Prevalence of Thrombocytopenia in COVID-19 Isolated Patients

Article information Background: Sever Acute Respiratory Syndrome Coronavirus [SARS-COV-2], a new highly transmittable coronavirus, with many variants recently appearing and spreading rapidly around the world. Aim of the Work: To find out the prevalence of thrombocytopenia in COVID-19 patients, and the association between the severity of thrombocytopenia and severity of the disease in COVID-19 patients. Patients and Methods: The current prospective study will include 300 patients with COVID-19 infection sector in Al Hussein University Hospital, Al-Azhar University, the inclusion Criteria included: Age between 18-60 years, positive nasopharyngeal swab PCR for COVID-19 RNA and isolated new-onset thrombocyte-penia, while the exclusion criteria included: history of liver cirrhosis or HCV, history of bone marrow disease or ITP, history of autoimmune disease or immunosuppressive therapy and previous treatment with platelet transfusion, danazol , or thrombopoietin receptor agonists, the eligible patients will be divided into 2 groups: group I: patients without thrombocytopenia, while group II: patients with thrombocytopenia. Results: The studied patients who developed thrombocytopenia were 95 / 300 patients [31.7%], with variable degrees of thrombocyte-penia, half of those patients with moderate thrombocytopenia died from COVID, while 5 / 15 patients [33.3%] of those who developed severe thrombocytopenia, died from COVID, with statistically significant difference, P-value= 0.01. Conclusion: Thrombocytopenia may be considered as a risk factor for mortality among patients who developed COVID infection.


INTRODUCTION
Sever Acute Respiratory Syndrome Coronavirus [SARS-COV-2], a new highly transmittable coronavirus, with many variants recently appearing and spreading rapidly around the world [1] .The virus causes a spectrum of diseases, named novel coronavirus disease 2019 [COVID-19] by the World Health Organization [WHO] [2] .
Thrombocytopenia is defined as low platelet count [less than 150 x 10 3 /L].Viral infections can be associated with thrombocytopenia duo to a variety of causes [3] , while hypo proliferative thrombocytopenia is observed at later stage of viral infection, the rapid development of thrombocytopenia in response to viral infection is generally mediated via enhanced platelet clearance/destruction [4] .
Of the patients affected by the 2003 SARS epidemic, 20 -25 % had thrombocytopenia, and these thrombocytopenic experienced greater morbidity/mortality [5] .As a coronavirus sharing 79% genomic sequence with SARS-CoV and the same cell entry receptor of angiotensin-converting enzyme II, it is possible that SARS-CoV 19 may cause thrombocytepenia in a similar way [6] .
The aim of the study is to find out the prevalence of thrombocytopenia in COVID-19 patients, and the association between the severity of thrombocytopenia and severity of the disease in COVID-19 patients.

Statistical analysis:
The numerical variables will be expressed as the mean ± standard deviation [SD].The COVID-19 severity and outcomes will be compared between all groups and statistically analyzed by the SPSS program.Categorical data were analyzed using the chi square test and the Fisher-exact test.Continuous data were analyzed by the t-test.A regression model was built for assessing various risk factors.P-value of 0.05 or less was considered as significant.
We found that elderly patients and those who developed AKI and septic shock were among the most affected patients with thrombocytopenia [table 1].
Regarding mortality, the incidence was higher among elderly patients and those with AKI, septic shock and thrombocytopenia [table 2].
The studied patients who developed thrombocytopenia were 95/300 patients [31.7%], with variable degrees of thrombocytepenia.Half of those patients with moderate thrombocytopenia died from COVID, while 5/15 patients [33.3%] of those who developed severe thrombocytopenia, died from COVID, with statistically significant difference, [P-value= 0.01].Worse degrees of thrombocytopenia were associated with higher incidence of mortality [p: < 0.05] as shown in table [3].

DISCUSSION
COVID 19 was a major healthcare devastating issue as it affected most of human beings, caused more than 6 million deaths in the period between Jan 2020 until now.Thrombocytopenia was the most common manifestation of the early epidemic of viral infection.It was observed in 20-55% of the SARS epidemic [7] .
Among COVID-19 patients, thrombotic complications become a major concern.These complications may cause thrombocytopenia which in turn may associate with disease severity [8] .Thrombocytopenia can prolong hospitalization, increase the need of ventilation, and increase patient mortality [9] .
Studying the relationship between thrombocytepenia as a prognostic factor, and the severity of disease was the aim of this work.
Our results showed that there were 15% of cases associated with moderate or severe thrombocytopenia; 80% of them died from COVID-19 complications [p value 0.001].APACHE trial showed that, a low platelet count correlates with higher disease severity scores such as Multiple Organ Dysfunction Score [MODS], Simplified Acute Physiology Score [SAPS] II, and Acute Physiology and Chronic Health Evaluation [APACHE] II [14] .
Our results showed that those patients who had serious complications of COVID-19, like AKI and septic shock, were associated with significant incidence of thrombocytopenia [p value 0.002, 0.001], respectively.Zou et al. explained that, in the severe acute respiratory syndrome [SARS] outbreak, thrombocytopenia was reported to occur in up to 55% of patients and was identified as a significant risk factor for mortality Platelet count, with hypoxemia, were the only two variables used by Zou et al. for developing a SARS prognostic model which displayed 96.2% accuracy [5] .
In our study, mortality from COVID-19, were prominent with elderly [OR: 0.3; P:0.001], thrombocytopenia [OR: 0.6; P: 0.004], AKI [OR: 0.3; P: 0.001], and septic shock [OR: 0.3; P: 0.002].Other studies also supported this finding.Jin et al. [15] reported that platelets were correlated with COVID-19 disease severity.Sayad et al. [12] study was also reported that thrombocytopenia could be important indicator of severe COVID-19 which might associate with mortality.According to the systematic review and Meta-analysis reported by Lippi et al. [16] , thrombocytopenia increased the risk of disease severity more than five times more likely.
Because platelets play a major role in thrombogenesis, an increased platelet activation will lead to platelet aggregation and platelet spreading, which will lead to thrombosis in COVID-19.It has been shown that the incidence of thromboembolic events in severe patients and non-survivors is much higher than non-severe patients and survivors [17] .
Early detection and timely thromboprophylaxis can lower the incidence of thrombosis.Zhang et al. [20] demonstrated that thromboprophylaxis halved the incidence of deep-vein thrombosis in patients with COVID-19, with the Padua prediction scores being 4 or higher.
The explanation for thrombocytopenia in COVID-19, were enrolled in multi-centric trials, we can assume that thrombocytopenia may develop by platelets destruction, platelets consumption or bone marrow depression.In viral infection and inflammation which lead to lung damage.Damaged lung tissues and pulmonary endothelial cells may activate platelets in the lungs, resulting in aggregation and formation of microthrombi, which increases platelet consumption.Most patients with COVID-19 who have had thrombocytopenia, have elevated D-dimer levels and impaired coagulation time [21] .COVID-19 may increase levels of autoantibodies and immune complexes, resulting in specific destruction of platelets by the immune system.A study reported that the phenomenon of immune-mediated thrombocytepenia in patients infected with HIV-1 is widespread [22] .Coronaviruses are also able to infect bone marrow cells, resulting in abnormal hematopoiesis [23] .
The age factor was a dependent risk factor for thrombocytopenia incidence, as by using univariate and multi-variate analysis, there was a statistically significant difference as regard the age.We noticed that elderly have had a higher incidence of thrombocytopenia, [OR: 1.2; P: 0.001], it's not related to comorbidities as we found in this work, since there was no statistically significant difference as regards chronic comorbidities both groups who developed thrombocytopenia, or not developed.
Consideration of thrombocytopenia to be a prognostic factor for mortality related to COVID 19, not due to bleeding, as there was no history of bleeding, reported in COVID-19 patients during hospitalization.Bikdeli et al. [24] reported that the frequency of bleeding events was 0 in 35 COVID-19 patients who suffered from a prolonged activated partial-thromboplastin time [aPTT].
Our results also showed that elevated PDW was significantly associated with disease severity [P-value = 0.001].Platelet distribution width reflects the variation in the size of platelets.It increases when platelets destruction increases and when the new large immature platelet production raises for compensation.A study conducted by Bhandary et al. [25] also showed that PDW was significantly associated with disease severity and it was higher in severe cases.
Tire et al. [26] also revealed that PDW had a statistical difference between outpatients, patients who received standard treatment in the hospital and patients who had to be connected to a mechanical ventilator [ICU patients].
Another COVID-19 related issue is emerging to be cause of thrombocytopenia in the patients, COVID vaccines, emerging data has suggested that thrombocytopenia events may likely occur unevenly across the three COVID-19 vaccines, with higher events among vaccinated persons with the Oxford-AstraZeneca vaccine relative to the Pfizer BioNTech vaccine, but further data is needed [27] .

Conclusion:
Thrombocytopenia is frequent among patients with COVID-19 and linked to increased mortality.Mortality is increased with the severity of thrombocytopenia.

Table [ 3
]: Relation between thrombocytopenia grades and mortality