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PMC:7386875 JSONTXT 18 Projects

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Id Subject Object Predicate Lexical cue
T1 0-85 Sentence denotes The Emerging Threat of (Micro)Thrombosis in COVID-19 and Its Therapeutic Implications
T2 87-95 Sentence denotes Abstract
T3 96-273 Sentence denotes The recent emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the ensuing global pandemic has presented a health emergency of unprecedented magnitude.
T4 274-499 Sentence denotes Recent clinical data has highlighted that coronavirus disease 2019 (COVID-19) is associated with a significant risk of thrombotic complications ranging from microvascular thrombosis, venous thromboembolic disease, and stroke.
T5 500-636 Sentence denotes Importantly, thrombotic complications are markers of severe COVID-19 and are associated with multiorgan failure and increased mortality.
T6 637-894 Sentence denotes The evidence to date supports the concept that the thrombotic manifestations of severe COVID-19 are due to the ability of SARS-CoV-2 to invade endothelial cells via ACE-2 (angiotensin-converting enzyme 2), which is expressed on the endothelial cell surface.
T7 895-1255 Sentence denotes However, in patients with COVID-19 the subsequent endothelial inflammation, complement activation, thrombin generation, platelet, and leukocyte recruitment, and the initiation of innate and adaptive immune responses culminate in immunothrombosis, ultimately causing (micro)thrombotic complications, such as deep vein thrombosis, pulmonary embolism, and stroke.
T8 1256-1405 Sentence denotes Accordingly, the activation of coagulation (eg, as measured with plasma D-dimer) and thrombocytopenia have emerged as prognostic markers in COVID-19.
T9 1406-1562 Sentence denotes Given thrombotic complications are central determinants of the high mortality rate in COVID-19, strategies to prevent thrombosis are of critical importance.
T10 1563-1841 Sentence denotes Several antithrombotic drugs have been proposed as potential therapies to prevent COVID-19-associated thrombosis, including heparin, FXII inhibitors, fibrinolytic drugs, nafamostat, and dipyridamole, many of which also possess pleiotropic anti-inflammatory or antiviral effects.
T11 1842-2148 Sentence denotes The growing awareness and mechanistic understanding of the prothrombotic state of COVID-19 patients are driving efforts to more stringent diagnostic screening for thrombotic complications and to the early institution of antithrombotic drugs, for both the prevention and therapy of thrombotic complications.
T12 2149-2349 Sentence denotes The shifting paradigm of diagnostic and treatment strategies holds significant promise to reduce the burden of thrombotic complications and ultimately improve the prognosis for patients with COVID-19.
T13 2351-2522 Sentence denotes The rapidly evolving coronavirus disease 2019 (COVID-19) global pandemic is one of the greatest public health challenges since the Spanish flu pandemic over 100 years ago.
T14 2523-2728 Sentence denotes Since the discovery of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19, millions of cases have been diagnosed worldwide resulting in hundreds of thousands of deaths.
T15 2729-2878 Sentence denotes With no current effective therapy or vaccine for COVID-19, the enormous number of cases and deaths due to COVID-19 is likely to continue to increase.
T16 2879-3296 Sentence denotes In this regard, although the adverse effects of COVID-19 were initially considered to primarily affect the respiratory tract by causing pneumonia and acute respiratory distress syndrome (ARDS), it has now become apparent that COVID-19 is associated with a prothrombotic state, which can manifest as microvascular thrombosis, venous, or arterial thrombosis, the presence of which usually portends an adverse prognosis.
T17 3297-3465 Sentence denotes Thus, there is an urgent need to understand how SARS-CoV-2 induces a prothrombotic state to develop effective therapeutic approaches for COVID-19-associated thrombosis.
T18 3466-3597 Sentence denotes This review will detail the significant emerging clinical findings of the prothrombotic status of patients suffering from COVID-19.
T19 3598-3774 Sentence denotes We then provide an overview of the inherent links between the immune response and thrombosis, and how these mechanisms may help explain the prothrombotic effects of SARS-CoV-2.
T20 3775-3917 Sentence denotes Finally, we will use this data to explore available therapeutic approaches for the prevention and treatment of COVID-19-associated thrombosis.
T21 3918-4219 Sentence denotes Given the relative lack of data to date demonstrating the precise mechanisms of the link between SARS-CoV-2 infection, thrombosis, and clinical outcomes, we also highlight experimental data from other viral infections and thromboinflammatory disorders that are likely relevant to SARS-CoV-2 infection.
T22 4220-4390 Sentence denotes Further research is urgently required to clearly define how SARS-CoV-2 infection results in thrombotic complications and how this impacts the disease course and severity.
T23 4391-4613 Sentence denotes Therefore, this review will hopefully spark further interest and research, and importantly raise awareness of the importance of anticoagulation in patients with COVID-19 for both the prevention and treatment of thrombosis.
T24 4615-4650 Sentence denotes Coronaviruses Causing Human Disease
T25 4651-4875 Sentence denotes Since the beginning of the 21st century, 3 beta coronaviruses have been found to cause severe respiratory illness in humans, including SARS-CoV, MERS-CoV (Middle Eastern respiratory syndrome coronavirus), and now SARS-CoV-2.
T26 4876-4971 Sentence denotes Coronaviruses reside in many animal hosts and can adapt to different species, including humans.
T27 4972-5356 Sentence denotes The proximal origin of SARS-CoV and SARS-CoV-2 is thought to be bats, while the reservoir host for MERS-CoV is the dromedary camel.1–3 Previous data suggest that in order for coronaviruses to exhibit efficient zoonotic transmission, the virus must undergo natural selection in an animal host (ie, intermediary species) such that it acquires features affording tropism to human tissue.
T28 5357-5843 Sentence denotes To date, the intermediate host for SARS-CoV-2 is not known, however, a closely related coronavirus to SARS-CoV-2 has been identified in Malayan pangolins.4 Moreover, it remains to be established whether SARS-CoV-2 has acquired genomic changes within an intermediate animal host before the occurrence of human transmission, or whether a SARS-CoV-2 progenitor may have undergone genomic changes during undetected human-to-human transmission, ultimately resulting in the current pandemic.3
T29 5844-6009 Sentence denotes In humans, these coronaviruses gain entry into host cells by way of their transmembrane spike (S) GP (glycoprotein), which comprises an S1 and S2 subunit (Figure 1).
T30 6010-6605 Sentence denotes The S1 subunit is responsible for binding to the host cell receptor, and the S2 subunit assists with viral and host cell fusion.1 While the MERS-CoV S GP binds to DPP-4 (dipeptidyl peptidase 4) expressed on epithelial tissue, both SARS-CoV-2 and SARS-CoV bind to human cells via the ACE-2 (angiotensin-converting enzyme 2) receptor.5 In addition to having different amino acid residues within the RBD (receptor-binding domain) of the S protein compared to SARS-CoV, another novel structural feature of SARS-CoV-2, is the presence of a polybasic furin cleavage site, at the junction of S1 and S2.
T31 6606-7287 Sentence denotes Cleavage of the S protein by cellular proteases, including furin and TMPRSS-2 (transmembrane protease serine 2), is speculated to play an important role in the infectivity and host range of SARS-CoV-2, although its functional significance regarding how this feature may mediate SAR-CoV-2 transmissibility and pathogenicity is yet be fully elucidated.1 In the context of COVID-19-associated thrombosis, understanding how these structural differences of SARS-CoV-2 may relate to the prothrombotic phenotype of COVID-19 is likely to be of fundamental importance given the significantly higher rates of thrombosis observed in SARS-CoV-2, compared with SARS-CoV and MERS-CoV infections.
T32 7288-7297 Sentence denotes Figure 1.
T33 7299-7459 Sentence denotes Proposed mechanisms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, and coronavirus disease 2019 (COVID-19)-associated thrombosis.
T34 7460-7615 Sentence denotes SARS-CoV-2 gains entry to host lung epithelial cells by the binding of the transmembrane spike (S) glycoprotein to ACE-2 (angiotensin-converting enzyme 2).
T35 7616-7693 Sentence denotes The S1 subunit of the S protein binds to ACE-2 and mediates viral attachment.
T36 7694-7850 Sentence denotes Proteolytic cleavage of the S protein at the S1/2 junction by the proteases, furin, and TMPRSS-2 (transmembrane protease serine 2), facilitates viral entry.
T37 7851-7915 Sentence denotes SARS-CoV-2 can also directly invade endothelial expressed ACE-2.
T38 7916-8092 Sentence denotes Infected cells undergo pyroptosis leading to the release of danger-associated molecular patterns (DAMPs) and triggering the release of proinflammatory cytokines and chemokines.
T39 8093-8361 Sentence denotes The activated endothelium upregulates the expression of VWF (von Willebrand factor) and adhesion molecules including ICAM (intercellular adhesion molecule)-1, αvβ3, P-selectin and E-selectin leading to recruitment of platelets and leukocytes and complement activation.
T40 8362-8470 Sentence denotes Neutrophils release neutrophil extracellular traps (NETS), causing direct activation of the contact pathway.
T41 8471-8885 Sentence denotes Complement activation potentiates these mechanisms by increasing endothelial and monocyte tissue factor (TF), further platelet activation and amplifies endothelial inflammation, which increases production of proinflammatory cytokines from the endothelium including IL (interleukin)-1, IL-8, RANTES (regulated on activation, normal T-cell expressed and secreted), IL-6, and MCP (monocyte chemoattractant protein)-1.
T42 8886-8998 Sentence denotes The hypoxic environment can induce HIFs (hypoxia-inducible factors) which upregulates endothelial TF expression.
T43 8999-9105 Sentence denotes These mechanisms ultimately lead to the unchecked generation of thrombin, resulting in thrombus formation.
T44 9106-9290 Sentence denotes The fibrin degradation product, D-dimer, which is a marker of coagulation activation, appears to be a strong prognostic marker associated with high mortality in patients with COVID-19.
T45 9292-9332 Sentence denotes SARS-CoV-2 and Its Impact on Coagulation
T46 9333-9504 Sentence denotes An emerging threat of the COVID-19 pandemic is the propensity of SARS-CoV-2 to cause microvascular, venous, and arterial thrombosis, and thereby exacerbating organ injury.
T47 9505-10406 Sentence denotes Patients with severe COVID-19 appear to have a hyperinflammatory response, which is linked to the development of ARDS and multiorgan failure.6 However, it is now well appreciated that the innate immune response and thrombotic response are closely linked (Figure 2) and accordingly in patients with severe COVID-19 there is a correlation with elevated acute phase reactants, such as fibrinogen and CRP (C-reactive protein), which may contribute to COVID-associated hypercoagulability.7–9 Moreover, these biomarkers and acute phase reactants are associated with adverse clinical outcomes and increased severity of infection.7,9,10 In addition, abnormal coagulation parameters, including prolonged prothrombin time and activated partial thromboplastin time, are found to be associated with a higher mortality from COVID-19, demonstrating the significance of coagulation abnormalities in this population.3
T48 10407-10416 Sentence denotes Figure 2.
T49 10418-10457 Sentence denotes Mechanisms regulating immunothrombosis.
T50 10458-10747 Sentence denotes In vascular homeostasis, the endothelium possesses anti-inflammatory and antithrombotic properties due to the expression of CD39, nitric oxide (NO), and prostacyclin in addition to the natural anticoagulants, TFPI (tissue factor pathway inhibitor), activated protein C, and thrombomodulin.
T51 10748-11025 Sentence denotes In the setting of infection or inflammation, endothelial cells upregulate the expression of VWF (von Willebrand factor) and adhesion molecules such as ICAM (intercellular adhesion molecule)-1, αvβ3, P-selectin and E-selectin, promoting the adhesion of leukocytes and platelets.
T52 11026-11230 Sentence denotes Activated platelets release chemokines CXCL1, PF (platelet factor)-4, CXCL5, CXCL7, CCL3, RANTES (regulated on activation, normal T-cell expressed and secreted), and CCL7 to enhance leukocyte recruitment.
T53 11231-11300 Sentence denotes Leukocytes interact with platelets via several receptor/ligand pairs.
T54 11301-11542 Sentence denotes These include platelet P-selectin binding to its cognate receptor PSGL (P-selectin glycoprotein)-1 on leukocytes, GP-Ib on platelets interacting with Mac-1 on monocytes and neutrophils, and GPIIb/IIIa binding to SLC44A2/CTL-2 on neutrophils.
T55 11543-11828 Sentence denotes Activated platelets release polyphosphate (polyP), which activates the contact pathway, and HMGB (high mobility group box)-1, which enhances monocyte recruitment and monocyte tissue factor (TF) expression, thereby amplifying thrombin generation by way of the TF pathway of coagulation.
T56 11829-11994 Sentence denotes Neutrophils release neutrophil extracellular traps (NETs) which promote thrombosis via activation of the contact pathway and the binding and activation of platelets.
T57 11995-12282 Sentence denotes Finally, complement activation leads to the recruitment of leukocytes and upregulates TF expression, amplifies platelet activation and upregulates endothelial expression of proinflammatory cytokines, including IL (interleukin)-1, IL-6, IL-8, and MCP (monocyte chemoattractant protein)-1.
T58 12283-12485 Sentence denotes These mechanisms result in excess thrombin generation, which potentiates the activation of platelets, leukocytes, and endothelium via PARs (protease-activated receptors) and culminates in a fibrin clot.
T59 12486-12567 Sentence denotes Plasma D-dimer measurement is emerging as a direct prognostic marker in COVID-19.
T60 12568-12966 Sentence denotes In this regard, D-dimer, a fibrin degradation product released when plasmin cleaves cross-linked fibrin, appears to be higher in patients with severe COVID-19 when compared with nonsevere disease.11–15 Subsequently, further studies have highlighted that patients who do not survive COVID-19 have an elevated D-dimer level, and D-dimer continues to increase during admission before death.10,12,16,17
T61 12968-13024 Sentence denotes Interplay Between Ethnicity, Coagulation, and Thrombosis
T62 13025-13444 Sentence denotes Epidemiological data have demonstrated that race and ethnicity influence the risk of developing venous thromboembolism (VTE), with Blacks found to have the highest rate of incident VTE when compared with other ethnic groups, and Asians and Pacific Islanders having a lower rate of VTE than Whites.18,19 The underlying mechanisms for these racial differences are likely complex and to date remain to be fully understood.
T63 13445-13968 Sentence denotes Previous data have suggested that higher Factor VIII levels, VWF (von Willebrand Factor) levels and lower Protein C levels observed in African populations may account for some of the racial differences in thrombotic risk.20 In addition, recent data have highlighted important racial differences in platelet reactivity to thrombin, with platelets from Black patients commonly exhibiting polymorphisms in the PAR (protease-activated receptor)-4 that are associated with a markedly enhanced aggregation response to thrombin.21
T64 13969-14460 Sentence denotes Interestingly, however, studies evaluating Chinese and White populations have demonstrated that abnormal coagulation parameters are associated with severe infection and poor prognosis from COVID-19 regardless of ethnicity.10,12,16,22 Additionally, as discussed below, rates of thrombosis in COVID-19 appear increased regardless of the ethnic group studied, but the recognized and striking differences between racial groups are important to consider in the context of the SARS-CoV-2 pandemic.
T65 14462-14492 Sentence denotes COVID-19 and Venous Thrombosis
T66 14493-14596 Sentence denotes Current research has highlighted that rates of VTE in patients with COVID-19 appear markedly increased.
T67 14597-15660 Sentence denotes Indeed, the cumulative incidence of VTE is reported to be between 25% and 49% of patients with severe COVID-19 with pulmonary embolism being the most common thrombotic complication.23–25 Importantly, even with the use of VTE thromboprophylaxis, the risk of VTE appears to remain elevated.24,26 Interestingly, when compared with non-COVID ARDS, patients with COVID-19 ARDS have a substantially increased rate of pulmonary embolism diagnosis (2.1% versus 11.7%, respectively, P=0.008) and patients diagnosed with a thrombotic complication have more than a 5-fold increase in all-cause mortality.25,27 Recently, 2 autopsy series have revealed that in patients with COVID-19 who were not clinically suspected to have VTE ante mortem, deep vein thrombosis, or pulmonary embolism was a common finding at autopsy (reported in 7/12 [58%] and 11/11 [100%], respectively).28,29 Furthermore, a small study found massive pulmonary embolism to be the direct cause of death in over 30% of patients, highlighting the important interplay between COVID-19 and venous thrombosis.29
T68 15662-15694 Sentence denotes COVID-19 and Arterial Thrombosis
T69 15695-15823 Sentence denotes In addition to VTE, there are emerging reports that the rate of arterial thromboembolism is increased in patients with COVID-19.
T70 15824-16123 Sentence denotes Indeed, several groups have now reported rates of acute ischemic stroke of between 3% and 5% in patients admitted to hospital with COVID-19 and, in addition, preliminary reports suggest that these ischemic strokes are affecting younger people without traditional cardiovascular risk factors.24,30,31
T71 16124-16848 Sentence denotes Furthermore, acute myocardial injury commonly complicates the clinical course of severe COVID-19 and is reported in up to 20% of hospital presentations with an adverse impact on mortality.32 The underlying cause of myocardial injury is not yet evident, but it is speculated that in addition to potential damage from hypoxia or severe sepsis, SARS-CoV-2 may directly damage myocardial tissue by way of ACE-2 signaling, which is discussed further below.33 As such, controlling for underlying cardiovascular risk factors in patients with COVID-19 remains a priority due to the association with increased severity of disease, in addition to a 5-fold increase in mortality in patients with underlying cardiovascular disease.34,35
T72 16850-16887 Sentence denotes COVID-19 and Microvascular Thrombosis
T73 16888-17004 Sentence denotes In addition to macrovascular complications, there is a strong association of COVID-19 with microvascular thrombosis.
T74 17005-17989 Sentence denotes Pulmonary microvascular thrombosis has been previously described in autopsies as a complication of severe ARDS and has subsequently been reported to complicate ARDS during outbreaks of other coronaviruses, including SARS-CoV and MERS-CoV.36–41 However, this feature appears more pronounced in severe SARS-CoV-2 infection, with histology from patients with COVID-19-associated respiratory failure demonstrating a 9-fold increase in the prevalence of alveolar-capillary microthrombi when compared with patients with influenza.42 In this regard, autopsy findings have shown that, in addition to the expected features of diffuse alveolar damage found in ARDS, platelet-fibrin thrombi are a common microscopic finding in the small pulmonary vasculature, occurring in 80% to 100% of lungs examined at autopsy.43–45 In combination with other reported thrombotic events, the emerging microvascular thrombotic complications indicate a strong interaction between the SARS-CoV-2 and coagulation.
T75 17990-18196 Sentence denotes Below, we review the underlying known mechanisms for thrombosis and the growing body of work that implicates SARS-CoV-2 as a key player driving many molecular processes underpinning pathological thrombosis.
T76 18198-18271 Sentence denotes COVID-19 and the Endothelium—Hijacking the Guardian of Vascular Integrity
T77 18272-18628 Sentence denotes The primary site of human infection with SARS-CoV-2 is the lung, where S1 attaches with high affinity to ACE-2 expressed on lung alveolar type II epithelial cells (Figure 1).1,2,5 The replication and release of virus from infected cells results in pyroptosis, a highly inflammatory form of cell death that is a common feature among many cytopathic viruses.
T78 18629-19343 Sentence denotes PRR (Pattern recognition receptors), such as TLR (Toll-like receptors), subsequently detect the release of pathogen-associated molecular patterns, and intracellular danger-associated molecular patterns, such as ATP and DNA, which evokes an intense inflammatory reaction and triggers the release of proinflammatory chemokines and cytokines from neighboring cells (Figure 1).46 Strikingly, SARS-CoV-2 has been found to contain multiple single-stranded RNA fragments that can be recognized by TLR-7 and TLR-8, similar in numbers to MERS-CoV but more than SARS-CoV.47 The recognition of SARS-CoV-2 by these receptors may contribute to innate immune hyperactivation and the cytokine storm often seen in severe COVID-19.
T79 19344-19928 Sentence denotes In the setting of SARS-CoV-2 infection, the vascular endothelium appears to be targeted directly by the virus as well as the milieu of proinflammatory cytokines elicited by the immune response.48 ACE-2 is also expressed widely in extrapulmonary sites including blood vessels, heart, kidney, and intestine.49,50 Accordingly, viral RNA has been detected in urine and stool samples from patients with COVID-19.51,52 In this regard, it is currently hypothesized that viral entry via endothelial-expressed ACE-2 represents a mechanism by which the virus can enter and infect other tissues.
T80 19929-20029 Sentence denotes Recent experimental data have highlighted the ability of COVID-19 to infect human endothelial cells.
T81 20030-20376 Sentence denotes Indeed, human blood vessel organoids, which closely resemble human capillaries, contain viral RNA after exposure to COVID-19 in vitro.53 Strikingly, the application of human recombinant soluble ACE-2 markedly inhibited viral infection in human capillary organoids, pointing to a direct role for endothelial ACE-2 in viral uptake in blood vessels.
T82 20377-20716 Sentence denotes Intriguingly, the uptake of SARS-CoV-2 into cells is associated with the downregulation of ACE-2 expression.54,55 This appears to play an important role in promoting a proinflammatory and prothrombotic milieu since ACE-2 plays a pivotal role in regulating the RAS (renin-angiotensin system), by degrading angiotensin II to angiotensin 1–7.
T83 20717-20963 Sentence denotes While angiotensin II induces vasoconstriction and promotes a proinflammatory/prothrombotic phenotype, angiotensin 1–7 opposes these effects via binding to the MAS receptor, which is widely expressed including on endothelial cells and platelets.55
T84 20964-21883 Sentence denotes Interestingly, patients with SARS-CoV-2 have been demonstrated to have increased levels of IL (interleukin)-6, IL-1β, IFN (interferon)-γ, MCP-1 (monocyte chemoattractant protein 1), MIP (macrophage inflammatory protein), and IP10 (CXCL10).11 These proinflammatory cytokines can disrupt endothelial function and integrity leading to the release of VWF, upregulation of adhesion molecules, such as ICAM (intercellular adhesion molecule)-1, integrin αvβ3, P- and E-selectin, and the production of endothelial cytokines and chemokines.56,57 Thus, the endothelium adopts a proinflammatory and procoagulant phenotype that supports the recruitment of platelets and leukocytes.58,59 Furthermore, these changes are associated with the downregulation of the natural anticoagulants and corresponding upregulation of endothelial tissue factor (TF, CD142).57 Moreover, a common finding in patients with COVID-19 is profound hypoxia.
T85 21884-22345 Sentence denotes Although not formally tested in the context of SARS-CoV-2 infection, hypoxia is also likely to induce a prothrombotic endothelial phenotype since vascular hypoxia induces the activation of HIFs (hypoxia-inducible transcription factors) that have been demonstrated to upregulate endothelial TF expression while downregulating the natural anticoagulants, Protein S and TFPI (tissue factor pathway inhibitor), thus imparting a procoagulant endothelial phenotype.60
T86 22346-22566 Sentence denotes A recent case series of autopsy sections from patients with COVID-19 aligns with these experimental findings described above and highlight the ability of COVID-19 to infect endothelial cells and cause endothelial injury.
T87 22567-22929 Sentence denotes Sections of lung, kidney, and intestine from patients with COVID-19 demonstrate evidence of viral inclusion within endothelial cells, in addition to histological evidence of endothelial inflammation and cell death.48 These data point to a direct role of COVID-19 in promoting systemic microvascular dysfunction which potentially promotes a prothrombotic state.53
T88 22931-22976 Sentence denotes Platelets—First Responders in Innate Immunity
T89 22977-23100 Sentence denotes Platelets are the second most abundant cell in the circulation with >1 trillion patrolling the vasculature at any one time.
T90 23101-23350 Sentence denotes Therefore, in addition to their well-appreciated role in mediating hemostasis, they serve important immune functions.61,62 Platelets are equipped with a number of receptors and granular proteins affording them important roles in the immune response.
T91 23351-23525 Sentence denotes Indeed, activated platelets release a number of chemokines from their alpha and dense granules that facilitate leukocyte recruitment to sites of vascular injury/inflammation.
T92 23526-23870 Sentence denotes These include CXCL1, PF-4 (platelet factor 4/CXCL4), CXCL5, NAP-2 (CXCL7), and CCL3, RANTES (regulated on activation, normal T-cell expressed and secreted) (CCL5), and CCL7.63 The release of these chemokines by platelets enhances leukocyte recruitment and adhesion to platelet thrombi and also serves to modulate leukocyte functional responses.
T93 23871-24137 Sentence denotes Moreover, while lacking a nucleus, platelets express IL-1β mRNA that can be translated and secreted as mature IL-1β by activated platelets.64 Further supporting the recruitment of leukocytes, platelets express a range of receptors that facilitate leukocyte adhesion.
T94 24138-25565 Sentence denotes Activated platelets express P-selectin which allows leukocyte tethering via leukocyte expressed PSGL-1 (P-selectin glycoprotein ligand 1), while GP-Ib facilitates stable adhesion via binding to the leukocyte integrin Mac-1.65,66 More recently, platelets have been observed to have the unique ability to migrate, scavenge, and bundle bacteria up, thereby presenting them to neutrophils for phagocytosis and triggering the release of neutrophil extracellular traps (NETs), which can be induced by the P-selectin/PSGL-1 interaction as well as the recently described platelet GPIIb/IIIa (αIIbβ3, CD41/CD61) interaction with SLC44A2 (CTL-2) on neutrophils.67–69 Activated platelets further support coagulation by the release of inorganic polyphosphate (PolyP) from platelet dense granules which drives intravascular thrombin formation due to its ability to activate FXII.70 Last, activated platelets release microvesicles, small particles ranging in size from 100 to 1000 nm, that are enriched in lipid and can carry a range of cargo including cytokines and chemokines, such as IL-1β, CXCL4, CXCL7, and CCL5, growth factors, microRNA, and mitochondria.71 Moreover, CRP has recently been demonstrated to bind platelet microvesicles and activate complement via binding C1q.72 Thus, the release of platelet microvesicles can regulate immune responses by mediating a range of target cells, particularly leukocytes and endothelial cells.
T95 25567-25654 Sentence denotes COVID-19 and Platelets—Sentinels of Viral Infection and Modulators of Adaptive Immunity
T96 25655-25753 Sentence denotes The most well-studied effect of SARS-CoV-2 on platelets pertains to its effect on platelet number.
T97 25754-26234 Sentence denotes Thrombocytopenia has been reported as a common finding in severe COVID-19 with a recent meta-analysis demonstrating that thrombocytopenia was associated with a 5-fold increased risk of severe disease.14,16,73,74 The degree of thrombocytopenia in severe COVID-19 is usually mild and does not appear to be a common feature in nonsevere COVID-19.73 Whether thrombocytopenia is a direct effect of SARS-CoV-2 or multifactorial in the setting of severe illness remains to be elucidated.
T98 26235-26430 Sentence denotes To date, there is a relative paucity of data regarding how SARS-CoV-2 may influence platelet function and potentially contribute to the prothrombotic phenotype observed in patients with COVID-19.
T99 26431-26817 Sentence denotes However, there is now a large body of evidence demonstrating that viruses can directly interact with platelets thus potentially modulating their thrombotic and inflammatory function.75,76 Indeed, platelets are endowed with a large repertoire of adhesion receptors and immune receptors such as TLRs, FcγRIIa, and CXC/CCL receptors in addition to possessing the ability to engulf virions.
T100 26818-26962 Sentence denotes Influenza, like SARS-CoV-2, is a single-stranded RNA virus which has been demonstrated to activate platelets via TLR-7 and the FcγRIIa receptor.
T101 26963-28490 Sentence denotes The activation of platelet TLR-7 by viral RNA can evoke a range of functional responses which support thrombus formation, including platelet degranulation, the formation of platelet-leukocyte aggregates and platelet C3 release which in turn stimulates NETosis.75–78 In addition, previous work focusing on platelet activation by viruses has demonstrated that HSV-1 (herpes simplex virus 1) can induce thrombi via FcγRIIa on platelets and that the influenza strain H1N1 can activate platelets, both in a FcγRIIa- and thrombin-dependent fashion, thus leading to platelet GPIIb/IIIa activation, arachidonic acid metabolism, and platelet microvesicle release.79,80 Corresponding mouse studies have emphasized an important role of platelets in H1N1 infection since mice infected with sublethal doses of H1N1 demonstrated large numbers of activated platelets in their lung tissue in addition to platelet-leukocyte aggregates and microvascular thrombosis.81 Interestingly, inhibition of the major platelet adhesion receptor, GPIIb/IIIa, resulted in a protection from fatal influenza and a reduction in lung inflammation and microvascular thrombosis.81 Moreover, recent studies have demonstrated that platelets from patients with influenza contain virus particles, while human platelets appear to have the ability to internalize the influenza virus.77 Thus, a key outstanding area of research regarding the effects of SARS-CoV-2 and thrombosis pertains to how this virus interacts with platelets to mediate platelet number and function.
T102 28491-28673 Sentence denotes In this regard, understanding if SARS-CoV-2 can be internalized and activate platelet TLR-7 and whether the ACE-2 receptor is expressed on platelets remain core unanswered questions.
T103 28674-28861 Sentence denotes This is likely to be critical to understanding the link between COVID-19 and the prothrombotic phenotype given the key role of platelets in co-ordinating the thromboinflammatory response.
T104 28862-29442 Sentence denotes A prominent clinical feature of severe COVID-19 is the occurrence of respiratory decompensation typically 1 week after initial symptom onset.82 This clinical trajectory appears to correlate with the time course of the adaptive immune response to SARS-CoV-2, with T- and B-cell responses to SARS-CoV-2 being detected ≈1 week after symptom onset.46 Given it is postulated that this respiratory decompensation is driven by pulmonary microvascular thrombosis, understanding the intersection between thrombosis and the adaptive immune response to SARS-CoV-2 is of significant interest.
T105 29443-29627 Sentence denotes These interactions are likely important since platelets have previously been demonstrated to be key modulators of adaptive immunity in the context of a range of inflammatory disorders.
T106 29628-29867 Sentence denotes Platelets play an important role in regulating T-cell trafficking by facilitating the recruitment of T lymphocytes to sites of vascular injury or infection.83 Moreover, platelets enhance T-cell functional responses via multiple mechanisms.
T107 29868-30197 Sentence denotes For example, platelets express major histocompatibility complex class 1 molecules and can, therefore, directly activate T cells in an major histocompatibility complex class 1 dependent manner,84 while platelet-derived PF-4 and serotonin can regulate Th17 expansion85 and naïve T-cell activation and proliferation,86 respectively.
T108 30198-30801 Sentence denotes The importance of platelets in mediating T-cell recruitment and trafficking is underscored by data demonstrating that platelets play a fundamental role in the accumulation of cytotoxic T cells, and virus-induced organ damage, in a murine model of acute viral hepatitis.87 Akin to the bidirectional relationship between platelets and other leukocyte subsets, the activation of T cells amplifies platelet aggregation with more recent data highlighting an important role for T cells recruited to sites of venous thrombosis in orchestrating the inflammatory response and subsequent thrombus resolution.88,89
T109 30802-31497 Sentence denotes In addition to mediating T-cell functions, platelets can increase B-cell immunoglobulin (Ig)G1, IgG2, and IgG3 production.90 This is potentially significant in the setting of COVID-19 since the development of antiphospholipid antibodies, such as anti-β2 glycoprotein IgG antibodies, have been described in association with thrombosis in patients with COVID-19.91 In addition, a cohort study from France describes a large percentage of patients with severe COVID-19 demonstrate a detectable lupus anticoagulant.27 However, whether the presence of antiphospholipid antibodies in COVID-19 plays a role in COVID-19-associated thrombosis or represents merely an association remains to be established.
T110 31498-31727 Sentence denotes Nevertheless, delineating how platelets modulate the adaptive immune response to SARS-CoV-2 and the role adaptive immunity plays in mediating thrombosis and organ injury will be crucial in uncovering novel therapeutic strategies.
T111 31729-31783 Sentence denotes Leukocytes—Innate Immune Cells as Actors in Thrombosis
T112 31784-32796 Sentence denotes The recruitment of leukocytes to a thrombus not only aids the immune response but also serves to facilitate platelet activation and coagulation.92 Activated platelets facilitate neutrophils to release NETs, which are a matrix of DNA decorated with neutrophils granule proteins, such as MPO (myeloperoxidase), cathepsin G, and neutrophil elastase.93,94 NETs appear to be a primary defence mechanism to invading pathogens and as such have been demonstrated to trap and kill bacteria and fungi in addition to sequestering viruses.94,95 However, NETs have also been implicated in the pathogenesis of arterial and venous thrombosis in addition to a range of pathologies, including disseminated intravascular coagulation, sepsis, preeclampsia, vasculitis, and systemic lupus erythematosus.96,97 In the context of thrombosis, the release of the highly negatively charged NETs can trap erythrocytes and activate platelets.98 Moreover, NETs serve as a scaffold and potent activator of coagulation via multiple mechanisms.
T113 32797-33394 Sentence denotes Indeed, neutrophil elastase associated with NETs degrades the anticoagulant protein, TFPI, thereby enhancing TF activity and thrombin generation.96 Histones activate platelets via TLR-2 and TLR-4 and enhance fibrin formation, while the contact activation system, via FXII activation, is initiated by negatively charged DNA.96,99 The activation of FXII not only initiates coagulation but also has important proinflammatory properties by way of its ability to liberate the generation of bradykinin, upregulate neutrophil function, and the generation of monocyte-derived proinflammatory cytokines.100
T114 33395-34518 Sentence denotes Activated leukocytes, principally monocytes, and neutrophils, upregulate TF in response to proinflammatory cytokines, predominantly IL-6, and subsequently act to enhance coagulation.101,102 Additionally, monocytes provide a major source of intravascular TF by way of monocyte-derived, TF-bearing microvesicles.103,104 The major danger-associated molecular pattern, HMGB (high mobility group box protein)-1 released by platelets during inflammation has also been shown to be modified by leukocytes, thus facilitating its ability to co-ordinate thrombosis.105 Indeed, platelet-derived HMGB-1 is oxidized by activated monocyte-derived reactive oxygen species, thereby imparting HMGB-1s prothrombotic potential acting in a paracrine fashion to enhance platelet activation, monocyte TF expression and NET formation, and ultimately thrombin generation.105 Interestingly, it has been highlighted that type 1 interferons, a key family of widely expressed cytokines required for the co-ordinated innate immune response to bacterial and viral pathogens, enhance the release of HMBG1 thus enhancing the procoagulant activity of TF.106
T115 34520-34587 Sentence denotes COVID-19 and Leukocytes—Adding Fuel to the Thromboinflammatory Fire
T116 34588-34722 Sentence denotes The formation of NETs from activated neutrophils represents an innate immune response that aims to corral and kill invading pathogens.
T117 34723-34882 Sentence denotes However, while having an important immune function, the Janus face of NETosis is the exacerbation of tissue injury, inflammation, and intravascular thrombosis.
T118 34883-35409 Sentence denotes In the context of respiratory viruses, H1N1 infection has been linked to the excessive formation NETs in a mouse model of viral pneumonitis.95 Moreover, the infiltration of neutrophils at sites of infection and the risk of ARDS development has been demonstrated in a range of other pandemic respiratory viruses, such as H1N1, SARS-CoV, and MERS-CoV.107,108 There is now data demonstrating that patients with COVID-19 exhibit elevated levels of NETs in serum as measured by cell-free DNA, MPO-DNA, and citrullinated histone H3.
T119 35410-36016 Sentence denotes The levels of MPO-DNA and citrullinated histone H3 were higher in patients receiving mechanical ventilation compared with those not requiring any supplemental oxygen suggesting that levels of NETs correlate with disease severity.109 Interestingly, the finding that the level of NETs correlated with elevations in D-dimer and sera from patients with COVID-19 could induce NETosis in purified neutrophils suggests that NETs, by way of their ability to generate thrombin, via activation of FXII, and activate platelets, may play an important role in mediating the prothrombotic phenotype observed in COVID-19.
T120 36017-36228 Sentence denotes One of the striking observations in severe COVID-19 is the correlation between inflammatory markers, such as CRP, ferritin and IL-6 and a raised D-dimer, the latter reporting on an activated coagulation pathway.
T121 36229-36686 Sentence denotes Although a full discussion regarding the pathological hyperinflammatory response observed in severe COVID-19 is beyond the scope of this review, there is mounting evidence that monocytes/macrophages play a central role in this process.104 This is perhaps best highlighted by the observation that patients with severe COVID-19 in ICU exhibit a significant expansion of CD14+CD16+ monocytes producing IL-6 compared with nonhospitalized patients with COVID-19.
T122 36687-36837 Sentence denotes As discussed above, this is particularly relevant in the context of thrombosis given the bidirectional relationship between monocytes and coagulation.
T123 36838-36953 Sentence denotes First, activated platelets form heterotypic aggregates with monocytes in the setting of infection and inflammation.
T124 36954-38583 Sentence denotes Platelet-monocyte aggregates may play a role in mechanical occlusion of the microvasculature in addition to altering platelet and monocyte functional responses.110,111 In this regard, platelets induce monocyte NF-κB (nuclear factor κ light-chain-enhancer of activated B cells) signaling and thereby modulate monocyte effector functions and induce the synthesis of the proinflammatory cytokines IL-8 and MCP-1.112 Moreover, platelet P-selectin induces monocyte TF expression and upregulates the expression of monocyte Mac-1 (αMβ2, CD11b/CD18).113,114 The platelet-derived chemokines, PF-4 and CXCL-12, enhance monocyte survival and facilitate differentiation into macrophages,115,116 while activated platelets also enhance the phagocytic activity of macrophages.117 A consistent feature of COVID-19 is the finding that patients with existing cardiovascular risk factors are at an increased risk of severe COVID-19 and have higher fatality rates from the disease.34,35 It is noteworthy that oxidized phospholipids, which are strongly associated with atherosclerosis, have been detected in the lungs of patients with SARS-CoV.118,119 OxPLs (oxidised phospholipids) are generated by reactive oxygen species and play important roles in regulating inflammation given their demonstrated roles in promoting monocyte TF production, monocyte activation, and endothelial cell activation.104 The oxidized phospholipid, oxPAPC, has been demonstrated to play a central role in the pathogenesis of a murine model of SARS-induced acute lung injury in a process linked to monocyte/macrophage activation via the TLR-4-TRIF-TRAF-6-NF-κB pathway.119
T125 38585-38650 Sentence denotes COVID-19 and Complement—Connecting Innate Immunity and Thrombosis
T126 38651-38786 Sentence denotes The complement cascade is another important arm of the innate immune system that has been implicated in COVID-19-associated thrombosis.
T127 38787-39930 Sentence denotes Activation of the complement system, and vascular deposition of complement components, is linked to a range of thrombotic microangiopathies, including antiphospholipid syndrome and atypical hemolytic uremic syndrome.120 Recent histological findings from biopsies obtained from patients with severe COVID-19 have demonstrated the extensive deposition of the terminal complement components, C5b-9 (membrane attack complex) and C4d, in addition to the MASP-2 (mannose-binding lectin-associated serine protease) within the microvasculature.121 Strikingly, these vessels largely exhibited microvascular thrombi and, furthermore, the SARS-CoV-2 spike glycoprotein colocalized with C5b-9 and C4d in a subset of cases.121 These findings appear consistent with a recent Chinese study where lung sections from patients with severe COVID-19 all revealed strong complement staining, while patients with severe COVID-19 have also been described to have elevated serum C5a levels.122 Mechanistically, it has been suggested that the nucleocapsid (N) protein of SARS-CoV-2 binds to MASP-2 thereby triggering complement activation and amplifying tissue injury.
T128 39931-40308 Sentence denotes The activation of the complement pathway leads to enhanced production of endothelial cytokines, such as IL-1, IL-8, RANTES, IL-6, and MCP-1, and also upregulates the expression of important endothelial adhesion molecules, such as P-selectin and VWF.120,123 Moreover, the anaphylatoxins C5a and C3a, act to facilitate the recruitment and activation of monocytes and neutrophils.
T129 40309-40892 Sentence denotes Complement activation also directly induces a prothrombotic phenotype via C5a induction of neutrophil TF expression, C5b-7 monocyte TF expression, and C5b-8/C5b-9 mediated platelet activation.124,125 Furthermore, CRP has been described as a complement pathway activator and the correlation of its plasma level with COVID-19 severity highlights another potential link between immune and complement system.72 These observations have attracted major interest in exploring the role of complement directed therapies in COVID-19 patients, in particular, in COVID-19 mediated thrombosis.126
T130 40894-40953 Sentence denotes Thrombin—at the Intersection of Thrombosis and Inflammation
T131 40954-41066 Sentence denotes The canonical role of thrombin is the enzymatic cleavage of fibrinogen to fibrin to ensure efficient hemostasis.
T132 41067-41192 Sentence denotes However, thrombin also exerts pleiotropic proinflammatory effects on endothelial cells, platelets, and leukocytes (Figure 3).
T133 41193-41326 Sentence denotes In the context of viral infection, the coagulation cascade is activated as a host defence mechanism to try and limit pathogen spread.
T134 41327-41879 Sentence denotes Indeed, a number of viruses have been demonstrated to directly activate coagulation, including HIV, Ebola, Coxsackie virus, and Dengue.127 Previous data have highlighted that a major mechanism by which viral infection can induce a procoagulant phenotype pertains to the upregulation of TF expression by virus-infected endothelial cells and endothelial TLR-3 signaling in response to virus-derived pathogen-associated molecular patterns.128,129 However, excessive activation of coagulation and thrombin generation can result in deleterious consequences.
T135 41880-42149 Sentence denotes Thrombin also signals via the PARs, which are widely distributed on a broad range of cells, including platelets, epithelial cells, immune cells, astrocytes, and neurons.130 There are 4 members of the PAR receptors, PAR 1–4, all of which are G protein-coupled receptors.
T136 42150-42511 Sentence denotes Thrombin efficiently cleaves and activates PAR-1, -3, and -4.131,132 Thus, in addition to being a potent platelet agonist, thrombin also activates immune effector and endothelial cells.133,134 Indeed, thrombin-induced activation of leukocytes results in the production of several cytokines and growth factors while also upregulating leukocyte adhesive function.
T137 42512-43349 Sentence denotes Thrombin-induced endothelial activation, via PAR-1, induces the production of a range of proinflammatory cytokines and chemokines, including IL-6, IL-8, PAF (platelet-activating factor), and MCP-1, while also triggering the expression of the proadhesive molecules ICAM-1, E- and P-selectin.133–135 Accordingly, PAR signaling has been demonstrated to modulate the immune response to a number of viruses.127 In this regard, the inhibition of coagulation with an FVIIa/TF nematode anticoagulant protein in a model of Ebola virus reduced D-dimer levels, intravascular thrombosis, IL-6, and MCP-1 concentrations and improved survival in treated animals.136 Therefore, the disruption of the normal regulatory mechanisms governing thrombin production and activity occurs in the face of viral sepsis and the ensuing thromboinflammatory response.
T138 43350-43571 Sentence denotes Thus, given the raised D-dimer levels observed in patients with severe COVID-19, it is likely that dysregulation of the thrombin production is a feature of the prothrombotic phenotype associated with SARS-CoV-2 infection.
T139 43572-43581 Sentence denotes Figure 3.
T140 43583-43676 Sentence denotes Proposed role of thrombin in coronavirus disease 2019 (COVID-19)-associated immunothrombosis.
T141 43677-43998 Sentence denotes Infection of endothelial cells by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and liberation of viral danger-associated molecular pattern (DAMPs) results in endothelial activation with the upregulation of tissue factor (TF) and adhesion molecule expression in addition to endothelial cytokine production.
T142 43999-44072 Sentence denotes This leads to the recruitment and activation of leukocytes and platelets.
T143 44073-44192 Sentence denotes Activated leukocytes release neutrophil extracellular traps (NETs) and monocyte-derived, TF-bearing microvesicles (MV).
T144 44193-44247 Sentence denotes Activated platelets release polyP from dense granules.
T145 44248-44344 Sentence denotes This initiates intravascular thrombin generation via the TF and contact pathways of coagulation.
T146 44345-44528 Sentence denotes Thrombin exerts its thrombotic effect by activating platelets through the platelet PAR (protease-activated receptor)-1/4 in addition to mediating the cleavage of fibrinogen to fibrin.
T147 44529-44651 Sentence denotes Furthermore, thrombin possesses proinflammatory functions due to its ability to activate endothelial cells and leukocytes.
T148 44652-45018 Sentence denotes Thrombin activates endothelial cells via the endothelial PAR-1 receptor, leading to upregulation of IL-6, IL-8, PAF (platelet-activating factor), and MCP (monocyte chemoattractant protein)-1 in addition to the adhesion molecules P-selectin, E-selectin and ICAM (intercellular adhesion molecule)-1, all of which serve to increase leukocyte recruitment and activation.
T149 45019-45145 Sentence denotes Similarly, monocyte and T-cell functions are enhanced by thrombin activation of monocyte and T-cell expressed PAR-1 and PAR-3.
T150 45146-45333 Sentence denotes The resultant endothelial cell, platelet, and leukocyte interactions establish a positive feedback loop, which further promulgates ongoing thrombin generation leading to immunothrombosis.
T151 45334-45533 Sentence denotes This thrombotic phenotype likely results in the clinical manifestations seen in COVID-19, including pulmonary embolism (PE), microvascular thrombosis, ischemic stroke, and deep vein thrombosis (DVT).
T152 45535-45585 Sentence denotes Targeting Thrombosis for the Treatment of COVID-19
T153 45586-45839 Sentence denotes The high rates of thrombotic complications observed in patients with severe COVID-19, combined with the current lack of an effective therapy for SARS-CoV-2, has led to significant interest regarding the use of antithrombotics for patients with COVID-19.
T154 45840-46013 Sentence denotes In this regard, antithrombotic drugs which possess anti-inflammatory and/or antiviral properties have already entered clinical trials and will be discussed below (Figure 4).
T155 46014-46023 Sentence denotes Figure 4.
T156 46025-46108 Sentence denotes Treatments for targeting coronavirus disease 2019 (COVID-19)-associated thrombosis.
T157 46109-46305 Sentence denotes Heparins, including unfractionated heparin (UFH) and low molecular weight heparin (LMWH), bind antithrombin (AT), and potentiate the inhibitory effect of AT on coagulation factors Xa and thrombin.
T158 46306-46641 Sentence denotes Furthermore, UFH may have antiviral effects by having the ability to bind the receptor-binding domain of the S protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in addition to potentially acting as a decoy for naturally expressed heparan sulfate thus reducing the ability of the virus to bind to and invade cells.
T159 46642-46766 Sentence denotes The putative anti-inflammatory effects of UFH is related to its ability to bind danger-associated molecular pattern (DAMPs).
T160 46767-46916 Sentence denotes Inhibitors of FXII block the contact factor pathway of coagulation, initiated by NETs, and also appear to have pleiotropic anti-inflammatory effects.
T161 46917-47122 Sentence denotes Antiplatelet agents, such as dipyridamole, nafamostat, and aspirin inhibit platelet activation, which can inhibit NETosis and the release of platelet-derived DAMPs such as HMGB (high mobility group box)-1.
T162 47123-47226 Sentence denotes Nafamostat may inhibit the TMPRSS-2 (transmembrane protease serine 2) and therefore impede viral entry.
T163 47227-47319 Sentence denotes Fibrinolytics, such as tPA (tissue-type plasminogen activator), degrade cross-linked fibrin.
T164 47321-47336 Sentence denotes Anticoagulation
T165 47337-48016 Sentence denotes The strikingly increased prevalence of thrombotic complications has led to many hospitals instituting the routine administration of strict VTE prophylaxis with either low molecular weight heparin or unfractionated heparin and also resulting in several groups using intermediate or full-dose anticoagulation to prevent these thromboembolic phenomena.137,138 Preliminary reports have suggested that low molecular weight heparin treatment reduces mortality in COVID-19 patients with an elevated D-dimer or elevated sepsis-induced coagulopathy score.139 The heparins are widely used anticoagulants which inhibit coagulation by the antithrombin mediated inhibition of FXa or thrombin.
T166 48017-48532 Sentence denotes However, aside from their effects on anticoagulation, the heparins appear to have pleiotropic effects that may provide unique advantages in the context of viral infection, including anti-inflammatory effects by way of their ability to bind to danger-associated molecular patterns, such as HMGB-1, and proinflammatory cytokines.140,141 Unfractionated heparin has a similar structure as heparan sulfate, the sulfated polysaccharide present on cell surfaces and extracellular matrix, with repeating disaccharide units.
T167 48533-48632 Sentence denotes In contrast, low molecular weight heparin is a modified heparin with shorter polysaccharide chains.
T168 48633-49608 Sentence denotes Intriguingly, heparan sulfate has previously implicated as a docking site for a number of viruses, thus facilitating cellular attachment of the virus and subsequent viral infection.142,143 Indeed, heparin, acting as a decoy receptor for naturally expressed heparan sulfate, has been shown to inhibit the binding of the SARS coronavirus to cells in vitro.144 While ACE-2 is the major receptor that mediates viral entry into cells, heparan sulfate has previously been demonstrated to play an important role in facilitating coronavirus entry into cells by functioning as an adhesion receptor for the virus on the cell surface thereby allowing the increased density of viral particles on the cell surface which then facilitates ACE-2-mediated cell entry.145 Recent studies have directly investigated the link between heparin and SARS-CoV-2 and suggest that heparin can directly bind with the spike protein of the SARS-CoV-2 virus and, therefore, may have antiviral properties.146
T169 49609-49922 Sentence denotes Another interesting aspect of how the SARS-CoV-2 virus may be influenced by the use of heparin as anticoagulant is the previous observation that FXa can cleave the spike protein of SARS-CoV to render it more efficient in invading cells.147 However, to date, this aspect remains to be investigated with SARS-CoV-2.
T170 49923-50234 Sentence denotes These data have led some groups to propose specifically engineered heparins for the treatment of COVID-19, while clinical trials are underway to investigate the effects of low dose, and full-dose, anticoagulation with heparin on clinical outcomes for patients with COVID-19 (URL: https://www.clinicaltrials.gov.
T171 50235-50606 Sentence denotes Unique identifiers: NCT04344756 and NCT04345848).142 It is important to note that given the potential for heparin therapeutics to cause heparin-induced thrombocytopenia, but reassuringly, despite both thrombocytopenia and thrombosis being common complications of COVID-19, the development of heparin-induced thrombocytopenia appears limited to individual case reports.148
T172 50608-50659 Sentence denotes Inhibition of the Contact Factor Activation Pathway
T173 50660-50817 Sentence denotes The inhibition of FXII as means to inhibit the thromboinflammatory response incited by severe COVID-19 appears an attractive and rational therapeutic target.
T174 50818-52131 Sentence denotes Activation of the contact pathway is initiated by FXII activation by negatively charged molecules such as NETs, which are increased in severe COVID-19 patients, and platelet-derived PolyP.100 This leads to the generation of thrombin and the activation of bradykinin, of which the latter in particular results in downstream complement activation and the production of inflammatory cytokines.149 Importantly, therapeutic inhibition of FXIIa demonstrates protection from occlusive thrombus formation in animal models of thrombosis without impeding hemostasis.150 Treatment with an inhibitory FXIIa antibody in animal models of systemic inflammatory response syndrome, using a lethal E coli challenge, have shown that FXIIa inhibition improves survival and decreases a number of inflammatory markers including complement activation, neutrophil degranulation, and IL-6.151–153 Importantly, the potential safety of FXII inhibitors is highlighted by the fact that FXII-deficient individuals display no bleeding phenotype, and there is no known effect on immune function.154 A FXIIa inhibitory antibody has recently entered clinical trials for the treatment of hereditary angioedema and therefore represents a promising novel combination of antithrombotic and anti-inflammatory drugs (URL: https://www.clinicaltrials.gov.
T175 52132-52164 Sentence denotes Unique identifier: NCT03712228).
T176 52166-52209 Sentence denotes Fibrinolysis as a Novel Therapy in COVID-19
T177 52210-52520 Sentence denotes Other therapies targeting coagulation are being examined regarding their potential therapeutic utility in COVID-19, including fibrinolytic agents such as tPA (tissue-type plasminogen activator). tPA converts the inactive enzyme plasminogen to plasmin leading to the subsequent breakdown of cross-linked fibrin.
T178 52521-52680 Sentence denotes The interest in tPA has emerged from the concept that ARDS is characterized by significant local inflammatory reaction in addition to a hypofibrinolytic state.
T179 52681-52916 Sentence denotes As discussed previously, severe COVID-19 can result in ARDS, which promotes mass upregulation of inflammatory cytokines and leukocytes, and can result in extensive thrombin generation, fibrin formation, and microvascular thrombosis.155
T180 52917-53441 Sentence denotes The use of systemic tPA in preclinical and human models of ARDS demonstrates improved oxygenation, and a case report of tPA use in severe COVID-19 showed an initial improvement in oxygenation during tPA infusion, but this effect was lost after tPA therapy ceased.156–158 However, the benefits of tPA may be offset by the considerable risk of major bleeding seen in nonstroke clinical trials,159 which has led to the consideration of nebulized therapy to increase local concentrations and reduce systemic coagulation effects.
T181 53442-53661 Sentence denotes Recent clinical trial data suggest that, in severe ARDS, nebulized fibrinolytic therapy is associated with improved oxygenation and ventilatory parameters, which may be another plausible treatment option in COVID-19.155
T182 53663-53721 Sentence denotes Antiplatelet Agents as Potential Therapeutics for COVID-19
T183 53722-54267 Sentence denotes A recent meta-analysis has demonstrated that antiplatelet therapy is associated with improved mortality from sepsis.160 Interestingly, the majority of data linking antiplatelet therapy with these improved clinical outcomes relates to aspirin.161 In this regard, recent experimental data have highlighted that targeting platelets with aspirin prevents intravascular coagulation and neutrophil-mediated microvascular thrombosis in a mouse model of bacterial sepsis.162 However, to date, the effect of aspirin in COVID-19 remains to be established.
T184 54268-54450 Sentence denotes Several other therapies with antiplatelet effects, including dipyridamole and nafamostat, are currently being evaluated for their potential role in reducing the severity of COVID-19.
T185 54451-55055 Sentence denotes The antiplatelet agent dipyridamole has recently been reported to suppress SARS-CoV-2 replication in vitro, with some early data suggesting that use of adjunct dipyridamole may improve the clinical course in severe COVID-19.163 Finally, the role of nafamostat, a serine protease inhibitor which has antiplatelet effects and is currently marketed in Asia for the treatment of disseminated intravascular coagulation and pancreatitis, is being evaluated.164 Nafamostat is known to inhibit TMPRSS-2, and in preclinical studies, serine protease inhibitors are able to block SARS-CoV-2 infection of lung cells.
T186 55056-55310 Sentence denotes Prior studies of nafamostat demonstrated that the drug has potential in blocking MERS-CoV infection in vitro, suggesting a potential role for this drug in reducing the burden of severe COVID-19.5,165 The RACONA Study (URL: https://www.clinicaltrials.gov.
T187 55311-55429 Sentence denotes Unique identifier: NCT04352400) is a double-blind trial set to evaluate the efficacy of this agent in severe COVID-19.
T188 55430-55618 Sentence denotes Nonetheless, it remains to be seen if any of these investigational therapies by virtue of their antiplatelet or antiviral effects will play a substantial role in the treatment of COVID-19.
T189 55620-55643 Sentence denotes Summary and Conclusions
T190 55644-55777 Sentence denotes The emergence of the SARS-CoV-2 virus and the ensuing global pandemic has presented unprecedented healthcare and economic challenges.
T191 55778-55974 Sentence denotes A key clinical feature of severe COVID-19 seems to be a highly prothrombotic state, which is linked to excess rates of arterial, venous and microvascular thrombosis, and adverse clinical outcomes.
T192 55975-56264 Sentence denotes Emerging evidence suggests that SARS-CoV-2 can infect endothelial cells with the associated immune response and ensuing activation of inflammatory pathways resulting in dysregulation of the endothelium, leukocyte activation, NET generation, complement deposition, and platelet consumption.
T193 56265-56403 Sentence denotes These pathways can conspire to unleash a prothrombotic state (immunothrombosis), which may result in significant thrombotic complications.
T194 56404-56663 Sentence denotes Accordingly, there remains much interest, and an urgent clinical need, to precisely delineate the mechanisms by which SARS-CoV-2 infection causes thrombotic complications in the hope that new insights into this process will yield novel therapeutic approaches.
T195 56664-56757 Sentence denotes This is especially pressing in the absence of an effective therapy or vaccine for SARS-CoV-2.
T196 56758-57040 Sentence denotes Thus, in the context of COVID-19 the intersection of innate and adaptive immunity, inflammation, and thrombosis has been thrust into the global spotlight, and the challenge is now to urgently find therapeutic concepts to disrupt this unholy trinity in the face of a global pandemic.
T197 57041-57258 Sentence denotes The growing awareness and understanding of thrombotic complications in patients with SARS-CoV-2 infection will contribute to a more rigorous diagnostic approach resulting in the earlier detection of thrombotic events.
T198 57259-57480 Sentence denotes Importantly, the shift towards the early institution of antithrombotic therapy for the prevention and treatment of COVID-19-associated thrombosis will hopefully translate into improved outcomes for patients with COVID-19.
T199 57482-57500 Sentence denotes Sources of Funding
T200 57501-57505 Sentence denotes J.D.
T201 57506-57631 Sentence denotes McFadyen is supported by a National Health and Medical Research Council (NHMRC) and Heart Foundation Early Career Fellowship.
T202 57632-57634 Sentence denotes H.
T203 57635-57765 Sentence denotes Stevens is supported by the Monash University RTP Scholarship, Wheaton Family Scholarship, and HSANZ New Investigator Scholarship.
T204 57766-57768 Sentence denotes K.
T205 57769-57837 Sentence denotes Peter is supported by an NHMRC Senior Principal Research Fellowship.
T206 57839-57850 Sentence denotes Disclosures
T207 57851-57856 Sentence denotes None.
T208 57858-57896 Sentence denotes Nonstandard Abbreviations and Acronyms
T209 57897-57933 Sentence denotes ACE-2angiotensin-converting enzyme 2
T210 57934-57973 Sentence denotes ARDSacute respiratory distress syndrome
T211 57974-58006 Sentence denotes COVID-19coronavirus disease 2019
T212 58007-58028 Sentence denotes CRPC-reactive protein
T213 58029-58056 Sentence denotes DPP-4dipeptidyl peptidase 4
T214 58057-58071 Sentence denotes GPglycoprotein
T215 58072-58115 Sentence denotes HIFshypoxia-inducible transcription factors
T216 58116-58151 Sentence denotes HMGBhigh mobility group box protein
T217 58152-58179 Sentence denotes HSV-1herpes simplex virus 1
T218 58180-58219 Sentence denotes ICAM-1intercellular adhesion molecule 1
T219 58220-58233 Sentence denotes IFNinterferon
T220 58234-58247 Sentence denotes ILinterleukin
T221 58248-58287 Sentence denotes MCP-1monocyte chemoattractant protein 1
T222 58288-58343 Sentence denotes MERS-CoVMiddle Eastern respiratory syndrome coronavirus
T223 58344-58378 Sentence denotes MIPmacrophage inflammatory protein
T224 58379-58397 Sentence denotes MPOmyeloperoxidase
T225 58398-58432 Sentence denotes NETsneutrophil extracellular traps
T226 58433-58496 Sentence denotes NF-κBnuclear factor κ light-chain-enhancer of activated B cells
T227 58497-58526 Sentence denotes PAFplatelet-activating factor
T228 58527-58561 Sentence denotes PAR-4protease-activated receptor 4
T229 58562-58594 Sentence denotes PRRpattern recognition receptors
T230 58595-58633 Sentence denotes PSGL-1P-selectin glycoprotein ligand 1
T231 58634-58701 Sentence denotes RANTESregulated on activation, normal T-cell expressed and secreted
T232 58702-58728 Sentence denotes RBDreceptor-binding domain
T233 58729-58786 Sentence denotes SARS-CoV-2severe acute respiratory syndrome coronavirus 2
T234 58787-58822 Sentence denotes TFPItissue factor pathway inhibitor
T235 58823-58845 Sentence denotes TLRToll-like receptors
T236 58846-58885 Sentence denotes TMPRSS-2transmembrane protease serine 2
T237 58886-58922 Sentence denotes tPAtissue-type plasminogen activator
T238 58923-58948 Sentence denotes VTEvenous thromboembolism
T239 58949-58973 Sentence denotes VWFvon Willebrand Factor
T240 58974-59029 Sentence denotes * J.D.M. and H.S. contributed equally to this article.
T241 59030-59083 Sentence denotes For Sources of Funding and Disclosures, see page 584.