key: cord-1031750-u5dytbxp authors: Görlinger, Klaus; Dirkmann, Daniel; Gandhi, Ajay; Simioni, Paolo title: COVID-19 associated coagulopathy and inflammatory response: what do we know already and what are the knowledge gaps? date: 2020-07-21 journal: Anesth Analg DOI: 10.1213/ane.0000000000005147 sha: 2fbb4be65e2a75c7a9c8653234be9058dda973ba doc_id: 1031750 cord_uid: u5dytbxp Patients with COVID-19 frequently experience a coagulopathy associated with a high incidence of thrombotic events leading to poor outcomes. Here, biomarkers of coagulation (such as D-dimer, fibrinogen, platelet count), inflammation (such as interleukin-6) and immunity (such as lymphocyte count) as well as clinical scoring systems (such as SOFA, ISTH DIC and SIC score) can be helpful in predicting clinical course, need for hospital resources (such as ICU beds, intubation and ventilator therapy, and ECMO) and patient’s outcome in patients with COVID-19. However, therapeutic options are actually limited to unspecific supportive therapy. Whether viscoelastic testing can provide additional value in predicting clinical course, need for hospital resources and patient’s outcome or in guiding anticoagulation in COVID-19 associated coagulopathy is still incompletely understood and currently under investigation (eg, in the ROHOCO study). This paper summarizes what we know already about COVID-19 associated coagulopathy and – perhaps even more importantly – characterizes important knowledge gaps. Damage-associated molecular patterns in the SOFA score of 2 points or more, which is associated with an in-hospital mortality greater than 10%. 35 Early phase of bacterial sepsis is characterized by hypercoagulability due to tissue factor expression on circulating monocytes and micro-particles, increased fibrinogen plasma concentration, platelet activation and subsequent dysfunction, and hypofibrinolysis/fibrinolysis shutdown. 36, 37 Tissue factor expression on circulating monocytes and micro-particles is triggered by bacterial toxins (lipopolysaccharides) and other pathogen-associated molecular patterns (PAMPs) via NF-kappaB1 activation and subsequent induction of plasminogen activator inhibitor type 1 (PAI-1) and pro-inflammatory cytokines such as interleukin-6 (IL-6) ( Figure 1 ). [38] [39] [40] Tissue factor expression on circulating cells and micro-particles, changes in clot firmness and hypofibrinolysis can be detected by thromboelastometry (Figure 2) . 41 The innate immune system is based on physical (e.g., epidermis and ciliated respiratory epithelium) and chemical (e.g., gastric acid) barriers to infection, as well as on different cell can result in multiple organ failure and death. 25, 55 Which patient will benefit from anti-inflammatory drugs in COVID-19? General treatment with corticosteroids is not recommended in COVID-19 since it may delay virus clearance and promote superinfection. 56 However, some authors recommend dexamethasone 20 mg/day for 5 days and then 10 mg/day for 5 days in patients with ARDS within 24 hours after ARDS diagnosis. 28, 57 The indication must be discussed with the ICU team. Ethnicity has major effects on thrombotic risk, with a 3-4-fold lower risk in Chinese compared to Caucasians and a significantly higher risk in African-Americans. 60 There are many reasons for this increased mortality in patients older than 60 years including a higher likelihood of co-morbidities (diabetes, obesity, chronic obstructive pulmonary disease, chronic heart disease, chronic renal disease, thrombosis), decreased organ function reserves, prolonged hospitalization times, generally weaker immune response (immunosensescence), and chronic inflammatory diseases. Older adults also experience persistent T cell exhaustion in part due to constant low-level inflammation, thought to be caused by accumulation of self-debris brought on by a decrease in the ability to clear them. This process, often called "inflammaging" is characterized by elevated baseline levels of the cytokines IL-6, IL-1, and TNF-alpha. [70] [71] About 60% of COVID-19 patients are male. 72 Notably, transmembrane protease serine subtype 2 (TMPRSS2) is both the most frequently altered gene in primary prostate cancer and a critical factor enabling cellular infection by coronaviruses, including SARS-CoV-2. The modulation of its expression by sex steroids could contribute to the male predominance of severe infections and given that TMPRSS2 has no known indispensable functions, and inhibitors (e.g., camostat) are available, it is an appealing target for prevention or treatment of respiratory viral infections. 73 Two studies on the efficacy and safety of camostat therapy alone or in combination with hydroxychloroquine in COVID-19 are running, actually (NCT04321096 and NCT04338906). On the one hand, hypofibrinolysis/fibrinolysis shutdown (lysis index 60 min after CT; LI60 ≥ 96.5%) and hypocoagulability (decreased maximum clot firmness; MCF ≤ 55 mm) in thromboelastometry have been shown to predict increased mortality in bacterial sepsis. [43] [44] [45] [46] Furthermore, early platelet dysfunction predicts mortality in bacterial sepsis. 37 (Figure 2) . 74 in thromboelastometry persists in the first five days but it deceases ten days after, without returning to normal values. 81 Antithrombin levels and platelet count did not decreased in these patients, but fibrinogen, FIBTEM MCF and IL-6 levels decrease in parallel during recovery (Figure 1) . The good correlation between fibrinogen and IL-6 (r = 0.711; P = 0.003) and the procoagulant viscoelastic pattern in COVID-19 patients with acute respiratory distress syndrome was also confirmed by Ranucci et al. 82 85 Here, the best predictive value was provided by the combination of elevated D-dimer (>2.6 µg/mL) and fibrinolysis shutdown (TEG LY30 = 0%). In patients presenting neither elevated D-dimer nor fibrinolysis shutdown, the incidence of venous thromboembolism was 0% and for renal failure with the need for dialysis 14%. In contrast, in patients presenting elevated D-dimer and fibrinolysis shutdown, the incidence of venous thromboembolism was 50% and for renal failure with the need for dialysis 80%. Accordingly, thrombolytic therapy might be reasonable, in particular in patients with sudden deterioration of oxygenation and signs of pulmonary hypertension and right ventricular failure. 86 Actually, the value of thrombolytic therapy with tissue plasminogen activator (tPA) is under clinical investigation (NCT04356833, NCT04357730). 29, 87 Notably, a FIBTEM MCF cutoff < 13 mm provides a sensitivity of 94% and a specificity of 80% to predict bleeding complications in patients with acute ischemic stroke undergoing thrombolytic therapy with tPA. 88 This might help selecting the right patients for thrombolytic therapy. In contrast to viral hemorrhagic fever such as Dengue, there is only one report regarding hemorrhagic problem in patients with COVID-19. Here, Joob et al. presented observations from Thailand with 1 out of 41 COVID-19 patients presented mild bleeding (petechiae). 94 Due to the high incidence of VTE and PE, thromboprophylaxis is recommended in all hospitalized COVID-19 patients and should also be maintained for 7-14 days at home after hospital discharge in case of pre-existing or persisting VTE risk factors. 23, 24 However, the optimal drug and dose for thromboprophylaxis in COVID-19 patients is actually unknown. LMWH or UFH is used in most centers. 17 A Comprehensive Literature Review on the Clinical Presentation, and Management of the Pandemic Coronavirus Disease Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia The impact of deep vein thrombosis in critically ill patients: a meta-analysis of major clinical outcomes Incidence of thrombotic complications in critically ill ICU patients with COVID-19 High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients Incidence of venous thromboembolism in hospitalized patients with COVID-19 Humanitas COVID-19 Task Force. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Clinical Research in Intensive Care and Sepsis Trial Group for Global Evaluation and Pathological evidence of pulmonary thrombotic phenomena in severe COVID-19 Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans Diagnostic Utility of Clinical Laboratory Data Determinations for Patients with the Severe COVID-19 Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study D-dimer levels on admission to predict in-hospital mortality in patients with Covid-19 Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease Performance of age-adjusted D-dimer cut-off to rule out pulmonary embolism Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism: the ADJUST-PE study Age-adjusted D-dimer cut-off in the diagnostic strategy for deep vein thrombosis: a systematic review Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy Difference of coagulation features between severe pneumonia induced by SARS-CoV2 and non-SARS-CoV2 ISTH interim guidance on recognition and management of coagulopathy in COVID-19 Emergence of Institutional Antithrombotic Protocols for Coronavirus COVID-19 and haemostasis: a position paper from Italian Society on Thrombosis and Haemostasis (SISET) Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China COVID-19, ECMO, and lymphopenia: a word of caution Interleukin-6 may predict survival in extracorporeal membrane oxygenation treatment Clinical Characteristics of 138 Hospitalized Patients With Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study Prominent changes in blood coagulation of patients with SARS-CoV-2 infection Scientific and Standardization Committee on DIC, and the Scientific and Standardization Committee on Perioperative and Critical Care of the International Society on Thrombosis and Haemostasis. Diagnosis and management of sepsis-induced coagulopathy and disseminated intravascular coagulation Advance in the management of sepsis-induced coagulopathy and disseminated intravascular coagulation COVID-19 related severe hypercoagulability in patients admitted to intensive care unit for acute respiratory failure The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) The interaction between pathogens and the host coagulation system Whole blood impedance aggregometry as a biomarker for the diagnosis and prognosis of severe sepsis NF-κB signaling in inflammation COVID19 coagulopathy in Caucasian patients Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans Social Vulnerability and Racial Inequality in COVID-19 Deaths in Chicago 4G/5G polymorphism of PAI-1 gene is associated with multiple organ dysfunction and septic shock in pneumonia induced severe sepsis: prospective, observational, genetic study The 4G/4G Genotype of PAI-1 Polymorphism Is Associated with Higher Plasma PAI-1 Concentrations and Mortality in Patients with Severe Sepsis The NFKB1 promoter polymorphism (-94ins/ delATTG) alters nuclear translocation of NF-κB1 in monocytes after lipopolysaccharide stimulation and is associated with increased mortality in sepsis Hydrocortisone fails to abolish NF-κB1 protein nuclear translocation in deletion allele carriers of the NFKB1 promoter polymorphism (-94ins/delATTG) and is associated with increased 30-day mortality in septic shock Clinical relevance of 13 cytokine gene polymorphisms in Chinese major trauma patients Older age and comorbidity are independent mortality predictors in a large cohort of 1305 COVID-19 patients in Michigan, United States Estimating excess 1-year mortality associated with the COVID-19 pandemic according to underlying conditions and age: a population-based cohort study Immunosenescence in aging: between immune cells depletion and cytokines up-regulation Inflammaging decreases adaptive and innate immune responses in mice and humans Clinical Characteristics of Coronavirus Disease 2019 in China SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor Rotation Thromboelastography for Assessment of Hypercoagulation and Thrombosis in Patients with Cardiovascular Diseases Rotational thromboelastometry predicts thromboembolic complications after major non-cardiac surgery Thromboelastometry hypercoagulable profiles and portal vein thrombosis in cirrhotic patients with hepatocellular carcinoma Thromboelastography maximum amplitude predicts postoperative thrombotic complications including myocardial infarction Relationship between transfusion of blood products and the incidence of thrombotic complications in neonates and infants undergoing cardiac surgery Rotational thromboelastometry predicts care level in Covid-19. medRxiv preprint Thromboelastographic results and hypercoagulability syndrome in patients with coronavirus disease 2019 who are critically ill Evaluation of coagulation function by rotation thromboelastometry in critically ill patients with severe COVID-19 pneumonia The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome Hypercoagulability of COVID-19 patients in Intensive Care Unit. A Report of Thromboelastography Findings and other Parameters of Hemostasis Thromboelastometry and D-dimer elevation in COVID-19 Fibrinolysis Shutdown Correlates to Thromboembolic Events in Severe COVID-19 Infection Fibrinolytic abnormalities in acute respiratory distress syndrome (ARDS) and versatility of thrombolytic drugs to treat COVID-19 Salvage use of tissue plasminogen activator (tPA) in the setting of acute respiratory distress syndrome (ARDS) due to COVID-19 in the USA: a Markov decision analysis Thromboelastometry profiles in patients undergoing thrombolytic therapy for acute ischaemic stroke False low fibrinogen levels in COVID-19 patients on direct thrombin inhibitors Fibrinogen levels in COVID-19 patients and their measure under direct thrombin inhibitors Technologies to optimize the care of severe COVID-19 patients for healthcare providers challenged by limited resources People's Liberation Army Professional Committee of Critical Care Medicine Scientific Reviewer Committee. Thrombo-Inflammation in Cardiovascular Disease: An Expert Consensus Document from the Third Maastricht Consensus Conference on Thrombosis Hemorrhagic Problem Among the Patients With COVID-19: Clinical Summary of 41 Thai Infected Patients Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A meta-analysis COVID-19 cytokine storm: the interplay between inflammation and coagulation Prophylactic Platelet Transfusions for Critically Ill Patients with Thrombocytopenia: A Single-Institution Propensity-Matched Cohort Study Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial Prophylactic Preprocedure Platelet Transfusion Is Associated With Increased Risk of Thrombosis and Mortality Pro-inflammatory effects after platelet transfusion: a review COVID-19 and its implications for thrombosis and anticoagulation Direct oral anticoagulant plasma levels' striking increase in severe COVID-19 respiratory syndrome patients treated with antiviral agents: The Cremona experience Detecting clinically relevant rivaroxaban or dabigatran levels by routine coagulation tests or thromboelastography in a cohort of patients with atrial fibrillation