key: cord-282183-k0pn0ie2
authors: Spiezia, Luca; Campello, Elena; Cola, Marco; Poletto, Francesco; Cerruti, Lorenzo; Poretto, Anna; Simion, Chiara; Cattelan, Annamaria; Vettor, Roberto; Simioni, Paolo
title: More severe hypercoagulable state in acute COVID-19 pneumonia as compared to other pneumonia.
date: 2020-10-01
journal: Mayo Clin Proc Innov Qual Outcomes
DOI: 10.1016/j.mayocpiqo.2020.09.002
sha: 
doc_id: 282183
cord_uid: k0pn0ie2

Objective To conduct a comprehensive evaluation of coagulation profiles — via traditional and whole blood thromboelastometry tests — in COVID-19 positive vs. COVID-19 negative patients admitted to medical wards for acute pneumonia. Patients and Methods We enrolled all consecutive patients admitted to Internal Medicine wards of Padova University Hospital between 7 March and 30 April 2020 for COVID-19-related pneumonia (cases) vs. non-COVID-19 pneumonia (controls). A group of healthy subjects acted as baseline for thromboelastometry parameters. Results Fifty-six cases (mean age 64±15 yrs, M/F 37/19) and 56 controls (mean age 76±11 yrs, M/F 35/21) were enrolled. Cases and controls showed markedly hypercoagulable thromboelastometry profiles vs. healthy subjects, mainly characterized by a significantly shorter propagation phase of coagulation (Clot Formation Time, CFT) and significantly increased maximum clot firmness (MCF) (p <0.001 in all comparisons). COVID-19 patients with pneumonia had significantly shorter CFT and higher MCF (p <0.01 and <0.05, respectively in all comparisons) vs. controls. Conclusion Patients admitted to internal medicine wards for COVID-19 pneumonia presented a markedly prothrombotic state, which seems peculiar to COVID-19 rather than pneumonia itself.

The novel coronavirus (SARS-CoV-2) infection which spread rapidly worldwide from China in late December 2019, has been linked to several coagulation abnormalities. Tang N. et al. reported that elevated D-dimer levels, prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT) were common findings in COVID-19 patients and correlated with a worse prognosis 1 . Significantly elevated D-dimer plasma levels in patients with a more severe infection were also confirmed by two pooled data analyses 2, 3 . Interestingly, we and two other Italian groups recently reported hypercoagulable whole blood profiles in COVID-19 patients admitted to Intensive Care Units for acute respiratory failure [4] [5] [6] . The hypercoagulability observed in COVID-19 patients may be responsible for the high prevalence of both arterial and venous thrombotic events 7, 8 . Moreover, the association between coagulation activation and more severe infection may explain the better outcome observed in patients undergoing anticoagulant therapy (e.g. heparin) 9 . To the best of our knowledge, no study published in the literature so far has conducted a comprehensive evaluation of coagulation profiles as it relates to the comparison between COVID-19 and non COVID-19 patients with pneumonia. Therefore, we aimed to study traditional and whole blood thromboelastometry profiles -via a ROTEM ® sigma apparatus (Instrumentation Laboratory Werfen, Barcelona, Spain) -in a group of patients consecutively admitted to Internal Medicine wards of Padova University Hospital for acute pneumonia: cases were COVID-19 patients with pneumonia and controls were patients with pneumonia from different etiology.

All consecutive patients admitted between 7 March and 30 April 2020 to COVID-19 medical wards of Padova University Hospital with a confirmed diagnosis (i.e. positive nasopharyngeal J o u r n a l P r e -p r o o f swabs) of acute COVID-19 pneumonia were considered for enrollment. An equal number of patients admitted to Internal Medicine wards (non COVID-19 area) over the same period of time for acute pneumonia and with a negative COVID-19 nasopharyngeal swab acted as controls. For the diagnosis of acute pneumonia, we referred to The National Institute for Health and Care Excellence (NICE) Pneumonia guideline 10 . In particular, the suspicion of pneumonia was prompted by the onset over the past three days, of at least two symptoms among the following: cough, newly expressed fatigue, pain while breathing, anosmia, myalgia or confusion; and the presence of at least two signs among the following: temperature > 38°C, respiratory rate > 20 breaths per minute, heart rate > 100 beats per minute or focally depressed or altered breathing sounds or dullness to percussion. The diagnosis was confirmed in each patient by chest X-rays.

Exclusion criteria were: pregnancy, known congenital discoagulopathies, age < 18 or > 90 years, Child's C liver disease, severe chronic kidney disease, active cancer, pre-existing hematological disorders, and ongoing anticoagulant therapy. It bears noting that during the enrollment of our study population, it was not standard practice in our hospital to initiate anticoagulant therapy in COVID-19 patients upon admission. Thus, after obtaining informed consent from each enrolled patient, we collected the following data within 6 hours of admission: i) demographic characteristics, clinical data and SOFA (Sequential Organ Failure Assessment) score; ii) two BD hypercoagulable thromboelastometry profile was defined as shorter CTs and/or CFTs, and/or higher MCF than controls as well as healthy subjects 11 .

The sample size calculation was based on pilot observations and the following assumptions: i) expected mean (± Standard Deviation -SD) increase in MCF to identify hypercoagulable profiles ≥3 (±4) mm 10 ; ii) power 90%; iii) alpha 0.05. Therefore, we needed two groups (COVID-19 vs. non COVID-19 pneumonia) of at least n. 45 patients each. Categorical variables were summarized as counts and percentages. Continuous variables were expressed as mean ± J o u r n a l P r e -p r o o f SD. The normality assumption was assessed using the Shapiro-Wilk normality test. Chi-square test and Student's t-test were used where appropriate to compare cases vs. controls. Lower and upper values of the reference ranges for ROTEM ® parameters were determined in the population of healthy subjects using the 2.5 th and 97.5 th percentile, respectively. A p-value < 0.05 was considered statistically significant. All statistical analyses were performed by GraphPad Prism 8 (GraphPad Software Inc., CA, USA). Table 1 . No significant differences were observed between groups as it relates to the main clinical and laboratory data. In particular, traditional coagulation parameters were similar between cases and controls. Only white blood cells count (p <0.001), CRP (p <0.001) and procalcitonin (p=.03) were significantly higher in non-COVID-19 pneumonia vs. COVID-19 pneumonia. ROTEM ® parameters (see Table 2 

The results of our study show that COVID-19 patients admitted to medical wards for acute pneumonia had markedly hypercoagulable profiles on whole blood thromboelastometrycompared to COVID-19 negative patients with pneumonia -mainly characterized by a significantly shorter propagation phase of the clot formation and significantly increased clot firmness. These findings appear to suggest that the markedly hypercoagulable profiles on whole blood in COVID-19 patients with pneumonia vs. controls may be attributable to the SARS-CoV-2 infection specifically, rather than pneumonia itself. Although several papers, including one by our group, have previously reported COVID-19-related hypercoagulability in patients admitted to Intensive Care Units 4-6 , the present study focuses more closely on the comparison of coagulation profiles between COVID-19 patients with acute pneumonia and non COVID-19 patients with acute pneumonia. Furthermore, though previous reports found that traditional coagulation parameters (e.g. D-dimer, factor VIII, fibrinogen and von Willebrand factor) were able to identify hypercoagulable profiles in COVID-19 patients 6,12 , we observed no significant differences between cases and controls in our study population as it pertains to traditional coagulation tests. Moreover, as previously reported 13 , we found no evidence of consumptive coagulopathy in COVID-19 patients.

From a clinical standpoint, the marked increase of coagulation capability observed in our study J o u r n a l P r e -p r o o f may account for the high risk of thromboembolic events observed in COVID-19 patients with acute pneumonia 7, 8 . Hence the beneficial effect of administering low molecular weight heparin, either at prophylactic or therapeutic dosages, to reduce the incidence of thrombotic events and mortality 9, 14 . Another clinical implication of hypercoagulability -but specifically, the significant increase of clot firmness in FIBTEM assay -stems from the markedly increased capability of fibrin to polymerize which may lead to microcirculation thrombosis (i.e. occlusive microthrombi in pulmonary small vessels) and fibrin deposition in alveolar and interstitial lung spaces, ultimately resulting in the development of acute respiratory failure in COVID-19 patients.

Some of the limitations of our study must be addressed. Firstly, the lack of standardization of the thromboelastometry device which limits data comparison across different laboratories. In this regard, the use of a fully automated tool such as the ROTEM ® sigma reduces intra-and inter-test variability and therefore provides more standardized and comparable data. Furthermore, the use of ROTEM ® sigma, a closed, cartridge-based, fully-automated viscoelastic testing system allows to safely manage hazardous samples such as COVID-19, thus minimizing the risk of contamination 15 . Secondly, despite our best efforts to closely match our control group to cases, the former ended up being rather heterogeneous comprising both patients with bacterial and viral pneumonia. Finally, the relatively low sample size did not allow to adjust the statistical analyses for specific confounding factors (e.g. age, obesity, SOFA score) which we know from the literature may singlehandedly yield hypercoagulable ROTEM ® profiles 16 .

In conclusion, our findings indicate that COVID-19 patients admitted to Internal Medicine wards 

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