Prothrombotic hemostasis disturbances in patients with severe COVID-19: Individual daily data

This data article accompanies the manuscript entitled: “Prothrombotic Disturbances of hemostasis of Patients with Severe COVID-19: a Prospective Longitudinal Observational Cohort Study” submitted to Thrombosis Research by the same authors. We report temporal changes of plasma levels of an extended set of laboratory parameters during the ICU stay of the 21 COVID-19 patients included in the monocentre cohort: CRP, platelet count, prothrombin time; Clauss fibrinogen and clotting factors II, V and VIII levels, D-dimers, antithrombin activity, protein C, free protein S, total and free tissue factor pathway inhibitor, PAI-1 levels, von Willebrand factor antigen and activity, ADAMTS-13 (plasma levels); and of two integrative tests of coagulation (thrombin generation with ST Genesia) and fibrinolysis (global fibrinolytic capacity - GFC). Regarding hemostasis, we used double-centrifuged frozen citrated plasma prospectively collected after daily performance of usual coagulation tests. Demographic and clinical characteristics of patients and thrombotic and hemorrhagic complications were also collected from patient's electronic medical reports.


Keywords:
Clauss fibrinogen and clotting factors II, V and VIII levels, D-dimers, antithrombin activity, protein C, free protein S, total and free tissue factor pathway inhibitor, PAI-1 levels, von Willebrand factor antigen and activity, ADAMTS-13 (plasma levels); and of two integrative tests of coagulation (thrombin generation with ST Genesia) and fibrinolysis (global fibrinolytic capacity -GFC). Regarding hemostasis, we used double-centrifuged frozen citrated plasma prospectively collected after daily performance of usual coagulation tests. Demographic and clinical characteristics of patients and thrombotic and hemorrhagic complications were also collected from patient's electronic medical reports.  Corresponding instruments and reagents of laboratory hematology for: platelet count, prothrombin time, Clauss fibrinogen and clotting factors II, V and VIII levels, D-dimers levels, PAI-1 levels, antithrombin activity, protein C activity, free protein S antigen, total and free tissue factor pathway inhibitor antigens, von Willebrand factor antigen and activity, ADAMTS-13 levels), thrombin generation, and global fibrinolytic capacity (GFC); and C-reactive protein.

Data format
Raw: Public repository. Analyzed : Tables and figures  Parameters for data collection Laboratory data: Clinical laboratory tests that describe disturbances of hemostasis of ICU patients, severely affected with CoViD-19: primary hemostasis (platelet count, von Willebrand factor antigen and activity; ADAMTS-13 activity); coagulation (prothrombin time, Clauss fibrinogen, clotting factors II, V and VIII levels, in vitro thrombin potential), natural anticoagulants (antithrombin activity, protein C activity, free protein S antigen, total and free tissue factor pathway inhibitor antigens); and fibrinolysis (D-dimers levels, PAI-1 activity, global fibrinolytic capacity

Value of the Data
• The data reported with individual time-courses during the ICU stay show the variability of hemostasis parameters over time and between individuals, suggesting varying thrombotic risks and the need for individualization of thrombotic prophylaxis, with frequent reassessments. • They can benefit to all physicians and scientists dealing with COVID-19.
• These data will be helpful to design further prospective studies focusing on COVID-19 hemostasis disorders: which parameters to measure and at which frequency.

Data Description
Demographic and clinical characteristics of observed ICU patients are shown in Table 1 . Values correspond to median (with interquartile and min-max ranges) for quantitative data and to number (percent) for qualitative data.
Baseline (D0) was defined as ICU admission (in Namur or elsewhere; 11 patients were transferred from the ICU of another Belgian hospital), but the laboratory-monitoring period was restricted to the Namur ICU stay. Tests on D0 were often missing due to delays in patients' inclusion. Table 2 represents the changes over time of hemostasis parameters along ICU stay of 21 severe COVID-19 patients. Observation period has been arbitrarily subdivided into three timeintervals of 10 days starting from D1. For each patient and time-interval, parameters medians were calculated. Medians and interquartile ranges of patient's medians are presented for the three time-intervals. Minimum and maximum values observed are also represented. D-dimers plasma levels are expressed in fibrinogen equivalent units (FEU) and 'reference ranges' depicted correspond to DIC thresholds according to the ISTH definition with the reagents we used [2] .
The figures represent the changes over time of measured hemostasis parameters during the ICU stay of each of the 21 patients. Blue lines represent the reference range locally determined, or previously published under similar analytical conditions, or according to the manufacturer's (see figure legends). Stars represent the follow-up period of the patients; orange stars represent the day of diagnosis of a thrombotic complication (which might be delayed form the actual onset) ( Figs. 1-22 ).

Patients
All patients admitted to the intensive care unit (ICU) of the CHU UCL Namur for an RT-PCR confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection from March 27 to April 24, 2020 were considered for inclusion. Twenty-one patients were finally included, one patient being excluded because of major therapeutic limitation (i.e. refusal of tracheal intubation).
Results of ST Genesia TGA are relative to reference plasma and expressed as ratios (temporal parameters) or percentages (thrombin concentration-related parameters). Hémostase Périopératoire (GIHP) were implemented in Namur from April 2, 2020 [4] . Patients were screened for deep vein thrombosis (DVT) within a week after Namur ICU admission, and then once a week unless a thrombotic event occurred. Pulmonary embolism (as a matter of fact could be in situ arterial thrombosis) was diagnosed directly by contract CT scan or indirectly by transesophageal ultrasonography (for unstable patients that cannot be transferred safely to the Radiology Department). Bleeding events were defined as minor or major according to ISTH definitions [5] .

Blood samples
Blood samples were collected from the arterial line as part of clinical patients' care and at least once a day around 4a.m. Serum was prepared from plastic tubes containing alumina silicate as coagulation activator (Vacuette, Greiner Bio One, Kremsmünster, Austria), whole blood was collected in K2-ethylenediaminetetraceatic acid (EDTA) tubes (Vacuette, Greiner Bio One) and plasma was prepared from 109 mM citrate tubes (Vacuette, Greiner Bio One) using double centrifugation (1500 g, 15 min, room temperature). Plasma samples were frozen at -80 °C and thawed at 37 °C for 5 min immediately before analysis.

Laboratory tests
Laboratory tests were performed on 4a.m. samples whenever possible or on the temporally closest samples.
CRP levels were measured on a Vitros 5600 Integrated System (Ortho Clinical Diagnostics, Belgium) with CRP Gold Latex reagents (DiAgam, Ghislenghien, Belgium) and platelet count on a Sysmex XN-20 analyzer with Cellpack reagent (Sysmex Corporation, Kobe, Japan).
The following laboratory tests were performed with a STA-R Max (Stago, Asnières-sur-Seine) and reagents from Stago: prothrombin time (STA-NeoPTimal; expressed as percentage [6] ), after neutralizing heparin with hexadimethrine bromide (25 μg/mL; polybrene, Sigma Aldrich, Saint-Louis, United States) [ 3 , 7 ]. Global fibrinolytic capacity was measured using the Lysis Timer instrument (Hyphen Biomed, Neuville-sur-Oise, France; SD Innovation, Frouard, France, respectively) with dedicated reagents (Hyphen Biomed) [8] . ADAMTS-13 activity was measured using the Technozym® ADAMTS-13 Activity ELISA kit (Technozym, Technoclone, Vienna, Austria). Von Willebrand activity was measured with an AcuStar analyser (Instrumentation Laboratory, Bedford, USA) and HemosIL AcuStar VWF:RCo reagent (Instrumentation Laboratory). Most analyses were intended to be performed once a day whenever possible. Some analyses were purposely performed only every 5 days (i.e. vWF antigen and activity, ADAMTS-13, total and free TFPI, tissue-type plasminogen activator) or every other day (protein C activity, free protein S antigen). The percentage of days with available data for the whole observation period is represented in Table 3 .    LT, lag time; ttP, time to peak, pH, peak height; ETP, endogenous thrombin potential; TFPI, tissue factor pathway inhibitor.

Ethics Statement
The observation was performed in accordance with the Declaration of Helsinki and after approval of the Ethics Committee of the CHU UCL Namur (NUB: B0392020 0 0 0 031).

Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that have or could be perceived to have influenced the work reported in this article.