SN Comprehensive Clinical Medicine (2020) 2:2631–2636

https://doi.org/10.1007/s42399-020-00607-3

COVID-19

COVID-19 and Hematology—What Do We Know So Far?

Harshwardhan Khandait 1 & Garima Gandotra 2 & Sonali Sachdeva 2 & Courtney A. Kramer 3 & Derek Nye 3 &
Reshma Golamari 4 & Rohit Jain 4

Accepted: 20 October 2020 / Published online: 27 October 2020

# Springer Nature Switzerland AG 2020

Abstract
The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), the causative agent of the novel coronavirus disease 2019
(COVID 19), was reported to the World Health Organization in late 2019. This disease quickly evolved into a public health
concern and was declared a pandemic on March 11, 2020. COVID-19’s high transmission rate and potential to cause a spectrum
of systemic diseases makes it imperative for researchers and clinicians worldwide to collaborate and develop a strategy to manage
and contain this disease. Studies have shown a wide range of hematological abnormalities and virus-related coagulopathies in
affected patients, resulting in an increased propensity to develop serious thrombotic complications or disseminated intravascular
coagulation (DIC) in severe cases. The fatal implications of coagulopathy in the form of pulmonary embolism (PE), myocardial
infarction (MI), and cerebral infarction compelled us to study in-depth the pathophysiology and treatment options related to
COVID-19. This analysis reviews published reports on patients with confirmed SARS-COV-2 infection and associated coagu-
lopathy, defined as abnormalities in the coagulation parameters prothrombin time (PT), activated partial thromboplastin time
(aPTT), antithrombin time, fibrinogen, fibrin degradation products, and D-dimer. In this review, we present the hematological
manifestations of COVID-19, focusing on virus-associated coagulopathy and relevant pathophysiology, clinical outcomes, and
treatment.

Keywords COVID-19 . Coagulopathy . SARS-CoV-2

Introduction is primarily a respiratory illness, cardiac manifestations, gas-

trointestinal complications, and hematological manifestations
A series of clinically similar pneumonia cases were reported in are among other features commonly reported. The most com-
Wuhan, China, to the World Health Organization (WHO) on mon complications reported during the course of the disease
December 31, 2019, by the Wuhan Municipal Health include ARDS (3.4%), disseminated intravascular coagulation
Commission. On January 9, 2020, the pathogenic cause was (DIC) (0.1%) [2], cardiac injury, and multiple organ dysfunc-
reported to be a novel coronavirus, and the WHO declared it a tion syndrome (MODS) [3, 4]. The most prevalent comorbid-
pandemic on March 11, 2021 [1]. As of September 11, 2020, ities in hospitalized patients have been found to be hyperten-
the WHO has reported 27,973,127 confirmed COVID-19 sion (21.1%), cardiovascular diseases (4.2%), and respiratory
cases and 905,426 deaths worldwide [1]. While COVID-19 diseases (2.4%), further increasing their risk of developing
complications with COVID-19 [5]. This article describes he-
This article is part of the Topical Collection on Covid-19 matological findings during, and complications as a result of,
COVID-19 infection.
* Harshwardhan Khandait
[email protected]

1
Hematological Findings and Complications
Government Medical College and Hospital, Medical Square,
Nagpur 440003, India
In patients with COVID-19, the most prevalent hematological
2
Lady Hardinge Medical College, Delhi, India findings observed in a complete blood count (CBC) include
3
Penn State College of Medicine, Hershey, PA, USA lymphopenia (83.2%), thrombocytopenia (36.2%),
4
Division of Hospital Medicine, Department of Medicine, Penn State leukocytopenia (33.7%), and neutrophilia (34.5%) [2, 6]. Of
Hershey Medical Center, Hershey, PA, USA note, other significant laboratory findings representing
2632 SN Compr. Clin. Med. (2020) 2:2631–2636

inflammatory markers are elevations in erythrocyte sedimen- receptor-binding domain (RBD) of the SARS-CoV-2 helps
tation rate (ESR) (93.8%), serum ferritin (78.5), C-reactive to structurally differentiate it from other coronaviruses. RBD
protein (CRP) (60.7%), and procalcitonin (5.5%) [2, 6]. is also utilized to bind ACE-2 receptors found in abundance
Median hemoglobin levels have been found to be lower in on respiratory tract cells during the initial infection phase, as
patients with severe COVID-19 disease, such as those who well as multiple other organ tissues as the disease progresses
are admitted to an intensive care unit (ICU), who require me- [17, 18]. By binding to the ACE-2 receptor on Type II
chanical ventilation, or who succumb to death [2]. pneumocytes of the lung, SARS-CoV-2 can dysregulate the
Among the various hematological manifestations of kallikrein/kinin system and initiate the coagulation cascade
COVID-19, coagulopathic abnormalities have recently [19]. The downregulation of ACE-2 leads to angiotensin II–
emerged as important markers of negative prognosis, such as mediated vascular dysfunction, also possibly implicated in the
elevated D-dimer (23.3%), prolonged PT (2.1%), prolonged development of a hypercoagulable state in infected patients.
aPTT (9.7%) [6]. Tang et al. demonstrated a significant dif- The thrombotic milieu seen with COVID-19 infection may
ference in the levels of PT, D-dimer, and fibrin degradation be a result of direct endothelial and microvascular damage by
products (FDP) between survivors and non-survivors of the virus, followed by inflammation and the excessive release
COVID-19 in patients at a Wuhan hospital [7]. Another retro- of cytokines which further aids the development of a
spective cohort study by Zhou showed an increase in hospital prothrombotic state [20–22]. An increase in the complement
mortality among patients with a D-dimer level > 1 μg/dl [8]. factor C5b-C9 has been shown to create extensive capillary
These coagulopathic factor elevations suggest a procoagulant damage in the lungs and skin of COVID-19 patients. This
state in COVID-19, which often manifests as both venous and suggests that terminal complement activation could be the
arterial thrombosis, and in severe cases can progress to DIC cause of endothelial damage and thrombosis in these patients
[2]. Lupus anticoagulant has been detected with an incidence [23]. Finally, an imbalance of the renin-angiotensin-
as high as 90%, further supporting the presence of a hyperco- aldosterone system (RAAS) creates increased levels of angio-
agulable state [9]. Furthermore, the presence of tensin II, relative to angiotensin I. This imbalance manifests as
antiphospholipid antibodies in affected patients may contrib- unregulated inflammation and oxidative stress, leading to dys-
ute to coagulopathy via secondary antiphospholipid syndrome functional endothelium, and further contributing to thrombo-
[10]. A similar conclusion regarding the findings was drawn sis [24].
by another review by Temgoua et al. [11]. There is evidence that ACE-2 receptors are expressed
The thrombotic complications that have been observed in on lymphocytes, which the virus utilizes to cause a direct
patients with COVID-19 include deep vein thrombosis cytotoxic effect, leading to lymphopenia [25]. COVID-19
(DVT), pulmonary embolism (PE), I.V. catheter–associated may also attack hematopoietic stem cells in the bone mar-
thrombosis, acute myocardial infarction (MI), limb ischemia, row via the ACE-2 receptor, therefore depleting all forms
and cerebrovascular thrombosis [12, 13]. In a study of criti- of blood cells [26]. Previous studies have demonstrated
cally ill patients admitted to the ICU, the cumulative incidence that viral TNFα induction during the cytokine storm me-
of thrombotic complications was reported to be 31% [14]. In diates cell apoptosis [27]. Additional experiments have
patients with COVID-19, the prevalence of venous thrombo- shown that the acidification of culture medium results in
embolism is approximately 20%, with 3% suffering from the death of a subset of T cells [28]. A similar mechanism
stroke [15]. The incidence of venous thromboembolic compli- may occur in the COVID-19 disease state, where hypoxia
cations, such as DVT and PE, is higher when compared to and blood flow stasis due to endothelial damage creates
arterial thromboembolic events such as ischemic stroke, MI, an acidic environment, resulting in immune cell apoptosis.
or systemic arterial embolism [27% versus 3.7%, respectively] Specific COVID-19 related morphological change has
[14]. Among venous thrombosis events, the prevalence of PE been observed in lymphocytes, with a predominance of
has been observed to be the highest, now thought to be “in reactive cells showing lymphoplasmacytic characteristics
situ” thrombosis in pulmonary vessels [16]. Thus, the effect of [29].
SARS-COV2 on the hematological system is a diverse and Zini et al. observed changes in circulating neutrophils and
evolving cause of concern due to its numerous complications platelets, suggesting the existence of disturbed myelopoiesis
and rising mortality. in patients with severe, systemic COVID-19 infection [30]. A
review by Violetis concluded that the neutrophilia could be
due to the “cytokine storm.” It could also be an indicator of a
Pathophysiology superimposed bacterial infection [31]. In addition to platelet
structural changes, a reduction in absolute platelet count has
The Coronavirus family are enveloped, single-stranded, been observed. These findings could be attributed to COVID-
positive-sense RNA viruses with spike glycoproteins, com- 19 infection destroying hematopoietic precursors in the mar-
posed of two subunits—S1 and S2—on their surface. The row and megakaryocytes in the lungs. Another proposed
SN Compr. Clin. Med. (2020) 2:2631–2636 2633

mechanism is the destruction of platelets by virus-induced Clinical Outcomes

autoantibodies, which form immune complexes, and are then
cleared from the body. In addition to these potential processes, Hematological laboratory findings can be utilized to deter-
the consumption of platelets during the coagulation cascade mine the severity and prognosis of COVID-19 infection.
and thrombi formation further lowers platelet levels [32]. Thrombocytopenia has been shown to be associated with an
The clinical manifestations and laboratory findings of increased risk of severe disease and COVID-19-related mor-
COVID-19 are similar to those seen in secondary tality [34]. In a meta-analysis by Zhao et al., lymphopenia was
hemophagocytic lymphohistiocytosis (sHLH), which is linked to a threefold increase of severe COVID-19 disease
defined by T cell overactivation leading to the production [35]. Wu et al. assessed risk factors associated with ARDS
of granulocyte-macrophage colony-stimulating factor and death in patients with COVID-19 and reported that an
(GM-CSF) and interleukin-6 (IL-6). GM-CSF stimulates increase in neutrophils was directly linked to adverse out-
CD14+ CD16+ inflammatory mononuclear macrophages comes and mortality [6].
to produce IL-6 and a plethora of other inflammatory me- Abnormalities in coagulation parameters, such as increased
diators [33]. This phenomenon may be responsible for the prothrombin time (PT) and activated partial thromboplastin
mass destruction of immune cells via activation of mono- time (aPTT), elevated fibrinogen, fibrin degradation products
nuclear macrophage system and excessive cytokine re- (FDP), and D-dimer levels, have also been shown to be im-
lease. Figure 1 depicts the pathophysiology of hematolog- portant prognostic factors in patients with COVID-19 pneu-
ic changes in COVID-19. monia [7]. Numerous studies focusing on hematologic

Fig. 1 Pathophysiology of hematologic changes in COVID-19

2634 SN Compr. Clin. Med. (2020) 2:2631–2636

abnormalities in COVID-19 patients indicate the presence of a function analyzer [43]. Patients with prolonged PT or APTT
co-existing coagulopathy, which may predispose to thrombot- > 1.5 times, TEG R time > 10 min, are candidates for fresh
ic complications, including venous thromboembolism (VTE), frozen plasma infusion [43].
PE, arterial thromboembolism, MI, cerebral infarction, and In acute coronary syndrome with plaque rupture, the use of
DIC [36]. There has also been documentation of in situ throm- dual antiplatelet and anticoagulants is recommended in accor-
bus formation in the coronary circulation, leading to MI [37]. dance with standard guidelines, unless contraindicated [44].
Bangalore et al. reported 18 cases of COVID-19 with ST- Differentiation between myocarditis, nonspecific myocardial
elevation MI and elevated D-dimer levels, suggesting the role injury, and plaque rupture is important as the former two con-
of COVID-19-associated coagulopathy in coronary thrombo- ditions do not require intervention [45]. Transthoracic echo-
sis [38]. cardiography (TTE) can be utilized prior to intervention to
There is also an emerging role for biomarkers, such as assess regional wall motion abnormalities. In ST-elevation
LDH, procalcitonin, ferritin, IL-6, and cardiac troponin-1, myocardial infarction (STEMI), the risk (of transmission and
which have been found to be significantly elevated in non- delay in treatment) benefit ratio must be considered and se-
survivors compared to survivors of COVID-19 [8]. Plasma lected cases may receive fibrinolysis [45]. In STEMI, the de-
levels of CRP have also been shown to correlate with disease cision to proceed to the catheterization laboratory is guided by
lethality and indicate poor survival chances in COVID-19 the severity of STEMI, the severity of COVID-19 in patients,
[39]. A case series by Liu et al. demonstrated that increasing and the risk of transmission.
eosinophils may be an indicator of improvement in the Heparin is generally avoided in DIC but is recommended in
COVID-19 disease [40]. It has also been noted that hypoalbu- DIC associated with COVID-19 [14]. Unless clinically neces-
minemia is a predictor of mortality, independent of age and sary, long-acting antiplatelet drugs should be discontinued
comorbidity burden [41]. Furthermore, a rise in neutrophil/ [36]. In cases with active bleeding, the transfusion of blood
lymphocyte count and neutrophil/platelet count may point to- products can be considered, with platelet concentrate admin-
wards a heightened risk of myocardial injury and mortality istered to maintain counts > 50*109/l and fresh frozen plasma
[42]. in patients with deranged PT/ APTT ratio or decreased fibrin-
ogen [36].
The pathophysiology of thrombosis in COVID-19 is
Treatment unique; therefore, its management through standardized ther-
apy cannot be validated. A study by Klok et al. failed to
The American Society of Hematology has recommended the demonstrate the benefit of prophylactic LMWH in critically
use of either low molecular weight heparin (LMWH) or ill patients admitted to the ICU [14]. Therefore, it cannot be
fondaparinux for thromboprophylaxis in COVID-19- assumed that prophylactic LMWH in standard doses is the
associated hypercoagulability, except in cases where the risk standard of care in preventing thrombotic complications asso-
of bleeding supersedes thrombosis risk [38]. In those with ciated with COVID-19. We suggest the use of VTE risk strat-
existing contraindications for anticoagulation, pneumatic ification systems for COVID-19 patients, such as the Caprini
compression devices could be initiated instead. A regulatory score and Padua Model [45]. The British Society of
agency approved regimen may be used for Hematology recommends using the ISTH DIC score for prog-
thromboprophylaxis after discharge, such as a first dose of nosticating patients with severe COVID-19 infection and tai-
betrixaban 160 mg, followed by 80 mg daily for 35–42 days, loring the treatment accordingly [46]. Large-scale, random-
or rivaroxaban 10 mg daily for 31–39 days [38]. Therapeutic ized trials will be required to establish treatment guidelines
anticoagulation is initiated in patients with confirmed cases of and also determine whether anti-inflammatory drugs may be
VTE, with patient comorbidities and co-existing conditions beneficial, considering that inflammation plays an important
dictating the choice of treatment- either low molecular weight role in COVID-19-associated thrombosis.
heparin, unfractionated heparin, or direct anticoagulants. If
necessary, reduced antithrombin III levels can be replenished
with fresh frozen plasma [43]. Conclusion
PE management in COVID-19 patients follows a standard-
ized guideline with hemodynamically stable patients receiving Initially thought to affect predominantly the lungs, COVID-19
anticoagulation with close monitoring and severe cases receiv- is a systemic disease with the potential to affect numerous
ing fibrinolysis. In unstable patients or if systemic fibrinolysis organs systems. The role of laboratory parameters is increas-
is contraindicated, catheter-directed therapies can be utilized. ingly being utilized in the diagnosis, prediction of adverse
Patients with COVID-19-associated coagulopathy should be clinical outcomes, and prognosis in hospitalized COVID-19
evaluated with viscoelastic coagulation tests including patients. Given the strong prognostic value of hematologic
thromboelastography (TEG) and a coagulation and platelet abnormalities and their relative ease in monitoring, they
SN Compr. Clin. Med. (2020) 2:2631–2636 2635

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