Characterising COVID-19 as a Viral Clotting Fever: A Mixed Methods Scoping Review

Justin Marley^1* and Nisha Marley^2
*Correspondence: Justin Marley, Essex Partnership University NHS Foundation Trust, Essex, United Kingdom, Email:

Keywords

COVID-19 • Coagulopathy • Clotting fever • Abridged Thematic Analysis (ATA) • Genome

Introduction

On December 1^st 2019, the first patient with Pneumonia of unknown origin was reported in Wuhan, China followed by several cases associated with the Huanan seafood market reported by the Health Commission of Hubei province on December 31^st 2019 [1-3]. The illness was associated with a novel Coronavirus, SARS-COV-2 which was isolated and characterized [4]. The resulting infection has been termed COVID-19.

Epidemiological characteristics of COVID-19 have been characterized and facilitated using SARS-COV2 genome sequencing [5-8]. Verity, et al. estimated the overall infection fatality rate in China at 0.66% (95% CI 0.39- 1.66) [9]. The case fatality ratio varies according to age with 0.32% (0.27- 0.38) in those aged less than 60 years and 13.4% (11.2-15.9) in those aged 80 years or older. A number of risk factors were identified for more severe illness including chronic cardiac disease, diabetes and obesity [10,11]. Factors affecting the transmission dynamics of SARS-COV2 have been identified and informed public health measures [12-14].

Asymptomatic presentation has been well described and is essential in understanding transmission dynamics but fever is recognized as a prominent clinical feature occurring in 98.6% of 138 symptomatic patients in an early study [15,16]. Other studies have confirmed the significance of fever which has been reported in 83-98% of symptomatic cases [17-21]. Further studies have characterized the longer-term consequences of COVID-19 which has been termed ‘Long COVID’ [22]. Whilst the classical presentation of COVID-19 is described as bilateral pneumonia with acute respiratory distress syndrome in more severe cases, extrapulmonary manifestations have been described including neurological, renal, dermatological, cardiac and gastrointestinal symptoms [23-25]. Silent hypoxia has been described in COVID-19 and can present a clinical challenge in routine practice [26].

An abnormal coagulation state is an important finding in COVID-19 with similarities to other coronavirus infections including MERS and SARS [27- 31]. D-Dimer levels were found to be elevated in a study of 1099 patients with COVID-19 and other coagulation abnormalities have been identified [20,32].

In this scoping review we focus on the COVID-19-related coagulopathy. We firstly provide an overview of SARS-COV2 and the pathological findings identified in COVID-19. We then outline the typical host response to a viral infection as well as the clotting cascade and then Virchow’s triad which underlies our analytical framework. We consider three important pathologies in COVID-19 which have featured in the early discussions around the COVID-19-related coagulopathy-ARDS, DIC and septicaemia. These pathologies inform our initial analysis of the literature.

SARS-COV-2

Coronaviruses are single-stranded RNA viruses and are positive sense which means they can be read as mRNA by the ribosomes in the host cell and then translated into proteins [33]. Taxonomically SARS-COV2 is a member of the suborder Coronoavirineae and the genus Betacoronaviridae which specifically infect mammals [33]. Although viruses are not classified as living organisms, the sequence of events leading to replication is described as a life cycle, outlines six steps in the virus life cycle: Attachment, penetration, uncoating, gene expression and genome replication, assembly and release [34].

During attachment, the virus attaches to the surface of the host cell followed by entry into the cytoplasm (penetration) and shedding of the viral capsid (uncoating). The viral RNA is then read (gene expression and genome replication) and then the gene products are assembled into a virion (assembly) and released from the cell (release).

Turning to coronaviruses there are four main structural proteins-spike, envelope, membrane and nucleocapsid [33]. The SARS-COV2 spike protein is divided into two functional components: S1 binds the receptor on the host cell and S2 facilitates the fusion of the virus with the host cell membrane. Like SARS, SARS-COV2 binds the ACE-2 receptor on the host cell. The ACE-2 receptor is found in tissues throughout the body [35]. SARS-COV2 also requires the priming action of trans-membrane serine protease 2 (TMPRSS2) which activates the SARS-COV2 spike protein so that the virus can fuse with the cell membrane (Figure 1) [36,37].

Literature Review

The degree of glycosylation of the S-protein is thought to interfere with the adaptive immune response by reducing the likelihood of antibody formation [33]. The open reading frames coding for the structural proteins are contained within one third of the genome and the genome also codes for accessory proteins [33]. The virus then appropriates the cell machinery to generate replication organelles including double-membrane vesicles. Viral RNA is transferred into the organelles which offer protection against the host cell’s cytosol-based RNA-sensing immune mechanisms [33]. SARS- COV2 has 79-86% sequence homology with SARS-COV or SARS-COV-like viruses [38].

A further consideration is the effect of the virus on the host and this is inferred from a range of studies. Cardot-Leccia, et al. found evidence of reduced pericytes in alveolar capillaries together with thinning of the walls of the alveolar capillaries and venules [39]. Bouhaddou, et al. present the results of a phosphoproteomics survey in SARS-COV2 infected cells and found evidence of induction of cell cycle arrest and p38 MAPK activation amongst other findings [40].

Bösmüller, et al. in a post-mortem series (n=4) found evidence of progression of pulmonary pathology with findings typical of ARDS in the more severe cases of pathology [41]. In milder pathology they found evidence of increased mRNA expression of IL-1 beta and IL-6 as well as capillaritis with the presence of neutrophils and also microthromboses in the capillaries Tabary et al. review the pathological findings in COVID-19 and summaries the findings in the lungs, gastrointestinal tract, liver, kidney, skin, heart blood, spleen and lymph nodes, brain, blood vessels and placenta [42]. Hepatocyte degeneration is noted in the liver as well as an altered vascular structure. Diffuse alveolar damage and lymphocyte infiltration is found in the lungs. Intramural non-occlusive thrombi and fibrin deposition are found in the placenta. Necrosis of the keratinocytes and Langerhans cell nests are found in the skin. Inflammatory cell infiltrates and endotheliitis are found in the blood vessels. Sinus fibrosis and white pulp atrophy are found in the spleen. Axonal injuries and leukocyte infiltration are found in the CNS. Proximal acute tubule injury, tubular necrosis and interstitial fibrosis are found in the kidneys. The post-mortem findings will represent the more severe end of COVID-19 in general depending on the cause of death which may limit generalisation.

The host response to viral infections

The human immune system is broadly divided into the adaptive and innate immune response and what follows is a simplified account of their function so as to contextualize subsequent material in this paper. The innate immune system responds to novel microbes in the early phase of an infection in contrast with the adaptive immune system which predominantly recognizes and responds to a previously encountered microbe. The innate immune system includes physical barriers in the body together with a range of cells including phagocytes (neutrophils and macrophages), mast cells, natural killer cells and the complement cascade [43]. The adaptive immune system consists mainly of B and T-lymphocytes. The T-lymphocytes recognize antigens on microbes, referred to as epitopes upon which the T-cell will clone itself to increase the number of circulating T-cells capable of recognizing the antigen [43]. In this case the T-cell has not previously encountered the microbe and is thus referred to as a naieve T-cell although any subsequent encounters will result in a more effective initial adaptive immune response. T-cells are further divided into helper T-cells which activate B-cells to respond to antigens and cytotoxic T-cells which are capable of killing other cells. T-cells and B-cells have antigen-receptors on their cell surface but B-cells are also capable of secreting antibodies that mirror their cell-surface antigen-receptor [43]. Antibody secretion results in binding of the antibody to the antigen in a process referred to as opsonisation. Opsonisation causes the affected antigen-containing body (e.g. cell) to be targeted by phagocytes which proceed to kill target cells.

The clotting cascade

Coagulation is the process by which a liquid changes to a solid or semisolid state. Coagulation of blood is essential in haemostasis, the process which prevents blood leaking from damaged blood vessels. The haemostatic system is a balance between procoagulant and anticoagulant mechanisms [44]. On the one hand the platelets adhere to damaged surfaces and aggregate whilst fibrin forms a clot. Fibrin has complex physical properties and the conditions in which fibrin clots are formed determine the structure of the clot which in turn influences the fibrinolytic susceptibility.

There are a number of anticoagulant mechanisms that provide a counterbalance. There are four main antithrombotic systems-the fibrinolytic system and the systems involving protein C and S, Tissue Factor Pathway Inhibitor (TFPI) and antithrombin. The fibrinolytic system degrades fibrin clots in a complex interplay which features the activation of plasminogen to plasmin which then acts on fibrin. Tissue plasminogen activator activates plasminogen [45].

The clotting cascade is the mechanism by which clotting is initiated and amplified in response to triggers. The clotting cascade can in the simplest form be divided into the intrinsic pathway, the extrinsic pathway and the common pathway. The clotting cascade consists of a number of clotting factors. Historically the clotting factors received many names with one factor receiving 14 different names [46]. The nomenclature of the clotting factors was rationalised in a series of meetings of the International Committee for the Nomenclature of Blood Clotting Factors between 1955 and 1958 and resulted in the use of Roman numerals. A selection of clotting factors with Roman numeral equivalents is shown in Table 1 and note that the first four factors are referred to by the clotting factor names rather than the Roman numerals (Table 1) [47].

Table 1. Clotting factors names with equivalent Roman numerals.

The extrinsic pathway is initiated with the exposure of Factor VII to Tissue Factor. Tissue Factor is expressed on circulating particles released by monocytes and platelets and components of the vascular subendothelium including smooth muscle cells and fibroblasts [44]. Expression of Tissue Factor results from damage to the blood vessel walls. The exposure of Factor VII to Tissue Factor leads to activation of Factor VII (Factor VIIa). Factor VIIa then activates Factor X in the common pathway (Figure 2).

The intrinsic pathway is also known as the contact pathway [48]. The intrinsic pathway is initiated in vivo by the inflammatory response. The intrinsic pathway in vitro can be initiated when the blood comes into contact with glass and other artificial surfaces. In the intrinsic pathway, Factor XII is activated to Factor XIIa. Factor XIIa then activates Factor XI to Factor XIa which in turn activates Factor IX to Factor IXa. Factor IXa then activates Factor VIII to Factor VIIIa (Figure 3).

The intrinsic and extrinsic pathways both act on the common pathway via activation of Factor X to Factor Xa. Factor Xa then activates Factor V to Factor Va. Finally Factor Va activates Prothrombin (formerly known as Factor II) (Figure 4). There is evidence to suggest that the intrinsic pathway’s role is to amplify the extrinsic pathway [47].

Virchow’s triad

Virchow’s triad is a well-established model of coagulation and provides a central framework for the interpretation of the data in this paper. Virchow’s triad is named after the 19^th century physician Dr Rudolph Virchow. Prior to Virchow there were different explanations for coagulation. Hippocrates advocated the model of the four humors which was further refined by Galen and remained dominant for 1300 years [49,50]. This model described pathology as resulting from an imbalance in the four humors. Organs had special functions (e.g. the spleen was believed to remove black bile) and deep vein thrombosis was believed to result from retention of humor [51,52]. This model was eventually displaced.

Dr Richard Wiseman, royal physician to King Charles II, identified stasis and the characteristics of the blood as causes of thrombosis in a paper published in 1676 thus identifying two of the components of Virchow’s triad [53]. In the late nineteenth century, Jean Cruvielhier, a French pathologist promoted an inflammatory theory of thrombosis. Virchow reacted against this theory and following experimental work, published his seminal work on thrombosis and emboli in 1856.

Virchow focused on pulmonary emboli and viewed them as originating in the deep veins. Rather than accounting for the process of thrombogenesis, Virchow identified a triad of effects resulting from the thrombus as well as explaining the propagation of the thrombus [53]. Over the next one hundred and sixty-five years, the meaning of Virchow’s triad has been reworked and this interpretation is supported by accumulating evidence.

Virchow’s triad as it is now understood refers to three factors that predispose towards coagulation: Stasis of the blood, vessel wall damage and hypercoagulability. Whilst individual components of the triad are more easily investigated the simultaneous in vivo characterisation of all three components is technically more challenging. Differentiate arterial thrombi arising from ruptured atherosclerotic plaques and venous thrombi resulting from a combination of immobility, inflammation and hypercoagulability. There are numerous factors that lead to hypercoagulability and describe a central role for Tissue Factor.

Blood flow is another key feature of Virchow’s triad. Laminar flow describes a streamlined flow which contrasts with turbulent flow in which some parts of a liquid will travel at a different velocity resulting in different characteristics of the overall flow. Atherosclerotic plaques create stenosis and can produce turbulent flow with high shear rates contrasting with low shear rates downstream of a plaque. The downstream area with low shear rates can predispose to thrombogenesis.

In areas of low shear (post-stenotic), viscosity increases and many factors predispose to thrombosis [54]. The white platelet-rich head of the arterial thrombi in the highshear region is contrasted with the red tail of the thrombus in the low-shear region which is rich in red-cells.

In summary, Virchow’s triad involves a complex interplay between three factors that can each predispose to coagulation but together form a potent combination.

Investigating COVID-19 related coagulopathies

Three possible aetiologies for a hypercoagulable state in COVID-19 are listed in Table 2 and were used in the initial examination of the literature in this paper (Table 2).

Table 2. Pathologies relevant to COVID-19 related coagulopathy.

Sepsis

Sepsis is an important differential for COVID-19-related coagulopathy. The sepsis definition was revised in 2016 by a taskforce of the European Society of Intensive Care Medicine and the Society of Critical Care Medicine and the resulting definition was termed sepsis-3 [55]. Sepsis-3 defines sepsis as a combination of infection with a dysregulated immune response and organ dysfunction. The construct of severe sepsis was removed in this definition and more severe pathology is described with the construct of septic shock which includes circulatory involvement (vasopressors are required to achieve a MAP ≥ 65 mmHg) and cellular and metabolic abnormalities (with serum lactate levels >2 mmol/l). Previously the construct of the Systemic Inflammatory Response Syndrome (SIRS) was used in the definition of sepsis. In SIRS there is a normal immune response occurring with or without an infective aetiology [43]. The taskforce determined that SIRS did not have construct validity for sepsis.

Organ dysfunction in sepsis has been assessed using the SOFA score and in the sepsis-3 definition an increase of at least 2 points is used as a threshold for organ failure. The SOFA score has been specifically developed for the evaluation of organ failure in severe sepsis [56]. A number of practical drawbacks with the use of the SOFA score led to the development of the qSOFA score which is simpler to use in clinical practice and also referenced in the sepsis-3 definition [55]. Suggest that organ dysfunction is functional rather than structural and may reflect an adaptive hibernation-like mechanism [57].

Sepsis commonly leads to coagulation with elevated D-Dimers, fibrinolysis and turnover of thrombin markers [58]. Clinically significant haemostatic changes have been identified in up to 70% of patients with sepsis [59]. Levi describes a central role for cytokines in sepsis-related coagulopathy with IL-1, IL-6 and Tumour Necrosis Factor having a prominent role [59].Also notes that fibrinolysis may be downregulated and there is a reduction in the levels of Protein C/S, TFPI and antithrombin all of which may contribute to a coagulopathy. And also notes the important balance between inflammation and sepsis-related coagulopathy [59]. Iba. et al. published their findings from the development of the sepsis-induced coagulopathy scoring system which has been widely used [60].

The importance of sepsis in COVID-19 has been recognized with the development of consensus guidelines for the management of sepsis in a critical care setting [61]. Provide an example of COVID-19-related coagulopathy with sepsis in a case where ophthalmic artery occlusion developed despite thromboprophylaxis [62].

ARDS

Acute Respiratory Distress Syndrome (ARDS) is a syndrome of respiratory failure that is predominantly diagnosed and managed in an ICU setting. ARDS was first described in 1967 and the definition has changed in response to practical and prognostic challenges [63,64]. The Berlin definition were published in 2012 (ARDS Definition Task Force) and include a threshold value for PaO₂/FiO₂, bilateral chest infiltrates evident on chest imaging, an absence of atrial hypertension or a threshold value for the pulmonary arterial pressure and an acute onset. ARDS was graded into mild, moderate and severe and requirements were made for PEEP or CPAP thresholds.

A number of treatment approaches have been developed for ARDS including prone positioning, mechanical ventilation, fluid therapy, cell-based therapy and surfactant therapy although some are experimental [65-69]. The consensus guidelines for treatment of sepsis in a critical care setting include the management of ARDS [61].

Mitchell reviews the relationship of thromboinflammation to acute lung injury in COVID-19. There is noted to be damage to the endothelium and thrombosis in the perialveolar capillaries [70]. Mitchell notes the antithrombotic and anti-inflammatory mechanisms of the vascular endothelium and that in COVID-19 there is loss of the contact with the basement membrane, exposing procoagulant factors. And also notes the influx of neutrophils and macrophages seen in COVID-19 in response to acute lung injury and their role in promoting thrombosis and inhibiting fibrinolysis [70]. The Berlin definition does not include the construct of Acute Lung Injury (ALI) due to inconsistencies in the use of the terminology although this is referenced in the older literature and refers to a milder form of lung injury [71].

Wheeler and Rice outline a number of relationships that are relevant to the question of COVID-19-related coagulopathy [72]. They note that up to 50% of cases of acute lung injury result from sepsis but also patients with acute lung injury may be more likely to develop sepsis.Also note that there is increased tissue factor expression, fibrin generation and impaired fibrinolysis sharing similarities to the pathology seen in sepsis. Note that in more severe cases of sepsis, the lung is usually involved and they suggest that this may be related to the extensive capillary network with exposure to the endothelial cells [72]. The relationship between sepsis and ARDS is important not just in terms of coagulation but also for the risk of sepsis with prolonged ventilation [73].

ARDS has been identified in COVID-19 but the utility of the syndrome has been questioned [74]. COVID-19-related ARDS may arise in multiple non-specialist settings which together with the silent hypoxia associated with COVID-19 has potential implications for the early recognition of ARDS in COVID-19. The association of ARDS with coagulopathy means that this is an important consideration in the aetiology of COVID-19-related coagulopathy.

Disseminated intravascular coagulation

Disseminated Intravascular Coagulation (DIC) is an excessive activation of coagulation that can lead to significant mortality and morbidity. The 2001 definition by the International Society on Thrombosis and Haemostasis (ISTH) describes DIC as an acquired and generalized intravascular activation of coagulation [75]. DIC is associated with many diseases and conditions (Table 3).

Table 3. Aetiology of disseminated intravascular coagulation adapted from McKay, De Gopegui, et al. and Venugopal.

Activation of coagulation is recognized as a part of the host response to infection in sepsis [76]. In DIC, the coagulation response is pathological and can result from the host response to infection. Semeraro, et al. describe the mechanisms of sepsis-related coagulopathy including disseminated intravascular coagulation [77]. One of the mediators of the relationship between the host response to infection and coagulopathy is complement and Kurosawa et al. review the complex relationship between complement and coagulation [78].

Iba, et al. distinguishes between the microthrombosis that occurs predominantly in capillary venules in DIC and in arterioles in thrombotic microangiopathy [79]. The distinction between thrombotic microangiopathy and DIC is also covered by [80]. Toh, et al. notes the importance of the multidisciplinary team in decision making with DIC as well as the nuances of interpretation of the haematological parameters [81]. Wada, et al. distinguish four types of DIC according to their characteristics and recommend stratifying DIC according to these types when undertaking diagnosis and treatment [82]. Papageorgiou, et al. reviews the treatments approaches for DIC [83].

There is an emerging evidence base for DIC in COVID-19. In a position statement by the Italian Haematology Society, DIC was suggested as a cause of the hypercoagulable state in COVID-19 [84]. Levi argues that COVID-19-related coagulopathy is distinct from DIC and notes that the thrombocytopenia is not as profound as expected in DIC, that most patients with COVID-19 would not reach the criteria for overt DIC and that there isn’t evidence for excessive thrombin production [85]. Lillicrap on the other hand cites the evidence that the criteria for overt DIC are more likely in nonsurvivors of COVID-19 [86].

Joob and Wiwanitkit describe a case of COVID-19 with petechial rashes and low platelet count, initially diagnosed as Dengue fever [87]. Dengue fever is also associated with DIC which in turn can result in petechial rashes. This case highlights the diagnostic challenges in COVID-19.

Aim

The primary aim of this study was to determine if clotting pathology in COVID-19 occurs in the presence or absence of sepsis, disseminated intravascular coagulopathy and ARDS.

The secondary aims of this study were to use an iterative approach within the scoping review to:

1. Characterize the clotting pathology in COVID-19 with reference to the literature
2. To utilize the identified characteristics to develop a testable model
3. To identify knowledge gaps
4. To make recommendations on research methodology based on the findings
5. To generate testable hypotheses in addition to those in the model

Methodology

The PRISMA extension for scoping reviews checklist was used for this paper and was a key framework for this paper [88]. Additionally we developed a number of the methods used in this scoping review which we outline below.

Overall structure of study

To test the hypothesis that there was a clotting mechanism independent of ARDS, sepsis and DIC we used a simple search strategy to identify the main papers. We described the quantitative findings and also applied a thematic analysis to identify themes both for the clinical findings in relation to the coagulopathy as well as the suggested explanatory mechanisms. We then utilized an iterative semi-structured search strategy to identify further papers relevant to the results of the thematic analysis for explanatory mechanisms [89]. These papers were utilized in the development of a theoretical framework for the characterization of the COVID-19-related coagulopathy.

Protocol and registration

There was no protocol due to the exploratory and iterative nature of the scoping review and no registration given the need to avoid a delay due to the COVID-19 pandemic.

Rationale for using a mixed methods scoping review

Whilst there is evidence to suggest that COVID-19 is associated with a coagulopathy, there are diverse views on this coagulopathy and a number of potential mediators as above. COVID-19 has only recently been described and the evidence base is developing. Given the above, a scoping review was selected in favour of a meta-analysis or systematic review where the research questions are clearer and the research evidence base may be well-developed. A mixed methods approach was used to maximise the yield from the identified studies.

Literature search for papers with evidence of clotting

As this is a scoping review, broad search terms were used to identify evidence of clinically significant clotting disorders. The search terms used in the Pubmed database are shown in Table 4.

Table 4. PubMed search terms.

The inclusion and exclusion criteria are shown in Table 5. The COVID-19 initiative has made COVID-19 related papers available during the pandemic [90]. We therefore included only papers that were freely available including through the COVID-19 initiative as this review did not receive any external funding (Table 5).

Table 5. Inclusion and exclusion criteria.

The abstracts were evaluated and after exclusions, the remaining papers were examined in detail and further exclusions took place. We excluded papers that did not present any of the data for patients with COVID-19 separately from patients without COVID-19 as this was needed for the analysis.

Analysis of main papers

Software: We used Microsoft Excel® for Windows 365 to store and analyse the data. We used Microsoft PowerPoint for the Diagram Mapping.

Data analysis: A template was created using an Excel spreadsheet and the data was filled on analysing the papers. Several columns were used to describe the pathology where more than one pathology existed in the same patient. We utilized reports of pathology, descriptions of imaging findings, operative findings, autopsy and biopsy evidence. In cases where there was clear evidence of end-organ ischaemia, we counted this as a thromboembolic event and grouped this together with clotting episodes where thromboembolism was identified or inferred from the evidence (e.g. loss of patency of a blood vessel on imaging).

For each of the studies we collected information on the number of cases, individual thromboembolic complications, sex, mortality, number of non-COVID-19 or non-thromboembolic cases and whether information was recorded on D-Dimers, fibrinogen, platelet count, prothrombin time, PaO2/ FiO2, bilateral chest infiltrates evident on chest imaging, an absence of atrial hypertension or a threshold value for the pulmonary arterial pressure, acuteness of onset, confirmation of ARDS, sepsis, DIC, antithrombin, Protein C, whether respiratory rate or blood pressure were recorded, whether qSofa or SOFA score were recorded, mental status, main country of authors. We looked for evidence of randomisation or blinding as well as a power analysis.

Whilst the analysis was underway we identified a further potential mediator of the COVID-19-related coagulopathy - activation of the alternative complement pathway and added this to the analysis of the 56 papers [91]. Where clarification was needed, we contacted the authors of the papers.

A subset of 34 papers was identified in which individual patient data was available including sex, age and pathology. This enabled us to look at sex as a biological variable. The data was aggregated and analysed, further separated according to outcome and sex and comparisons between groups based was undertaken. We utilised a two proportion Z-test to determine the statistical significance of the difference in proportions between various sample proportions.

We used the Benjamini and Hochberg procedure to correct for multiple comparisons using a false discovery rate of 0.25 [92,93].

Abridged thematic analysis and validated abridged thematic analysis: A qualitative analysis was undertaken, using what we refer to as an Abridged Thematic Analysis (ATA) which we extended this with a Validated Abridged Thematic Analysis (VATA) (Figure 5). The 56 main papers are classed as a secondary source for the purposes of thematic analysis (Figure 5) [94].

We abridged the thematic analysis by removing the coding process and working out the themes as we moved through the papers. We have outlined the process in Figure 6 to enable this to be reproduced (Figure 6).

The application of the abridged thematic analysis was two-fold

1. Firstly we looked for any characterization of the coagulopathy. We identified any distinct characteristics reported by the authors based on their clinical findings and determined if they qualified as a theme and if so which theme. When we had identified all of the themes, we then quantified the frequency of the theme in the papers.

2. Secondly we looked for explanatory mechanisms for the COVID-19- related coagulopathy.Again we identified the themes and organized them into an initial structure. We then validated the themes with an exploratory literature search. We then restructured the taxonomy. We refer to this as Validated Abridged Thematic Analysis (VATA).

Exploratory literature search: The exploratory literature search involved using specified search terms in Pubmed and selecting English language articles that were freely available including under the COVID-19 agreement and which were predominantly meta-analyses or systematic reviews in order to gain a rapid overview of the subject. We used these together with case studies or case series. We also used ‘forward searching’ from within the citations index of identified papers as well as personal knowledge of papers we were already familiar with [95,96]. For more selective questions we used additional resources including MedRxiv (RRID:SCR_018222), bioRxiv (RRID:SCR_003933), DOAJ - Directory of Open Access Journals (RRID:SCR_004521) and AMEDEO: The Medical Literature Guide (RRID:SCR_002284). We thus used a combination of primary, secondary and tertiary literature (Grewal et al.). We have included search terms used in the exploratory literature search as part of the VATA as open data in the supplemental data.

Indexing the results from the validated abridged thematic analysis: After validating the identified themes against the clinical literature, we then reorganized the themes and documented a justification for the final taxonomy of themes. We used alphanumeric identifiers to label the themes. We also utilized the resulting taxonomy to generate a narrative summary which is presented at the end of the paper.

Diagram mapping

We mapped the final taxonomy of themes onto corresponding diagrams using the alphanumeric identifiers and a set of rules which we outline below.

1. Each diagram is labelled with an alphanumeric identifier which maps onto the taxonomy
2. Concepts/constructs/phenomenon are represented by boxes with text descriptions
3. The relationships between concepts/constructs/phenomenon are identified by arrows
4. The arrows are colour coded according to the strength of evidence for the relationship and whether the evidence exists in the COVID-19 literature or in the general (i.e. non-COVID-19) literature.
5. The arrows encompass a broad range of logical relationships resulting from deductive, inductive and abductive reasoning based upon the evidence.
6. The relationships encompass multiple ontological levels

Results

Results of main literature search

The initial results of the literature search are shown in Figure 6 and include the dates of the searches. The searches identified a total of 608 papers which were reduced to 71 papers after a review of the abstracts and finally 56 papers after inspection of the full text and application of the inclusion/exclusion criteria. A number of the papers reported on mixed clotting/ischaemic pathologies (e.g. stroke and lower limb deep vein thrombosis) and so the final 56 papers are pooled. The final papers are listed in Table 6.

Table 6. Summary of identified studies.

Country of publication of included papers

The countries of publication are shown in Figure 7. There were no authors based in Africa, Oceania or South America. The authors of 84% of the papers included in the analysis were based in five countries (Italy, USA, France, Spain and China) (Figure 7).

Table 7. Descriptive statistics for thromboembolic/ischaemic events in the 56 papers.

Thromboembolic/Ischaemic events in 56 papers

The descriptive statistics for thromboembolic/ischaemic events in the 56 papers are shown in Table 7.

The analysis shows that just over 4% of the total number of patients in all the studies had a combination of COVID-19 and thromboembolic/ ischaemic events. Furthermore the average number of thromboembolic/ ischaemic events was above 1.

The distribution of the average number of ischaemic/clotting events per patient is illustrated in Figure 8. The spread of the data was not normally distributed but instead was skewed towards the mode which was one thromboembolic/ischaemic event per patient (Figure 8).

The number of thromboembolic/ischaemic events is categorised in Table 8. Strokes are differentiated according to the description. Where the occluded artery/arteries are not identified, the pathology has been identified through the infarcted regions. Several infarcted regions may result from the occlusion of a single artery but the location is not predictable due to anatomical variants and collateral circulation and therefore in these cases the distinct regions are counted. Skin livedo and necrosis are counted as thromboembolic/ischaemic events although data was not available in these cases on the potentially relevant arterial patency (e.g. acute limb ischaemia). Upper limb DVT was differentiated according to the absence or presence of a catheter with the latter group being included with medical deviceassociated clotting (Table 8).

Table 8. Thromboembolic/ischaemic/clotting events in 56 main papers.

Table 9 shows the number and percentage of papers reporting a range of syndromes, diagnoses and blood test results relevant to COVID-19- related coagulopathy. The D-Dimers and platelet count were the two most frequently reported parameters in the 56 papers (Table 9).

Table 9. Number (%) of papers reporting clinical variables/diagnoses/syndromes for 56 main Pa-pers.

ARDS

Out of the fifty-six main papers, seven studies provided evidence of ARDS with a total of 159 patients with COVID-19 and ARDS. With the exception of these were all case studies or case series and are shown in Table 10 [97]. Helms et al. reported 150 patients with 64 thrombotic complications and without evidence of disseminated intravascular coagulation [97]. The authors also compared the patients with COVID-19 and ARDS to a group with ARDS but without COVID-19. They reported a significantly increased likelihood of thrombotic events in the patients with COVID-19 (Odds Ratio 2.6 [1.1-6.1], p=0.035). The SOFA scores did not differ between the two groups (Table 10).

Table 10.  Papers with ARDS confirmation.

Sepsis

In the 56 main papers, two of the papers provide evidence of sepsis and are shown in Table 11. Norse, et al. report the case of a 62-year-old man who developed mesenteric ischaemia requiring bowel surgery and later died of septic shock [98]. In another paper the sepsis results from an E.Coli infection comorbid with COVID-19 and there is mesenteric ischaemia (Table 11) [99].

Table 11.  Papers confirming sepsis.

There are other papers where sepsis is discussed but the confirmation is less clear. Barrios Lopez, et al. report on 4 cases of ischaemic stroke with COVID-19 and suggest septic shock as a cause [100].

Other papers mention the use of the SOFA or qSOFA score which are intended for use in sepsis although they have been used for critically ill patients more generally and are shown in Table 12.

Table 12. Papers with SOFA/qSOFA/SIC score.

La Mura et al. mentions both the diagnosis and the SOFA score [99]. Poggiali et al. present two cases of COVID-19 who present with venous thromboembolism [101]. They present their findings with the Sepsis-Induced Coagulopathy (SIC) score as evidence for this pathology. The main focus of Helms, et al. is on ARDS although they exclude DIC (depending on the scoring system) and have included aggregated SOFA scores [97].

Disseminated intravascular coagulation

DIC was specifically confirmed or excluded in four papers which are shown in Table 13.

Table 13.  Papers confirming or excluding DIC.

Helms, et al. have used different scoring systems to assess DIC in patients and identified between 0 and 6 patients with DIC depending on the scoring system [97].

Klok, et al. excluded DIC in all cases while identified eight patients with overt DIC [102,103]. Klok, et al. excluded DIC in all cases [102]. Lodigiani, et al. identified 8 patients with DIC, with 25% of patients manifesting thromboembolic events and 88% of patients dying underlining the important consequences of DIC [103]. Valdivia, et al. reports a single case of acute limb ischaemia with DIC and death [104]. Helms, et al. investigated DIC as a secondary outcome and used various scoring methods to ascertain caseness [97]. No patients were identified with DIC using the ISTH “overt” score, 6 cases of DIC were identified using the JAAM-DIC score and 22 patients were identified using the SIC score indicating those at risk of DIC. Thus there was evidence of thromboembolic complications in patients with COVID-19 and where DIC had both been confirmed and excluded.

A subset of 34 studies with demographic data

We identified a subset of 34 studies which contained individual information on the age and gender of the patient as well as the corresponding pathology, enabling a more detailed characterisation of the pathology. The 34 studies are listed in Table 14.

Table 14.  34 papers with individual clinical information on pathology, gender and mortality.

In the 34 studies, the distribution of thromboembolic/ischaemic events per patient was similar to Figure 7, being skewed towards the mode value of 1 thromboembolic/ischaemic event per patient with a range of 1-8. The results are shown in Tables 8-12. In the limb ischaemia group, eight of the patients had been reported from one study where the data had been published selectively for patients that had died (i.e. individual data was not available for patients that had not died).

The 34 papers included 119 patients with COVID-19 and thromboembolic/ ischaemic events and the overall results are shown in Table 15. All of the studies are based in a hospital setting. There are a number of patients with multiple thromboembolic/ischaemic events but the numbers are counted for each type of event and the sum is therefore greater than the number of patients. 38% of the patients in this group died. The percentage of deaths varied from just under 8% in those with stroke-related thromboembolic events to just fewer than 77% in those with acute limb ischaemia (Table 15).

Table 15. Results from analysis of cases from 34 papers with individual data.

The results from the analysis of the female cases in the 34 papers are shown in Table 16. 32% of the patients in this group died. The deaths associated with each type of thromboembolic/ischaemic event ranged from 21% with cardiac thromboembolic/ischaemic events to 100% with acute limb ischaemia. The results from the analysis of the male cases in the 34 papers are shown in Table 17. There were just over twice as many males as females in the 34 papers and 40% of the patients in this group died. There were eight deaths reported in one of the studies where the data was not available for those who survived. The deaths associated with each type of thromboembolic/ischaemic event ranged from 18% with pulmonary emboli to 75% with acute limb ischaemia (Tables 16 and 17).

Table 16. Analysis of female cases in 34 papers with individual data.

Table 17.  Analysis of male cases in 34 papers with individual data.

We also compared the results in the 34 papers for those who died and those who survived. The results for the cases of those who died are shown in Table 18 where the average age is 73. The four main types of thromboembolic/ischaemic events in this group in increasing percentages were thromboembolic/ischaemic events in the splanchnic arteries (20%), stroke-related events including the carotid arteries (24%), acute limb ischaemia (24%) and cardiac thromboembolic/ischaemic events (33%) (Tables 18 and 19).

Table 18. Calculating difference between proportions using Z-test: F-Female, M -Male, FP-Female Proportion of sample, MP- Male Proportion of sample, F PC-Female Proportion of Cases, M PC-Male Proportion of Cases, D-Difference between pro-portions (smaller value subtracted from larger), SP- Sample Proportion for test statistic calculation, SE-Standard Error, TS-Test Statistic, p- P-value.

Table 19. Analysis of cases where patients died in 34 papers with individual data.

The results of the analysis of the patients that survived in the 34 papers are shown in Table 20. The average age in this group was 74 and there were twice as many men as women in this group. The four main types of thromboembolic/ischaemic events in this group in increasing percentages were pulmonary emboli (16%), venous thromboembolic events not including pulmonary emboli (19%), cardiac thromboembolic/ischaemic events (26%) and stroke-related events including the carotid arterie (32%) (Tables 19 and 20).

Table 20.  Analysis of cases where patients survived in 34 papers with individual data.

D-dimers

One paper reported the units (Fibrinogen equivalent units or D-Dimer units) and there were 27 values which cited a laboratory reference range for interpretation of the results. The other values in the studies did not include the units or reference range and so our analysis was limited to the 27 values which cited the reference range. We therefore expressed the results as multiples of the reference range and the results of the analysis are shown in Tables 21 and 22

Table 21. D -number who died, S- number who survived, DP-proportion of sample who died, SP- proportion of sample who survived, D-difference between proportions with smaller value subtracted from larger value, SaP -sample proportion for test statistic calculation, SE-standard error, TS-test statistic, p- p-value.

Table 22. Analysis of D-Dimer results expressed as multiples of upper limit of laboratory reference range.

Benjamini-Hochberg procedure applied to values in Tables 18 and 21 with exception of deaths in cases of acute limb ischaemia. F-Female, M-Male, D-Deaths, S-Survival, p-p-value, (i/m) Q rank/number of values x false discovery rate (0.25)

Fever

The papers in which the confirmation or exclusion of fever were reported are shown in Table 26. From these papers we identified 150 patients and these are summarized (Tables 23-26).

The results show that there were 1.5 times as many patients with COVID-19 and thrombo-embolic events that were reported to have fever compared to those without fever.

Table 23.  Analysis of fibrinogen results expressed as multiples of upper limit of laboratory reference range.

Table 24. Clinical correlates of 10 highest (D-Dimer/Reference range) values.

Table 25. Patients with fever.

Table 26.  Studies in which the exclusion or confirmation of fever is reported.

Reported characteristics of thromboembolic events in COVID-19

The 56 identified papers were analyzed and a thematic analysis was undertaken relating to the clinical thromboembolic/ischaemic features reported in patients with COVID-19. The themes are summarised in Table 27.

Table 27.  Percentage of papers containing comments on specified clinical features of COVID-19.

No known risk factors: This was the most commonly reported characteristic of thromboembolic events in COVID-19 in the papers. Escalard, et al. report on two patients under the age of 50 with developed stroke without risk factors [105]. Fara, et al. report one previously healthy 33-year old lady who developed a thrombus in the common carotid artery extending to the internal carotid artery and associated with a middle cerebral artery thrombus [106]. Wang, et al. report on two patients with stroke and no underlying medical risk factors including a patient in their 40’s [107]. Gunasakeren, et al. report on a 40-year old lady without prior medical history with a large right middle cerebral artery stroke [108]. Yaghi, et al. report on several patients who developed stroke with no significant medical history including two patients in their 40’s who died [109]. Barrios- Lopez, e al. found no aetiology for stroke in two of their patients apart from hypercoagulation and systemic inflammation which were assumed to be COVID-19 related [100]. Vigueir, et al. report on a 73-year old man with common carotid artery thrombosis with ischaemic stroke but no medical history or vascular risk factors [110].

Stefanini, et al. present a case series of STEMI which includes four patients between the ages of 45 and 67 with no medical risk factors [111]. Xiao, et al. presents a 62-year old man with inferior wall MI but without medical risk factors [112]. Poggiali, et al. report on a 64-year old man without significant medical history who presented with a combination of deep vein thrombosis and subsegmental pulmonary embolism [101]. Diago- Gomez, et al. present a previously healthy 50-year old who developed aortic thrombosis with acute limb ischaemia, DVT and stroke and a 69-year old male with no significant medical history who developed aortic thrombosis and pulmonary embolism [113].

High in-hospital mortality: Escalard, et al. report 60% mortality in their series of ten patients with large vessel stroke [105]. Wang, et al. presents a series of five patients with stroke with an average age of 52.8 years and a mortality of 60% [107]. Benussi, et al. reports high in-hospital mortality in a COVID-19 cohort although not distinguishing between those with stroke and without [114]. Morassi, et al. report 83% mortality in their case series of six patients with stroke [115]. Yaghi, et al. compared their series of thirty two patients with COVID-19 and stroke with a control group and found an increased mortality in the COVID-19 group after adjusting for age and NIHSS score with an odds ratio of 64.87 (95% CI 4.44-987.28) [109]. Middledorp, et al. presented their findings in 199 patients with COVID-19 who were admitted to hospital [116]. They found that venous thromboembolism was associated with high mortality and calculated a hazards ratio of 2.7 (95% confidence interval 1.3-5.8).

Cui, et al. report 40% mortality in twenty patients with COVID-19 and lower limb deep vein thrombosis [117]. Bellosta, et al. report 40% mortality in their series of twenty patients with acute limb ischaemia [118]. Kaafarani, et al. report on 141 critically ill patients with COVID-19 of which there were four cases of mesenteric ischaemia and one case of hepatic necrosiss [119]. Although they do not distinguish between the ischaemia and non- ischaemic pathology in the mortality, overall they report a mortality of 40% in those requiring surgery.

Thromboembolic events despite anticoagulant or antiplatelet treatment: Escalard, et al. report in their case series that four out of ten patients with large vessel stroke were prescribed anticoagulant or antiplatelet treatment and one patient was on a combination of anticoagulant and dual antiplatelet treatment prior to the stroke [105]. Zayet, et al. report on a patient who was being treated with apixaban for atrial fibrillation and subsequently developed ischaemic stroke in multiple areas [120]. Morassi, et al. in their case series describe a patient with a previous myocardial infarct who was being treated with dual antiplatelet therapy and developed multiple ischaemic strokes and pulmonary embolism [115]. They also report a man in his 80’s who was on aspirin but developed multiple ischaemic strokes and in hospital whilst receiving treatment with aspirin, clopidogrel and enoxaparin he developed another stroke. They further report on a lady in her 70’s who despite treatment with aspirin and warfarin develops multiple ischaemic strokes. They report on a man in his late fifties who despite treatment with Enoxaparin develops a dural sinus thrombosis but also a cerebral haemmorhage. Barrios Lopez, et al. report on a patient who develops ischaemic stroke whilst on bemiparin (a low weight molecular heparin) and another patient with known atrial fibrillation taking acenocoumarol prior to an ischaemic stroke [100].

Lodigiani, et al. draws attention to the high rate of arterial and venous thromboembolic events in patients with COVID-19 in their study (8%) despite anticoagulant prophylaxis and they believe that the figure may be higher due to undetected cases [103]. Lacour, et al. report on a patient in his late 60’s with an anterior STEMI who is started on dual antiplatelet therapy and a bolus of heparin [121]. Despite this he experienced another thrombus in the left anterior descending artery and after several interventions including IV unfractionated heparin experiences another thrombosis in the left anterior descending artery and dies. Middledorp, et al. in their cohort study reported on the development of venous thromboembolism in twentyfive patients (13% of the cohort) despite thromboprophylaxis [116].

Klok, et al. report the case of a lady in her 80’s who was started on low molecular weight heparin and who went on to develop a deep vein thrombosis [122]. Giacomelli, et al. report on a 67-year old man with an aortic graft and aspirin prophylaxis who was commenced on Enoxaparin prophylaxis after admission [123]. Despite this the graft occluded and he later died.

Asymptomatic prior to thromboembolic event: Escalard, et al. report two patients (20% of their sample) who were asymptomatic prior to large vessel stroke [105]. Wang, et al. presents a case series of five patients all of whom were normal two-and-a-half hours prior to presentation with stroke [107]. Yaghi, et al. present five patients with ischaemic stroke who were asymptomatic prior to presentation [109]. Oxley, et al. report two patients with no COVID-19 symptoms prior to presentation with large vessel stroke [124]. Stefanini, et al. presents twenty-four patients who presented with STEMI as the first clinical feature of COVID-19 [111]. Xiao, et al. report on two patients who present with sudden chest pain in the absence of other symptoms and confirmed acute myocardial infarct [112]. Lacour, et al. presents the case of a man in his sixties who is asymptomatic apart from chest pain with confirmation of myocardial infarct and is similarly asymptomatic prior to re-presenting with stent thrombosis [121].

Cryptogenic/Without any source of thromboembolism: Fara, et al. report two cases of patients without obvious sources of thromboembolism including unremarkable echocardiography and no patent foramen ovale [106]. Yaghi, et al. report cryptogenic strokes in most of their patients (21/32 (65.6%)) [109]. Valderrema, et al. report on a case of middle cerebral artery stroke with internal carotid artery thrombosis in the absence of patent foramen ovale or a cardiac embolus [125]. Barrios-Lopez, et al. could not identify any source of emboli in two patients with ischaemic stroke and determined that this was secondary to a COVID-19-induced hypercoagulable state [100]. Stefanini, et al. report in their case series that 11 (39.3%) patients did not have evidence of obstructive coronary artery disease [111]. Diago-Gomez, et al. report on four cases of aortic thrombosis without atrial fibrillation or previous pro-thrombotic disease and attributed this to a COVID-19-induced hypercoagulable state [113].

Multi-territory stroke: In their case series Escalard, et al. report that fifty-percent of the patients with COVID-19 and stroke had multi-territory stroke involving the middle cerebral artery plus posterior or anterior cerebral artery involvement [105]. Zayet, et al. describe two cases with ischaemic strokes affecting multiple vascular territories [120]. Wang, et al. report one case with both anterior and posterior circulation ischaemic stroke [107]. Morassi, et al. report multiple bilateral ischaemic strokes and suggest an embolic aetiology [115].

Rethrombosis: Escalard, et al. report four patients (40%) with reocclusion within twenty-four hours in their case series of ischaemic stroke [105]. Wang, et al. describes their experience with mechanical thrombectomy in ischaemic stroke patients with COVID-19 [107]. They report two cases in which recanalisation with a stent retriever was followed by reocclusion within minutes and which they attributed to a hypercoagulable state. Bellosta, et al. report twenty cases of acute limb ischaemia with revascularization. They identify a high rate of technical and clinical failure and attribute this to a hypercoagulable state [118].

Mild symptoms prior to initial presentation: Escalard, et al. report fifty percent of patients in their case series as presenting with mild symptoms at stroke onset [105]. Fara, et al. present one case of a lady who was coughing prior to stroke but otherwise had no symptoms [106].

Minimal or no improvement after revascularisation for stroke: Escalard, et al. reports no significant neurological improvement in any of their patients 24 hours after mechanical thrombectomy for stroke [105]. Benussi, et al. reported worse neurological outcome for COVID-19 patients with stroke compared to a control group without COVID-19 [114].

No recanalisation after one pass for stroke: The ability to recanalise an occluded blood vessel at first pass is associated with better outcome. Escalard, et al. reported an absence of first-pass effect for recanalisation in their series of ten patients with COVID-19 and ischaemic stroke [105]. Wang, et al. report an average of just under three passes with the stent retriever to achieve recanalization [107].

Clot fragmentation with embolisation with intervention: Wang, et al. report on the fragmentation of clots with intervention in a case series of patients with ischaemic strokes [107]. They report on the intervention in one patient where aspiration was used initially with resulting embolisation from the carotid bulb thrombus distally. After using a stent-aspiration approach there was further embolisation of the thrombus into the middle cerebral artery. They report another case involving stent-aspiration of a thrombus in the internal carotid artery which embolised to the anterior cerebral artery. They report on another patient where a thrombus in the basilar artery was treated with a combination of balloon-guide catheter and aspiration resulting in embolisation to the posterior cerebral arteries. In another case they describe embolisation of fragments of a thrombus from the middle cerebral artery following stent-aspiration.The authors confirmed distant emboli in 100% of their cases. They also confirm embolisation into a different vascular territory in 40% of their cases which they contrast with a rate of 4.5% in a study involving patients without COVID-19 [126].

Unusual location of clots: Vigueir, et al. report a case of a floating thrombus in the common carotid artery [110]. They note that this is an unusual location for strokes resulting from occlusion within the cervicocephalic arteries and particularly in the absence of atheroma or dissection. They cite evidence that this location occurs in less than 1% of strokes involving the cervico-cephalic arteries [127].

Non-detachable residual clots: Bellosta, et al. describes the need for an additional surgical procedure in the treatment of acute limb ischaemia due to the occurrence of residual non-detachable clots [118].

Desert foot: Desert foot refers to the occlusion of all of the main arteries of the foot. Bellosta, et al. refers to several cases of desert foot in their case series of 20 patients with acute limb ischaemia [118].

Low rate of successful revascularisation of acute limb ischaemia: Bellosta, et al. reports a low rate of successful revascularisation in their case series of acute limb ischaemia [118]. They note that patients receiving intravenous heparin did not undergo reintervention and low oxygen saturation was significantly associated with unsuccessful revascularisation.

Thrombosis of a graft: Giacomelli, et al. report on a case of a man in his late sixties with an abdominal aortic aneurysm that had been repaired with an aortic graft six years previously [123]. At admission to hospital, the graft was patent. His overall condition deteriorated and nine days after admission, the graft was completed occluded with a thrombus and the patient died before revascularisation was possible.

Clotting of medical devices: Helms, et al. report on 150 patients with COVID-19 who were admitted to four intensive care units in France [128]. They report circuit clotting with the use of renal replacement therapy. They also report the thrombotic occlusion of the centrifugal pumps in patients receiving Extracorporeal Membrane Oxygenation (ECMO). The centrifugal pump needed replacing after between 4 and 7 days. They also report that the average lifespan of the renal replacement therapy circuit was reduced by 50%. The authors hypothesized that the occlusion of the centrifugal pumps was due to a combination of ultrafiltration and high fibrinogen levels

Results of exploratory literature search

We screened over 12,000 references from the clinical and scientific literature as well as references from prior and successive searches. The search strategy was determined from the specified aetiology unless there was sufficient evidence from the existing material.

COVID-19 related coagulopathy aetiologies suggested in the 56 main papers

We identified 50 COVID-19 coagulopathy-related mechanisms suggested in the 56 main papers and have listed them in Table 28. Some of the mechanisms were mentioned by single authors whilst others such as a hypercoagulable state were mentioned by most of the authors (Table 28).

Table 28. Coagulopathy-related aetiologies in COVID-19 suggested in 56 main papers.

Hypercoagulable/thrombophilic state: In most of the main papers, the authors suggest that the coagulopathy results from a hypercoagulable state. Also termed a thrombophilic state, the hypercoagulable state is one which there is an increased likelihood of clotting or else a severe clotting response [129]. In this section we treat this primarily as resulting from a change in the components of the blood although more general properties such as viscosity are considered in other sections.

Many studies have reported on the haematological, biochemical and immune parameters in COVID-19. Henry, et al. in their meta-analysis examined 21 studies (n=3377), identifying 27 altered laboratory values in severe or fatal COVID-19 [130]. These included elevated prothrombin time, elevated D-Dimer, elevated CRP, IL-6 and myoglobin, cardiac troponin I and decreased platelet count. In a meta-analysis of coagulation dysfunction in COVID-19 (Jin et al. 2020) analyzed 22 studies (n=4889) and found higher D-Dimer levels and prolonged prothrombin time in patients with more severe COVID-19. Non-survivors were more likely to have higher D-Dimer levels, decreased platelet count and increased prothrombin time compared to survivors.

Di Minno, et al. completed a meta-analysis looking at sixty subjects with 5487 patients with severe COVID-19 and 9670 patients with mild COVID-19 [131]. They also found evidence of higher D-Dimer levels in non-survivors compared to survivors while non-survivors had lower platelet levels. In another meta-analysis of patients with COVID19, 34 studies were included (n=6492) [132]. They found that patients with severe COVID-19 had lower platelet count, higher D-Dimer levels, higher fibrinogen, longer prothrombin time and shorter activated partial thromboplastin time. Again non-survivors were more likely to have higher D-Dimer levels. Ibañez, et al. found evidence of elevated D-Dimers and hypofibrinolysis in a prospective cohort study with COVID-19 in an ICU setting and suggest that the lungs are the source of the elevated D-Dimers [133].

Receptor-Mediated-ACE-2 receptor-mediated pathways: Siddamreddy, et al. suggests that SARS-COV2 can cause myocardial injury via the ACE-2 receptor [134]. Ciaglia, et al. suggests that a reduced expression of ACE-2 receptors in older adults may increase susceptibility to more severe COVID-19 [135].

The Renin-Angiotensin System (RAS) plays a central role in fluid homeostasis. There are a number of molecules, receptors and enzymes involved in the RAS (Figure 9). One of the key functions is the tonic control of blood pressure which can be contrasted with the actions of the baroreceptors which drive changes more rapidly. Aldosterone release is an end-result of the action of Angiotensin II on the AT1 receptor which causes the retention of sodium in exchange for potassium. In hyperaldosteronism there is elevated blood pressure with hypokalaemia (Figure 9).

Miesbach describes a reduction in ACE-2 receptors with SARS-COV2 infection and cites evidence of increased Angiotensin II levels in patients with COVID-19 [136]. Further outlines the mechanisms by which an increase in Angiotensin II levels could predispose to coagulation. Draws attention to the role of Angiotensin II in promoting smooth muscle cell proliferation which can contribute to atherosclerotic plaques, that Angiotensin II promotes the expression of Tissue Factor which in turn initiates coagulation and also promotes the expression and release of Plasminogen Activator Inhibitor-1 (PAI-1) which in turn inhibits fibrinolysis and promotes thrombus formation [136]. Senchenkova, et al. provides evidence of a role for IL-6 and T-Cells in Angiotensin II-induced thrombo-inflammation [137]. Spillert, et al. demonstrated an in-vitro procoagulant effect of Angiotensin II using a modified recalcification time test [138]. Lamas-Barreiro, et al. note that the relationship between ACE-2 receptor activity and angiotensin II levels varies between organs [139]. Bryson, et al. has in a model shown a protective effect from Angiotensin II-induced hypertension through antagonism of a prostaglandin receptor [140]. Prostaglandins can inhibit platelet aggregation and it has been suggested that Eicosanoids such as prostaglandins may play a key role in COVID-19 [141,142].

Nguyen, et al. Suggest that Angiotensin II’s actions may be mediated in part through reactive oxygen species (ROS) signaling [143]. The evidence for a more ubiquitous presence of RAS is outlined by [144]. Veras, et al. found evidence of ACE-2 receptor and serine protease involvement in activation of NET’s [145]. Fang and Schmaier review the role of the MAS receptor and the relationship between kallikrein/kinin and the RAA system in thrombosis [146].

In terms of ACE-2 receptors, a NICE review found no evidence to suggest that ACE-inhibitors or Angiotensin Receptor Blockers either increased the risk of contracting COVID-19 or else lead to a more severe manifestation of COVID-19 [147].

In their case study, report their findings in a man with COVID-19, ARDS and septic shock who experienced a marked response to the administration of angiotensin II [148]. The authors discuss these findings whilst noting that a similar response has been found in non-COVID-19-related sepsis. Liu, et al. found elevated plasma angiotensin II levels in patients with severe COVID-19 compared to a control group with COVID-19 [149].

Garvin, et al. analysed gene expression data from bronchial lavage specimens in patients with COVID-19 and used the Summit supercomputer to analyse the results [150]. Their findings support the role of a bradykinin storm, an amplifying circuit of bradykinin production in response to the infection and mediated by RAS. They also found that the levels of hyaluronic acid were elevated and note that hyaluronic acid is associated with thrombosis. They suggest that the hyaluronic acid produces a gel in the lungs which interferes with the oxygenation of blood and thereby predisposes to hypoxaemia. Garvin, et al. looked at mRNA levels and found a reduction in ACE mRNA expression as well as an upregulation in ACE2 mRNA expression which may be expected to reduce the production of Angiotensin II [150]. The mRNA levels do not necessarily correlate strongly with protein levels. The correlation between mRNA expression and protein levels (R2) was 0.4 across species in one study [151]. This would suggest that the protein levels should be measured in preference to the mRNA or else in conjunction with this as de Sousa, et al. suggest that as much as 70% of the variance between mRNA and protein levels is accounted for by a combination of measurement accuracy and post-translation factors such as protein degradation [151].

Kusadasi, et al. also note the inter-relationship of the Renin-Aldosterone- Angiotensin system, complement system, Kinin-Kallekrein system and coagulation system as well as the relationship to ACE-2 while Urwyler, et al. report their initial findings with the use of Conestat Alfa In COVID-19, which targets the Kallikrein-Kinin system [152,153]. Curran, et al. provides a model of pathology in COVID-19 involving a number of systems including the RAAS system and suggests that COVID-19 disrupts regulatory networks [154]. Wiese, et al. hypothesise that pathology in COVID-19 arises from an upregulation of the classical arm of the RAS pathway and a downregulation of the ‘protective arm’ of the RAS pathway [155]. Czick, et al. suggests a role for RAS imbalance in multiple aspects of COVID-19 [156].

Akoumianakis, et al. note the relationship between obesity and dysregulation of the RAAS axis as well as myocardial and lung injury and suggest that this relationship may be relevant in COVID-19 [157]. In the Dyhor-19 Study Villard, et al. demonstrates a correlation between CRP and Aldosterone levels and COVID-19 severity [158]. Dudoignon, et al. found that half of patients with COVID-19 and ARDS had acute kidney injury and this was significantly associated with activation of the RAAS with patients having high levels or renin and aldosterone on admission [159].

Santamarina, et al. provide evidence of ventilation/perfusion (V/Q) mismatch in the lungs and draw attention to two findings-well perfused areas of damaged lung and poorly perfused areas of healthy lung [160]. They suggest this may explain the benefit of the proning position in patients with COVID-19 and ARDS. To partially explain this they suggest that Angiotensin II in COVID-19 results in vasoconstriction in the lungs and disrupts the ventilation/perfusion matching resulting in areas of healthy lung that are well perfused. Lang, et al. found evidence of pulmonary perfusion abnormalities in COVID-19 which supports the notion of disrupted perfusion/ventilation matching in COVID-19 secondary to RAA system disruption [161].

Sepsis related

SIRS via IL-6: Valderrema, et al. suggest the septic inflammatory response syndrome (SIRS) mediated by IL-6 as one of the mechanisms that predisposes to ischaemic stroke in COVID-19 [125]. Barrios Lopez, et al. cites evidence that severe inflammation occurs during the acute phase of COVID-19 [100]. The difference between sepsis and SIRS is one of organ dysfunction and a dysregulated immune response in sepsis in contrast with SIRS. If we consider a thromboembolic event then organ dysfunction is a function of the location of the event. The key question is whether there is a dysregulated immune response and in asking this question it can be argued that SIRS cannot lead to a clotting event as this cannot be considered a healthy response. The new sepsis consensus definition has removed the construct of SIRS, although there is an argument for the utility of SIRS [162]. We will not consider this further although we will add a section for IL-6 separately below. Also we consider septic shock on the continuum with sepsis and refer back to the introduction for discussion of the procoagulant mechanisms including DIC.

IL-6: The suggestion of a key role for IL-6 in COVID-19 pathology is a basis for the recommendation for trialling IL-6-related therapies in COVID-19 [163]. Kuppalli and Rasmussen suggest a potentially important role for IL-6 in the host response to SARS-COV2 and cite evidence for a reduced type- 1 helper T-cell (Th1) antiviral response [164]. However Leisman, et al. as well as Sinha, et al. outline the evidence against a central role for IL-6 in COVID-19 [165,166].

Liu, et al. found a correlation between IL-6 levels and disease severity [167]. Luo, et al. found a correlation between both IL-6 levels and CD8+ T cell counts and mortality [168]. Zhao, et al. found IL-6 to be elevated in the later stages of severe COVID-19 but found that RANTES, a chemokine, was elevated earlier in the course of illness [169]. Mansouri, et al. present a case of COVID-19 in which IL-6 and other parameters normalised after treatment with Colchicine and this was accompanied by a rapid improvement in presentation [170].

Towards a model of COVID-19 related coagulopathy

In our paper, we draw together the findings from many studies to develop a testable model and the diagram mapping (Figures 10-21). This is a simple model with several components and is described by causal relationships but without quantitative descriptions of those same relationships. The purpose of this model is to serve as a starting point for further enquiry and to enable other researchers to refute or confirm these relationships or to quantify and expand upon them, thereby improving the understanding of the COVID-19- related coagulopathy (Figure 10-21).

Revised aetiologies for COVID-19

The revised aetiologies have been organised into categories following the preceding analysis. The general evidence is then considered for each potential aetiology and categorised as weak, moderate or strong. The general evidence refers to the evidence for this aetiology leading to a coagulopathy independently of COVID-19 and this is contrasted with the evidence for this aetiology leading to a coagulopathy in cases of COVID-19. The revised aetiologies then form the basis for the development of the model together with the corresponding narrative description

Conclusion

We conclude with a summary of the main findings in this paper and determine from our evidence that SARS-COV2 infection leads to a viral clotting fever syndrome with high mortality although the prevalence is unclear from this data. COVID-19 is a polycoagulopathy with Multiple Clotting Mechanisms (MCM’s) causing serious clinical thromboembolic sequalae. Our findings are based on a population that was hospitalised and of more advanced age. Fever occurred in most but not all of the patients with this presentation and therefore the clotting fever syndrome is an indication that if both fever and clotting events occur that COVID-19 should be considered as a differential. The absence of fever or thromboembolic events should not discount COVID-19. The D-dimer is a key prognostic indicator in COVID-19 and bears special significance as a marker of underlying thromboembolic events. In the most severe cases, the D-Dimers were elevated up to some 200-fold over the upper limit of the reference range with significant clinical correlates.

Overall we found an average of 1.3 thromboembolic events per patient but these were predominantly arterial rather than venous in nature albeit where we had classified pulmonary emboli as arterial rather than venous on the basis of the vessel anatomy rather than the consideration of the flow of blood towards or away from the heart. This is particularly relevant in COVID-19 given the distribution of ACE-2 receptors in the smooth muscle cells which in turn are more densely arranged in the arterial vasculature. Of note is that we found not a single case of pulmonary vein thrombosis in the 56 main papers whilst pulmonary arterial emboli were found in abundance.

We found that there were five main groups of arterial thromboembolic events according to arterial territories-splanchnic arteries, coronary arteries, pulmonary arteries, the femoral and other arteries of the lower limbs as well as the cortical and subcortical arterial supply but particularly the middle cerebral arteries. The involvement of these territories leads to characteristic signs and symptoms which are well-established in the literature and where further work can lead to clinical algorithms and the development of public health messages with sufficient evidence. We also identified carotid artery thromboemboli in association with strokes and many authors drew attention to this important finding. Thrombi were also found in the aorta and the heart. We found sporadic reports of the involvement of the veins with the exception of the deep veins in the lower limbs which were more frequently identified. Of special note is the occurrence of thromboembolic/clotting events in association with medical devices which we use broadly to include catheters, ECMO centrifuges and dialysis machines. The occurrence of upper limb DVT’s was predominantly associated with catheters.

A combination of more general factors in the setting of either mild or severe illness may also contribute. The insensible fluid loss from diarrhoea and vomiting may lead to dehydration and electrolyte disturbances. Periods of immobility may increase the risk of a lower limb DVT. Hypokalaemia and hyponatraemia may both predispose to atrial fibrillation which in turn results in cardiac muscle stasis and generation of thrombi and subsequent thromboembolic events. The disruption of the RAA system may impact on the correction of these disturbances.

On analysis of a subset of papers, we were able to quantify other findings albeit on the basis of a small sample size which limits our ability to generalise these findings and suggests that these findings need to be further validated. We found sex differences amongst the occurrence of arterial thromboembolic events as well as differences in mortality. We draw special attention to the occurrence of acute limb ischaemia in COVID-19 which is associated with a particularly high mortality albeit with evidence of selection bias in the data we analysed and which merits further attention.

The qualitative analysis identified the general clinical findings with an experiential (clinical) account. Thus clots were described in unusual locations, occurring in multiple territories and with unusual findings such as desert foot. During interventions, the thromboemboli were found to be friable, breaking away and further embolising into new territories. Repeated occlusion of arteries was identified after recanalisation and in one case the clot was altogether undetachable from the arterial wall necessitating an alternative surgical procedure. Thromboemboli occurred despite prophylactic anticoagulation. Patients would present with serious clinical thromboembolic events after being either asymptomatic or else with an apparently mild course of the illness.

In terms of the validated abridged thematic analysis, we were able to assess the content validity of the proposed aetiological mechanisms by means of an examination of the literature. This was not limited to the papers screened in an exploratory literature search but also with reference to the other papers we had examined for the purposes of this scoping review. By means of an iterative process utilised in thematic analysis we were then able to assemble the selected mechanisms into taxonomy. Furthermore we were able to translate the taxonomy into a rudimentary symbolic representation, a process which may be of use to other clinicians and researchers investigating this field of enquiry as the model can be extended and refined.

In theoretical terms, we utilised Virchow’s triad as a means of structuring the taxonomy. We were able to confirm overarching themes of hypercoagulability, vascular wall involvement and to a lesser degree stasis. The primary pathology would appear to be the viral invasion of the endothelium which is mediated via the ACE-2 receptors which together with heparin sulfate affords the virus a route for entry into the cells. Once inside the cells, the virus appropriates the cellular machinery and escapes RNA intracellular sensing mechanisms by means of the construction of replication organelles including double membrane vesicles. The RNA sensing mechanisms typically trigger an interferon response upon successful detection and it should be noted that the interferon response or lack thereof appears critical in determining the subsequent course of the illness. An exaggerated interferon response may result in a mild illness and possibly chilblains as a dermatological finding. A delayed interferon response may result in a more severe course and this may be of more relevance to the risk of coagulopathy and the concept of immunosenescence may also be relevant.

Following the invasion of the endothelium, there is found to be endotheliitis and also various degrees of thrombosis in the small blood vessels. From our examination of the literature there appear to be many details requiring clarification but there are a few events which appear to be more robustly supported in the literature. Firstly the endothelium is specialised according to the organ in which it is located. In the lungs, the blood vessels have a physiological function of ventilation-perfusion matching whilst in the kidneys this forms part of the filtration mechanism. The viral invasion appears to degrade the function of the endothelium and it would appear that together with a disruption of the RAA axis likely resulting from the utilisation of the ACE-2 receptors, there is a subsequent degradation of ventilation-perfusion matching and glomerulofiltration if those organs are affected. The ventilation-perfusion mismatch is likely to account for the phenomenon of silent hypoxia which is of significant consequence in clinical management and hypoxaemia contributes to the risk of a coagulopathy. A disruption in glomerulofiltration results in impaired plasma filtration with significant consequences for various homeostatic mechanisms including those of the electrolytes.

The consequences of the invasion of the endothelium by the virus can also be considered in terms of thromboinflammation. The construct of thromboinflammation is well supported in the literature and it is clear that platelet activation plays a significant role in COVID-19. The key question here is the role of the endothelial glycocalyx. There is evidence of disruption of the glycocalyx in COVID-19 and this would result in a local prothrombotic environment and would lead to platelet activation. One of the components of the glycocalyx is heparin sulfate which is required for viral entry into the cells and so the disruption of the glycocalyx would be more likely secondary to viral invasion of the endothelium. A special role may be played by hyaluronan with evidence that in COVID-19 it leads to the creation of a gel in the lungs which may contribute to hypoxaemia. With the seeding of the virus in the lungs and then in the endothelium of other blood vessels, thromboinflammation would result in the generation of a thrombus. The properties of the thrombus would predispose to embolisation including a possible contribution from components of the locally disrupted glycocalyx. The arterial wall would be an ongoing source of thrombogenesis. The role of susceptibility factors is also of importance and in particular endothelial dysfunction is related to the metabolic syndrome. This likely contributes to a low grade inflammatory, prothrombotic potential and a possible vulnerability to viral invasion.

Another important aspect of the pathology is the role of the neutrophils. One clear finding is the presence of NETs and when taken together with the evidence of apoptosis and related mechanisms, a key feature of COVID-19 is exposure of intracellular material to the extracellular environment. Thus while the virus has carefully avoided detection in the intracellular space through the replication organelles, the intracellular material of the host cells is exposed. There is thus the potential for the host immune system to generate an autoimmune response. Furthermore if the tissue destruction is overwhelming and the clearance insufficient then there may be a large amount of circulating antibody complexes leading to a type- III hypersensitivity response in a minority of cases. This in turn can lead to deposition of immune complexes in the skin, kidneys and vasculature with the latter resulting in a vasculitis which can predispose to further thromboembolic events.

Finally returning to the original question in this paper, we found evidence of thromboembolic events with and without each of sepsis, DIC and ARDS.

Limitations of the Study

There were a number of drawbacks in the study.

1. The search strategy to identify the main papers was not rigorous.

The search strategy was simple. A more rigorous approach may have yielded more results. Nevertheless we identified a number of robust studies and our methodology allowed for us to optimise the extraction of useful information from identified papers.

2. The search terms in the main search may have biased the outcome.

We used search terms which could have biased the study towards identifying thromboembolic events in specific anatomical locations such as strokes and pulmonary emboli. Nevertheless we identified other anatomical locations through the search.

3. The search strategy for exploring the various hypotheses for the aetiology was unstructured and prone to bias.

We acknowledge the limitations of the unstructured search strategy. The goal of this search was not to be definitive in answering questions but primarily to explore and test the various hypotheses that had been generated as the validation stage of the Validated Abridged Thematic Analysis (VATA). The diverse hypotheses cover many theoretical domains and analysis requires a pragmatic approach but also enables triangulation and quality assurance.

Publication bias may be expected but we discounted hypotheses. We also included systematic reviews and meta-analyses that typically address this.

4. In the qualitative analysis, the absence of coding increases the risk of omissions from the identified themes or else misinterpretation.

The omission of coding was a pragmatic decision which is based on theoretical considerations. Content validity is tested by triangulation with an established evidence base. Whilst there is a risk of omission due to oversight, we have judged the benefits to outweigh the risks in terms of rapidly summarizing themes.

5. The patients in the 56 main papers were all hospital-based and therefore the findings do not generalise to all patients with COVID-19.

We acknowledge that more severe COVID-19 featured in many of the papers. Nevertheless a number of patients experienced thromboembolic events after an asymptomatic period or else having mild symptoms. The VATA and model-building drew on a wider literature base. Although not generalizable to all patients with COVID-19 we have characterised a syndrome that results from COVID-19.

Funding

There was no external funding.

Acknowledgements

We would like to extend our immense gratitude to family, friends and colleagues whose support has been essential in managing the many challenges we have faced in this pandemic.

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