Keywords
covid-19 - coagulopathy - thrombosis - inflammation
Introduction
Coronavirus disease of 2019 (COVID-19) is a viral infection caused by the severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2).[1]
[2]
[3]
[4] Because of its highly contagious nature and global spread, it was declared a pandemic
by WHO since early March 2020.[5] SARS-CoV-2 comprises of positive-sense single-stranded RNA genome harboring a surface
glycoprotein known as spike protein, or S proteins. These proteins are believed to
be responsible for the tropism toward the specific receptors present on the cell surface
of the target organism. The virus specifically targets respiratory epithelium via
angiotensin converting enzyme 2 (ACE2) receptor, thereby making its entry into the
host cells.[6] ACE2 receptors are highly expressed in many different cell types, including lung
alveolar cells, cardiac myocytes, and vascular endothelium.[7] Primarily, SARS-CoV-2 is transmitted by inhaling viral particles, facilitating their
entry into the respiratory tract.[1] Additionally, the virus disseminates through fomite transmission, depending on the
different surfaces and varied time intervals in which the virus can persist.[8] The initial presentation of COVID-19 overlaps with that of other viral syndromes
and includes fever, cough, fatigue, shortness of breath, headache, diarrhea and myalgias.[9]
[10]
[11] However, the respiratory distress syndrome accompanying COVID-19 may differ from
traditional acute respiratory distress syndrome caused by other viruses of the same
family. Despite the extremity of hypoxemia in this infection, there is ongoing lung
damage, marked by increased respiratory compliance and shunt fraction along with heightened
recognition of systemic features of a hypercoagulable state. The alteration in coagulation
parameters caused by SARS-CoV-2 infection can be termed ‘COVID-19 induced coagulopathy’
(CIC), which may cause various adverse cardiovascular complications, ultimately leading
to death in some patients.[12]
[13] CIC is different from the classic DIC observed in the case of sepsis. Coagulation
changes in the COVID-19 patients though mimic that of DIC but are not identical. In
the patients with COVID-19 infection, a strong local pulmonary thrombotic microangiopathy
along with the direct endothelial cell infection by the viral particles is induced
that inflict the coagulopathic response. The elevated plasma D-dimer level is the
most remarkable abnormal coagulation feature in the case of severe COVID-19 patients.
Whereas, in sepsis-associated DIC, a more profound thrombocytopenia is reported. In
addition, DIC patients exhibit much lower levels of clotting factors and significant
decrease in plasma concentrations of coagulation inhibitors like antithrombin and
protein C. These features are not observed in CIC.[14]
Furthermore, patients who have certain co-morbidities, in particular as associated
with cardiovascular disease, are speculated to have the worst prognosis among COVID-19
patients. Amidst the cardiovascular comorbid conditions, patients with diabetes are
more likely to have severe infection. Other comorbidities, such as chronic obstructive
pulmonary disease, liver and renal diseases, have also been associated with poor disease
progression. Several studies, as well as case reports, suggest patients with severe
infection present with coagulation dysfunction, as evident from a rise in blood D-dimer,
lactate dehydrogenase and total bilirubin levels. Standard coagulation parameters,
like partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT)
and platelet count show slight or no change in the initial presentation of the disease.
Only 5% of the reported cases exhibit prolonged PT and 6% prolonged aPTT as an initial
manifestation of the disease.[15] However, with progression of disease and severity there is progressive prolongation
of PT, whereas aPTT appears to remain largely unchanged in non-fatal COVID-19 cases
vs fatal cases, with no significant correlation with disease severity or mortality.[16] Initial clinical studies showed patients with elevated level of troponin indicative
of cardiac injury, but due to lack of imaging data such as cardiac magnetic resonance
imaging (MRI) or echocardiography, the mechanism remained unclear. Significantly higher
deaths are reported in patients with cardiac injury (51.2%) as compared with those
without any cardiovascular complication (4.5%).[17] Also, there is speculation that the virus may act through direct cell damage upon
ACE2 receptor binding, causing a systemic inflammatory response with an arising cytokine
storm, destabilizing coronary plaques, and aggravating hypoxia, which represent risk
factors for thrombotic events.[16]
SARS-CoV-2 may have a direct effect on hemostasis or it may act indirectly by creating
pathological effects such as hypoxia and inflammation that may predispose COVID-19
patients to thromboembolic events. Preliminary data are suggestive that hemostatic
abnormalities such as CIC, occur in COVID-19 patients.[16]
[18] Also, the heightened inflammatory response causing cytokine storm, severe illness,
and underlying traditional risk factors may all predispose an infected patient to
thrombotic events or other cardiovascular manifestations ([Fig. 1]).[19] Therefore, an understanding of CIC mediated thrombotic complications in COVID-19
is of utmost importance for better management of the severe cases of the infection.
In the present review we summarize all the interpretations of the characteristics
of CIC till date with its implications for thrombosis and its management. We also
present clinical findings related to coagulation parameters in infected patients with
incidences of thromboembolic events and probable therapeutic measures for the effective
management of the disease.
Fig. 1 Depiction of effect and manifestation of COVID-19 and associated cardiovascular implications.
Thrombotic Incidences in COVID-19 Patients Exhibiting CIC
Thrombotic Incidences in COVID-19 Patients Exhibiting CIC
Up to November 2021, more than 253.1 million cases of COVID-19 have been reported
globally accounting for ∼5.1 million deaths.[20] There are also reports of asymptomatic carriers[15]
[16]
[21]
[22]). The association of abnormal coagulopathy with infection was first observed in
the initial reports from Wuhan, China showing 6% elevation in aPTT, 5% in PT and 36%
in D-dimer in the first 99 patients admitted to a hospital.[23] These patients showed increased inflammatory markers, including interleukin-6 (Il-6),
erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP).[15] The initial reports were suggestive of high risk of thromboembolic complications
in these patients. With the progression of the pandemic, numerous other reports have
revealed prolonged PT, high D-dimers, along with high levels of fibrinogen and high
CRP, lymphocytopenia and mild thrombocytopenia.[8]
[18] A systemic review consisting a total of 36 studies including the patients requiring
ICU placement, presented the pooled incidence rate of 28% (95% CI, 22–34%) for venous
thromboembolism (VTE).[24] Micro-thrombosis formation was noted in 80% of lung autopsies from fatal COVID-19
cases.[25] High incidence of VTE (31%) resulting in complications such as pulmonary embolism
(PE) (80%), as well as arterial thrombosis (3.7%), has been reported in COVID-19 patients
by Klok et al.[26] In [Fig. 2],[16]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36] we have summarized the incidences of venous thromboembolism (VTE) reported in COVID-19
patients, according to different studies.
Fig. 2 Thromboembolic complications in COVID-19 patients.[16]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
Molecular Mechanism Resulting in CIC Mediated Thrombosis
Molecular Mechanism Resulting in CIC Mediated Thrombosis
Endotheliitis and Hyperinflammation
Endotheliitis and hyperinflammation initiates CIC. The main site of viral infection
in humans is lung alveolar type II epithelium, where the spike protein S1 attaches
itself to the ACE-2 receptor.[6]
[9] The virus replicates in the infected cells causing inflammatory response resulting
in pyroptosis. The receptors of innate immunity like TLR (Toll-like receptors) detect
danger-associated molecular patterns (DAMPs) such as ATP and DNA released after pyroptosis
and evoke intense inflammatory responses along with release of proinflammatory chemokines
and cytokines from neighboring cells[37] ([Fig. 3]). Also, TLR-7 and TLR-8 recognizes the multiple single-stranded RNA fragments of
SARS-CoV-2, thus contributing to innate immune hyper activation and causing a cytokine
storm.[38] Thus, upon infection, the vascular endothelium, which is a guardian of vascular
integrity, gets hijacked by the virus and then exposed to the milieu of proinflammatory
cytokines elicited by the innate immunity.[39] All the studies conducted have hypothesized that the entry of the virus via endothelial-expressed
ACE-2 paves the way by which the virus can enter and infect other tissues.
Fig. 3
Mechanism of CIC induced Thrombosis: The viral particles enter the host through ACE-2 receptors found on endothelial cells
(EC) of respiratory pathway resulting in endothelial activation and dysfunction that
leads to pyroptosis and cytokine storm. This in turn causes platelet activation and
upregulation of tissue factor (TF) and fragment (1 + 2). The spiked inflammatory response
along with downregulation of anticoagulant and fibrinolytic pathway leads to formation
of thrombus.
ACE-2 is also highly expressed in various extrapulmonary sites, including blood vessels,
heart, kidney, and intestine.[40]
[41] Clinical data from infected patients have revealed increased levels of IL-6, IL-1β,
MCP-1 (monocyte chemo-attractant protein 1), MIP (macrophage inflammatory protein),
IFN (interferon)-γ, and IP10 (CXCL10).[1] Disruption of endothelial function and integrity by these proinflammatory cytokines
leads to release of von Willebrand factor (VWF), upregulation of adhesion molecules
such as ICAM (intercellular adhesion molecule)-1, integrin αvβ3, P- selectin, E-selectin
and endothelial tissue factor (TF, CD142).[42]
[43] The sudden activation of endothelial cells causes elevated VWF antigen (VWF:Ag)
levels. The function of VWF is mediated through proteolysis guided by von Willebrand
factor-cleaving protease, which is also known as a disintegrin and metalloprotease
with thrombospondin type 1 motif, member 13 (ADAMTS-13). It is hypothesized that in
the case of COVID-19 infection, ADAMTS-13 regulation of VWF multimer distribution
is impaired resulting in procoagulant state.[44] Ilaria et al reported a significant change in the VWF-ADAMTS13 axis in infected
patients, with an increase in VWF:Ag to ADAMTS13 activity ratio, which is strongly
associated with disease severity. This imbalance in the ratio of VWF level to ADAMTS13
increases the hypercoagulable state of COVID-19 patients and thereby risk of micro-thrombosis.[45] Thus, this cascade of events cause endothelium to adopt a procoagulant phenotype,
which is then supportive of platelet and leukocyte recruitment and marks the initiation
of CIC.[46]
[47]
IL-6, a crucial cytokine that is markedly increased in severe COVID-19, is an activator
of coagulation that induces TF expression along with increased production of fibrinogen
and platelets.[48]
[49]
[50] Increased Angiotensin II (ATII) expression, along with proinflammatory cytokines
and antiphospholipid antibodies are responsible for TF activation and overexpression
in the infected patients. Thus, it is likely that the overexpression of TF in COVID-19
is related to the pathogenesis of the disease.[51] The researchers have looked for correlation between TF expression and the severity
of COVID-19 and found that TF expression both in monocytes and extracellular vesicles
is associated with severity of disease.[52]
[53] This is because TF can increase its expression during localized hypoxia of lungs
in the case of COVID-19 infection and generate a thrombotic phenotype, which is observed
to be regulated by extracellular RNA activated Toll-like receptor 3-activated protein
1 signaling.[54] This in turn initiates extrinsic cascade of coagulation and spiked inflammatory
response. This inflammation further causes endothelitis in CIC.
These observations are in alignment with clinical autopsy of COVID-19 patients, as
viral inclusion within the endothelial cells is seen in sections of lungs and kidney,
thus highlighting the ability of virus to cause endothelial injury after infection.
These findings are augmented with histological evidence of endothelial inflammation
and cell death by viral load.[39] Together, these findings suggest a direct role of SARS-CoV-2 in promoting systemic
microvascular dysfunction causing a prothrombotic milieu.[48]
Role of Platelets CIC Mediated Thrombosis
In severe cases of COVID-19, one of the common findings is thrombocytopenia. A recent
meta-analysis reveals association of thrombocytopenia with 5-fold increase in risk
of severe infection.[49] The recent studies demonstrated that severe COVID-19 cases often have cardiovascular
comorbidities suggestive of thrombocytopenia or platelet apoptosis as a major contributor
of virus pathogenesis.[50]
[55] Other molecular events involved in SARS-CoV-2 pathogenesis, like inflammation, hypoxia,
immune system activation, endothelial activation and dysfunction can lead to platelet
apoptosis as well as activation, resulting in increased thrombotic events.[55]
[56]
[57]
[58] Patient autopsies from those with severe SARS-CoV-2 infection show platelet-rich
thrombotic microangiopathy.[59]
[60]
[61] The presence of arterial and venous thrombus through-out the lungs is suggestive
of CIC influenced platelet hyperactivation that in turn increases the severity of
the disease by exacerbating inflammation. Platelets express a wide repertoire of adhesion
as well as immune receptors, like FcγRIIa, CXC/CCL receptors and TLRs along with an
ability to engulf virions. SARS-CoV-2 has been demonstrated to activate platelets
via TLR-7 and the FcγRIIa receptors, which evokes an array of functional responses
that support thrombus formation, including formation of platelet leuckocyte aggregates,
platelet degranulation, and so on.[62]
[63]
[64]
[65] Activated platelets expressing CD40L and P-selectin interact with neutrophils and
release α-granules along with complement C3 and different cytokines like CC-chemokine
ligand 2 (CCL2), CCL3, CCL7, IL-7, IL-8, IL-1β.[66]
[67] These findings correlate with the clinical data of COVID-19 patients, as the level
of these cytokines have been reported to be significantly elevated in these patients
compared with healthy controls.[68] Previous studies with dengue virus show that platelets release IL-1β that results
in increased permeability.[69] The release of IL-1β and other cytokines by platelets in response to SARS-CoV-2
possibly causes COVID-19 associated ARDS. As seen in COVID-19 pathology, parallel
to cytokine release, another important event in ARDS, is recruitment of neutrophils
to the pulmonary vasculature.[70] The molecular mechanism by which activated platelets binds to neutrophils and lead
to rolling of platelet-bound neutrophils on the endothelium, is termed as ‘secondary
capture’. This plays a pivotal role in the initiation of immune-thrombosis.[71] The transmigration of the platelets to the alveolar lumen is mediated by binding
of activated platelets to neutrophils and results in the formation of edematous lungs,
which leads to further platelet activation.[70] This series of events leads to formation of neutrophil extracellular traps (NETs).
Recent reports suggest that NETs trigger thrombo-inflammation in COVID-19 patients,[70] causing vascular thrombosis and high risk of mortality.[72] Taken together, platelet activation along with apoptosis are contributors to the
severity of pathology of COVID-19, which includes thrombosis and the cytokine storm.
Along with mediating T cell function and leukocyte aggregation, platelets also increase
B cell immunoglobulin (Ig) G1, IgG2, and IgG3 production.[73] This finding is significant in the light of COVID-19 as formation of antiphospholipid
antibodies, like anti-β2 glycoprotein IgG antibodies, are associated with thrombosis
in patients with COVID-19.[74] A cohort studied from France has demonstrated that a large percent of severe COVID-19
patients exhibits a detectable lupus anticoagulant.[75] However, it still remains to be established whether the presence of antiphospholipid
antibodies in SARS- CoV-2 patients plays a role in infection-associated thrombosis
or represents merely an association. Nevertheless, deciphering the ways platelets
modulate the adaptive immune response to COVID-19 and the role played by adaptive
immunity mediating thrombosis will be crucial in uncovering novel therapeutic strategies
to combat the disease.
Prediction of CIC Severity and Occurrence of Thrombotic Events
Prediction of CIC Severity and Occurrence of Thrombotic Events
Analysis of Coagulation and Inflammatory Parameters
There are 6 baseline coagulation tests that should be performed to measure the extent
of CIC in infected patients. These are PT, aPTT, D-dimer, fibrinogen, fibrin degradation
products (FDP) and platelet count. These tests represent traditional tests used to
help assess bleeding or thrombotic risk. Additional laboratory measures to evaluate
CIC associated inflammation are C-reactive protein (CRP), erythrocyte sedimentation
rate (ESR), ferritin, procalcitonin, and high-sensitivity cardiac troponin. Inflammatory
markers such as CRP, ESR are elevated in COVID-19 patients. These markers are also
associated with the occurrence of thrombosis. We discuss below the potential utility
of the 6 baseline coagulation tests that can be used to help access the severity of
disease and predict the future course of medical intervention.
-
PT: In the initial stage of the disease, PT is normal or near-normal in most COVID-19
patients. Only 5% cases showed prolonged PT during the initial manifestation of the
disease.[16] However, there is significant change in the PT profile in critically ill COVID-19
patients having CIC.[70]
[71] Critically ill patients show an average increase 1.9s in PT as compared with non-fatal
or critical cases. Also, as the severity of the disease progress, ∼48% of critically
ill patient exhibit marked and progressive increase in PTs.[19] Thus, an upward trending PT can add clinical evaluation in monitoring progression
of the disease, in particular fatal or critical cases. That is, progressive increase
in PTs can be considered a warning sign and a predictor of increased risk of mortality.
-
aPTT: the aPTT profile is often unaltered in COVID-19 patients, and only a fraction
(6%) of patients shows prolonged aPTT.[16] There is no significant difference in the average aPTT between fatal and non-fatal
cases of infection. Also, no significant correlation was observed between aPTT and
disease severity or mortality.[19] Therefore, the aPTT cannot be considered as reliable indicator of CIC and disease
progression in COVID-19. Also, the aPTT cannot be associated with prevalence of VTE
in COVID-19 cases.
-
D-dimer: quantitative D-dimer is used routinely as a biomarker for exclusion/diagnosis
and prediction of recurrence of VTE.[76]
[77] 36% of reported cases have showed elevated levels of D-dimer (approximately, 0.9 mg/L).[12]
[16] An elevated D-dimer level is observed in fatal cases as compared with non-fatal
cases (mean level of 2.4 vs 0.5 mg/L) and is inversely correlated with the survival
of patient.[12]
[78] Additionally, non-survivors have shown steady and progressive elevation in D-dimer
level, whereas in COVID-19 survivors the levels remain constant or improves.[79] Endothelial dysfunction caused by viral entry results in elevated levels of D-dimer
along with thrombin and FDPs, inflammation and hypoxia resulting in CIC which can
lead to pulmonary congestion mediated by thrombosis.[79] These findings suggest D-dimer to be highly prognostic in COVID-19. Evaluation of
D-dimer level may also aid in identifying patients that could benefit from anticoagulant
therapy.
-
Fibrinogen: Most COVID-19 patients show elevated (4.55 g/L) fibrinogen in the initial
stage of the disease. The degree of elevation correlates with increased IL-6 levels
but not with mortality.[17]
[79] Il-6 is an important mediator of inflammation and in COVID-19, inflammation precedes
coagulation. As the disease progress, there may be a progressive decrease in the fibrinogen
level, and at a late course of the disease is strongly associated with mortality.
Approximately 29% of critically ill patients had fibrinogen <1 g/L, but this happens
at the last stage of the disease.[17] Thus, fibrinogen levels cannot be used for prognosis of the initial phase of COVID-19,
but progressive deterioration may reflect a poor prognosis.
-
FDPs: FDP levels are relatively constant in both mild cases and initial presentation
of the disease. However, critically ill patients admitted to ICU showed significantly
higher levels of FDP. The approximate levels of FDP in survivors are 4 μg/mL vs 7.6 μg/mL
in the non-survivors. The elevation of D-dimer is followed by elevation of FSP. Though
D-dimer is more sensitive marker for coagulopathy during the initial phase of the
disease, FSP can also be considered prognostic for the COVID-19 infection as progressive
elevation of FSP level correlates with mortality[17]
-
Platelet count: Platelet count is mostly unaltered or slightly reduced in most cases
of COVID-19 and thrombocytopenia is reported in only 12–36% of total cases.[12]
[16]
[19] Platelets play a crucial role in progression of coagulopathy and in the development
of thrombosis (explained in the earlier section of the review). Severe thrombocytopenia
correlates with progression of disease as more than 55% of critically ill COVID-19
patients have a platelet count of <100 × 109/L.
Therapeutic Perspectives
The lack of specific therapy against SARS-CoV2 and significant association of thrombotic
complications with severe COVID-19 has led to exploration of anti-thrombotics as a
choice of drug for infected patients. Antithrombotic drugs having anti-inflammatory
and/or antiviral properties are also under clinical trial. Anticoagulants are first
choice of antithrombotic therapy. VTE prophylaxis with either low molecular weight
heparin or unfractionated heparin is commonly applied to COVID-19 patients.[79]
[80] Initial clinical reports suggested that administration of low molecular weight heparin
reduces the death rate in COVID-19 patients with an elevated sepsis-induced coagulopathy
score or an elevated D-dimer level.[81]
[82] Heparins, apart from being effective anticoagulants seem to have pleiotropic effects
by way of their ability to bind to DAMPs, such as HMGB-1, and proinflammatory cytokines
that may be additionally therapeutic in the context of viral infection, including
anti-inflammatory effects.[82]
[83] Recent findings are suggestive of other links between heparin and SARS-CoV-2, for
example that the antiviral properties of heparin can be attributed to its ability
to bind with the spike protein of the SARS-CoV-2 virus directly.[84] Similar results have been shown after docking of a major protease (PDB id 6y2e)
of COVID-19 with heparin. It showed binding with affinity -11.8 Kcal/mol ([Fig. 4]). But the use of heparins in COVID-19 cases is limited to individual case reports
because of the potential for heparin therapeutics to cause heparin-induced thrombocytopenia.[85]
Fig. 4
Binding of heparin with COVID-19 main protease: (A). Ligplot view of blind docking of main protease of COVID-19, (PDB: 6y2e) with heparin
(Pubchem: 772). For a given protein-ligand docked PDB file, LigPlot automatically
generates schematic diagrams as represented by hydrogen bonds and by hydrophobic contacts.
Green dashed lines between the atoms involved represent the hydrogen bonds and an
arc with orange spikes pointing toward the ligand atom they contact with represents
the hydrophobic contacts. (B). Hydrophobicity surface view of protease bound to heparin: image as created by chimera
represents “hydrophobicity surface” that is dodger blue for the most hydrophilic,
to white, to orange red for the most hydrophobic.
Another therapeutic approach is the use of inhibitors of the contact factor activation
pathway. Inhibition of thrombo-inflammatory response by inhibition of FXII also appears
to be an attractive therapeutic target. Activation of FXII by negatively charged molecules
like NETs and platelet derived PolyP initiates activation of contact pathway. The
level of NETs and PolyP is reported to be upregulated in severe COVID-19 patients.[86] Activation of contact pathway causes thrombin generation and bradykinin activation.
This in turn causes downstream complement activation and production of inflammatory
cytokines.[87] It has been demonstrated in animal models of thrombosis that inhibition of FXIIa
gives protection from occlusive thrombus formation without impeding hemostasis.[88] The potential safety of FXII inhibitors is attributed to the fact that administered
individuals display no bleeding disorder, and there is no reported effect on immune
function.[89] Therefore, a FXII inhibitory antibody can be a promising novel combination of antithrombotic
and anti-inflammatory drugs that can be used in COVID-19. Another therapeutic approach
that may help in COVID-19 includes fibrinolytic agents such as tPA (tissue-type plasminogen
activator). This interest in tPA has emerged from the concept that ARDS is marked
by significant local inflammatory reaction along with a hypofibrinolytic state. As
described earlier, severe COVID-19 may cause ARDS that can result in microvascular
thrombosis, extensive thrombin generation and fibrin formation, because of mass upregulation
of inflammatory cytokines and leukocytes.[90] In reports of its use in severe infection case, an initial improvement was observed
after tPA infusion.[91]
[92]
[93] Antiplatelet therapies are also potentially promising in managing COVID-19 associated
thrombosis. The majority of clinical findings associating antiplatelet therapy with
improved outcomes relates to aspirin.[94] Recent experimental data has shown that aspirin prevents neutrophil mediated microvascular
thrombosis and intravascular coagulation by targeting platelets in a mouse model of
bacterial sepsis.[95] Still, the effect of aspirin in assisting in COVID-19 symptoms remains to be established.
Various other antiplatelet therapeutics, including dipyridamole and nafamostat, are
currently being accessed for their potential to reduce the severity of COVID-19. Recently
it has been reported that dipyridamole suppresses SARS-CoV-2 replication in vitro.
The earlier studies with same drug suggest that use of adjunct dipyridamole may improve
the clinical course in severe cases of COVID-19.[96] Nafamostat, a serine protease inhibitor that is marketed in Asia for the treatment
of DIC and pancreatitis is being evaluated for its role in helping with COVID-19 associated
coagulopathy because of its antiplatelet effect.[97]
[Fig. 5] depicts a flow chart for management of COVID-19 associated VTE. With all the available
evidence-based guidelines for the treatment of COVID-19, it can be said that the current
therapies are inadequate as they do not substantially reduce morbidity and mortality.
However, with the new molecular mechanistic insights emerging from the concerted efforts
of biomedical research, more opportunities will arise to identify potentially safe
and effective therapeutic strategies for COVID-19.
Fig. 5
Flow chart for management of COVID-19 associated VTE. Abbreviations: Prothrombin time (PT), Platelet count (PC), Intensive care unit (ICU),
Low molecular weight heparin (LMWH), Un-fractioned heparin (UFH).
Conclusion
This pandemic has jeopardized the security and stability of the entire human race
for an unknown future duration, plunging it into uncharted territory, leaving all
of us feeling powerless in the face of an infectious and invisible threat. The emergence
of the virus has presented unprecedented healthcare and economic challenges globally.
The decoding of pathological manifestations of this virus becomes paramount in the
management of this disease. A crucial clinical feature of severe COVID-19 infection
is presence of prothrombotic milieu, which is associated with increased rates of arterial,
venous and microvascular thrombosis, along with adverse clinical outcomes. Emerging
evidence from the experimental findings reveal that SARS-CoV-2 can infect endothelial
cells and invoke immune response. This results in activation of inflammatory pathways
causing endothelium dysregulation, leukocyte activation, NET generation, complement
deposition, and thrombocytopenia. All these events together conspire to unleash a
prothrombotic state (immune-thrombosis) that leads to significant thrombotic complications.
Nevertheless, uncovering the precise mechanisms of SARS-CoV-2 infection and associated
thrombotic complications is required to infer novel therapeutic approaches. Thus,
in the context of this pandemic, the intersection of adaptive and innate immunity
with inflammation and thrombosis has been thrust into the global spot-light. With
the growing experimental evidences and understanding of thrombotic complications in
SARS-CoV-2 infection, more rigorous diagnostic approaches resulting in early detection
of thrombotic events can be developed. Also, the use of antithrombotic therapy for
the prevention and treatment of COVID-19-associated thrombosis will help in improving
disease outcomes in COVID-19 patients.
