A case series of coagulopathy in preterm or growth-restricted term neonates born to mothers with antenatal SARS-CoV-2 infection: Neonatal post-COVID-19 coagulopathy?

Paediatric multi-system inflammatory syndrome in the form of multi-system inflammatory syndrome in children (MIS-C) and neonatal multisystem inflammatory syndrome (MIS-N) are being reported all over the world. While MIS-C is seen few weeks after active severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection in the same child, MIS-N is proposed to be occurring in neonates after active SARS-CoV-2 infection in the mother in antenatal period and hyperimmune response to the transplacentally transferred maternal IgG antibodies specific to SARS-CoV-2. Most of the cases which develop MIS-N present with cardiac findings in the form of rhythm disturbances. In this article, we report data, clinical presentation and management of 15 preterm and growth-restricted term neonates who presented with bleeding in the first 2 days of life. The coagulopathy could not be explained by the common causes of bleeding in this population and was refractory to the general line of management. Laboratory results had signs of hyperimmune response (raised procalcitonin [PCT], C-reactive protein [CRP]) and remarkably deranged coagulation profile (very high d-dimer levels with normal platelet counts and normal-to-high fibrinogen values). Most of the mothers had history of symptomatic COVID-19 infection in the antenatal period, and although all (including neonates) were negative by real-time polymerase chain reaction for SARS-CoV-2, serological testing showed positivity for IgG fraction of antibodies specific to SARS-CoV-2, but negative for IgM antibodies. This observation was similar to the phenomenon of MIS-N; however in our study, the hyperinflammatory response primarily affected the coagulation system. Although COVID-19 coagulopathy has been described in adults, it has been reported in the presence of severe active SARS-CoV-2 infection, unlike a delay of several weeks seen in our study. Hence, the term 'Neonatal post-COVID-19 coagulopathy' as proposed in this article needs further research and validation.

Acute thrombosis of portal, lienal, superior mesenteric and inferior mesenteric veins as a rare complication of COVID-19

Since the first SARS-CoV-2 case in humans wasreported at the end of 2019, a pandemic of COVID-19 disease spread around theworld, causing not only respiratory symptoms, but also a hypercoagulable statein some patients with severe forms of infection. In this case report we present a young male patient with nocomorbidities, who presents in the ER with severe abdominal pain. Physical examination,laboratory tests and imaging showed acute portal, splenic and mesenteric veinthrombosis. After he had been hospitalised the nasopharyngeal swab was positivefor SARS-CoV-2. He was treated in ICU UH Dubrava for COVID-19 patients (PRIC) withtherapeutic doses of low molecular weight heparin, and when the PCR swab forSARS-CoV-19 was negative, he was transferred to Haematology ward where theyperformed tests and excluded some of the most common diseases associated withhypercoagulability, and in a good condition he was discharged from thehospital. © 2022 Hrvatski Lijecnicki Zbor. All rights reserved.

Platelet-driven coagulopathy in COVID-19 patients: in comparison to seasonal influenza cases.

BACKGROUND: One year into the coronavirus diseases 2019 (COVID-19) pandemic we analyzed the blood coagulopathy in severe and non-severe COVID-19 patients and linked to those of influenza patients for a comparative study. METHODS: We reported 461 COVID-19 patients and 409 seasonal influenza patients admitted at separated medical centers. With their demographic data and medical history, hematological profiles with coagulation characters were emphasized, and compared between two cohorts before and after treatment. RESULTS: For 870 patients included in this study, their median age was (64.0, 51.0-76.0), and among them 511 (58.7%) were male. Hypertension, diabetes, cardiovascular diseases, and bronchitis constituted the leading comorbidities. Upon hospital admission blood test results differentiated COVID-19 patients from influenza cases, and for COVID-19 patients, leukocytosis, neutrophilia, lymphocytopenia, and thrombocytopenia were associated with disease severity and mortality. In addition, COVID-19 cohort demonstrated a prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT), increased INR, shortened thrombin time and decreased fibrinogen, compared to those in influenza cohort, leaving D-dimer levels indistinguishably high between both cohorts. Platelet hyperreactivity in COVID-19 is more evident, associated with worse hyper-inflammatory response and more refractory coagulopathy. For severe COVID-19 patients administered with anticoagulants, bleeding incidence was substantially higher than others with no anticoagulant medications. CONCLUSIONS: Comparison of coagulation characteristics between COVID-19 and influenza infections provides an insightful view on SARS-CoV-2 pathogenesis and its coagulopathic mechanism, proposing for therapeutic improvement.

Owren's Disease: A Rare Deficiency.

Factor V deficiency is a rare bleeding disorder, which may be due to acquired inhibitors or biallelic mutations. Factor V deficiency due to homozygous or compound heterozygous mutation (also known as Owren's disease or parahemophilia) has an estimated prevalence of one in one million people. A 22-year-old female was admitted for evaluation of longstanding menorrhagia. Anatomic abnormalities were excluded, and prolonged prothrombin time (PT) and partial thromboplastin time (PTT) were identified. Mixing studies followed by specific factor assays and genetic testing enable identification of factor V deficiency, for which fresh frozen plasma (FFP) or factor V concentrates are therapeutic. Specific clotting factor assay followed by mixing studies and genetic studies is essential for the diagnosis of congenital factor V deficiency. Deranged PT and activated partial thromboplastin time (APTT) with normal factor I level must be evaluated for the disorder of clotting factors and must be managed by FFP administration or plasma-derived factor V concentrate wherever available.

[Ophthalmological care of SARS-CoV-2 positive patients in intensive care units]. / Ophthalmologische Betreuung von stationären, intensivpflichtigen SARS-CoV-2-positiven Patienten.

Early ophthalmological care of patients in intensive care with SARS-CoV­2 (Severe-Acute-Respiratory-Syndrom-Corona-Virus-2) infections is very time-consuming; however, this approach might prevent other ophthalmological diseases, such as lagophthalmos. There is no difference in ophthalmological treatment between SARS-CoV­2 positive and other intensive care patients. Due to the small number of cases in our observational study, a specific ophthalmological clinical pattern related to SARS-CoV­2 infections cannot currently be identified; however, the increased occurrence of subconjunctival hemorrhage in intensive care SARS-CoV­2 patients is remarkable. It remains unclear how ocular symptoms in SARS-CoV­2 infections are related or how they occur in different stages of the disease. Therefore, further studies are necessary for representative statements.

Pathogenic lipid-binding antiphospholipid antibodies are associated with severity of COVID-19.

BACKGROUND: Coronavirus disease 19 (COVID-19)-associated coagulopathy is a hallmark of disease severity and poor prognosis. The key manifestations of this prothrombotic syndrome-microvascular thrombosis, stroke, and venous and pulmonary clots-are also observed in severe and catastrophic antiphospholipid syndrome. Antiphospholipid antibodies (aPL) are detectable in COVID-19 patients, but their association with the clinical course of COVID-19 remains unproven. OBJECTIVES: To analyze the presence and relevance of lipid-binding aPL in hospitalized COVID-19 patients. METHODS: Two cohorts of 53 and 121 patients from a single center hospitalized for PCR-proven severe acute respiratory syndrome-coronavirus 2 infection were analyzed for the presence of aPL and clinical severity of COVID-19. RESULTS: We here demonstrate that lipid-binding aPL are common in COVID-19. COVID-19 patients with lipid-binding aPL have higher median concentrations of C-reactive protein and D-dimer, and are more likely to have a critical clinical course and fatal outcome. Lipid-binding aPL isolated from COVID-19 patients target the recently described cell surface complex of lysobisphosphatidic acid (LBPA) with the protein C receptor (EPCR) to induce prothrombotic and inflammatory responses in monocytes and endothelial cells. We show that B1a cells producing lipid-reactive aPL of the IgG isotype circulate in the blood of COVID-19 patients. In vivo, COVID-19 aPL accelerate thrombus formation in an experimental mouse model dependent on the recently delineated signaling pathway involving EPCR-LBPA. CONCLUSIONS: COVID-19 patients rapidly expand B1a cells secreting pathogenic lipid-binding aPL with broad thrombotic and inflammatory effects. The association with markers of inflammation and coagulation, clinical severity, and mortality suggests a causal role of aPL in COVID-19-associated coagulopathy.

Sex Differences in the Incidence and Risk Factors of Myocardial Injury in COVID-19 Patients: A Retrospective Cohort Study.

Male novel coronavirus disease (COVID-19) patients tend to have poorer clinical outcomes than female patients, while the myocardial injury is strongly associated with COVID-19-related adverse events. Owing to a lack of corresponding data, we aimed to investigate the sex differences in the incidence of myocardial injury in COVID-19 patients and to identify the potential underlying mechanisms, which may partly account for the sex bias in the incidence of adverse events. This retrospective study included 1,157 COVID-19 patients who were hospitalized in Huoshenshan Hospital from 12 March 2020 to 11 April 2020. Data on the patients' demographic characteristics, initial symptoms, comorbidities and laboratory tests were collected. Totally, 571 (49.4%) female and 586 (50.6%) male COVID-19 patients were enrolled. The incidence of myocardial injury was higher among men than women (9.2 vs. 4.9%, p = 0.004). In the logistic regression analysis, age, and chronic kidney disease were associated with myocardial injury in both sexes. However, hypertension [odds ratio (OR) = 2.25, 95% confidence interval (CI) 1.20-4.22], coronary artery disease (OR = 2.46, 95% CI 1.14-5.34), leucocyte counts (OR = 3.13, 95% CI 1.24-7.86), hs-CRP (OR = 4.45, 95% CI 1.33-14.83), and D-dimer [OR = 3.93 (1.27-12.19), 95% CI 1.27-12.19] were independent risk factors only in the men. The correlations of hs-CRP and D-dimer with hs-cTnI and BNP were stronger in the men. The incidence of myocardial injury in COVID-19 patients is sex-dependent, predominantly in association with a greater degree of inflammation and coagulation disorders in men. Our findings can be used to improve the quality of clinical management in such settings.

Thromboelastography Profile of Patients with COVID-19 Admitted to Intensive Care Unit: A Single-center Retrospective Study from India.

Coronavirus disease (COVID-19) causes thromboinflammation resulting in a high incidence of venous thromboembolism (VTE) events, which occur in significant numbers despite giving standard thromboprophylaxis with low-molecular-weight heparins. Various markers and tests have been evaluated and found to have a strong association with the worse prognosis of the disease. Common coagulation markers like D-dimer and fibrinogen give more of a static picture of coagulation, whereas viscoelastic tests like thromboelastography (TEG) provide an understanding of the coagulation function and help in better interpretation. We conducted a retrospective analysis of TEG values of 32 patients with COVID-19 admitted to the intensive care unit (ICU). Hypercoagulation as defined by TEG-coagulation index (CI) higher than the upper limit of the normal reference range (NRR) is found in 62.5% of the patients. There is also a clear representation of hypercoagulability as reflected by TEG-R, TEG-K, and TEG-LY30 values lower than or toward the lower limit of NRR, and TEG-ANGLE, TEG-MA, and TEG-CI values higher than or toward the upper limit of NRR which is more pronounced in severe forms of the disease, both in comparison to NRRs and other non-COVID ICU patients. Findings are similar to that of earlier studies in patients with COVID-19 except for the LY30, which is retained in the majority of our patients. Thromboelastography can be a useful tool to understand and screen for COVID-19-related hypercoagulability and may help predict VTE events. The potential of TEG to determine the optimal anticoagulant therapy needs to be evaluated in larger prospective studies. How to cite this article: Saseedharan S, Talla VB, Chiluka A. Thromboelastography Profile of Patients with COVID-19 Admitted to Intensive Care Unit: A Single-center Retrospective Study from India. Indian J Crit Care Med 2020;24(12):1218-1222.

COVID-19 Infection-Related Coagulopathy and Viscoelastic Methods: A Paradigm for Their Clinical Utility in Critical Illness.

Hypercoagulability and thrombosis remain a challenge to diagnose and treat in severe COVID-19 infection. The ability of conventional global coagulation tests to accurately reflect in vivo hypo- or hypercoagulability is questioned. The currently available evidence suggests that markedly increased D-dimers can be used in identifying COVID-19 patients who may need intensive care unit (ICU) admission and close monitoring or not. Viscoelastic methods (VMs), like thromboelastography (TEG) and rotational thromboelastometry (ROTEM), estimate the dynamics of blood coagulation. The evaluation of coagulopathy by VMs in severe COVID-19 infection seems an increasingly attractive option. Available evidence supports that COVID-19 patients with acute respiratory failure suffer from severe hypercoagulability rather than consumptive coagulopathy often associated with fibrinolysis shutdown. However, the variability in definitions of both the procoagulant profile and the clinical outcome assessment, in parallel with the small sample sizes in most of these studies, do not allow the establishment of a clear association between the hypercoagulable state and thrombotic events. VMs can effectively provide insight into the pathophysiology of coagulopathy, detecting the presence of hypercoagulability in critically ill COVID-19 patients. However, it remains unknown whether the degree of coagulopathy can be used in order to predict the outcome, establish a diagnosis or guide anticoagulant therapy.

Increased Dead Space Ventilation and Refractory Hypercapnia in Patients With Coronavirus Disease 2019: A Potential Marker of Thrombosis in the Pulmonary Vasculature.

OBJECTIVES: Mortality rates in intubated coronavirus disease 2019 patients remain markedly elevated. Some patients develop sudden refractory hypercapnia and hypoxemia not explained by worsening pulmonary parenchymal disease. This case series highlights clinical findings and management of coronavirus disease 2019 patients with refractory hypercapnia despite maximal/optimal ventilatory support. Hypercapnia could not be explained by worsening lung disease or other common factors, and thus, a pulmonary vascular etiology was suggested. The pillars of management were targeted to improve pulmonary vascular patency via aggressive anticoagulation and support right ventricular function. DATA SOURCES: Four consecutive patients with confirmed coronavirus disease 2019 infection with sudden hypercapnia and hypoxemia were included. DATA SYNTHESIS: There was sequential development of: 1) severe hypercapnia attributable to marked elevation of dead space without radiographic changes; 2) concomitant coagulopathy manifest by an increase in d-dimer levels; 3) progressive shunt with consequent hypoxemia; and 4) right ventricular dysfunction. Management included extracorporeal Co2 removal, direct thrombin inhibition, pulmonary vasodilators, and inotropic support. Marked improvement in Pao2 allowed reduction in Fio2 in all patients, extracorporeal Co2 removal was discontinued in three patients over the ensuing 3 weeks, and one patient was discharged home. CONCLUSIONS: We speculate that thromboinflammation with pulmonary microvasculature occlusion leads to a sudden increase in dead space and shunt resulting in severe hypercapnia and hypoxemia in coronavirus disease 2019 patients. Early identification of these physiologic and clinical biomarkers could trigger the institution of therapies aiming to reverse the hypercoagulable state and support right ventricular function.

Treatment of Acute Ischemic Stroke due to Large Vessel Occlusion With COVID-19: Experience From Paris.

BACKGROUND AND PURPOSE: Higher rates of strokes have been observed in patients with coronavirus disease 2019 (COVID-19), but data regarding the outcomes of COVID-19 patients suffering from acute ischemic stroke due to large vessel occlusion (LVO) are lacking. We report our initial experience in the treatment of acute ischemic stroke with LVO in patients with COVID-19. METHODS: All consecutive patients with COVID-19 with acute ischemic stroke due to LVO treated in our institution during the 6 first weeks of the COVID-19 outbreak were included. Baseline clinical and radiological findings, treatment, and short-term outcomes are reported. RESULTS: We identified 10 patients with confirmed COVID-19 treated for an acute ischemic stroke due to LVO. Eight were men, with a median age of 59.5 years. Seven had none or mild symptoms of COVID-19 at stroke onset. Median time from COVID-19 symptoms to stroke onset was 6 days. All patients had brain imaging within 3 hours from symptoms onset. Five patients had multi-territory LVO. Five received intravenous alteplase. All patients had mechanical thrombectomy. Nine patients achieved successful recanalization (mTICI2B-3), none experienced early neurological improvement, 4 had early cerebral reocclusion, and a total of 6 patients (60%) died in the hospital. CONCLUSIONS: Best medical care including early intravenous thrombolysis, and successful and prompt recanalization achieved with mechanical thrombectomy, resulted in poor outcomes in patients with COVID-19. Although our results require further confirmation, a different pharmacological approach (antiplatelet or other) should be investigated to take in account inflammatory and coagulation disorders associated with COVID-19.