antitrypsin. Despite the lack of clinical data, it is suspected that SDP may be less effective than FFP in the treatment of complex coagulopathies. We therefore conducted a prospective trial to study the impact of SDP and FFP on haemostasis and fibrinolysis in complex coagulopathy after open-heart surgery. MATERIALS AND METHODS: Patients received either 600 ml of SDP (n = 36) or 600 ml of FFP (n = 31) at an infusion rate of 30 ml/min. The following parameters were measured before treatment and 60 min after termination of plasma infusion: prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, factor VIII, antithrombin, protein C (PC), free PS and PS activity, prothrombin fragments F1+2 (F1+2), D-dimers (DD), fibrinogen degradation products (FDP), plasmin-plasmin inhibitor complexes (PPI), plasminogen, PI and alpha(1)-antitrypsin. RESULTS: The rise in fibrinogen, factor VIII, antithrombin, PC, free PS, alpha(1)-antitrypsin and plasminogen, and the decrease in PT and APTT, did not significantly differ between the two study arms. However, PS activity did not increase after SDP infusion but did show a significant elevation after infusion with FFP. PI declined significantly after SDP and remained uninfluenced by FFP. Neither SDP nor FFP had any significant influence on F1+2, DD or FDP. However, a significant decrease in PPI levels caused by both types of plasma indicated a reduction in hyperfibrinolysis. Clinical haemostasis evaluation revealed no significant difference between the two treatment regimens. No adverse reactions were observed. CONCLUSION: With the exception of PS and PI, SDP and FFP improved haemostasis and fibrinolysis to a similar degree. The clinical significance of these findings has to be determined in patients with severe acquired PS and PI deficiency requiring plasma transfusions.     

COVID-19 and liver dysfunction: Epidemiology,association and potential mechanisms

Currently, there have been more than one hundred million confirmed cases of coronavirus disease 2019 (COVID-19), with two million deaths worldwide. This has caused a huge medical burden. Severe COVID-19 patients can experience multi-organ damage, including cardiac injury, kidney injury, and liver injury. About 2.0%–4.9% of COVID-19 cases involve patients with preexisting liver diseases. Additionally, preexisting liver diseases were reported and associated with severity (odds ratio (OR) or risk ratio (RR) = 1.48–1.70) and mortality (OR or RR = 1.08–2.65) among COVID-19 patients. Furthermore, the prevalence of liver injury was 16%–29% in COVID-19 patients. Higher prevalence of liver injury may worsen prognosis in patients (severity: OR or RR = 1.9–2.6; mortality: OR or RR = 1.1–4.0). The mechanisms of this association between liver injury and severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection are complex, including direct cholangiocyte damage induced by SARS-COV-2, cytokine storm, and drug-induced liver injury. In particular, drug-induced liver injury may be the most important reason. This review discusses the epidemiology of COVID-19 and liver dysfunction as well as potential mechanisms underlying the association between COVID-19 and liver dysfunction or other preexisting liver diseases. However, the association between preexisting liver diseases and COVID-19 prognosis and potential mechanisms underlying these associations require further prospective studies.     

Brief Report: Altered amino acid profile in patients with SARS-CoV-2 infection

Low plasma arginine bioavailability has been implicated in endothelial dysfunction and immune dysregulation. The role of arginine in COVID-19 is unknown, but could contribute to cellular damage if low. Our objective was to determine arginine bioavailability in adults and children with COVID-19 vs. healthy controls. We hypothesized that arginine bioavailability would be low in patients with COVID-19 and multisystem inflammatory syndrome in children (MIS-C). We conducted a prospective observational study of three patient cohorts; arginine bioavailability was determined in asymptomatic healthy controls, adults hospitalized with COVID-19, and hospitalized children/adolescents <21 y old with COVID-19, MIS-C, or asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection identified on admission screen. Mean patient plasma amino acids were compared to controls using the Student’s t test. Arginine-to-ornithine ratio, a biomarker of arginase activity, and global arginine bioavailability ratio (GABR, arginine/[ornithine+citrulline]) were assessed in all three groups. A total of 80 patients were included (28 controls, 32 adults with COVID-19, and 20 pediatric patients with COVID-19/MIS-C). Mean plasma arginine and arginine bioavailability ratios were lower among adult and pediatric patients with COVID-19/MIS-C compared to controls. There was no difference between arginine bioavailability in children with COVID-19 vs. MIS-C. Adults and children with COVID-19 and MIS-C in our cohort had low arginine bioavailability compared to healthy adult controls. This may contribute to immune dysregulation and endothelial dysfunction in COVID-19. Low arginine-to-ornithine ratio in patients with COVID-19 or MIS-C suggests an elevation of arginase activity. Further study is merited to explore the role of arginine dysregulation in COVID-19.     

Protein C system defects in Indian children with thrombosis

As ethnic variations are known to exist in inherited genetic defects, the clinico-haematological profile of Indian children with thrombophilia may be different from that of Caucasians. The aim of the study was to analyse the phenotypic and genotypic causes of thrombophilia in Indian children. Forty patients with arterial (21 patients) and venous (19 patients) thrombosis were the subjects of the study. Their age ranged from 6 days to 15 years. All of the patients were initially screened by Pro C Global assay. Activated protein C resistance (APCR) was measured. In cases with low Pro C Global values, protein C (PC), protein S (PS) and factor V G1691A, prothrombin G20210A and MTHFR C677T polymorphism were tested in all 40 cases. Of the 21 patients with arterial thrombosis, 4 (19%) had PC deficiency, 7 (33.3%) had PS deficiency and 1 (4.8%) had combined deficiency of PC and PS. Of the 19 patients with venous thrombosis, 5 (26.3%) each had PC and PS deficiency and 4 (21%) had combined PC and PS deficiency. Heterozygous factor V G1691A defect was seen in one (4.8%) patient with arterial thrombosis and three (15.8%) patients with venous thrombosis. Heterozygous MTHFR C677T polymorphism was seen in five (23.8%) patients with arterial thrombosis and in four (21%) patients with venous thrombosis. Prothrombin G20210A polymorphism was absent in all patients and controls. Protein C system defect is common in Indian children with thrombosis.     

Characteristic Electrocardiographic Manifestations in Patients With COVID-19

Cardiac involvement has been reported in patients with COVID-19, which may be reflected by electrocardiographic (ECG) changes. Two COVID-19 cases in our report exhibited different ECG manifestations as the disease caused deterioration. The first case presented temporary SIQIIITIII morphology followed by reversible nearly complete atrioventricular block, and the second demonstrated ST-segment elevation accompanied by multifocal ventricular tachycardia. The underlying mechanisms of these ECG abnormalities in the severe stage of COVID-19 may be attributed to hypoxia and inflammatory damage incurred by the virus.     

COVID-19 and hepatorenal syndrome

Coronavirus disease 2019 (COVID-19) is a highly infectious disease which emerged into a global pandemic. Although it primarily causes respiratory symptoms for affected patients, COVID-19 was shown to have multi-organ manifestations. Elevated liver enzymes appear to be commonly observed during the course of COVID-19, and there have been numerous reports of liver injury secondary to COVID-19 infection. It has been established that patients with pre-existing chronic liver disease (CLD) are more likely to have poorer outcomes following COVID-19 infection compared to those without CLD. Co-morbidities such as diabetes, hypertension, obesity, cardiovascular and chronic kidney disease frequently co-exist in individuals living with CLD, and a substantial population may also live with some degree of frailty. The mechanisms of how COVID-19 induces liver injury have been postulated. Hepatorenal syndrome (HRS) is the occurrence of kidney dysfunction in patients with severe CLD/fulminant liver failure in the absence of another identifiable cause, and is usually a marker of severe decompensated liver disease. Select reports of HRS following acute COVID-19 infection have been presented, although the risk factors and pathophysiological mechanisms leading to HRS in COVID-19 infection or following COVID-19 treatment remain largely unestablished due to the relative lack and novelty of published data. Evidence discussing the management of HRS in high-dependency care and intensive care contexts is only emerging. In this article, we provide an overview on the speculative pathophysiological mechanisms of COVID-19 induced HRS and propose strategies for clinical diagnosis and management to optimize outcomes in this scenario.