Questions about COVID‑19 associated coagulopathy: possible answers from the viscoelastic tests

Journal of Clinical Monitoring and Computing (2022) 36:55–69
https://doi.org/10.1007/s10877-021-00744-7

REVIEW PAPER



Questions about COVID‑19 associated coagulopathy: possible answers
from the viscoelastic tests
Vittorio Pavoni1 · Lara Gianesello2 · Maddalena Pazzi1 · Pietro Dattolo3 · Domenico Prisco4

Received: 20 May 2021 / Accepted: 9 July 2021 / Published online: 15 July 2021
© The Author(s), under exclusive licence to Springer Nature B.V. 2021


Abstract
Abnormal coagulation parameters are often observed in patients with coronavirus disease 2019 (COVID-19) and the severity
of derangement has been associated with a poor prognosis. The COVID-19 associated coagulopathy (CAC) displays unique
features that include a high risk of developing thromboembolic complications. Viscoelastic tests (VETs), such as thromboe-
lastometry (ROTEM), thromboelastography (TEG) and Quantra Hemostasis Analyzer (Quantra), provide “dynamic” data
on clot formation and dissolution; they are used in different critical care settings, both in hemorrhagic and in thrombotic
conditions. In patients with severe COVID-19 infection VETs can supply to clinicians more information about the CAC,
identifying the presence of hypercoagulable and hypofibrinolysis states. In the last year, many studies have proposed to
explain the underlying characteristics of CAC; however, there remain many unanswered questions. We tried to address some
of the important queries about CAC through VETs analysis.

Keywords COVID-19 · Coagulopathy · Viscoelastic tests · Thromboembolic events


1 Introduction microvascular thromboses in available postmortem autopsies
[6]; microvascular thrombosis may promote hypoxia through
Severe acute respiratory syndrome coronavirus 2 (SARS- increased dead space leading to ventilation/perfusion (V/Q)
CoV-2) infection is characterized by a diffuse endothelial mismatch or by promoting hypoxic vasoconstriction.
dysfunction and a hyperinflammation state that leads to a In the literature, a link between coagulation abnormali-
cytokine storm which enhances the risk of thrombotic com- ties and severe SARS-CoV-2 infection has been described
plications. Multiple studies have reported a high incidence [7] and several studies have found an association between
of venous thromboembolism (VTE) in coronavirus-2019 increased plasma D-dimer levels and unfavorable prognosis
disease (COVID-19) patients, in particular pulmonary in COVID-19 patients [8]. However, in severe COVID-19,
thrombosis (79%) [1–5]. Moreover, patients with severe the pulmonary inflammation can cause fibrin deposits within
COVID-19 manifested by acute respiratory distress syn- alveoli and pulmonary extravascular space, as confirmed in
drome (ARDS), have demonstrated extensive pulmonary autopsies series [9] and the lysis of these deposits could
contribute to the rise of D-dimer which would be thus not
specific of intravascular fibrin formation [10, 11].
* Lara Gianesello Patients with SARS-CoV-2 infection presented a pecu-

liar form of coagulopathy, termed COVID-19 associated
1
Emergency Department and Critical Care Area, Anesthesia coagulopathy (CAC). CAC results from complex interac-
and Intensive Care Unit, Santa Maria Annunziata Hospital, tions between regulators of inflammation and coagulation;
Bagno a Ripoli, Florence, Italy it is characterized by unique laboratory features different
2
Department of Anesthesia and Intensive Care, Orthopedic from either disseminated intravascular coagulation (DIC)
Anesthesia, University-Hospital Careggi, Largo Palagi, 1, and sepsis induced coagulopathy (SIC), such as the lack of
50139 Florence, Italy
consumption of platelets and coagulation factors. Increased
3
Nephrology Unit Florence 1, Santa Maria Annunziata fibrinogen, fibrin degradation products, prothrombin time
Hospital, Bagno a Ripoli, Florence, Italy
(PT) and activated partial thromboplastin time (aPTT),
4
Department of Experimental and Clinical Medicine, have been described in patients with COVID-19 compared
University of Florence, Florence, Italy


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to healthy controls [12, 13]. Despite their dissemination and To explore the extrinsic pathway, the systems use activa-
ease of interpretation, these measurements focus on quantity tors such as tissue factor (TF) alone (extrinsically-activated
rather than functionality of clotting components and provide assay, EXTEM) or in combination with Kaolin (RAPID-
information on clot formation, but do not address clot stabil- TEG). The contribution of fibrin on the clot amplitude is
ity and dissolution. explored using additive platelets inhibitors [i.e. Abciximab
Viscoelastic tests (VETs), such as rotational throm- for TEG (Functional Fibrinogen, FF assay) and cytochalasin
boelastometry (ROTEM, Tem Innovations, Munich, Ger- D (FIBTEM assay) for ROTEM].
many), thromboelastography (TEG System, Haemonetics) Based on time–resistance associations, TEG and ROTEM
and Quantra (Quantra System, HemoSonics LLC, Char- are characterized by tracings that represent a picture which
lottesville, VA), are global hemostasis assays able to assess starts from the beginning of clot formation throughout its
coagulation function, platelets and fibrinogen contribution to lysis. In particular, TEG and ROTEM are able to detect both
clot formation and fibrinolytic components [14–17]. These hypo- and hyperfunctional stages of the clotting process and
devices have been utilized in trauma and surgical care as an are reliable rapid tests for the diagnosis of hyper or hypofi-
adjunct to conventional coagulation tests for guiding resus- brinolysis [28–30]. In Fig. 1 the parameters obtained in TEG
citation and transfusion strategies [18, 19]. In addition to and in ROTEM and their meaning are shown.
the use in patients with a hypocoagulable state and bleed- Quantra System is based on technology called sonic esti-
ing tendency, VETs have been successfully used to detect mation of elasticity via resonance, or sonorheometry [31,
hypercoagulable states in the setting of malignancy [20], 32]. A multi-well plastic cartridge (Quantra QPlus) which
trauma [21–23], intensive care unit (ICU) admission [24] includes four test channels allows to perform four parallel
and surgery [25, 26]. and independent measurements using different lyophilized
Recently, VETs appeared to play a role in assessing CAC. reagent combinations in each channel. This technology is
The purpose of this narrative review is to analyze the litera- composed of three fundamental steps. First, an ultrasound
ture on the ability of VETs to evaluate the CAC, through pulse is transmitted in the blood sample to generate a shear
possible answers to clinical questions. wave, causing the sample to resonate. A series of ultrasound
“tracking” pulses is then sent within the sample and the
returning echoes are used to estimate the sample motion. The
2 The viscoelastic tests: parameters shear modulus of the sample is calculated by analyzing the
and interpretation sample motion pattern. This process is repeated every four
seconds to form a signature curve that shows shear modulus
VETs (i.e. ROTEM, TEG and Quantra) are assays that meas- vs. time. From this curve, the start of clot formation, or clot
ure changes in viscoelastic properties of whole blood. TEG time, and the stiffness of the clot can be directly estimated.
and ROTEM are based on the same concept, described by The combination of these two parameters provides infor-
Hartert [27], and measure the “shear modulus” of the clot, mation about the functional role of the coagulation factors,
which represents its tendency to deform by the action of fibrinogen, and platelets in the sample. The Quantra system
opposing forces. The shear modulus is defined as the ratio does not provide a TF activated clotting time (CT) and is
between shear stress and shear strain; it is not constant and limited to assess the intrinsic pathway (activation by kaolin).
changes along the process of clotting. In TEG a blood sam- Furthermore, hyperfibrinolysis can only be detected in the
ple is injected in a cylindrical sample cup which rotates Quantra system using a specific cartridge (QStat cartridge)
slowly through an area of 4.45°, every 5 s, along the longi- [33]. No data are available whether the Quantra system can
tudinal axis; a free pin is immersed in the blood and, as long detect fibrinolysis shutdown which is an important issue in
as the coagulation process begins, it detects the variation bacterial sepsis and COVID-19 [34–37].
of strength between the pin and the cup wall. In ROTEM The principal parameters evaluated in Quantra System
the mechanism is the opposite, as it is the pin which moves are shown in the Fig. 2.
through an area of 4.75°, while the cup is fixed. Moreover,
in TEG, the movement is detected by a torsion wide and not
optical as in the ROTEM device; this makes the TEG 5000 3 Hypercoagulability and hypofibrinolysis
system more sensitive to movement artifacts. Actually, the in COVID‑19 patients: two sides
new TEG 6s device is using an ultrasound technology. of the same coagulopathy?
TEG and ROTEM explore the coagulation pathway using
added activators and additives. In TEG the most widely During infection, the coagulation cascade is activated as a
activator used is Kaolin (K-TEG) to explore the intrinsic physiological host defense to limit the spread of the patho-
coagulation pathway. Its ROTEM equivalent is the INTEM, gens [38]. In COVID-19 patients the severe inflammatory
which uses ellagic acid and phospholipids as activators. state can lead to severe derangement of hemostasis and

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