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Islam, A.; Cockcroft, C.; Elshazly, S.; Ahmed, J.; Joyce, K.; Mahfuz, H.; Islam, T.; Rashid, H.; Laher, I. Coagulopathy of Dengue and COVID-19: Clinical Considerations. Trop. Med. Infect. Dis. 2022, 7, 210.
Islam, Amin
Cockcroft, Christopher
Elshazly, Shereen
Ahmed, Javeed
Joyce, Kevin
Mahfuz, Huque
Islam, Tasbirul
Rashid, Harunor
Laher, Ismail
Thrombocytopenia and platelet dysfunction commonly occur in both dengue and COVID-19 and are related to clinical outcomes. Coagulation and fibrinolytic pathways are activated during an acute dengue infection, and endothelial dysfunction is observed in severe dengue. On the other hand, COVID-19 is characterised by a high prevalence of thrombotic complications, where bleeding is rare and occurs only in advanced stages of critical illness; here thrombin is the central mediator that activates endothelial cells, and elicits a pro-inflammatory reaction followed by platelet aggregation. Serological cross-reactivity may occur between COVID-19 and dengue infection. An important management aspect of COVID-19-induced immunothrombosis associated with thrombocytopenia is anticoagulation with or without aspirin. In contrast, the use of aspirin, nonsteroidal anti-inflammatory drugs and anticoagulants is contraindicated in dengue. Mild to moderate dengue infections are treated with supportive therapy and paracetamol for fever. Severe infection such as dengue haemorrhagic fever and dengue shock syndrome often require escalation to higher levels of support in a critical care facility. The role of therapeutic platelet transfusion is equivocal and should not be routinely used in patients with dengue with thrombocytopaenia and mild bleeding. The use of prophylactic platelet transfusion in dengue fever has strained financial and healthcare systems in endemic areas, together with risks of transfusion-transmitted infections in low- and middle-income countries. There is a clear research gap in the management of dengue with significant bleeding.
Citation: Islam, A.; Cockcroft, C.;Elshazly, S.; Ahmed, J.; Joyce, K.;Mahfuz, H.; Islam, T.; Rashid, H.;Laher, I. Coagulopathy of Dengue andCOVID-19: Clinical Considerations.Trop. Med. Infect. Dis. 2022, 7, 210.https://doi.org/10.3390/tropicalmed7090210Academic Editors: Peter A. Leggat,John Frean and Lucille BlumbergReceived: 21 July 2022Accepted: 22 August 2022Published: 25 August 2022Publisher’s Note: MDPI stays neutralwith regard to jurisdictional claims inpublished maps and institutional affil-iations.Copyright: © 2022 by the authors.Licensee MDPI, Basel, Switzerland.This article is an open access articledistributed under the terms andconditions of the Creative CommonsAttribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).Tropical Medicine and Infectious DiseaseReviewCoagulopathy of Dengue and COVID-19: Clinical ConsiderationsAmin Islam 1,2,*, Christopher Cockcroft 1, Shereen Elshazly 1,3 , Javeed Ahmed 4, Kevin Joyce 1, Huque Mahfuz 5,Tasbirul Islam 6, Harunor Rashid 7,8 and Ismail Laher 91 Department of Haematology, Mid & South Essex University Hospital NHS Foundation Trust,Prittlewell Chase, Westcliff-on-Sea SS0 0RY, UK2 Department of Haematology, Queen Mary University of London, Mile End Road, London E1 3NS, UK3 Adult Haemato-Oncology Unit, Faculty of Medicine, Ainshams University, Cairo 11566, Egypt4 Department of Microbiology and Virology, Mid & South Essex University Hospital NHS Foundation Trust,Westcliff-on-Sea SS0 0RY, UK5 Department of Haematology and Oncology, Combined Military Hospital, Dhaka 1206, Bangladesh6 Department of Pulmonology and Critical Care Medicine, Indiana School of Medicine, Lafayette, IN 47907, USA7 National Centre for Immunisation Research and Surveillance, The Children’s Hospital at Westmead,Westmead, NSW 2145, Australia8 Sydney Institute for Infectious Diseases, The University of Sydney, Westmead, NSW 2145, Australia9 Department of Anesthesiology, Pharmacology & Therapeutics, Faculty of Medicine,The University of British Colombia, Vancouver, BC V6T 1Z3, Canada* Correspondence: amin.islam@qmul.ac.ukAbstract: Thrombocytopenia and platelet dysfunction commonly occur in both dengue and COVID-19 and are related to clinical outcomes. Coagulation and fibrinolytic pathways are activated duringan acute dengue infection, and endothelial dysfunction is observed in severe dengue. On the otherhand, COVID-19 is characterised by a high prevalence of thrombotic complications, where bleedingis rare and occurs only in advanced stages of critical illness; here thrombin is the central medi-ator that activates endothelial cells, and elicits a pro-inflammatory reaction followed by plateletaggregation. Serological cross-reactivity may occur between COVID-19 and dengue infection. Animportant management aspect of COVID-19-induced immunothrombosis associated with thrombo-cytopenia is anticoagulation with or without aspirin. In contrast, the use of aspirin, nonsteroidalanti-inflammatory drugs and anticoagulants is contraindicated in dengue. Mild to moderate dengueinfections are treated with supportive therapy and paracetamol for fever. Severe infection such asdengue haemorrhagic fever and dengue shock syndrome often require escalation to higher levels ofsupport in a critical care facility. The role of therapeutic platelet transfusion is equivocal and shouldnot be routinely used in patients with dengue with thrombocytopaenia and mild bleeding. The useof prophylactic platelet transfusion in dengue fever has strained financial and healthcare systems inendemic areas, together with risks of transfusion-transmitted infections in low- and middle-incomecountries. There is a clear research gap in the management of dengue with significant bleeding.Keywords: COVID-19; cross-reactivity; dengue; haemorrhage; thrombocytopenia; thrombosis1. IntroductionThe exponential spread of COVID-19 that started early in 2020 resulted in one ofthe worst global pandemics of our lifetime, leading to a gauntlet of clinical challenges,including responding to unique patterns of coagulation anomalies. The COVID-19 out-break has further added to clinical challenges in tropical and subtropical regions of theworld, where dengue fever, caused by dengue virus (DENV) is also endemic. Similaritiesin clinical manifestations of COVID-19 and dengue fever often create diagnostic dilemmasin dengue-endemic countries with limited resources, often leading to delayed or evenincorrect diagnosis. Furthermore, there are growing concerns of cross-reactivity due topre-existing DENV-antibodies that potentially can enhance COVID-19 antibody-dependentTrop. Med. Infect. Dis. 2022, 7, 210. https://doi.org/10.3390/tropicalmed7090210 https://www.mdpi.com/journal/tropicalmedTrop. Med. Infect. Dis. 2022, 7, 210 2 of 18immune responses [1]. Mild to moderate thrombocytopenia are common to both conditionsbut have different clinico-pathological aetiologies and treatment approaches, making earlierdiagnosis key to preventing severe outcomes. Moreover, despite mild to moderate throm-bocytopenia in COVID-19 diseases, anticoagulation is an integral part of the treatmentprotocols of COVID-19 [2]. In contrast, treatment with anticoagulants is contraindicatedin dengue infections and non-steroidal anti-inflammatory agents are also avoided merelybecause of their theoretic risk of aggravated bleeding such as from the gastrointestinaltract [3]. There are concerns about the indiscriminate use of prophylactic platelet trans-fusions in dengue viral infections, especially in tropical dengue-endemic areas where theavailability of safe transfusion services remains a significant challenge due to greater risksof transfusion-transmitted infections and other immunological concerns.DENVs are the most important human arboviruses worldwide. Transmission ofdengue occurs via Aedes mosquitoes, producing four antigenically distinct serotypes(DENV-1 to DENV-4). Clinical presentations range from mild to more severe infections,with significant morbidities and mortalities in endemic areas. It is estimated that there arecurrently 50–100 million cases of dengue infections worldwide annually, with more than500,000 reported cases of severe forms of dengue infections such as dengue haemorrhagicfever (DHF) and dengue shock syndrome (DSS) [4]. The immunological cross-reactivityand common pathological processes, such as capillary leakage, thrombocytopenia, andcoagulopathy, between SARS-CoV-2 and DENV, make it difficult to distinguish their sharedclinical and laboratory characteristics (Table 1) [1]. Patients with dengue fever, includingthose with positive non-structural protein 1 (NS1) and/or IgM serology results, should bedifferentiated from those with SARS-CoV-2 infection, and if necessary, dengue IgM/IgGtesting should be repeated to identify co-infection or serological overlap [5]. It is necessaryto prepare for dengue outbreaks alongside controlling the COVID-19 pandemic, as aresurgence poses a very real threat [6].Table 1. Comparing dengue and COVID-19, based on data from Henrina et al. [7] and Centers forDisease Control and Prevention guidance [8].General Features: Dengue COVID-19VirologyFamily Flaviviridae CoronaviridaeDiameter 50 nm 65–125 nmGenetic Material ssRNA ssRNAPresentationIncubation 3–10 days 2 to 14 (median 4–5) daysFever Saddleback fever(with 2 peaks)No specific fever patterns. Defervescenceafter 6 days of illnessHeadache 45–95% 6.5–13.6%Myalgia 12% 15–44%Cough 21.5% 76%Dyspnoea 9.5–95.2% 55%Diarrhoea 6% 2–34%Abdominal pain 17–25% 2%Vomiting 30–58% 4–5%Trop. Med. Infect. Dis. 2022, 7, 210 3 of 18Table 1. Cont.General Features: Dengue COVID-19Cutaneous manifestationSkin flushing that blanch onpressure, petechiae, andconvalescent rashErythematous rash,urticaria,chickenpox-like vesiclesWarning signs:Persistent vomiting, mucosalbleeding, difficulty in breathing,lethargy/restlessness, posturalhypotension, liver enlargementand progressive increasesin haematocritDifficulty in breathing,persistent pain or pressure inthe chest, new confusion,inability to wake or stayawake, bluish lips or faceLaboratory FindingsThrombocytopenia 69.51–100% 12–36.2%Leukopenia 20–82.2% 25–29%Lymphopenia 63% 63%Raised AST 63–97% 31–35%Raised ALT 45–97% 24–28%Raised D-dimer 13–87% 46.4%2. Virology of DENVDENV is a single-stranded RNA virus of the Flaviviridae family. Each of the fourDENV serotypes vary in their epidemiological patterns, but some countries may havehyperendemicity with more than one serotype actively circulating at the same time [4], as inthe Indian subcontinent and South East Asia. There may be different genotypes with minorantigenic changes within the same serotype. Life-long immunity develops after infectionwith the same serotype, but with only a partial and short-lived immunity to anotherserotype. The recorded number of confirmed dengue cases may not accurately reflect thetrue burden of dengue, as many patients are asymptomatic or remain undiagnosed.The gold standard test to confirm dengue is by reverse transcriptase-PCR (rt-PCR)targeting regions within the genome of DENV. Resource-limited countries rely on detectingDENV IgG and IgM. The serology tests could cross-react with other flaviviruses; hence themainstay is testing for active viremia by rt-PCR [9]. Antigenic assays have recently been de-veloped that target NS1 which is secreted in infected mammalian cells. A serotype-specificmAb-based NS1 antigen-capture ELISA has reliable serotype specificity [10]. Whilst thecross-reactivity is observed in serological assays of DENV, there is no evidence that an infec-tion with DENV confers cross-infectivity to other viruses such as West Nile virus, JapaneseEncephalitis virus, or other arthropod-borne flaviviruses. An exception is cross-reactivityof DENV with yellow fever virus, the underlying cause of which remains unknown.3. Virology of COVID-19COVID-19 is caused by SARS-CoV-2, of the order Nidovirales within the familyCoronaviridae. It is an enveloped, positive-sense single-stranded RNA (+ssRNA) virus ofdimension between 65 and 125 nm [8]. Cell membrane attachment is achieved through aspike protein interaction with cell surface receptor angiotensin-converting enzyme receptor2 (ACE2), leading to membrane fusion and deposition of the virion’s genetic material intothe cytoplasm.New sub-variants of SARS-CoV-2 have emerged with varying clinical significance,including transmission rates and susceptibility to vaccination [11,12]. As a whole, SARS-CoV-2 shows structural similarities to two of its relatives, SARS-CoV (Severe Acute Respi-ratory Syndrome-Coronavirus) and MERS-CoV (Middle Eastern Respiratory Syndrome-Coronavirus) [11] both of which have caused recent epidemics.Trop. Med. Infect. Dis. 2022, 7, 210 4 of 184. Epidemiology of DengueDengue is the second most diagnosed cause of fever after malaria in travelers returningfrom low- and middle-income countries. The global incidence of dengue continues togrow, even though most cases are asymptomatic or mild and self-managed, suggestingthat case numbers are likely under-reported. Many cases are also misdiagnosed as otherfebrile illnesses [13]. Dengue is endemic in 129 countries with 390 million cases globallyper year, of which 96 million manifest clinically, with the majority (70%) of the burdenbeing in Asia [14,15]. Dengue is now spreading to new areas including Europe, withexplosive outbreaks also occurring. There were 2000 cases of dengue in the Madeira Islandsof Portugal in 2012, with imported cases detected in mainland Portugal and 10 otherEuropean countries.The largest recent outbreak of dengue was in 2019, when all the World Health Or-ganization (WHO) Regions were affected. The Region of the Americas alone reported3.1 million cases, with more than 25,000 cases classified as severe [16]. Dengue affectedseveral countries in 2020; however, cases drastically reduced by 55–65% with the advent ofthe COVID-19 wave in the year 2021 across the globe indicating an ‘inverse relationship’between the two diseases [17].Lifestyle changes and globalisation place severe limitations on the control of mosquitovectors to reduce dengue viral infections, in part due to rapid urbanisation in many counties.The increasing use of containers for water storage, such as automobile tyres and plasticcontainers, creates ideal sites for oviposition and larval habitats for Aedes aegypti mosquitoes.Most of the mosquito-control efforts directed at adult mosquitoes in the early 1970s usedexpensive methods that were largely ineffective. Changing human lifestyles creates morelarval habitats, thus facilitating dengue transmission by increasing mosquito populationsin areas with crowded human habitation [18].5. Epidemiology of COVID-19COVID-19 was first described in Wuhan province (China) in December 2019. Itquickly spread throughout the world and was designated a Public Health Emergency ofInternational Concern (PHEIC), the WHO’s highest level of alert, on 30 January 2020. Theresultant pandemic created dramatic lockdown measures across the globe that affectedinternational and local travel. There were over 541 million confirmed COVID-19 cases and6.3 million deaths reported to the WHO as of 4 July 2022 [19].SARS-CoV-2 is believed to have crossed the species barrier to humans from an animalreservoir, most likely from bats [20]. Transmission is believed to occur either through largedroplets or aerosols in the form of coughing or sneezing [21]. As such, the infection spreadsbest in densely packed communities, especially where physical distancing is not practiced,and where cough etiquette is not observed meticulously. There are also rare reports offaeco-oral or vertical transmissions [22].The incubation period is variably reported to be between 2 and 14 days [22,23]. Theperiod of infectivity extends from a few days before the symptom onset to several days post-symptom resolution [24]. Such a lag before the onset of warning signs and the cessation ofinfectivity, along with cases of asymptomatic spreading [25], allows COVID-19 to continueto spread even in a population vigilant of the signs and practicing symptomatic isolation.The spectrum of COVID-19 severity varies from asymptomatic to life-threatening/fatal infec-tion. Risk factors for severe infection include advanced age and presence of comorbidities [22](Table 2). Vaccinations have become the leading deterrent for severe illness and hospitalisation [26].Trop. Med. Infect. Dis. 2022, 7, 210 5 of 18Table 2. Risk factors for severe dengue and COVID-19, based on Centers for Disease Control andPrevention guidance [27–29].Dengue COVID-19Viral characteristicsViral titer correlates with disease severity.There may be strain and serotypedifferences in pathogenicity.Relationship between viral titer and severitypoorly understood.Certain variants, (via increased transmission,vaccine resistance etc.).Host factorsAge (infant)Women, especially pregnant women.Patients with chronic medicalconditions, including diabetes, asthma, obesityand heart disease.Patients with secondary DENV infection.Age (elderly)Pregnant/recently pregnant women.Comorbidities, such as chronic kidney disease,malignancy, chronic lung disease, dementia,cardiovascular disease, diabetes,immunosuppression,multiple comorbidities.At the time of writing, the global outbreak of COVID-19 is largely receding, with thelast peak recorded in January 2022 [19]. The WHO regions with the greatest burden ofdisease are the Americas, Europe and the Western Pacific region; however, inconsistenciesin global surveillance and reporting systems are likely to misrepresent the true magnitudeof the pandemic.6. Severe Dengue in Adults and InfantsThe risk of dengue infection in various patient groups is summarised in Table 2.6.1. Antibody-Dependent Enhancement and Severe DengueSevere dengue most commonly occurs in infants and adults with secondary dengueinfections (i.e., infection with a DENV type different from a previous DENV infection).The most widely cited hypothesis for this is antibody-dependent enhancement (ADE) ofdisease, which occurs when non-neutralising anti-DENV antibodies bind to, but do notneutralise, an infecting DENV. This virus-antibody complex allows for enhanced viral entryinto host cells (specifically dendritic cells and macrophages) and the virus replicates andgenerates higher viral titers in blood than when the anti-DENV antibody is not present,resulting in a ‘cytokine storm’ and exacerbating the disease.6.2. Severe Dengue among InfantsInfants in dengue-endemic areas have anti-DENV IgG antibodies at birth. Anti-DENVIgG antibodies are passed from a mother to foetus (IgM does not cross placenta). Thispassively transferred maternal anti-DENV IgG can protect the infant for a few months afterbirth, which can explain why the occurrence of dengue in infants under 4 months of age isunusual. However, as the maternal anti-DENV IgG titer falls 4–6 months after birth, ADEoutweighs neutralisation, and the infant is at higher risk for severe disease even with aprimary DENV infection. Children aged one year or more are not at increased risk.7. General Aspects of Platelets and HaemostasisPlatelets play an integral part in primary haemostasis by forming a thrombus at thesite of vascular injury; new platelets are produced daily to maintain a platelet count of150–400 × 109 platelets/L blood [30–32]. Activated platelets undergo actin-mediated shapechanges (from smooth discoid to spiny spheres) when passing through damaged bloodvessels. Various receptors for adhesive and clotting proteins in activated platelets thenattract other platelets to form a plug that limits vascular leakage [33].Platelets activate neutrophils, monocytes and lymphocytes to form platelet-leukocyteaggregates, and thus participate in immune responses. It is possible that platelet surfacereceptors such as toll-like receptors (TLRs) and glycoprotein V1 play roles in immuneresponses [34]. A haemostatic envelope which prevents excessive bleeding after vascularTrop. Med. Infect. Dis. 2022, 7, 210 6 of 18injury is formed by exposure to membrane-bound tissue factor (TF) that is constitutivelyexpressed on the cell surfaces of fibroblasts and muscle cells [35]. The conversion of factorX to Xa occurs after catalysis by TF-V11a, which further assembles the prothrombinasecomplex formed by factor Xa, factor Va, factor II (prothrombin) and Ca2+, resulting inthe generation of thrombin [36]. The semipermeable properties of endothelial cells aresupported by platelets in a well-recognised process, where platelet activation releasesproangiogenic molecules that mediate the migration and proliferation of vascular cells, andvessel organisation and stabilisation [37,38].8. Coagulopathy in DengueThrombocytopenia remains a potential indicator of clinical severity of dengue infec-tion as per WHO guidelines, with the most recent WHO guidelines (from 2009) describingrapid decreases in platelet count, or a count of less than 150,000 per microliter of blood [39].Coagulation and fibrinolytic pathways are activated during an acute dengue infection [40].Thrombocytopenia, coagulopathy and vasculopathy are related to the platelet and endothe-lial dysfunction observed in severe dengue. A recent study reports that mild to moderatethrombocytopenia occurs 3 to 7 days (significantly on the 4th day) after infection andreturns to normal levels on day 8 or 9 of infections in adult patients without shock [41].There is no clear relationship between the platelet count, disease severity and bleedingmanifestations in dengue viral infections in children [42]. A platelet count of 5 × 109/Land haematocrit (HCT) > 50 L/L (normal range 0.40–0.52) is associated with bleedingsymptoms in adults, though a study of 245 dengue patients showed there is no clear cor-relation between clinical bleeding and platelet count, whereas 81 non-bleeding patientshad a platelet count of <20 × 109/L [43], while another study of 225 patients demonstratedbleeding to be more frequent when the platelet count reached below 20 × 109/L [44].Most clinical guidelines recommend that platelet transfusions should be given topatients who develop serious haemorrhagic symptoms or when platelet count is be-low 10–20 × 109/L without haemorrhage. It is also advised that platelet transfusionshould be considered in patients with bleeding manifestations when platelet count is below50 × 109/L. However, the efficacy of platelet transfusions in dengue viral infection remainsa matter of debate. A study involving 106 children with DSS who had thrombocytopeniaand coagulopathy indicated no significant differences in bleeding manifestations betweenchildren who received platelets or not. Patients who received platelet transfusions hadmore transfusion-associated pulmonary oedema and longer hospital stays [45].Severe thrombocytopenia and the secondary effects of hypoxia due to prolonged shockresulting in acidosis can trigger disseminated intravascular coagulation (DIC) and majorhaemorrhagic manifestations in some patients. Despite less severe bleeding and someminor abnormalities of basic clotting tests, all major pathways of the coagulation cascadeare changed in children with DSS. Levels of proteins C, S and antithrombin are reducedsecondary to leakage through the vascular endothelium, and correlate with the severityof shock in critical dengue infections. Direct activation of fibrinolysis by DENV may besecondary to raised levels of TF, thrombomodulin and plasminogen activator inhibitor 1(PAI-1) which can then activate endothelial cells, platelets and monocytes.The details of the pathogenesis of thrombocytopenia and bleeding are poorly under-stood, with many hypotheses offered on the pathogenesis, such as that DENV directly orindirectly affects bone marrow progenitor cells by inhibiting their function and reducingproliferative capacities [46], as supported by findings that DENV induces bone marrowhypoplasia during acute phases of the disease [47]. In addition to low platelet counts, func-tional disruption of platelets is associated with deregulation of the plasma kinin system andthe immunopathogenesis of dengue [48]. Dengue viral infection induces platelet consump-tion due to DIC, platelet destruction due to increased apoptosis, lysis by the complementsystem and activation of antiplatelet antibodies [49]. Cytokines (e.g., TNF-α), interleukins(IL-2, IL-6, IL-8) and interferons (IFN-α and IFN-γ) also have roles in thrombocytopenia byTrop. Med. Infect. Dis. 2022, 7, 210 7 of 18suppressing haematopoiesis. Levels of these cytokines correlate with the clinical severityof dengue infection [50].Other comorbidities increase the risk of severity of dengue; for example, allergy ordiabetes increase the risk of DHF by 2.5 times, and hepatitis also increases the risk ofcomplications. Increases in viral infections, hyperferritinaemia and the activation of coagu-lation and fibrinolytic systems occur in children with dengue compared to those withouthyperferritinaemia. Other contributing factors to thrombocytopenia include cytokines,coagulation mediators, adhesive molecules and proteins, which encourage inflammatoryresponse promoting cell interactions between platelets, immune cells and the endothelium.In addition, thrombocytopenia resulting from decreased bone marrow production andincreased peripheral destruction of platelets, causes immune thrombocytopenia (ITP).NS1 correlates well with levels of viremia, and is particularly high in patients sufferingfrom DHF. Several mechanisms have been proposed by which NS1 contributes to thecoagulopathy seen in DHF, such as proinflammatory cytokine release via activation ofmacrophages, and activation of complement, whilst expressed on the surface of infectedcells and when released into the surrounding plasma, both of which contribute to endothe-lial damage and increase permeability, leading to DHF [51]. Anti-NS1 (a cross-reactiveanti-dengue antibody) and prM (structural precursor-membrane protein), and coronavirusE proteins all target platelets, endothelial cells and coagulation molecules. This processcontributes to endothelial damage, macrophage activation and more platelet dysfunction,ultimately leading to further worsening of coagulopathy. Increased vascular fragility andimpaired platelet function leads to haemorrhage, which can further contribute to plasmaleakage in DHF/DSS [52]. There may also be other more complex mechanisms involved indengue immunopathogenesis, platelet dysfunction and thrombocytopenia [53].9. Thrombocytopenia Associated with COVID VaccinesThrombotic thrombocytopenia syndrome (TTS), a complication of COVID-19 vaccines,involves thrombosis and thrombocytopenia with infrequent arterial thrombosis. TTS ap-pears to mostly affect females aged between 20 and 50 years old, with no predisposingrisk factors conclusively identified so far. Cases are characterised by thrombocytopenia,higher levels of D-dimers than commonly observed in venous thromboembolic events(VTE), inexplicably low fibrinogen levels and worsening thrombosis. Hyper-fibrinolysisassociated with bleeding can also occur. Antibodies that bind platelet factor 4, like thoseassociated with heparin-induced thrombocytopenia, have also been identified but in theabsence of patient exposure to heparin treatment. TTS is an extremely rare but increasinglyrecognised serious adverse event related to thromboembolism at unusual sites, such ascerebral venous sinus thrombosis (CVST) or abdominal thromboses (splanchnic, mesentericor portal vein), all of which are associated with thrombocytopenia. ‘CVST with throm-bocytopenia’ is a rare subtype of cerebrovascular accident, with an incidence of 5.0 permillion in those receiving Vaxzevria (manufactured by AstraZeneca) and 4.1 per millionin those receiving mRNA-based vaccines, and the prevalence is three times greater inyounger to middle aged women (mean age 35). Several countries have suspended the useof adenovirus-vectored vaccines for younger individuals. The prevailing opinion is that therisk of developing COVID-19 disease, including thrombosis, far exceeds the extremely lowrisk of TTS associated with highly efficacious vaccines. Mass vaccination should continuebut with caution. Vaccines that are more likely to cause TTS (e.g., Vaxzevria) should beavoided in younger patients for whom an alternative vaccine is available [54]. The onlyvaccine currently known to cause ITP is the mumps, measles and rubella (MMR) vaccine,but with low incidence.10. Coagulopathy of Dengue versus COVID-19The clinical manifestation and magnitude of coagulopathy varies greatly in patients withdengue due to differences in viral virulence, routes of exposure and host conditions [55].Minor bleeding, including petechiae, epistaxis and bleeding gums, can occur and helpTrop. Med. Infect. Dis. 2022, 7, 210 8 of 18to recognise viral haemorrhagic fever in its early stages [56]. Unlike COVID-19, denguerarely causes respiratory dysfunction and/or acute lung injury. Vascular injury resultsin increased permeability, hypovolaemia and circulatory shock in the advanced stages ofsevere viral hemorrhagic fever.Shock can also occur in COVID-19. Multisystem inflammatory syndrome in children(MIS-C) and multisystem inflammatory syndrome in adults (MIS-A) are rare post-infectiouscomplications characterised by fever, systemic inflammation, abdominal pain and cardiacinvolvement. The symptoms usually occur late, while the sudden onset of severe systemicinflammation with shock is reminiscent of toxic shock syndrome in bacterial infections. Theaetiology of MIS-C and MIS-A is uncertain, but derangement of the autoimmune reaction isa possibility [57]. Increased vascular permeability in viral hemorrhagic fever also inducescoagulation defects that can result in severe bleeding [58].Systemic viral infection also induces an acute inflammatory and hypercoagulable state,causing DIC that increases the risk of multiorgan failure and death. However, except forEbola and Marburg, bleeding in haemorrhagic fevers is rarely a direct cause of death [59].Coagulopathy is common in filovirus diseases and also occurs in dengue. Petechiae,gingival and mucosal bleeding, and sustained bleeding at venipuncture site can occur inthese patients. These symptoms usually diminish within a week, but a small proportionof patients develop DHF with worsening of bleeding and shock [60]. In 1997, the WHOcharacterised typical DHF by four major clinical manifestations: (1) sustained high feverfor two to seven days; (2) a haemorrhagic tendency, such as a positive tourniquet test,or clinical bleeding; (3) thrombocytopenia (platelets ≤ 100 × 109/L); and (4) evidence ofplasma leakage manifested by haemoconcentration (>20% increase in hematocrit) or pleuraleffusion [61].The clinical features of coagulation disorders are quite different in COVID-19 anddengue (see Table 3). COVID-19 is characterised by a high prevalence of thrombotic compli-cations, with an estimated overall prevalence of VTE of 14.1% [62]. The incidence of VTE inCOVID-19 is at least threefold higher than in other viral respiratory infections [63]. In morecritically ill patients, the incidence of VTE is 45.6%, while it was 23.0% in non-ICU (intensivecare unit) patients [62]. Coagulopathy in COVID-19 is initiated by local lung injury, andfollowing the initial localised thrombo-inflammatory response, systemic hypercoagulabilitybecomes prominent. Coagulation tests including prothrombin time (PT) and activatedpartial thromboplastin time (aPTT) are usually normal; however, more sensitive viscoelastictesting demonstrates a hypercoagulable pattern mainly due to activated platelets [64]. SinceSARS-CoV-2 injures vascular endothelial cells, the loss of anticoagulant activity is anothercritical factor for prothrombotic changes. Internalisation of ACE2 to increase angiotensinII levels causes vasoconstriction, hyperinflammation, and the release of prothromboticsubstances such as von Willebrand factor (VWF), P-selectin, factor VIII and angiopoietin2 [65]. Bleeding rarely occurs in COVID-19, especially in advanced stages of critical illness.Increased haemorrhage is due to thrombocytopenia, platelet dysfunction and consumptivecoagulopathy often complicated by secondary infections [66].Table 3. Coagulation disorders in COVID-19 and dengue (based on Iba et al. [67]).General Dengue COVID-19Basic comparisons Consumptive coagulopathy is common Consumptive coagulation disorder is seen inlimited casesBleeding in VHF andthrombosis in COVD-19Increased permeability in viral haemorrhagicfever also induces coagulation defects that canresult in critical bleeding. The systemic viralinfection also induces an acute inflammatoryand hypercoagulable state causing DICCOVID-19 is characterised by a highprevalence of thrombotic complications.Infrequently, bleeding can occur, especially inadvanced stages of critical illnessTrop. Med. Infect. Dis. 2022, 7, 210 9 of 18Table 3. Cont.General Dengue COVID-19PathogenesisInfected dendritic cells and macrophages losetheir ability to regulate type I IFN levels, andlymphocytes undergo cell death. Inappropriatedendritic cell function perturbs the innateimmune system and increases vascularpermeability. Furthermore, the replicatedviruses disseminate throughout the body tosystemic reactions such as dysfunction of thevisceral parenchymal cells, platelet disabilityand coagulopathy which lead to DIC resultingin uncontrolled haemorrhageCOVID-19 directly infectsmacrophages/monocytes, provokinginflammation and thrombosis by releasingproinflammatory cytokines, and expressing TF.Activated neutrophils eject neutrophilextracellular traps and disruptantithrombogenicity by damaging glycocalyx.Thrombin activates endothelial cells, elicits aproinflammatory reaction, prothromboticchange and activates platelet aggregation.COVID-19 also infects endothelial cells bybinding to ACE2 and stimulates the release offactor VIII, VWF and angiopoietin 2, resultingin thrombosis11. Prior Exposure to DENV and COVID-19 SeverityIt is possible that prior exposure to DENV could provide some degree of cross-protection to SARS-CoV-2 infection, rendering it less severe in regions where dengueis endemic, as supported by a report from Singapore where a man and a woman (bothaged 57 years) were originally COVID-19 virus-positive and false-positive in serologicaltests for dengue, including DENV-IgM and IgG [68]. Reports are available which showthat sero-diagnostic tests for DENV yield false-positive results for SARS-CoV-2 and viceversa in dengue-endemic regions, thereby indicating potential cross-reactivity between theviruses. A recent study that tested the antigenic similarities of SARS-CoV-2 and DENVusing computational docking demonstrated that human DENV antibodies can bind tothe receptor binding domain of SARS-CoV-2 spike protein. Some of these interactionscan also potentially intercept human ACE2 receptor binding to the receptor-binding motif(RBM). Dengue serum samples predating the COVID-19 outbreak cross-reacted with theSARS-CoV-2 spike protein. Of importance is that the m396 and 80R antibodies (againstSARS virus) did not dock with RBM of SARS-CoV-2. It is probable that immunologicalmemory/antibodies to DENV in endemic countries could reduce the severity and spread ofCOVID-19. It is not known whether SARS-CoV-2 antibodies will hinder DENV infectionsby binding to DENV particles and reduce dengue incidence in the future, or even facilitateDENV infection by deploying ADE [69].12. Clinical Manifestations12.1. Haemorrhagic Manifestations of DengueMinor bleeding such as that in the nose, gums and gastrointestinal tract is occasionallyobserved in children without shock [70]. Mucosal bleeding is more common and of greaterseverity in adults. However, intracranial haemorrhage is very rare but can be a fatalcomplication [71]. Patients with profound or prolonged shock complicated by metabolicacidosis and/or DIC typically experience gastrointestinal bleeding. The clinical features ofdengue infection are summarised in Figure 1.Trop. Med. Infect. Dis. 2022, 7, 210 10 of 18Trop. Med. Infect. Dis. 2022, 7, x FOR PEER REVIEW 10 of 18 fatal complication [71]. Patients with profound or prolonged shock complicated by meta-bolic acidosis and/or DIC typically experience gastrointestinal bleeding. The clinical fea-tures of dengue infection are summarised in Figure 1. Figure 1. Systemic effects of dengue and time course of infection. 12.2. Thrombosis in COVID-19 Exaggerated inflammatory reactions occur during the advanced stages of COVID-19, including progression to acute respiratory distress syndrome (ARDS) and multi-organ failure, ultimately leading to shock, and the development of DIC [72]. The process is mul-tifactorial but is believed to largely revolve around a disproportionate inflammatory cas-cade and cytokine storm [73] dysregulating haemostatic failsafe mechanisms. Figure 2 summarises the stages and clinical features of classical COVID-19 infections. Several coexisting factors predisposing to increased thrombosis are observed throughout the progression of a COVID-19 infection and may manifest as thrombotic events such as myocardial infarction, pulmonary embolism or cerebrovascular disorders, with the highest rates reported among severe cases, particularly those needing ICU ad-mission [22]. However, there are reports of thrombosis in otherwise asymptomatic indi-viduals and occurring weeks after symptom resolution [72]. Mechanisms of coagulopathy include viral interaction with the renin angiotensin system (RAS) via its binding to ACE2 receptors in the lungs, leading to an upregulation of the prothrombotic angiotensin-II, a cytokine storm and complement activation, endothelial dysfunction and sepsis-driven and hypoxia-driven coagulopathy [72,74,75]. Severe COVID-19 has further been associ-ated with the shutdown of normal fibrinolysis, an essential failsafe in thrombotic homeo-stasis [76]. This is believed to be due to increased release of antifibrinolytic agents, most notably plasminogen activator inhibitor 1 (PAI-1) from activated platelets and damaged endothelium [77]. Thus, clots not only form more easily, but are broken down less effi-ciently once formed. Not all these mechanisms are confined to the severely ill patients, but new mechanisms will exacerbate disease progression. Thus, the risk of thrombosis persists i r . st ic ff t f ti r f i f ti .12.2. Thrombosis in COVID-19Exaggerated inflammatory reactions occur during the advanced stages of COVID-19,including progression to acute respiratory distress syndrome (ARDS) and multi-organfailure, ultimately leading to shock, and the development of DIC [72]. The process ismultifactorial but is believed to largely revolve around a disproportionate inflammatorycascade and cytokine storm [73] dysregulating haemostatic failsafe mechanisms. Figure 2summarises the stages and clinical features of classical COVID-19 infections.Several coexisting factors predisposing to increased thrombosis are observed through-out the progression of a COVID-19 infection and may manifest as thrombotic events suchas myocardial infarction, pulmonary embolism or cerebrovascular disorders, with thehighest rates reported among severe cases, particularly those needing ICU admission [22].However, there are reports of thrombosis in otherwise asymptomatic individuals andoccurring weeks after symptom resolution [72]. Mechanisms of coagulopathy include viralinteraction with the renin angiotensin system (RAS) via its binding to ACE2 receptors inthe lungs, leading to an upregulation of the prothrombotic angiotensin-II, a cytokine stormand complement activation, endothelial dysfunction and sepsis-driven and hypoxia-drivencoagulopathy [72,74,75]. Severe COVID-19 has further been associated with the shutdownof normal fibrinolysis, an essential failsafe in thrombotic homeostasis [76]. This is believedto be due to increased release of antifibrinolytic agents, most notably plasminogen activatorinhibitor 1 (PAI-1) from activated platelets and damaged endothelium [77]. Thus, clotsnot only for more easily, but are broken down less efficiently once formed. Not all thesemechanisms are confined to the severely ill patients, but new mechanisms will exacerbatedisease progression. Thus, the risk of t rombosis persists throug out a COVID-19 infection,with the risk of thrombosis being gr t r in more severely affected patients [78].Trop. Med. Infect. Dis. 2022, 7, 210 11 of 18Trop. Med. Infect. Dis. 2022, 7, x FOR PEER REVIEW 11 of 18 throughout a COVID-19 infection, with the risk of thrombosis being greater in more se-verely affected patients [78]. Figure 2. Typical stages of a COVID-19 infection and their clinical features. 13. Serological Cross-Reactivity between Dengue and COVID-19 It is often difficult to distinguish between COVID-19 and dengue owing to their shared clinical and laboratory features, including possible cross-reactivity. Failing to con-sider COVID-19 due to false-positive dengue serology can have serious implications and vice versa. In a report published from Israel using clinical data and serum samples from 55 individuals with COVID-19, dengue-specific antibodies were detected by lateral-flow rapid tests and enzyme-linked immunosorbent assay (ELISA) in 12 (21.8%) COVID-19 pa-tients compared to zero positive cases in a control group of 70 healthy individuals (p < 0.001). Of the 12 positive cases, nine had IgM positivity, two had IgG IgM positivity and one had both IgM and IgG IgM positivity. ELISA testing for dengue was positive in two additional subjects using envelope protein-directed antibodies but negative by lateral flow rapid testing. Out of 95 samples obtained from patients diagnosed with dengue be-fore September 2019, SARS-CoV-2 serology targeting the S protein was positive/equivocal in 21 (22%) (16 IgA, 5 IgG) versus 4 positives/equivocal in 102 controls (4%) (p < 0.001). Subsequent in silico analysis revealed possible similarities between SARS-CoV-2 epitopes in the HR2 domain of the spike protein and the dengue envelope protein. This finding supports possible cross-reactivity between DENV and SARS-CoV-2, which can lead to false-positive dengue serology among COVID-19 patients and vice versa—which has im-portant therapeutic and public health implications [79]. 14. Management Recommendations for COVID-19 Coagulopathy The best practice management of coagulopathy in the context of a COVID-19 infec-tion continues to evolve as new evidence emerges, and no guidance can adequately cover Figure 2. Typical stages of a COVID-19 infection and their clinical features.13. Serological Cross-Reactivity between Dengue and COVID-19It is often difficult to distinguish between COVID-19 and dengue owing to their sharedclinical and laboratory features, including possible cross-reactivity. Failing to considerCOVID-19 due to false-positive dengue serology can have serious implications and viceversa. In a report published from Israel using clinical data and serum samples from55 individuals with COVID-19, dengue-specific antibodies were detected by lateral-flowrapid tests and enzyme-linked immunosorbent assay (ELISA) in 12 (21.8%) COVID-19patients compared to zero positive cases in a control group of 70 healthy individuals(p < 0.001). Of the 12 positive cases, nine had IgM positivity, two had IgG IgM positivityand one had both IgM and IgG IgM positivity. ELISA testing for dengue was positive intwo additional subjects using envelope protein-directed antibodies but negative by lateralflow rapid testing. Out of 95 samples obtained from patients diagnosed with dengue beforeSeptember 2019, SARS-CoV-2 serology targeting the S protein was positive/equivocalin 21 (22%) (16 IgA, 5 IgG) versus 4 p sitives/equivocal in 102 controls (4%) (p < 0.001).Subsequent in silico analysis revealed possible similarities between SARS-CoV-2 epitopesin the HR2 domain of the spike protein and the dengu envelope protein. This findingsupports possible cross-reactivity betw en DENV and SARS-CoV-2, which can lead to false-positive dengue s rol gy among COVID-19 patients vice versa—which has importanttherapeutic an public hea th implications [79].14. Management Recommendations for COVID-19 CoagulopathyThe best practice management of c agulopathy in the contex of a COVID-19 infectioncontinues to evolve as new evidence emerges, and no guidance can adequately cover everypossible situation. However, some recommendations can be made regarding approachesto mitigate and treat coagulopathy in these patients. The scope of this paper does notcover all eventualities such as management of specific thrombotic syndromes (e.g., acuteTrop. Med. Infect. Dis. 2022, 7, 210 12 of 18coronary syndrome) in COVID-19, but instead lays out recommendations for generalprophylactic management.14.1. Mild COVID-19 InfectionAnticoagulation should not be commenced routinely in patients with mild, earlysymptoms, as the risk of coagulation disorders is the lowest in these patients who can betreated at home [75]. Appropriate counselling should be offered, including increased riskof coagulopathy, warning signs of clotting and basic measures for prevention (e.g., stayingwell hydrated, staying mobile).A risk–benefit analysis should be conducted for patients with other co-morbiditiesthat can increase coagulation risk. Anticoagulation should be continued in those already onanticoagulant therapy (for instance, a patient with pre-existing atrial fibrillation treated witha direct-acting oral anticoagulant). However, there are specific considerations concerningthe suitability of treatment in light of their current infection status, such as safe access tointernational normalised ratio (INR) clinics if a patient’s warfarin dosing is unstable, inwhich case an alternative anticoagulant may be more appropriate.14.2. Moderate to Severe COVID-19 InfectionIn patients with a COVID-19 syndrome severe enough to be admitted to hospital,management of thrombotic risk requires a more proactive approach. Close monitoring isrecommended for signs of either developing a VTE or coagulation abnormality and antico-agulation is recommended in the first instance, with or without mechanical prophylaxis.Specific agents and dosing will differ, and these should be sought from local ornational guidelines related to the place of treatment, and at the discretion of the cliniciantreating the patient. For instance, the National Institute of Clinical Excellence in the UKcurrently recommends that prophylactic low molecular weight heparin be offered to allCOVID-positive patients without contraindications, unless already receiving a suitableprophylaxis agent, with several considerations for escalating to a short-term therapeuticdosing regimen [80]; however, the optimal dosing in patients without evidence of currentVTE remains unclear [75].Monitoring of biochemical markers is recommended for inpatients, not only for diseaseprogression, but for signs of coagulopathy. Raised D-dimer levels are associated withincreased morbidity and mortality [72,78] and should be monitored at 2–3 day intervals [75].Though it is not generally recommended to dose anticoagulation treatment based onD-dimers [80], this can be used to identify a deteriorating patient, or the presence ofthrombus development.Severe COVID-19, as with many other critical conditions, represents an increasedrisk of developing DIC [72]. Close clinical and biochemical monitoring of signs of DIC isrecommended in the form of platelet counts and coagulation panels, including fibrinogenlevels and D-dimers. Decisions on the anticoagulation should be on a patient-to-patientbasis, with considerations balanced between the risks of thrombosis and bleeding. It isgenerally recommended that prophylactic anticoagulation be continued in the absence ofovert bleeding [75], and most reports suggest that incidence of life-threatening bleeding isless than that of major thrombosis [72]. Consultation with a local haematologist is advisedto optimise care in such cases.15. Management Recommendations in DengueGeneral Aspects of Management of DengueThere are three phases of clinical presentations of dengue infections: febrile, critical(leakage) and convalescence (Figure 1). The convalescent phase can be divided into early(24–36 h after shock or 48–60 h after leakage) and a later convalescence phase (36 h aftershock or 60 h after leakage). Disease manifestations are DHF (grades I and II) and DSS(grades III and IV). Expanded dengue syndrome is considered the most severe because thiscan lead to complications and death if not managed in a timely manner. Patients with DHFTrop. Med. Infect. Dis. 2022, 7, 210 13 of 18and DSS have different clinical presentations from other patients infected with dengue.Plasma leaks occur during the critical phases of DHF and DSS [81]. Most patients withdengue present with an undifferentiated febrile illness, but DHF/DSS occurs in only asmall number of patients. Early diagnosis of DHF/DSS is important to initiate managementpromptly to prevent shock, severe illness and death. Symptomatic and supportive treatmentis only needed during the early febrile phase. Dengue patients usually have high persistentfevers for 4–5 (range 2–7) days. Common signs and symptoms are severe headache,retro-orbital pain, myalgia, arthralgia and minor haemorrhagic manifestations such aspetechial rash, epistaxis, gum bleeding and coffee-ground vomiting. Haematemesis andmelena are both common symptoms. Haemoglobinuria is common on urine testing ofhaemolytic anaemias, especially in cases of thalassemia, other haemoglobinopathy andG-6-PD deficiency. Erythematous or maculopapular or petechial rash is especially commonin adults. Nausea and vomiting along with poor appetite and malaise are common butnonspecific symptoms [82].The use of an early tourniquet when diagnosing DHF and DSS is very helpful, whereblood pressure is measured using an appropriately sized cuff. Cuff pressure is increased toa value that is mid-way between systolic and diastolic pressure for 5 min, and the cuff isthen released. Results can be obtained after 1 min, or once normal skin circulation is noted.The test is regarded as positive if there are ≥310 petechiae/mm3 [83]. Paracetamol is theonly recommended antipyretic to treat fever, both in children and in adults; non-steroidalanti-inflammatory drugs and aspirin are contraindicated. Anti-emetics are allowed forpatients with nausea and vomiting. Other supportive and symptomatic medicines may beprovided at the physician’s discretion, depending on clinical signs and symptoms. Someexamples include anticonvulsants, anti-histamines and gastro protectives such as protonpump inhibitors. Antibiotics are not indicated unless superimposed secondary bacterialinfections are suspected.Shock or impending shock should be suspected in dengue patients with narrow pulsepressure (≤20 mmHg), hypotension, those with clinical signs of shock (rapid and weakpulse, mottled, cold and calmy skin, delayed capillary refill time (>3 s)), thrombocytopeniaand raised haematocrit (320%), leukopenia, which can be related to a poor appetite, clinicaldeterioration or significant bleeding during defervescence. Any patient with shock orimpending shock needs urgent hospitalisation for intensive monitoring of vital signs andprompt management [84].16. Management of Haemorrhage in DengueThe risk of clinically significant bleeding in dengue is unpredictable and often con-tributes to adverse outcomes. A large systematic review of 11 studies on prophylactic andtherapeutic interventions for bleeding in dengue failed to identify any effective interventionin preventing or treating clinically significant bleeding in dengue [85].A retrospective study evaluated 256 patients with dengue infection who developedthrombocytopenia (platelet count, <20× 103 platelets/µL) without prior bleeding, of which188 received platelet transfusions. Subsequent bleeding, platelet increases, and plateletrecovery times were similar between patients either receiving or not receiving platelettransfusions. Prophylactic platelet transfusion did not prevent bleeding in adult patientswith dengue infection [86]. Another multicentre, open-label, randomised controlled trial(RCT) assigned 372 patients to transfusion (n = 188) or control (n = 184) groups. Theintention-to-treat analysis shows clinical bleeding by day 7 or at hospital discharge occurredin 40 (21%) patients in the transfusion group and 48 (26%) patients in the control group(risk difference −4.98% (95% confidence interval (CI) −15.08 to 5.34); relative risk 0.81(95% CI 0.56 to 1.17); p = 0.16); however, significantly more adverse events occurred inthe transfusion group (5.81% (95% CI –4.42 to 16.01) versus 6.26% (95% CI 1.43 to 27.34);p < 0.01). No deaths were reported. The authors concluded that prophylactic platelettransfusion was not superior to supportive care in preventing bleeding in adult patientswith dengue and thrombocytopenia, and could be associated with adverse events [87].Trop. Med. Infect. Dis. 2022, 7, 210 14 of 18Some treatment recommendations are outlined below [85]:1. Prophylactic platelet transfusion should not be routinely prescribed based on lowplatelet counts in patients with dengue and no bleeding.2. Therapeutic platelet transfusion should not be routinely prescribed in patients withdengue with thrombocytopaenia and mild bleeding.3. There is insufficient evidence to support or refute the use of platelet transfusion inpatients with severe bleeding in dengue.4. There is a need for further, well-designed RCTs to evaluate the role of platelets andplasma transfusion in patients in both the prevention of bleeding and in the setting ofclinically significant bleeding in dengue infection.5. There is currently insufficient evidence regarding the role of rFVIIa, anti-D globulin,Ig or tranexamic acid in the prevention or treatment of bleeding in dengue infectionand there is a need for further research on these therapeutic agents.17. ConclusionsSignificant coagulation abnormalities, including thrombocytopenia, are common inboth dengue and COVID-19 infections. This review discusses their common pathogenesis,clinical features including potential serological false positivity, and diagnostic challengesespecially in dengue-endemic areas. We also review the importance of not transfusingplatelets routinely as this can further stress already stretched services globally.There are multiple complex mechanisms responsible for coagulation disturbances,thrombocytopenia and platelet dysfunction in dengue and paradoxical thromboembolismin COVID-19. The important aspects of treating COVID-19-induced immunothrombosisassociated with thrombocytopenia are anticoagulation with or without aspirin. However,aspirin, nonsteroidal anti-inflammatory agents and anticoagulants are contraindicated indengue infections.The importance of recognising the similar clinical presentations of both diseases andexcluding COVID-19 in the differential diagnoses in the setting of a dengue pandemic isparamount in preventing potential serious consequences in the current management ofDENV-induced thrombocytopenia. While both dengue fever and COVID-19 infections canresult in thrombocytopenia and coagulopathy, their clinical manifestations and manage-ment are quite different. Prevention and control strategies combined with vaccinationsare key to controlling disease burden. While successful vaccinations for dengue currentlyremain largely ineffective, COVID 19 vaccinations have largely been successful.Author Contributions: Conceptualisation, A.I.; resources, A.I., S.E., K.J., I.L. and C.C.; writing—A.I.,I.L, S.E., J.A. and C.C.; review—writing and editing, A.I., S.E., J.A., T.I., H.R., H.M., C.C. and I.L.;supervision, A.I. and I.L.; Figure 1 was original crafted by K.J., Figure 2 was original crafted by C.C.All authors have read and agreed to the published version of the manuscript.Funding: This work received no external funding.Institutional Review Board Statement: Not applicable.Informed Consent Statement: Not applicable.Data Availability Statement: No new data was created or analysed in this study. Data sharing is notapplicable to this article.Acknowledgments: Figures 1 and 2 were created with BioRender.com (accessed on 30 June 2022),with license to publish.Conflicts of Interest: The authors declare no conflict of interest.Trop. Med. Infect. 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Coagulopathy of Dengue and COVID-19 : Clinical Considerations
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