Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

South Australia is presently in the throes of major changes to its regulatory system governing land use, development of land and the development of planning policy against which development assessment decisions are to be made. Eventually the planning and development control system established under the Development Act 1993 (SA) will be replaced by a new system implemented by the Planning, Development and Infrastructure Act 2016 (SA) (the new Act).

COVID-19 Generated Changes to Planning and Development Controls in South Australia (preprint)

Beyond their important role in hemostasis, platelets play a crucial role in inflammatory diseases. This becomes apparent during sepsis, where platelet count and activation correlate with disease outcome and survival. Sepsis is caused by a dysregulated host response to infection, leading to organ dysfunction, permanent disabilities, or death. During sepsis, tissue injury results from the concomitant uncontrolled activation of the complement, coagulation, and inflammatory systems as well as platelet dysfunction. The balance between the systemic inflammatory response syndrome (SIRS) and the compensatory anti-inflammatory response (CARS) regulates sepsis outcome. Persistent thrombocytopenia is considered as an independent risk factor of mortality in sepsis, although it is still unclear whether the drop in platelet count is the cause or the consequence of sepsis severity. The role of platelets in sepsis development and progression was addressed in different experimental in vivo models, particularly in mice, that represent various aspects of human sepsis. The immunomodulatory function of platelets depends on the experimental model, time, and type of infection. Understanding the molecular mechanism of platelet regulation in inflammation could bring us one step closer to understand this important aspect of primary hemostasis which drives thrombotic as well as bleeding complications in patients with sterile and infectious inflammation. In this review, we summarize the current understanding of the contribution of platelets to sepsis severity and outcome. We highlight the differences between platelet receptors in mice and humans and discuss the potential and limitations of animal models to study platelet-related functions in sepsis.

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Platelets in Sepsis: An Update on Experimental Models and Clinical Data.

Coronavirus disease 2019 (COVID-19) represents a new pandemic caused by severe acute respiratory syndrome virus coronavirus 2 (SARS-CoV-2). A previous pooled analysis clearly identified elevated D-dimer levels as being associated with severity of COVID-19. Since then, several other studies have provided clearer support for this initial evidence. However, potentially under-recognized by those reporting on D-dimer is the considerable variation in reporting units for D-dimer, and thus also the potential for misreporting of D-dimer data based on poor or incomplete reporting. A PubMed search was used to identify recent papers reporting on D-dimers in COVID-19-based studies. We report that: (1) most publications did not identify either the manufacturer or D-dimer product used; (2) most did not identify whether D-dimer values were reported as D-dimer units (DDU) or fibrinogen equivalent units (FEU) (~2 × differences); (3) nearly half did not identify normal cut-off values; (4) some did not report numerical findings or units for D-dimer; (5) where reported, most identified units as either mg/L or µg/mL; (6) we identified at least four errors in reporting from 21 papers. It may not be possible to truly standardize D-dimer assays, but it should be feasible to harmonize D-dimer assays to a single unit of measurement.

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Reporting of D-dimer data in COVID-19: some confusion and potential for misinformation.

Patients with severe coronavirus disease 2019 (COVID-19) infections manifest coagulation abnormalities that have been associated with respiratory deterioration and death.1,2 In addition, many patients with severe COVID-19 infections develop venous thromboembolism, which seems to be related to the coagulopathy.3 It has also been suggested that undiagnosed pulmonary embolism contributes to a sudden deteriorationofpulmonaryoxygenexchangethat issometimesseen in patients with COVID-19 infections.4,5 The coagulopathy associatedwith COVID-19mimics other systemic coagulopathies that are regularly seen in severe infections, such as disseminated intravascular coagulation (DIC) or thrombotic microangiopathy (TMA).6–8 However, at the same time, the clinical and laboratory characteristics of the coagulation changes in COVID-19 are distinctly different from the common presentation of these conditions.

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Coronavirus Disease 2019 Coagulopathy: Disseminated Intravascular Coagulation and Thrombotic Microangiopathy-Either, Neither, or Both.

In December 2019, the first cases of infection with a novel human microorganism, now officially defined as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), were reported in Wuhan, China.1 On April 1, 2020, as we write, more than 800,000 cases of the novel coronavirus disease 2019 (COVID-19) have been reported worldwide, with more than 40,000 COVID-19–related deaths.2 Studies have reported disturbed coagulation in COVID-19 patients, including prolonged prothrombin time,3,4 decreased antithrombin,3 and increased fibrin degradation products such as D-dimer.3–7 This implies increased risk of thromboembolic disease, as well as bleeding and, for the most serious cases, development of disseminated intravascular coagulation (DIC),which, inonecase series,was reported inasmanyas71% of nonsurvivors of COVID-19.5 This commentary explores the potential role of platelets in COVID-19, including the link between thrombocytopenia and disease severity and the considerations for the potential role for platelet function and/or platelet activation testing in COVID-19 patients.

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Platelets in Coronavirus Disease 2019.

Disseminated intravascular coagulation (DIC) is a systemic activation of the coagulation system, which results in microvascular thrombosis and, simultaneously, potentially life-threatening haemorrhage attributed to consumption of platelets and coagulation factors. Underlying conditions, e.g. infection, cancer, or obstetrical complications are responsible for the initiation and propagation of the DIC process. This review provides insights into the epidemiology of DIC and the current understanding of its pathophysiology. It details the use of diagnostic biomarkers, current diagnostic recommendations from international medical societies, and it provides an overview of emerging diagnostic and prognostic biomarkers. Last, it provides guidance on management. It is concluded that timely and accurate diagnosis of DIC and its underlying condition is essential for the prognosis. Treatment should primarily focus on the underlying cause of DIC and supportive treatment should be individualised according to the underlying aetiology, patient's symptoms and laboratory records.

Disseminated intravascular coagulation: epidemiology, biomarkers, and management

Preeclampsia is a serious pregnancy-related complication. Platelets are potentially important in the pathogenesis of preeclampsia, and platelet function analyses may prove as sensitive preeclampsia biomarkers. This study aimed to systematically review and summarise the literature on platelet function markers in preeclampsia. This systematic review was conducted according to PRISMA and registered in PROSPERO. Relevant studies were identified through PubMed and Embase on 15/08/17. As platelet function markers platelet activation, platelet aggregation and platelet adhesion markers were included. If possible, relevant data were extracted for each marker to perform a meta-analysis of the mean difference between women with and without preeclampsia. All 69 included articles underwent quality rating. Some platelet activation markers, especially p-selectin and mean platelet volume (MPV), were significantly increased comparing the two groups of women, while others were not. The meta-analysis demonstrated that, overall, women with preeclampsia had significantly higher MPV than in women without preeclampsia. No significant difference was found regarding platelet aggreg`ation comparing the two groups. Platelet adhesion was investigated in noneof the included studies. In conclusion, further studies are warranted to investigate platelet activation markers future role as predictive markers in preeclampsia. MPV is suggested as the most promising biomarker for evaluating platelet function in preeclampsia.

Platelet function in preeclampsia - a systematic review and meta-analysis.

Excessive perioperative bleeding is associated with increased morbidity and mortality as well as increased economic costs. A range of whole blood laboratory tests for hemostatic monitoring has emerged, but their ability to predict perioperative bleeding is still debated. We conducted a systematic review of the existing literature assessing the ability of whole blood coagulation (thromboelastography [TEG]/thromboelastometry [ROTEM]/Sonoclot), platelet function tests, and standard plasma-based coagulation tests to predict bleeding in the perioperative setting. We searched PubMed and Embase, covering the period from 1966 to November 2016. In total, 99 original studies were included. The included studies assessed TEG/ROTEM/Sonoclot (n = 29), platelet function tests (n = 27), both test types (n = 8), and standard coagulation tests only (n = 18), and some (n = 17) investigated the predictive value of testing in patients receiving antithrombotic medication. In general, studies reported low positive predictive values for perioperative testing, whereas negative predictive values were high. The studies yielded moderate areas under receiver operator characteristics (ROC) curve (for the majority, 0.60–0.80). In conclusion, while useful in the diagnosis and management of patients with overt bleeding, whole blood coagulation and platelet function tests as well as standard coagulation tests demonstrated limited ability to predict perioperative bleeding in unselected patients. Therefore, we recommend that both whole blood and plasma-based coagulation tests are primarily used in case of bleeding and not for screening in unselected patients prior to surgery.

Predictive Value of Whole Blood and Plasma Coagulation Tests for Intra- and Postoperative Bleeding Risk: A Systematic Review.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening, hyperinflammatory disorder, characterized by multiorgan failure, fever and cytopenias. The diagnosis of HLH and its subtype Macrophage Activation Syndrome (MAS) remains a challenge. Interleukin 18 (IL-18) is emerging as a potential biomarker for HLH/MAS but is currently not a part of diagnostic criteria. This systematic review aimed to assess the potential role of IL-18 in the diagnosis and monitoring of HLH and MAS, and was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed and Embase were searched on 30 January 2020. Studies included all subtypes of HLH and a range of underlying disorders in both children and adults. A total of 14 studies were included. Generally, serum IL-18 was elevated in both primary and secondary HLH (> 1000 pg/ml) compared with other inflammatory conditions and with healthy individuals; thus, serum IL-18 may be able to discriminate between HLH and other inflammatory conditions. Significantly increased IL-18 (> 10 000 pg/ml) was also consistently described in MAS compared with other subtypes of HLH. The ability of IL-18 to distinguish MAS from systemic juvenile idiopathic arthritis (JIA) is less unambiguous, as IL-18 levels > 100 000 pg/ml were described in sJIA patients both with and without MAS. IL-18 may help to differentiate between HLH subtypes and other inflammatory conditions. As HLH and MAS are rare disorders, only few and relatively small studies exist on the subject. Larger, prospective multi-center studies are called for to assess the diagnostic precision of IL-18 for HLH and MAS.

Julie Brogaard Larsen

Papers

Platelets in Coronavirus Disease 2019.

Disseminated intravascular coagulation: epidemiology, biomarkers, and management

Platelet function in preeclampsia - a systematic review and meta-analysis.

Predictive Value of Whole Blood and Plasma Coagulation Tests for Intra- and Postoperative Bleeding Risk: A Systematic Review.

The role of interleukin-18 in the diagnosis and monitoring of hemophagocytic lymphohistiocytosis/macrophage activation syndrome - a systematic review.