Keywords
COVID-19 - pregnancy - platelet indices - mean platelet volume - platelet distribution
width
Palavras-chave
COVID-19 - gravidez - índices de plaquetas - volume médio de plaquetas - largura de
distribuição de plaquetas
Introduction
Coronavirus disease 2019 (COVID-19), first described in Wuhan, China, is associated
with a rapid inflammatory process and respiratory ailments. The hematological aspects
of this infection have also drawn concern, with thrombotic events taking centre stage,
showing a distinct concurrent coagulation disorder.[1] The reasons behind this are raised D-dimer, mild thrombocytopenia, and elongated
activated partial thromboplastin time.[2] Evidence has shown that platelets are crucial players in promoting inflammation,
remodeling, and tissue repair. The role of platelets in viral infection-mediated thrombosis
has already been discussed.[3]
[4] However, the role of platelets in COVID-19 remains ambiguous. Since the platelets
do not express the SARS-CoV-2 binding receptor (angiotensin-converting enzyme 2, ACE2),
how does the virus interact with the platelets and alter their function? Besides,
COVID-19 is characterized by significant inflammation, but reactive thrombocytosis
has not been documented. Mild thrombocytopenia is frequently present, and it is a
poor prognostic sign.[5]
[6] Endothelial damage, which is the hallmark of COVID-19 disease, releases the main
platelet agonists, sending the platelets into overdrive and altering their morphology
and function, which is the justifiable answer for the concerns previously mentioned.[7] Because of the urgent need to recognize the related thrombotic symptoms and the
clinical use of impaired coagulation tests to predict the risk and severity of the
affection, the present study aims to describe the hematological changes, specially
regarding the platelet indices, in pregnant women with confirmed COVID-19, to be included
in the catalogue-pathy panel for this disease. The innovative side of the present
study is its focus on platelet indices in cases of COVID-19 versus controls to support
the underlying pathogenesis for the established high risk of thromboembolism associated
with this infection, even in asymptomatic cases.
Methods
A retrospective case-control study was conducted at Al Yarmouk Teaching Hospital,
in Baghdad, Iraq, a tertiary referral hospital with an average of 400 to 600 deliveries
per month. The study involved a 100 pregnant women, 50 with confirmed COVID-19 infection
(case group), who attended the hospital antenatally, and 50 pregnant women without
COVID-19 (control group), who were diagnosed during routine screening and enrolled
over the 4 months of the study, from June 1st to October 1st, 2020. We tested both
groups for hematological parameters to analyze the blood changes caused by COVID-19.
The medical committee of the College of Medicine of Mustansiriyah University approved
the present study (under MOG 114) in July 2020. Informed written consent was obtained
from all participants.
All pregnant women who attended the hospital during the study period were preliminarily
screened for COVID-19, with a focus on the disease's symptomatology and the patients'
history of contact with affected individuals; a detailed clinical examination with
all precautions issued by local authorities regarding personal protective equipment
was performed. We took throat and nasal swabs of all admitted cases, and tested them
for SARS-CoV-2 antigen through the real-time polymerase chain reaction (RT-PCR). The
enrolled pregnant women were in the third trimester of pregnancy, and both study groups
were matched regarding age, body mass index (BMI). The exclusion criteria were co-morbidities
such as preeclampsia and rheumatological diseases, as well as other infections, because
they affect hematological variables. A critical case ended with maternal death was
excluded to eliminate the statistical bias associated with her extreme laboratory
investigation results. [Figure 1] shows the flowchart of the study sample.
Fig. 1 Flowchart of study sample.
The sample underwent a complete blood count, including: hemoglobin, total white blood
cells (with a differential count of lymphocytes and neutrophils), platelets and their
parameters namely the mean platelet volume (MPV) and the platelet distribution width
(PDW); the ratios of platelets to lymphocytes and of neutrophils to lymphocytes were
assessed and compared between the two groups. We recorded the neonatal birth weight
after delivery.
For the statistical analyses, we used the Statistical Package for the Social Sciences
(IBM SPSS Statistics, IBM Corp., Armonk, NY, US) software, version 24. The data were
expressed as means ± standard deviations/standard errors of the mean. We compare the
means of the normally-distributed data by The Student t-test. The ROC curve estimated the cutoff point for the significant parameters (MPV
and PDW). We set a significant difference when p < 0.05.
Results
The demographics of the sample are described in [Table 1]. However, a trend was noticed for the mean gestational age and neonatal birth weight,
36.53 weeks versus 37.5 weeks and 2.65 kg versus 2.86 kg for cases and controls respectively;
still, none of the parameters presented a statistically significant difference.
Table 1
Demographics of the study groups
|
Parameter
|
Case group; N = 50 (mean ± SD/SE)
|
Control group; N = 50 (mean ± SD/SE)
|
p-value
|
|
Maternal age (years)
|
27.14 ± 7.75/1.1
|
27.33 ± 3.79/0.69
|
0.9
|
|
Gestational age (weeks)
|
36.53 ± 2.71/0.38
|
37.5 ± 3.2/0.59
|
0.15
|
|
Body mass index (Kg/m2)
|
26.61 ± 3.4/0.37
|
28.45 ± 4.8/0.86
|
0.98
|
|
Neonatal weight (Kg)
|
2.65 ± 0.61/0.08
|
2.86 ± 0.56/0.1
|
0.13
|
Abbreviations: SD, standard deviation; SE, standard error of the mean.
[Table 2] shows the main hematological variables of both groups, and only the platelet indices
presented a statistically significant difference: the MPV was of 10.87 ± 66.92 fL
in the case group versus 9.84 ± 1.2 fL in the control group, and the PDW was of 14.82 ± 3.18
fL in the case group versus 13.3 ± 2.16 fL in the control group.
Table 2
Comparison of hematological parameters between the study groups
|
Parameter
|
Case group; N = 50 (mean ± SD/SE)
|
Control group; N = 50 (mean ± SD/SE)
|
p-value
|
|
Hemoglobin (gm/dl)
|
11.23 ± 1.54/0.18
|
11.74 ± 1.3/0.24
|
0.96
|
|
White blood cells (109/L)
|
11.1 ± 3.78/0.69
|
11.97 ± 4.93/0.7
|
0.41
|
|
Neutrophil count (109/L)
|
7.29 ± 3.71/0.53
|
8.13 ± 3.68/0.67
|
0.32
|
|
Lymphocyte count (109/L)
|
2.08 ± 0.49/0.9
|
2.15 ± 0.93/0.13
|
0.71
|
|
Platelet count (109/L)
|
204.24 ± 66.92/9.56
|
215.13 ± 54.4/9.9
|
0.45
|
|
Mean platelet volume (fL)
|
10.87 ± 66.92/9.56
|
9.84 ± 1.2/0.21
|
0.002*
|
|
Platelet distribution width (fL)
|
14.82 ± 3.18/0.46
|
13.3 ± 2.16/0.39
|
0.024*
|
|
Platelet/lymphocyte ratio
|
110.35 ± 53.21/7.6
|
107.13 ± 30.79/5.62
|
0.76
|
|
Neutrophil/lymphocyte ratio**
|
4.14 ± 3/0.42
|
4.19 ± 2.67/0.48
|
0.93
|
Abbreviations: SD, standard deviation; SE, standard error of the mean.
Note: *Statistically significant difference (p < 0.05);
[Figure 2] shows the cutoff value for the PDW (11.8 fL), which was associated with the highest
sensitivity (75.5%) and specificity (10%) (95% confidence interval [95%CI]: 0.51–0.73;
p < 0.05). The area under the curve (AUC) was of 0.627, showing a weak diagnostic marker.
Fig. 2 Receiver operating characteristic (ROC) curve for platelet distribution width (PDW).
[Figure 3] shows the cutoff value for the MPV (10.17 fL), which had a sensitivity of 69.4%
and a specificity of 73% (95%CI: 0.59–0.80; p < 0.05). The AUC was of 0.71, showing an excellent diagnostic marker.
Fig. 3 Receiver operating characteristic (ROC) Curve for mean platelet volume (MPV).
Discussion
The novel coronavirus has caused serious concerns worldwide, specially regarding its
impact on pregnancy and newborn safety.[8]
[9] The participants' demographics were in line with those described by London et al.[10] regarding maternal age and BMI, as their study included cases of at-term pregnant
women who tested positive for COVID-19 and were divided into symptomatic and asymptomatic
cases, with no statistical differences between the two groups.
Li et al.[11] analyzed the birth weight of COVID-19 cases versus controls, and showed no significant
differences. We can understand this if we recall that all of our participants were
mild to moderate cases. Severe cases and cases with pregnancy co-morbidities were
excluded from the study by Schwartz et al.[12] The hematological results of the present study were in line with those of the study
by Li et al.,[11] with no statistically significant difference regarding white blood cells and lymphocytes,
and contradicting reports of lymphopenia and leucopenia in hospitalized COVID-19 cases.[13]
In the present study, the case group showed a reduced neutrophil count, which is in
agreement with the studies by Wang et al.[14] and Manne et al.[15] Derangements in coagulation cascade, such as increased D-dimer, altered fibrinogen
level, and platelet level, play a role in thrombotic events in COVID-19.[16]
[17]
Thrombocytopenia secondary to COVID-19 showed a better outcome compared to the outcomes
of other more life-threatening viral infections, such as sever cases of influenza,
dengue fever, and SARS-CoV-1 infection.[17]
[18]
[19]
[20] Still, it is unclear whether COVID-19 alters the function of the platelets.[20] We verified significant differences between cases and controls regarding platelet
parameters in the current study, with the possibility that they play a role in the
raised risk of developing thrombosis, which is in line with the findings of the study
by Manne et al.[15] The platelet indices in reaction to viral infections were previously assessed in
patients with dengue fever in Sudan.[21] Dengue fever showed multiple similarities with COVID-19 regarding seroconversion
and the development of immunity. The researchers reported that a low platelet count
and MPV, as well as a rising PDW, were good predictors for cases of dengue fevers
with a cutoff value less than 9 fl for the MPV and more than 13 fl for PDW; both showed
a considerable sensitivity for dengue fever diagnosis.[21]
The PDW has been described in the thrombocytosis setting as an indicator of a reactive
process, while the MPV mostly unravels the etiology of thrombocytopenia. Identify
the risk of developing thrombosis for patients with the ischemic syndrome, and predict
the bad outcome after that. Obstetrics had its share of the clinical implications
of these parameters', including predicting gestational diabetes, preeclampsia, and
adverse neonatal outcomes in high-risk pregnancies.[22]
The strength of the present study is that it addresses platelet indices and correlates
them with COVID-19 infection as valuable markers to be added to the already-described
investigations for the COVID-19 diagnostic panel. Moreover, the present study has
a good sample size compared to earlier reports which had shortcomings in sampling
and analysis. The limitations are the lack of an analysis of severe and critical cases,
and of the impact of altered platelet parameters on maternal and fetal outcomes.
Conclusion
The MPV and PDW showed significant changes with the COVID-19 infection, even in asymptomatic
confirmed cases, and we recommend both parameters to be included in the diagnostic
panel of this infection.
