| |
Received: 7 September 2020    Revised: 14 October 2020    Accepted: 16 October 2020
DOI: 10.1111/ijlh.13381
REVIEW
The hematology laboratory’s response to the COVID-19
pandemic: A scoping review
Robert Bell1 | Gina Zini2,3  | Giuseppe d’Onofrio3
Yi-Shan Lee1 | John L. Frater1
1
Department of Pathology and Immunology,
Washington University, St. Louis, MO, USA
2
Fondazione Policlinico Universitario A.
Gemelli IRCCS - Roma, Rome, Italy
3
Università Cattolica del Sacro Cuore, Rome,
Italy
4
Robert J Tomsich Pathology and Laboratory
Medicine Institute, Cleveland Clinic,
Cleveland, OH, USA
Correspondence
John L. Frater, Department of Pathology and
Immunology, Washington University School
of Medicine, 660 South Euclid Avenue, Box
8118, St. Louis, Missouri 63110-1093.
Email: jfrater@wustl.edu
1 | I NTRO D U C TI O N
1.1 | Rationale
The COVID-19 pandemic originated in December 2019 in the capi-
1
tal of the Hubei Province of China, Wuhan. It is a viral illness, the
causative agent of which is a novel β-coronavirus, SARS-CoV-2.1
|
148     © 2020 John Wiley & Sons Ltd
 | Heesun J. Rogers4  |
Abstract
The ongoing COVID-19 pandemic has had a profound worldwide impact on the labo-
ratory hematology community. Nevertheless, the pace of COVID-19 hematology-re-
lated research has continued to accelerate and has established the role of laboratory
hematology data for many purposes including disease prognosis and outcome. The
purpose of this scoping review was to assess the current state of COVID-19 labora-
tory hematology research. A comprehensive search of the literature published be-
tween December 1, 2019, and July 3, 2020, was performed, and we analyzed the
sources, publication dates, study types, and topics of the retrieved studies. Overall,
402 studies were included in this scoping review. Approximately half of these stud-
ies (n = 202, 50.37%) originated in China. Retrospective cohort studies comprised
the largest study type (n = 176, 43.89%). Prognosis/ risk factors, epidemiology, and
coagulation were the most common topics. The number of studies published per day
has increased through the end of May. The studies were heavily biased in favor of pa-
pers originating in China and on retrospective clinical studies with limited use of and
reporting of laboratory data. Despite the major improvements in our understanding
of the role of coagulation, automated hematology, and cell morphology in COVID-19,
there are gaps in the literature, including biosafety and the laboratory role in screen-
ing and prevention of COVID-19. There is a gap in the publication of papers focused
on guidelines for the laboratory. Our findings suggest that, despite the large number
of publications related to laboratory data and their use in COVID-19 disease, many
areas remain unexplored or under-reported.
KEYWORDS
COVID-19, laboratory hematology, SARS-CoV-2, scoping review
Although the most clinically significant symptoms appear to be res-
piratory, with acute respiratory distress syndrome (ARDS) among
the most dire complications, a broad spectrum of multisystem ef-
fects has been described, which include damage to the kidney, brain,
and heart. 2-5
SARS-CoV-2 has a noteworthy effect on hematologic param-
eters, and alterations of the complete blood count (CBC) and
wileyonlinelibrary.com/journal/ijlh Int J Lab Hematol. 2021;43:148–159.
BELL et al.
hemostasis/ thrombosis laboratory-derived data have been identi-
fied as biomarkers of disease severity and mortality. Among these
are lymphopenia, neutrophilia, leukocytosis, thrombocytopenia,
prolongation of prothrombin time (PT) and activated partial throm-
boplastin time (aPTT), and elevated D-dimer and fibrin degradation
1,6-10
products (FDP).
There has been an immense output of scientific information in
response to the pandemic: a search of the Google Scholar data-
base for “COVID-19” performed on July 9, 2020, revealed a total of
1,220,000 results, and a simple search of PubMed yielded 30,302
studies. A survey of the COVID-19 literature performed in February
2020 demonstrated that a wide variety of topics were addressed
by these studies, most commonly prevention and control, outbreak
11
reporting, genetics, and transmissibility.
1.2 | Objectives
Several reviews have been published which address features of the
clinical phenomena and virology of COVID-19.12,13 There have also
been reviews published in the clinical laboratory literature, most of
which have a conventional narrative structure, which were limited
by the relatively small number of primary studies published in the
first months of the pandemic. However, the COVID-19 literature
focused on the clinical laboratory, including laboratory hematology,
has continued to grow. We therefore chose to perform a survey of
the current state of the laboratory hematology literature regarding
COVID-19. We chose the scoping review format as an appropriate
means to assess this body of work. A scoping review is an evidence-
based study which maps the available literature on a given topic and
details the characteristics of the body of literature, in an effort to
organize its key concepts and identify knowledge gaps.11,14 We de-
signed this scoping review to focus on topics of interest to the labo-
ratory hematology community and COVID-19.
2 |  M E TH O D
2.1 | Format
This study was performed using the Preferred Reporting Items for
Systematic Reviews and Meta-analyses (PRISMA) Extension for
Scoping Reviews (PRISMA-ScR), which contains a 27-point check-
list which serves as an adaptation of the PRISMA checklist (see
Table S1).15
2.2 | Search strategy
We conducted an electronic search in Medline (PubMed interface)
and Web of Science using the keywords “COVID-19” and synonyms
(“SARS-CoV-2”, “2019 novel coronavirus”, “2019-nCoV”, “Wuhan cor-
onavirus”, “novel coronavirus”, “Wuhan seafood market pneumonia
|
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virus”, “Wuhan virus”) AND “laboratory” and synonyms (“laborato-
rial”, “laboratories”). In addition, we screened the contents of 50 he-
matology and medicine journals to identify studies not found in the
database searches due to possible delays in indexing (see Table S2).
We limited our search to studies published between December 1,
2019, and July 3, 2020, the date of the search. This protocol has not
been registered. Individual authors were not contacted.
2.3 | Eligibility criteria
We included the COVID-19 literature related to the following labo-
ratory hematology topics published between December 1, 2019, and
July 3, 2020: coagulation, flow cytometry, cellular analysis, morphol-
ogy, standards and quality assurance, and biosafety. There was no
restriction of article type.
2.4 | Screened titles and abstracts
Titles and abstracts of all studies were screened by two of the au-
thors (RB and JLF). The full text of all studies considered for poten-
tial inclusion in the analysis was reviewed for suitability. For articles
published in Chinese, the full text was evaluated by a member of the
research team fluent in that language (Y-S L). Finally, the following
information was extracted for the included studies: (a) title, (b) first
author, (c) journal, (d) publication or posted date, (e) country from
which the study originated, (f) article type, and (g) topic (see Figure
S3). The content of the included studies was critically appraised by
all authors, who are experts in the field of laboratory hematology.
2.5 | Data analysis
To identify gaps in the literature, we performed a descriptive analy-
sis of the included studies. In the description, we included the jour-
nal in which the study was found, date of publication, article type,
and topic of the article. We also categorized the articles as case re-
ports, case series, comment, comment/opinion, editorial, guidance/
guideline or consensus statement, image/case presentation, letter to
the editor, meta-analysis, opinion, prospective study, retrospective
study, or review.
3 | R E S U LT S
3.1 | Search results
See Figure S3), which contains a flow chart of the screening process.
The database searches identified 5755 studies (4095 from PubMed,
1660 from Web of Science). To these studies, we added 253 papers
identified through a search of the contents of 50 hematology and
medicine journals. After the removal of duplicates, 4872 studies
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150       BELL et al.

TA B L E 1   Characteristics of COVID-19 studies included in the
review—journals (publishing > 1 paper) and country of origin (all
countries with > 4 papers)
Journal
Other
Journal of Thrombosis and
Haemostasis
British Journal of Haematology
Journal of Medical Virology
American Journal of Hematology
Clinical Chemistry and
Laboratory Medicine
Journal of Infection
Lancet Journals
Clinica Chimica Acta
remained. The titles and abstracts of the studies were reviewed,
and 4096 were excluded as being out of scope (ie, not concerning
laboratory hematology aspects of COVID_19). The full text of the
Number of remaining 776 papers was reviewed, resulting in the elimination of
Articles/ Percentage 374 additional studies, for similar reasons. Therefore, a total of 402
Studies (%)
articles were included in this review (see Table S4, which contains
the bibliographic information for the papers included in this study.
183 45.64% The full data set can be obtained from the corresponding author
55 13.72% upon any reasonable request).
37 9.23%
17 4.24% 3.2 | Characteristics of the included articles
12 2.99%
9 2.24% Of the 402 included studies, based on the address of the first au-
thor of the papers, the highest number was from China (n = 203,
8 2.00% 50.50%, see Table 1). The other top contributing countries were
8 2.00% the United States (n = 48, 11.94%), Italy (n = 34, 8.46%), the United
7 1.75% Kingdom (n = 26, 6.47%), and France (n = 15, 3.73%) (Table 1). The

Journal of Clinical Virology 6 1.50% article types (Table 2) could be classified into 14 groups, of which
the largest number were retrospective studies (n =  176, 43.89%),
Blood 5 1.25%
letters(n = 56, 13.97%), and reviews (n = 34, 8.48%).
Annals of Hematology 5 1.25%
Thrombosis Research 5 1.25%
Platelets 5 1.25%
3.2.1 | Sources of articles
Seminars in Thrombosis and 5 1.25%
Hemostasis
The studies were published in a large number of journals. Nearly,
Haemophilia 5 1.25%
half of these studies (n = 183, 45.64%, Table 1) appeared in journals
Journal of thrombolysis 4 1.00%
that published only 1 or 2 papers included in this review. The largest
Clinical Infectious Disease 4 1.00% number of articles was published by The Journal of Thrombosis and
International Journal of 4 1.00% Haemostasis (n = 55, 13.72%), The British Journal of Haematology
Laboratory Hematology
(n  = 37, 9.23%), The Journal of Medical Virology (n = 17, 4.24%),
Jama Journals 4 1.00%
The American Journal of Hematology (n = 12, 2.99%), and Clinical
Clinical Microbiology and 3 0.75% Chemistry and Laboratory Medicine (n = 9, 2.24%) (Table 1).
Infection
Blood Advances 2 0.50%
JCI Insight 2 0.50% 3.2.2 | Publication date
Pediatric Blood and Cancer 2 0.50%
Haematologica 2 0.50% A weekly breakdown of the number of articles published during the
New England Journal 2 0.50% study period is listed in Table 1. The number of published studies in
Country 2-week increments is illustrated in Figure 1. There was a steady in-
China 203 50.50% crease in the overall number of published articles over the course of
USA 48 11.94% the study period. The largest single day increase was on July 1, 2020,

Italy 34 8.46%
when 30 articles were published.

UK 26 6.47%
France 15 3.73%
3.2.3 | Topics
Iran 8 1.99%
Canada 7 1.74%
Each article was characterized as having a main topic belonging to
Spain 6 1.49%
1 of the following categories: prognostics, risk factors, epidemiol-
Belgium 5 1.24% ogy, coagulation, laboratory monitoring, hematology, treatment and
Greece 5 1.24% monitoring, pathophysiology, lessons and challenges, treatment,
Netherlands 5 1.24% screening/ prevention, molecular biology, and biosafety (Table 2).
BELL et al. |
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The topics most frequently encountered were clinical features and
observations (n =  103, 25.69%), prognostics/risk factors (n  = 80,
19.95%), epidemiology (n = 63, 15.71%), coagulation (n = 34, 8.48%),
and laboratory monitoring (n = 32, 7.98%). The mapping of the article
types with their corresponding topics is presented in Table 3, which
highlights gaps in the literature. Whereas retrospective studies of
the clinical features, epidemiology, and prognosis/ risk factors of
COVID-19 are well reported, other areas such as laboratory moni-
toring of COVID-19 disease, studies comparing the molecular bio-
logic features of COVID-19 to hematology findings (such as different
mutations), the role of hematology data in screening/prevention of
COVID-19 disease, and lessons and challenges to the hematology
laboratory associated with COVID-19 are relatively few.
The papers in this study utilized hematology laboratory data for a
variety of purposes, including the potential use of these parameters
to guide therapy and predict outcome. The percentages of papers
using coagulation and automated hematology data are illustrated
in Figures 2 and 3, respectively. D-dimer, PT, aPTT, and fibrinogen
were the most cited coagulation parameters. Platelet count, abso-
lute lymphocyte count, white blood cell count, and absolute neutro-
phil count were the most cited automated hematology parameters.
4 | D I S CU S S I O N
4.1 | Summary of evidence

Our scoping review, which is focused on the COVID-19 literature

TA B L E 2   Characteristics of COVID-19 studies included in the
relevant to laboratory hematology, demonstrates a marked increase
review—Type of article and Topic
in articles between December 1, 2019, and July 3, 2020. There are,
Number of articles/ Percentage however, gaps in study types and research fields that are evident
Characteristics studies (%) based on a critical evaluation of the literature. There is a clear bias in
Type of Article favor of retrospective clinical studies, letters to the editor, and nar-
Retrospective study 176 43.89% rative review articles. Prospective and case-control studies are un-
Letter 56 13.97% der-represented, a trend also observed in an earlier scoping review

Review 34 8.48% of the entire COVID-19 literature conducted in February 2020.11

Moreover, the number of papers categorized as guidelines or con-
Comment/Opinion 33 8.23%
sensus statements remains low, likely due to the rapid worldwide
Case reports 27 6.73%
spread of the pandemic and the challenges to national and interna-
Prospective study 18 4.49%
tional organizations. Despite the large number of papers reporting
Meta-analysis 16 3.99%
laboratory data, many de-emphasize the importance of hematology
Case series 13 3.24%
parameters. Approximately 40% of studies have a primary focus
Guidance/guideline or 11 2.74% on clinical features of SARS-CoV-2 infection and epidemiology,
consensus statement
and laboratory data are minimally reported. The largest contribut-
Editorial 6 1.50%
ing country by far has been China, and many articles by research-
Image/Case 4 1.00%
ers from other regions of the world that have been categorized as
Observational 3 0.75% reviews and meta-analyses are derived from data from China. The
Basic Research 2 0.50% degree to which this data is generalizable is unclear. Nevertheless,
Cross-sectional study 2 0.50% there has been a marked increase in the laboratory hematology-fo-
Topic cused COVID-19 literature since our earlier narrative review, most
Clinical Features & 103 25.69% notably in the fields of coagulation, automated hematology, and cell
Observations morphology.1
Prognostics/Risk factors 80 19.95%
Epidemiology 63 15.71%
Coagulation 34 8.48% 4.2 | Coagulation
Laboratory monitoring 32 7.98%
Hematology 31 7.73%
There have been several breakthroughs in our understanding of the
pathophysiology of COVID-19 disease related to acquired abnor-
Treatment and 27 6.73%
monitoring malities of coagulation, as reflected in this scoping review. There is

Pathophysiology 14 3.49% accumulating laboratory evidence related to abnormal coagulation

changes in COVID-19 infected patients, which may be a result of
Lessons and challenges 6 1.50%
profound inflammatory response, and not associated with intrinsic
Treatment 4 1.00%
procoagulant effect itself. A subset of severe pneumonia patients
Screening/Prevention 4 1.00%
developed viral sepsis, disseminated intravascular coagulation (DIC),
Molecular biology 2 0.50%
and multiorgan failure.16,17 Early reports from Wuhan, China, demon-
Biosafety 1 0.25%
strated abnormal results in coagulation parameters related to sepsis
152       |
Number of studies published per me interval
90
80
Number of studies (n)
70
60
50
40
30
20
10
0
Date (2020)
or DIC. One report with the first 99 hospitalized COVID-19 patients
showed elevated aPTT (6%), elevated PT (5%), elevated D-dimer
(36%) as well as inflammatory biomarkers such as interleukin-6 (IL-6),
18
erythrocyte sedimentation rate, and C-reactive protein.
report with 138 patients found higher D-dimer, progressive lym-
phopenia, and renal dysfunction in nonsurvivors compared to sur-
vivors during hospital course.19 A further study reported severely
ill COVID-19 patients (6.1%; 67/1099) including admission to ICU,
the use of mechanical ventilation or death had higher D-dimer lev-
els, suggesting extensive thrombin generation and fibrinolysis.
In a study of consecutive measurement of PT, aPTT, fibrinogen,
antithrombin, FDP, and D-dimer during 2-week hospitalization,
overall mortality was 11.5% (21/183). 22 The nonsurvivors demon-
strated significantly higher D-dimer and FDP levels, and longer PT
and aPTT compared to survivors on admission. The fibrinogen and
antithrombin levels were significantly reduced in nonsurvivors, and
D-dimer and FDP were markedly elevated in all nonsurvivors by the
late hospitalization. The progressive coagulation changes suggested
a common coagulation activation, dysregulated thrombin genera-
tion, impaired natural anticoagulants and fibrinolysis, indicating the
development of DIC. Overt DIC was developed more frequently in
nonsurvivors than survivors (71.4% vs 0.6%, respectively) in median
4 days from admission.16,23-25 High D-dimer level on admission or
increasing D-dimer over hospitalization is associated with increased
mortality of COVID-19 patients and can be used as an indicator of
prognosis.16,17,20,26-28 It is already described that individuals with
older age and co-morbidities such as atrial fibrillation or ischemic
heart disease are more likely to die from COVID-19 infection.
The most typical laboratory finding in COVID-19 associated coag-
ulopathy is an increased D-dimer, a relatively modest decrease in
platelet count, and a prolonged PT. 28
However, laboratory findings in patients with severe COVID-
19 showed a somewhat different pattern from sepsis-associ-
ated DIC. COVID-19 patients have a relatively modest decrease
in platelet count and very high D-dimer (>5 folds), which may
BELL et al.
F I G U R E 1   Graph of the studies
organized by date of publication in 2-week
increments [Colour figure can be viewed
at wileyonlinelibrary.com]
affect the DIC score of International Society on Thrombosis and
Haemostasis.16,25,27,28,31,32 A meta-analysis of nearly 400 COVID-
19 patients found significantly lower platelet count in patients with
Another more severe COVID-19 (weighted mean difference −31 × 10 9/L). 29
Patients with severe COVID-19 at presentation and D-dimer ele-
vated > 6-fold the upper limit of normal or a sepsis-induced coag-
ulopathy (SIC) score ≥ 4 were found to have decreased mortality
when treated with prophylactic doses of enoxaparin or unfraction-
ated heparin, unless there are contraindications.17,23,28,30 Based on
20,21
currently available laboratory data in COVID-19 patients, interim
guidance suggests monitoring coagulopathy in patients with se-
vere COVID-19 by measuring D-dimer, PT, and platelet count (in
decreasing order of importance) every 2-3 days. 28,29,31 The re-
searchers noted a statistically significant increase in D-dimer lev-
els, and PT, and decrease in fibrinogen levels in nonsurvivors at
days 10 and 14.16,29
Although the pathogenesis of the COVID-19-induced coagu-
lopathy has not yet been fully elucidated, the thromboinflamma-
tory pathway associated with COVID-19 infection may contribute
to potential clinical thromboembolic complications. Significant
inflammation in severe COVID-19 patients causes profound ac-
tivation of coagulation factors, platelet activation, systemic in-
flammatory response, or elevated cytokines (IL-6), and severe
endothelial cell activation and damage. This coagulopathy con-
tributes localized or systemic procoagulant or hypercoagulable
status.17,21,33,34 Procoagulant factor, factor VIII, and acute phase
reactants including fibrinogen were severely elevated in critically
17,29,30
ill patients with COVID-19. Natural anticoagulants such as protein
C, protein S, and antithrombin activity are mildly reduced in these
patients. 21,30,35-37 The imbalance of procoagulant and anticoagu-
lant factors can contribute hypercoagulability in critically ill pa-
tients and increase the risk of venous or arterial thromboembolic
complications with reported incidence of 5%-15%. Ischemic stroke
and limb ischemia, deep vein thrombosis, and pulmonary embo-
lism have been reported in critically ill COVID-19 patients. 21,28 As
 BELL et al.

TA B L E 3   Mapping of article types and study topics. Numbers correspond to number of articles in a given combination of article type/ study topic

Article Type

Guidance,
Comment Cross- Guideline, or
Basic Case Case Or sectional Consensus Case Meta- Observational Prospective Retrospective
Topic Research Reports Series Opinion Study Editorial Statement Image Letter Analysis Study Study Study Review

Biosafety 0 0 0 0 0 0 1 0 0 0 0 0 0 0
Clinical Features 0 18 9 3 0 0 0 1 9 2 0 2 52 7
Coagulation 0 1 1 4 0 3 2 0 12 0 0 1 5 5
Epidemiology 0 1 0 2 1 1 1 0 3 4 1 2 46 1
Hematology 0 5 1 2 0 0 1 3 7 2 0 2 8 0
Laboratory 0 0 0 2 1 0 1 0 3 4 0 2 12 7
Monitoring
Lessons and 0 2 0 3 0 1 0 0 0 0 0 0 0 0
Challenges
Molecular 0 0 0 1 0 0 0 0 0 0 0 1 0 0
Biology
Pathophysiology 0 0 1 5 0 1 0 0 2 0 1 1 0 3
Prognostics/Risk 1 0 0 1 0 0 0 0 10 4 1 5 49 9
Factors
Screening/ 0 0 0 1 0 0 2 0 0 0 0 0 1 0
Prevention
Treatment 1 0 0 1 0 0 0 0 1 0 0 0 1 0
Treatment and 0 0 1 8 0 0 3 0 9 0 0 2 2 2
Monitoring
|
      153
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154       BELL et al.

F I G U R E 2   Pie chart illustrating the coagulation testing data referenced in the studies [Colour figure can be viewed at wileyonlinelibrary.
com]

hypercoagulable condition was followed by the activation of fi-
brinolysis, significantly lower fibrinogen, and higher D-dimer, PT
and aPTT are noted in nonsurvivors than survivors. 30 High plasma
tissue type plasminogen activator (t-PA) level or elevated FDP is
also laboratory evidence of fibrinolysis in severe COVID-19 pa-
tients. Bleeding manifestations are not common in COVID-19 co-
agulopathy. Endothelial cell damage and a secondary deficiency of
ADAMTS13 related to severe inflammation can cause thrombotic
microangiopathy due to ultralarge von Willebrand factor multim-
ers. However, these findings remain to be investigated in severe
COVID-19 patients. 28 Hypercoagulability has been demonstrated
by whole blood thromboelastometry in ICU patients with acute re-
spiratory failure due to COVID-19, and the pattern shows shorter
clot formation time and higher maximum clot firmness, which
appears to be linked to massive increase in fibrinogen and fibrin
polymerization. 38 Antiphospholipid antibodies (APL), which are
important in diagnosis of antiphospholipid syndrome (APS), were
detected in a subset of critically ill COVID-19 patients. 21,37,39,40
One study reported APL in 47% (31/66) of critically ill patients.
IgA anti–β2 glycoprotein antibodies (B2GPA), IgA anticardiolipin
antibodies (ACA), and IgG B2GPA are common in decreasing order.
Interestingly, many patients with APA developed thrombotic
events, particularly cerebral infarction. It should be noted that
these antibodies can also arise transiently in patients with critical
illness and various infections. COVID-19 may trigger COVID-19-
induced-APS-like-syndrome. 39 Whether ACA or B2GPA antibodies
BELL et al.
F I G U R E 3   Pie chart illustrating the hematology testing data referenced in the studies [Colour figure can be viewed at wileyonlinelibrary.
com]
play a role in the pathophysiology of COVID-19 associated throm-
bosis remains to be clarified in larger series.40
4.3 | Automated hematology
Many studies in this review reported automated hematology data
and have established the important role of thrombocytopenia, lym-
phopenia, neutropenia, and other CBC abnormalities present at
initial presentation or during the course of treatment as potential
biomarkers associated with aggressive disease and poor outcome.
These were initially identified in early retrospective studies from
China, and data were later pooled in meta-analyses.1,6,8,10,41,42
A significant limitation of this data is that most of this informa-
tion was collected from retrospective studies as a single timepoint
|
      155
per patient and, when defined, was most often at initial presenta-
tion. We now know that automated hematology parameters may be
dynamic over the course of disease and convalescence, as reported
by many studies in this review.43-46 This implies that longitudinal
monitoring of these parameters may be significant.
The role of experimental CBC parameters and features avail-
able in the expanded CBC of many instruments has also been ex-
plored. For example, Wang et al have shown an increase of high
fluorescent lymphocytes (HFL) using the Sysmex XE-5000 blood
cell counter, compared to healthy subjects.47 Gérard et al have
found that 5%-10% of FBC from COVID-19 patients were flagged
by the blood cell counters (MO flag for the Beckman-Coulter DxH
800 and Blasts/AbnLymphs for the Sysmex X10) and required pe-
ripheral blood film assessment.48 An increased monocyte volume
distribution width has also been described using the Beckman
 |
156       BELL et al.
Coulter DxH 900 8 In only one case, a decreased myeloperoxidase
activity has been described in neutrophils and monocytes using
49
the ADVIA 2120.
Ratios between different white blood cell types or between
certain white blood cell types and platelets have been reported
as possibly useful diagnostic indicators in an extraordinary num-
ber of conditions. In COVID-19, in consideration of the frequent
combination of lymphocytopenia with neutrophilia, an increased
neutrophil-to-lymphocyte ratio has been found useful for prog-
50-54
nostic applications. Other possible indicators are the neutro-
51
phil-to-monocyte ratio and the neutrophil-to-platelet ratio.
4.4 | Cell morphology
Three types of lymphocytes with reactive morphological features
have been observed in COVID-19 patients' peripheral blood film: (a)
lymphoplasmocytoid cells, with eccentric nucleus, large deep blue
basophilic cytoplasm and, possibly, a clear paranuclear hof.1,49,55-
59
In addition, circulating plasma cells and cells with plasmablastic
features, such as immature chromatin and nucleoli,58 have been de-
scribed. (b) Reactive lymphocytes with large amounts of pale blue
48,49,58,59
cytoplasm frequently deformed by the adjacent erythro-
cytes58,59 similar to Downey type II cells of the infectious mono-
nucleosis.60 (c) Large granular lymphocytes48,49,60,61 considered a
representation of natural killer cells or cytotoxic T lymphocytes.
In addition, other peculiar lymphocyte atypical features have been
described, such as Mott cell-like lymphocytes, with prominent cy-
toplasmic inclusions, 55 apoptotic lymphocytes 49,61 pod formation,61
62
and smudge cells.
Many papers have indicated that, besides lymphocytopenia,
neutrophilia is an outstanding feature of COVID-19, especially in
patients with severe disease.1,47,49,63 Several groups have described
aspects of disorderly granulopoiesis, generally considered as asso-
ciated (as a co-cause or as an effect) with inflammation and cyto-
kine storm or, in a minority of studies, with bacterial superinfections.
Neutrophil granulocytes can have serious cytoplasmic and nuclear
dysmorphic features in patients with severe form of the disease
even at diagnosis, before any treatment.1 They include the following:
• hypergranular cytoplasm (dark, crowded, “toxic” type) 49,64
49
• presence of small basophilic, agranular cytoplasmic areas
• hypogranular cytoplasm49,65
• blue-green cytoplasmic inclusions in six patients who all died, in
neutrophils and monocytes, probably derived from lipid-rich lipo-
64
fuscin from necrotic liver cells
• nuclear hyposegmentation, sometimes with apoptotic chro-
matin,1 or C-shaped, fetus-like or ring-shaped nuclei or nuclear
detachment61
• absence of nuclear segmentation (pseudo Pelger-Huet nuclei),
with liquefied chromatin49
• apoptotic neutrophils in the circulation1,48,49; disintegrated or
smudged neutrophils57
• Myeloid left shift and immature granulocytes in peripheral blood
in the form of increased proportion of band cells,49 metamyelo-
cytes, myelocytes and promyelocytes or even blast with cytoplas-
mic granules.49,57,62
Eosinopenia has been described as frequent,66-69 but normal as
well as increased eosinophil count have also been described. Effect
of corticosteroids should be considered. In occasional patients, eo-
sinophil dysmorphism can be observed (trilobed or unsegmented
nucleus, hypogranular cytoplasm, multiple vacuoles).65
52
Monocytosis was observed frequently in patients infected with
MERS-CoV infection, caused by a coronavirus related to SARS-
CoV-2 .70 Activated monocytes have been reported as a good prog-
nostic indicator,61 while the presence of cytoplasmic blue-green
inclusions is observed in fatal cases.64
Hemophagocytosis has been described in bone marrow biopsies
in postmortem studies or on living patients.71,72
No specific red blood cell morphological anomalies have been
associated with COVID-19. In rare cases, the presence of circulating
erythroblasts has been observed on the peripheral blood film.56,62
Several authors have described the presence of large or giant
platelets in COVID-19, 49,57,65 with dysmorphic features, such as hy-
perchromatic granulomere, peripheral clear areas of different size,
and pseudopod-like protrusions.49 In patients with delayed phase
thrombocytopenia, a subset of 11.8% presented with delayed-onset
thrombocytopenia: in these cases, bone marrow aspirate showed
impaired maturation of megakaryocytes, with decreased proportion
of mature, platelet-producing megakaryocytes (less than five per
bone marrow smear).73
4.5 | Synthesis of results
One purpose of a scoping review is to provide the reader with
examples of gaps in the literature to guide future research ini-
tiatives. Our study identifies several gaps, which are illustrated
using the data mapping of the article types and their main topics.
(Table 3).
Publications specific to COVID-19 biosafety and the hematology
laboratory are distinctly lacking. Also, despite the obvious impor-
tance of laboratory hematology information in clinical management,
papers with a primary emphasis on the role of disease monitoring
and screening/ prevention are relatively few. Interestingly, although
several papers have described the dynamic changes in lymphocyte
count, platelet count, and other hematologic parameters in infected
patients, there has to date been few papers describing the role of
these or other laboratory hematology data as prognostic indica-
tors in the treatment and monitoring of disease. Finally, in view of
the role of hematology laboratory data as biomarkers of disease in
COVID-19, clinical practice guidelines and recommendations are im-
portant to provide a framework for clinicians and laboratorians to
direct patient care. To date, there have been few papers that discuss
this important issue.
BELL et al.
4.6 | Limitations
The major limitation of this study pertained to the search strategy.
Although the search was designed to be as comprehensive as pos-
sible, we may have missed very recent studies that were not indexed
by the cutoff date and studies of interest to laboratory profession-
als without the word “laboratory” in keyword, title, or abstract. A
broader search would have been impractical due to the current high
volume of the COVID-19 literature.
4.7 | Conclusions
This scoping review covers the COVID-19 literature relevant to clini-
cal hematology published between December 1, 2019, and July 3,
2020. There has been a progressive increase in published articles
over this time span which have clarified the role of coagulopathy in
the pathophysiology of severe COVID-19 infection and the use of
coagulation and automated hematology parameters as biomarkers
of disease. However, this body of literature is lacking in geographic
diversity and there are numerous knowledge gaps, which include
topics such as hematology laboratory biosafety, long-term moni-
toring of laboratory hematology data as biomarkers of outcome or
prognosis, and practice guidelines and recommendations Taking into
account the findings of the current study, researchers have a blue-
print to further progress this field.
C O N FL I C T O F I N T E R E S T
No conflict of interest has been declared by the authors.
AU T H O R C O N T R I B U T I O N S
RB wrote the manuscript, compiled data, and curated data. GZ, Gd’O,
and HJR wrote the manuscript. YL compiled data. JLF conceived and
designed the project, compiled data, and wrote the manuscript.
DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from
the corresponding author upon reasonable request.
ORCID
Gina Zini  https://orcid.org/0000-0003-0782-294X
Giuseppe d’Onofrio  https://orcid.org/0000-0003-1948-3092
Heesun J. Rogers  https://orcid.org/0000-0001-8491-224X
John L. Frater  https://orcid.org/0000-0002-4614-681X
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