Hematologic Complications in Patients Hospitalized With COVID 19 Infection
Hematologic Complications in Patients Hospitalized With COVID 19 Infection
Hematologic Complications in Patients Hospitalized With COVID 19 Infection
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75019, USA;
elisa.lin@utsw.edu (E.L.); ellen.araj@utsw.edu (E.A.); john.markantonis@utsw.edu (J.M.);
hung.luu@utsw.edu (H.L.)
* Correspondence: mingyi.chen@utsw.edu; Tel.: +1-214-648-4791
Abstract: Introduction: This review summarizes data from patients with COVID-19 requiring in-
tensive care unit (ICU) admission. The goals of this study are to showcase some morphological
anomalies found in peripheral blood smears from COVID-19 patients and to bring attention to how
some hematologic abnormalities in COVID-19 that correspond to disease severity and mortality.
Methods: We performed a retrospective analysis of hematologic parameters using peripheral blood
smear analysis from 31 COVID-19 patients hospitalized between April 2021 and January 2022. Results:
We found abnormal morphology that has not been previously reported. We also report that severe
lymphopenia, neutrophilia, acute hemolysis, hematologic malignancies, and increased LDH are
associated with ICU admissions, respiratory failure requiring intubation, and poor clinical outcome.
Conclusion: We propose these recommendations in the management of COVID-19 patients: 1. Early
diagnosis and follow-up of DIC; 2. Optimization of thromboprophylaxis regimen.
3. Results
3.1. Morphological Anomalies in Peripheral Blood Smears from COVID-19 Patients
The morphological abnormalities we found included nuclear and cytoplasmic gran-
ulations (Figures 1 and 2). In particular, we observed many crowded, dark granulations
in the cytoplasm (similar to “toxic” granules) and peripheral light blue agranular areas
(Figures 1 and 2). A few cases had many hypogranular cells (Figure 1). The abnormalities
in nuclear shape included increased frequency, not only of band forms, but also dysmor-
phic cells with the total absence of nuclear segmentation, consistent with pseudo-Pelger
morphology (Figure 2).
Apoptotic cells were frequently found with either liquefied, granulated nuclear chro-
matin, or deep blue cytoplasm; they may have been derived from different cell types (i.e.,
neutrophils and lymphocytes, respectively). Immature granulocytes, especially small mye-
locytes and metamyelocytes, were also frequently present in early-phase cases, sometimes
with small azurophilic granules (Figure 1). Typical features included normocytic anemia
with increased polychromasia, circulating nucleated RBCs, basophilic stippling, left-shifted
granulocytes with toxic granulations, lymphopenia, and thrombocytopenia (Figure 1).
Hematol.
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Rep. 2022,
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PEER REVIEW
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Hematol. Rep. 2022, 14 230
Figure1.
Figure
Figure Peripheralblood
1.1.Peripheral
Peripheral blood smear
blood smear analysis
smear analysis showing
showingincreased
showing increasedrouleaux
increased rouleauxformation,
rouleaux formation,
formation, normocytic
normocytic
normocytic anemia
ane-
ane-
withwith
mia
mia increased
with polychromasia,
increased
increased nucleated
polychromasia,
polychromasia, red blood
nucleated
nucleated red cells, cells,
red blood
blood basophilic stippling,
cells, basophilic
basophilic left-shifted
stippling,
stippling, granulocytes
left-shifted
left-shifted gran-
gran-
ulocytes
with toxic
ulocytes with toxic
toxic granulations,
granulations,
with lymphopenia,
lymphopenia,
granulations, and
and thrombocytopenia.
and thrombocytopenia.
lymphopenia, thrombocytopenia.
Figure 2.Peripheral
Figure 100× magnificationshowing
Peripheral smearatat100× showing a nucleatederythroid,
erythroid, a rareblast
blast with
Figure 2.
2. Peripheral smear
smear at 100× magnification
magnification showing aa nucleated
nucleated erythroid, aa rare
rare blast with
with
prominent
prominent nucleoli and immature chromatin pattern, a left-shifted myeloid series with immature
prominent nucleoli
nucleoli and
and immature
immature chromatin
chromatin pattern,
pattern, aa left-shifted
left-shifted myeloid
myeloid series
series with
with immature
immature
promyelocytesand
promyelocytes
promyelocytes andmetamyelocytes,
and metamyelocytes,and
metamyelocytes, andoccasional
and occasionalmonocytes.
occasional monocytes.
monocytes.
Peripheral blood
Apoptotic × magnification
smears at 100found often showed nucleated erythroids,
Apoptotic cells
cells were
were frequently
frequently found with
with either
either liquefied,
liquefied, granulated
granulated nuclear
nuclear chro-
chro-
rare
matin,blasts with prominent nucleoli and immature chromatin pattern, left-shifted myeloid
matin, or deep blue cytoplasm; they may have been derived from different cell types
or deep blue cytoplasm; they may have been derived from different cell types (i.e.,
(i.e.,
series with immature
neutrophils promyelocytes and metamyelocytes, and occasional monocytes
neutrophils and
and lymphocytes,
lymphocytes, respectively).
respectively). Immature
Immature granulocytes,
granulocytes, especially
especially small
small
(Figure 2).
myelocytes
myelocytes and
and metamyelocytes,
metamyelocytes, were
were also
also frequently
frequently present
present in
in early-phase
early-phase cases,
cases, some-
some-
times
times with
with small
small azurophilic
azurophilic granules
granules (Figure
(Figure 1).
1). Typical
Typical features
features included
included normocytic
normocytic
anemia
anemia with
with increased
increased polychromasia,
polychromasia, circulating
circulating nucleated
nucleated RBCs,
RBCs, basophilic
basophilic stippling,
stippling,
Hematol. Rep. 2022, 14 231
4. Discussion
4.1. Hematologic Abnormalities in COVID-19 Are Related to Disease Progression, Severity,
and Mortality
Many cases of severe COVID-19 have been characterized by dysregulated inflamma-
tion and coagulation activation [2]. Pro-inflammatory cytokine secretion, microangiopathic
vasculopathy, and B-cell secretion of specific SARS-CoV-2 antibodies in infected cells are
induced by the SARS-CoV-2 S (spike) protein binding to ACE2 receptors in epithelial
cells of the respiratory tract [9]. In particular, COVID-19 disease with marked hematologic
abnormalities exhibit a characteristic pattern, similar to a “cytokine storm”, in which inflam-
matory markers and cytokines dramatically increase and significant lymphopenia develops.
Furthermore, hypercoagulability is common in hospitalized COVID-19 patients [6,10].
Coagulation abnormalities such as prolonged PT and PTT, increased fibrin degradation
products, and severe thrombocytopenia can lead to disseminated intravascular coagula-
tion (DIC), which is life-threatening and necessitates continuous vigilance and prompt
intervention [10–13]. Both thrombotic and hemorrhagic pathologies should be noted in
these patients, as well as macro- and microthrombosis [13]. Three mechanisms have been
proposed to lead to thrombocytopenia in COVID-19 patients. The first is a decrease in
platelet production due to myelosuppression either from SARS-CoV-2 or from therapy.
Hematol. Rep. 2022, 14 232
The second mechanism is direct platelet destruction by the immune system. The last
mechanism purports that platelet aggregration in the lungs results in microthrombi and
therefore platelet consumption [4,14]. However, thrombocytosis has also been recorded in
patients with COVID-19; it is proposed that some concurrent early-stage bacterial infections
may induce neutrophilia, left-shifted granulocytes, and secondary thrombocytosis [15].
Therefore, COVID diagnosis and disease severity must be determined early so extended
pharmacological thromboprophylaxis with low-molecular-weight heparin (LMWH) regi-
men can be started early in the disease course. By doing so, appropriate management can
be planned before at-risk patients develop organ failure or shock [2].
5. Conclusions
Based on
on our
ourclinical
clinicalobservations
observationsand a series
and of studies,
a series we found
of studies, that severe
we found lym-
that severe
phopenia (<1.3(<1.3
lymphopenia × 10 ×
9 9
/L),10neutrophilia with left-shifted
/L), neutrophilia granulocytes
with left-shifted (>5 × 10(>5
granulocytes 9 9
/L),×acute he-
10 /L),
molysis,
acute HMs, increased
hemolysis, LDH (>225
HMs, increased LDHu/L), andu/L),
(>225 abnormal morphology
and abnormal are usually
morphology observed
are usually
in patients
observed inadmitted to the ICU
patients admitted whoICU
to the have
whorespiratory failure failure
have respiratory requiring intubation,
requiring acute
intubation,
renal failure,
acute and poor
renal failure, and clinical outcome
poor clinical (Figure
outcome 3). These
(Figure findings
3). These were were
findings consistent with
consistent
our literature
with review.
our literature This This
review. should prompt
should providers
prompt to intervene
providers earlyearly
to intervene to improve out-
to improve
outcomes.
comes.
Figure 3.
Figure 3. Summary
Summary of
ofhematologic
hematologiccomplications
complicationsobserved
observedininpatients
patientshospitalized
hospitalizedwith
withCOVID-19
COVID-
infection.
19 infection.
In light
In light of
of these
these findings,
findings, we
we propose
propose two
two important
important additional
additional recommendations
recommendations in
in
the management
the management of of future
future COVID-19
COVID-19 patients:
patients:
1. Early diagnosis and follow-up of DIC by applying the ISTH score, which can deter-
1. Early diagnosis and follow-up of DIC by applying the ISTH score, which can deter-
mine prognosis and guide appropriate critical care support.
mine prognosis and guide appropriate critical care support.
2. Optimization of thromboprophylaxis regimen with LMWH as first-line drug.
2. Optimization of thromboprophylaxis regimen with LMWH as first-line drug.
Author
Author Contributions: M.C.and
Contributions: M.C. andH.L.
H.L.designed
designedthethe study.
study. E.L.E.L. collected
collected rawraw
datadata of study,
of the the study,
car-
carried
ried out data analysis, graphing, and illustration. The first manuscript was written and revised by
out data analysis, graphing, and illustration. The first manuscript was written and revised by
E.L.
E.L. and
and M.C.;
M.C.; E.A.
E.A. and
and J.M.
J.M. provided
provided MRNs
MRNs for for patients who had
patients who had been
been inin the
the ICU
ICU for
for COVID-19.
COVID-19.
All
All authors
authors have
have read
read and
and agreed
agreed to
to the
the published
publishedversion
versionofofthe
themanuscript.
manuscript.
Funding: No
Funding: No funding
funding support
support was
was needed
needed for
for this
this study.
study.
Institutional
Institutional Review
Review Board Statement:The
BoardStatement: Thestudy
studywas
wasconducted
conducted inin
accordance with
accordance thethe
with Declaration
Declara-
of Helsinki,
tion and approved
of Helsinki, by theby
and approved Institutional Review
the Institutional Board Board
Review of the University of Texas
of the University ofSouthwestern
Texas South-
Medical
western Center
Medical(STU 122013-023).
Center (STU 122013-023).
Informed
Informed Consent Statement: The
Consent Statement: Thepatient
patientconsent
consentrequirement was
requirement waived
was by by
waived thethe
IRBIRB
as the patient
as the pa-
identifiers were decoded.
tient identifiers were decoded.
Data
Data Availability Statement: Data
Availability Statement: Data available
available on
on request
request from
from the
the authors.
authors.
Acknowledgments: The
Acknowledgments: The authors
authors would
would like
like to
to acknowledge
acknowledge Alagar
Alagar R.
R. Muthukumar
Muthukumar for
for his
his help
help in
in
providing
providing data
data for
for this
this study.
study.
Conflicts
Conflicts of Interest: The
of Interest: The authors
authors declare
declare no
noconflict
conflictof
ofinterest.
interest.
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