key: cord-0743485-10phij1x
authors: Terpos, Evangelos; Ntanasis‐Stathopoulos, Ioannis; Elalamy, Ismail; Kastritis, Efstathios; Sergentanis, Theodoros N.; Politou, Marianna; Psaltopoulou, Theodora; Gerotziafas, Grigoris; Dimopoulos, Meletios A.
title: Hematological findings and complications of COVID‐19
date: 2020-05-23
journal: Am J Hematol
DOI: 10.1002/ajh.25829
sha: b1212c0df1f8e55d19126c16a6a9ad9e61d97045
doc_id: 743485
cord_uid: 10phij1x

COVID‐19 is a systemic infection with a significant impact on the hematopoietic system and hemostasis. Lymphopenia may be considered as a cardinal laboratory finding, with prognostic potential. Neutrophil/lymphocyte ratio and peak platelet/lymphocyte ratio may also have prognostic value in determining severe cases. During the disease course, longitudinal evaluation of lymphocyte count dynamics and inflammatory indices, including LDH, CRP and IL‐6 may help to identify cases with dismal prognosis and prompt intervention in order to improve outcomes. Biomarkers, such high serum procalcitonin and ferritin have also emerged as poor prognostic factors. Furthermore, blood hypercoagulability is common among hospitalized COVID‐19 patients. Elevated D‐Dimer levels are consistently reported, whereas their gradual increase during disease course is particularly associated with disease worsening. Other coagulation abnormalities such as PT and aPTT prolongation, fibrin degradation products increase, with severe thrombocytopenia lead to life‐threatening disseminated intravascular coagulation (DIC), which necessitates continuous vigilance and prompt intervention. So, COVID‐19 infected patients, whether hospitalized or ambulatory, are at high risk for venous thromboembolism, and an early and prolonged pharmacological thromboprophylaxis with low molecular weight heparin is highly recommended. Last but not least, the need for assuring blood donations during the pandemic is also highlighted.

receptor. 1 Although it is well documented that COVID-19 is primarily manifested as a respiratory tract infection, emerging data indicate that it should be regarded as a systemic disease involving multiple systems, including cardiovascular, respiratory, gastrointestinal, neurological, hematopoietic and immune system. [2] [3] [4] Mortality rates of COVID-19 are lower than SARS and Middle East Respiratory Syndrome (MERS) 5 ; however, COVID-19 is more lethal than seasonal flu. Older people and those with comorbidities are at increased risk of death from COVID-19, but younger people without major underlying diseases may also present with potentially lethal complications such as fulminant myocarditis and disseminated intravascular coagulopathy (DIC). 6, 7 Herein, we summarize the numerous hematologic findings and complications of COVID-19 and we provide guidance for early prevention and management of the latter. 

During the incubation period, usually ranging from 1 to 14 days, and during the early phase of the disease, when non-specific symptoms are present, peripheral blood leukocyte and lymphocyte counts are normal or slightly reduced. Following viremia, SARS-CoV-2 primarily affects the tissues expressing high levels of ACE2 including the lungs, heart and gastrointestinal tract. Approximately 7 to 14 days from the onset of the initial symptoms, there is a surge in the clinical manifestations of the disease. This is with a pronounced systemic increase of inflammatory mediators and cytokines, which may even be characterized as a "cytokine storm." 8 At this point, significant lymphopenia becomes evident. Although more in-depth research on the underlying etiology is necessary, several factors may contribute to COVID-19 associated lymphopenia. It has been shown that lymphocytes express the ACE2 receptor on their surface 9 ; thus SARS-CoV-2 may directly infect those cells and ultimately lead to their lysis. Furthermore, the cytokine storm is characterized by markedly increased levels of interleukins (mostly IL-6, IL-2, IL-7, granulocyte colony stimulating factor, interferon-γ inducible protein 10, MCP-1, MIP1-a) and tumor necrosis factor (TNF)-alpha, which may promote lymphocyte apoptosis. [10] [11] [12] Substantial cytokine activation may be also associated with atrophy of lymphoid organs, including the spleen, and further impairs lymphocyte turnover. 13 Coexisting lactic acid acidosis, which may be more prominent among cancer patients who are at increased risk for complications from COVID-19, 14 may also inhibit lymphocyte proliferation. 15 20 Increased risk of ARDS during the disease course was significantly associated with increased neutrophils (P < .001), decreased lymphocytes (P < .001) in a bivariate Cox regression analysis.

Increased neutrophils (P = .03) were associated with increased risk of death. 20 Furthermore, lymphopenia and was also documented in approximately 40% of the first 18 hospitalized patients with COVID-19 in Singapore. 21 A more recent report on 69 patients confirmed the percentage of those with lymphocytopenia, whereas 20% had mild thrombocytopenia. 22 Interestingly, 69% of patients with a low lymphocyte count showed a reactive lymphocyte population including a lymphoplasmacytoid subset, which was not common in the peripheral blood of patients with SARS infection in 2003. [22] [23] [24] Flow cytometry did not reveal any inversion in the CD4+/CD8+ lymphocyte ratio. 22 However, functional studies have suggested that SARS-CoV-2 may impair the function of CD4+ helper and regulatory T-cells and promote the initial hyperactivation which is followed by rapid exhaustion of cytotoxic CD8+ T-cells. 25, 26 In Singapore, Fan et al. also found that patients requiring ICU support had significantly lower lymphocyte levels (P < .001) at baseline. 22 In another retrospective study including 52 critically ill patients from Wuhan, China, lymphopenia was reported in 85% of patients. 27 Lymphopenia was also prominent among critically ill patients with COVID-19 in Washington, USA. 28, 29 During hospitalization, nonsurvivors demonstrated a more significant deterioration in lymphopenia compared with those who survived (P < .05). 19 It has also been reported that patients with severe disease and fatal outcomes present with a decreased lymphocyte/white blood cell ratio both in admission (P < .001) and during hospitalization (P < .001) compared with those who survived. 26, 30 Contrary to non-survivors, survivors demonstrated a nadir of lymphocytes counted on day 7 from symptom onset and a subsequent restoration. 31 Therefore, serial assessment of lymphocyte count dynamics may be predictive of patient outcome. Tan et al have proposed a model based on lymphocyte counts at two time points; patients with less than 20% lymphocytes at days 10-12 from the onset of symptoms, and less than 5% at days 17-19 have the worst prognosis. 32 Recent studies have shown that myocardial injury among inpatients with COVID-19 is associated with increased mortality. 33, 34 In a prospective study in Wuhan, China including 416 consecutive patients 82 (19.7%) had documented myocardial injury. Compared with the others, these patients with myocardial injury had higher leukocyte (P < .001), lower lymphocyte (P < .001) and lower platelet counts (P < .001). 33 A retrospective study including 187 patients with COVID-19 from another hospital in Wuhan showed that patients with high troponin-T levels had leukocytosis (P < .001), increased neutrophils (P < .001) and decreased lymphocytes (P = .01). 34 A meta-analysis of nine studies has suggested that thrombocytopenia is significantly associated with the severity of the COVID-19 disease, with very high between-studies heterogeneity though; a more sizeable drop in platelet counts was noted especially in non-survivors. 35 Table 2 shows the results of main studies examining platelet counts in COVID-19 disease.

Interestingly, Qu et al showed that among 30 hospitalized patients with COVID-19, those presenting with a peak in the platelet count during the disease course had worse outcomes. 36 Interestingly, the platelet to lymphocyte ratio at the time of platelet peak emerged as an independent prognostic factor for prolonged hospitalization in the multivariate analysis. It was suggested that a high platelet to lymphocyte ratio may indicate a more pronounced cytokine storm, due to enhanced platelet activation. 36 2.2 | The emerging role of biomarkers procalcitonin, ferritin and C-reactive protein in the prognosis 

Coagulation disorders are relatively frequently encountered among COVID-19 patients, especially among those with severe disease. 30, 31 In a multicenter retrospective study during the first 2 months of the epidemic in China, 260 out of 560 patients (46.4%) with laboratory confirmed COVID-19 infection had elevated D-dimer (≥0.5 mg/L).

whereas And, the elevation was more pronounced among severe cases (59.6% vs 43.2% for non-severe ones). 16 The D-dimer dynamics can reflect the severity and their increased levels are associated with adverse outcomes among patients with community-acquired pneumonia. 38 Patients presenting with cardiac injury in the context of COVID-19 infection are more prone to coagulation disorders compared with those without cardiac involvement (P = .02). 33 Patients with high troponin-T levels may present more frequently with elevated PT (P = .005), activated partial thromboplastin time (APTT) (P = .003), and D-dimer (P < .001). 34 AMong 201 patients with COVID-19 pneumonia, increased PT was associated with increased risk of ARDS (P < .001), whereas increased levels of D-dimer were significantly associated with increased risk of ARDS (P < .001) and death (P = .002). 20 The difference in median levels of D-dimer between survivors and non-survivors was larger than that between the ARDS and non-ARDS groups, which might suggest that DIC-related complications may have led a subset of patients to death independently of ARDS. In a multicenter retrospective cohort study from China, increased D-dimer levels (>1 μg/mL) were significantly associated with in-hospital death in the multivariable analysis (P = .003). 31 Interestingly, The D-dimer levels showed a sequential increase in time among non-survivors compared with those who survived (P < .05). 19, 31 In another retrospective study by Tang et al, encompassing data from 183 consecutive patients with COVID-19, non-survivors had significantly higher D-dimer (P < .05), fibrin degradation products (FDP) levels (P < .05), and prolonged PT (P < .05) and APTT (P < .05) compared with survivors at initial evaluation. By the late hospitalization, the fibrinogen and AT levels were also significantly lower in nonsurvivors. 6 thrombomodulin that may be also helpful in this complex "immunothrombosis" process.

Last but not least, it is of outmost importance to consider the impact of the COVID-19 pandemic on the availability of blood products. Worldwide, insecurity and anxiety of being infected by SARS-CoV-2 along with measures of social isolation largely prevent blood donations. 49 Similarly, the pandemic crisis may hinder the donation of hematopoietic stem cells, as well. 50 However, the need for stem cell donors will remain constant and the need for blood donor will probably increase in order to support the critically ill COVID-19 patients. Therefore, the authorities should reformulate the infrastructure and apply all necessary safety precautions to prevent viral transmission. Effective public awareness campaigns on the importance of maintaining an adequate national blood supply, need for blood donors, and safety of the donation process should be disseminated continuously. 51 Furthermore, they should inform and educate the younger about the priceless role of blood donation and the life-saving value of hematopoietic stem cell donation. All of us should become aware of our collective responsibility and contribute to the well-being of the members of our society.

In conclusion, COVID-19 disease has prominent manifestations from the hematopoietic system and is often associated with a major blood hypercoagulability. Careful evaluation of laboratory indices at baseline and during the disease course can assist clinicians in formulating a tailored treatment approach and promptly provide intensive care to those who are in greater need. Preventive measures for thromboprophylaxis and early identification of potentially lethal complications including DIC in order to effectively intervene will improve patient outcomes, and will probably reduce the death rate overall and among infected patients without significant comorbidities. Continuous vigilance is necessary and urgent studies have to be planned to define whether optimal anticoagulation regimen with or without adjunctive antithrombotic therapies (eg, LMWH, antithrombin or thrombomodulin) may be helpful in patients with COVID-19.

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How to cite this article: Terpos E, Ntanasis-Stathopoulos I

Hematological findings and complications of COVID-19

No relevant conflict of interest to declare.

https://orcid.org/0000-0001-5133-1422Ioannis Ntanasis-Stathopoulos https://orcid.org/0000-0002-6328-

Efstathios Kastritis https://orcid.org/0000-0001-8191-5832Meletios A. Dimopoulos https://orcid.org/0000-0001-8990-3254