Review Article Coagulation disorders and thromboembolic disease in COVID-19: review of current evidence in search of a better approach Alberto García-Ortega1,2, David de la Rosa3, Grace Oscullo1,2, Diego Castillo-Villegas3, Raquel López-Reyes1, Miguel Ángel Martínez-García1 1 Pneumology Department, Hospital Universitario and Politécnico La Fe, 46026 Valencia, Spain; 2Medical Research Institute Hospital La Fe (IISLAFE), 46026 Valencia, Spain; 3Pneumology Department, Hospital Universitario Santa Creu i Sant Pau, 08041 Barcelona, Spain Contributions: (I) Conception and design: A García-Ortega, MA Martínez-García; (II) Administrative support: MÁ Martínez-García; (III) Provision of study materials or patients: All authors; (IV) Collection and assembly of data: A García-Ortega, R López-Reyes, G Oscullo; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Alberto García-Ortega. Respiratory Department, Hospital Universitario and Politécnico La Fe, Avenida Fernando Abril Martorell 106, 46026 Valencia, Spain. Email: albortgva@gmail.com. Abstract: The new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been an unprecedented global health problem, causing more than 20 million infections and more than 900,000 deaths (September 2020). The SARS-CoV-2 infection, known as COVID-19, has various clinical presentations, from asymptomatic or mild catarrhal processes to severe pneumonia that rapidly progresses to acute respiratory distress syndrome (ARDS) and multiple organ failure. In the last few months, much scientific literature has been devoted to descriptions of different aspects of the coagulation disorders and arterial and venous thrombotic complications associated with COVID-19, particularly venous thromboembolism (VTE). These studies have revealed that SARS-CoV-2 could lead to a prothrombotic state reflecting the high cumulative incidence of associated thrombotic events, particularly in patients admitted to intensive care units (ICUs). As regards the coagulopathy observed in association with SARS-CoV-2 infection, the mechanisms that activate coagulation have been hypothesized as being linked to immune responses, through the release of pro-inflammatory mediators that interact with platelets, stimulate the expression of tissue factor, induce an upregulation of plasminogen activator inhibitor-1, suppress the fibrinolytic system and lead to endothelial dysfunction, triggering thrombogenesis. D-dimer elevation has been recognized as a useful biomarker of poor prognosis, although the best cut-off point for predicting VTE in COVID-19 patients has still not been clarified. This review will try to update all the available scientific information on this important topic with enormous clinical and therapeutic implications. Keywords: Pulmonary embolism (PE); coronavirus disease 2019 (COVID-19); D-dimer; thrombosis; inflammation Submitted Sep 24, 2020. Accepted for publication Dec 18, 2020. doi: 10.21037/jtd-20-3062 View this article at: http://dx.doi.org/10.21037/jtd-20-3062 Introduction as being responsible for the outbreak of these respiratory infections and then named coronavirus disease 2019 In December 2019, the Chinese authorities reported (COVID-19) (1-3). atypical pneumonia clusters of unknown etiology in COVID-19 has been an unprecedented global health Wuhan. On 7 January 2020, a novel coronavirus from problem, causing more than 25 million infections and the Coronaviridae family, the new severe acute respiratory more than 900,000 deaths [Centres for Disease Control syndrome coronavirus 2 (SARS-CoV-2), was confirmed and Prevention (CDC), World Health Organization © Journal of Thoracic Disease. All rights reserved. J Thorac Dis 2021;13(2):1239-1255 | http://dx.doi.org/10.21037/jtd-20-3062 1240 García-Ortega et al. PE in COVID-19 (WHO); September 2020]. SARS-CoV-2 seems to enter a greater frequency of elevated D-dimer in patients with cells by endocytosis, through the binding of virus envelope more severe forms of presentation of COVID-19 (60% glycoprotein to the angiotensin-converting enzyme-2 vs. 43%; P=0.002) (2,15,16). Moreover, a comparison of receptor found in the cells of upper airways, lungs, heart the D-dimer values at admission of the more severely ill and gastrointestinal tract, as well as in the blood vessels (4). patients who would require treatment in an intensive care SARS-CoV-2 infection has various clinical presentations, unit (ICU) and those of the remaining COVID-19 patients from asymptomatic or mild catarrhal processes to severe confirmed that these values were higher in the former case pneumonia that rapidly progresses to acute respiratory (3,4). Along the same lines, Tang et al. found a relationship distress syndrome (ARDS) and multiple organ failure (1). between mortality from COVID-19 and D-dimer values Preliminary reports have suggested that COVID-19 in a retrospective study, with these values being almost infection can produce coagulation disorders, mainly in more 3.5 times higher in deceased patients (2.1 vs. 0.6 mg/L; severe forms of presentation, and predispose to thrombotic P=0.001) (7). Similarly, Zhou et al. published the data events and both arterial and venous thrombosis (2,3,5-10). from a retrospective series of 191 patients hospitalized for Furthermore, COVID-19 has commonly been associated COVID-19 in Wuhan (137 survivors, 54 non-survivors) with coagulopathy in most of the deceased patients. The and also found higher D-dimer values on admission in the data derived from all these publications on COVID-19- group of deceased patients than in that of the survivors (5.2 associated coagulopathy and thrombotic risk have generated vs. 0.6 mg/L; P<0.001), with a cut-off point of 1.0 mg/L an doubts and controversy about the best strategy for the independent risk factor for mortality [multivariable analysis thromboprophylaxis, diagnosis and anticoagulant therapy presented odds ratio (OR) 18.4; 95% confidence interval of venous thromboembolism (VTE), as reflected in the (CI): 2.6–128.6; P=0.0033] (8). A meta-analysis of 553 variability of the recommendations published by different COVID-19 patients (22% admitted to the ICU) established expert groups. a D-dimer cut-off point of 3.0 mg/L to identify severely ill Therefore, this manuscript summarizes the current patients (9). This correlation between the severity of the published literature regarding the key aspects of coagulation disease and the D-dimer values was also reported in another disorders and VTE risk in COVID-19, mainly focusing meta-analysis that found significantly higher D-dimer on pulmonary embolism (PE), and it addresses clinical values in patients with ARDS compared to non-ARDS issues in order to improve our approach to the prophylaxis, patients (P<0.001); moreover, within the group of ARDS diagnosis and management of VTE in COVID-19 patients. patients itself, those who died presented higher D-dimer We present the following article/case in accordance with values than the survivors (P<0.001) (16). the PRISMA reporting checklist (available at http://dx.doi. Another significant marker of coagulation related to the org/10.21037/jtd-20-3062). prognosis is the PT. Higher PT values have been associated with both the need for ICU management and greater mortality (3,7,8). Coagulation disorders associated with COVID-19 In short, COVID-19 patients present coagulation Various studies have suggested that SARS-CoV-2 induces disorders that are mainly defined by an elevated D-dimer, coagulation disorders, which are associated with poorer and this finding has proved to be associated with more outcomes. The most common pattern of coagulopathy severe forms of presentation, including ARDS and the need is characterized by increased levels of fibrinogen and for an ICU, as well as a higher mortality rate. D-dimer, a slight rise in the prothrombin time (PT) and the activated partial thromboplastin time (aPTT), and a Pathophysiology of COVID-19-associated mild thrombocytopenia (2-9,11-14). Of all these factors, coagulopathy the D-dimer is the one most consistently associated with COVID-19. The very first series of hospitalized patients Both the relationship between inflammation and in China already presented elevated levels of D-dimer haemostasis and the activation of the coagulation cascade (≥0.5 mg/L) in 46% of the cases (2). One study has in infections are well known, and basically explained by shown that COVID-19 patients present elevated levels of the pathophysiology of the immune-thrombotic response D-dimer, significantly higher than those found in healthy in situations involving sepsis (Figure 1) (17). Sepsis is thus controls (15). Even more importantly, early studies identified characterized by a pro-coagulant, pro-inflammatory and © Journal of Thoracic Disease. All rights reserved. J Thorac Dis 2021;13(2):1239-1255 | http://dx.doi.org/10.21037/jtd-20-3062 Journal of Thoracic Disease, Vol 13, No 2 February 2021 1241 Pathogens Tissue factor Monocyte Monocyte Excessive inmune response Cytokines release (IL1, IL2, IL6, G-CSF, IFN-γ, TNF-α, and others) Tissue factor NETs Neutrophils Platelet, neutrophil and Activated Endothelial cell endothelial cell activation platelets Granule proteins Hipercoagulability + Endothelial dysfunction Microthrombosis and macrothrombosis Clot Clot Clot Figure 1 Pathophysiology of coagulation activation in sepsis. The pathogens and its components stimulate the monocytes via specific receptors situated on the surface of their cells. The activated monocytes produce a hyperimmune response with the release of various cytokines and other inflammatory mediators that activate platelets, neutrophils and endothelial cells. A state of hypercoagulability and endothelial damage that modifies the properties of the endothelium from an anticoagulant to a procoagulant state through the interruption of the glycocalyx and the expression of the von Willebrand factor (VWF). Neutrophils, in their turn, express tissue factor and release granulated proteins and other procoagulant mediators, such as neutrophil extracellular traps (NETs) comprised of procoagulant DNA, histones and other molecular patterns associated with cellular damage. All the above leads to the development of micro- and macrothrombotic phenomena. Adapted from ref (17) [with permission of Sociedad Española de Neumología y Cirugía Torácica (SEPAR) copyright]. G-CSF, granulocyte colony-stimulating factor; TNF, tumor necrosis factor; IFN, interferon; IL, interleukin; NETs, neutrophil extracellular traps. anti-fibrinolytic state that involves many cell strains (such tissue factor, trigger and initiate coagulative extrinsic as monocytes, macrophages, neutrophils and the vascular cascades and release thrombotic mediators [e.g., neutrophil endothelium). Pathogens bind to specific receptors of cells extracellular traps (NETs)] that enhance platelet activation with innate immunity, triggering the release of various (18-23). cytokines and other inflammatory biomarkers. Cytokines The indiscriminate activation of this pathophysiological such as IL-6 and IL-8 act by activating the platelets and mechanism gives rise to the picture known as disseminated modifying the properties of the endothelium from an intravascular coagulation (DIC), which is characterized anti-coagulant to a pro-coagulant state by interrupting by the presence of thrombocytopenia, the consumption of the glycocalyx and activating clotting factors (e.g., von coagulation factors and high levels of fibrin degradation Willebrand factor). Furthermore, the neutrophils express products like D-dimer (18-20). © Journal of Thoracic Disease. All rights reserved. J Thorac Dis 2021;13(2):1239-1255 | http://dx.doi.org/10.21037/jtd-20-3062 1242 García-Ortega et al. PE in COVID-19 The mechanisms that activate coagulation in As regards hypercoagulability, we have already seen that COVID-19 have not been fully clarified but they appear coagulation disorders (mainly elevated D-dimer) suggest the to be more closely related to the inflammatory response existence of a pro-coagulant state in COVID-19 patients, than the specific virulent properties of the germen (11). particularly those who are critically ill. Thrombosis is the It has been shown, for example, that patients with severe final stage of inflammation. Therefore, hypercoagulability SARS-CoV-2 infection present an excessive inflammatory and the risk of thrombosis could be linked to local and response, with lymphopenia and high levels of ferritin, systemic inflammation more than to direct damage from the D-dimer and various cytokines (11,12). In fact, interleukin virus itself (26). (IL)-6 plays a fundamental role in the activation of the Hypoxia is another factor that could be involved extrinsic coagulation route (18). Accordingly, it has been in the coagulopathy associated with COVID-19. It is postulated that this hyper-inflammatory response in characteristic of cases of severe pneumonia, and its role COVID-19 patients, known as a cytokine storm, activates in the states of hypercoagulation and thrombosis has the coagulation cascade. The vascular endothelium seems been extensively studied (31-33). The cellular response to to play a crucial role in this pathophysiological hypothesis hypoxia results in the activation of transcriptional factors of immuno-thrombosis or thrombo-inflammation, and such as activator protein-1 (AP-1), early growth response data from studies in more severe patients support the protein 1 (Egr-1) and hypoxia-inducible factors (HIF). The existence of a link between inflammation and the pro- most fully investigated of these is HIF-1. Hypoxia leads coagulant state (13). Finally, in contrast to the pattern to the activation of the transcription factor HIF-1, which observed in the classic DIC that occurs in sepsis, the is responsible for activating a series of proteins involved thrombocytopenia associated with COVID-19 is mild and in the maintenance of vascular homeostasis (34), such as there is only a limited consumption of coagulation factors nuclear factor (NF)-κB, vascular endothelial growth factor (11,12,23). (VEGF) and erythropoietin (EPO). These proteins enhance In short, the most severe forms of COVID-19 infection a pro-coagulant state, as has been widely reported in give rise to an immune hyper-response that is associated cancer patients (35). Moreover, NF-κB factor mediates the with coagulation disorders. expression of genes encoding for inflammatory cytokines, tumor necrosis factor, chemokines, adhesion molecules and pro-coagulant factors, including the plasminogen activator Pathophysiology of acute VTE in COVID-19 inhibitor (PAI)-1 and tissue factor pathway inhibitor (36). infection As r egar ds th e path oph ysiology of en d o t hel i a l The thrombotic risk entailed in COVID-19 infection is dysfunction in COVID-19, pro-thrombotic changes an emerging problem that has been tackled by numerous in endothelial cells are the result of the inflammatory publications. VTE is a consequence of the interaction environment (Figure 1). Endothelial dysfunction causes the of different pro-thrombotic risk factors related to both expression of chemo-attractants and adhesion molecules the patient and the environment. COVID-19 patients needed to activate monocytes and macrophages, thereby often present risk factors for VTE, such as greater age producing tissue factor. Tissue factor then triggers and obesity, as well as hospitalization for an acute illness coagulative extrinsic cascades (16,31). (24,25). However, any explanation of a greater thrombotic Some authors have suggested that infection by SARS- risk due to COVID-19 itself would suppose that it acts CoV-2 facilitates the induction of endotheliitis in the on the main etiopathogenic mechanisms known in VTE: pulmonary vascular bed as a result of the rapid replication hypercoagulability, endothelial dysfunction and venous of the virus. This replication causes massive apoptosis stasis—Virchow’s triad of the primary inducers of thrombus of endothelial cells and triggers a loss of anti-coagulant formation. The pathophysiological mechanisms underlying function in the vascular lumen (26). the association between COVID-19 and thromboembolic Lastly, venous stasis in COVID-19 patients is mainly complications are still not completely understood, but they justified by reduced mobility due to the illness. seem to involve inflammation, blood hypercoagulability, In short, SARS-CoV-2 infection could provoke VTE hypoxia, immobility and DIC, all of which could predispose through the three classic mechanistic pathways of Virchow’s to the development of thromboembolic complications triad: hypercoagulability, endothelial dysfunction and (2,3,8,24,26-30). venous stasis. The evidence that is currently available © Journal of Thoracic Disease. All rights reserved. J Thorac Dis 2021;13(2):1239-1255 | http://dx.doi.org/10.21037/jtd-20-3062 1243 García-Ortega et al. PE in COVID-19 suggests that inflammation could be the key factor in (Figure 2). the pathophysiology of VTE in COVID-19 patients. Those studies that included patients admitted to a Accordingly, the most seriously ill patients develop an hospital ward who underwent an imaging test for suspected inflammatory state that could encourage the development VTE presented an incidence of PE and/or deep venous of thrombosis. thrombosis (DVT) below 5% (53,55). This rate of symptomatic VTE is not any higher than those obtained in early studies of patients without COVID-19 who were Microthrombosis in COVID-19 patients hospitalized for medical causes (63,64). COVID-19 patients often pass quickly to a situation of Critically ill patients have a high risk of developing VTE, ARDS and multiple organ failure (2). The pathophysiology with incidences ranging from 13 to 30% with no anti- of ARDS in severe cases of SARS-CoV-2 infection has thrombotic prophylaxis (65,66) and from 6% to 16% with largely been attributed to a hyper-immune host response. thromboprophylaxis (67). Similarly, COVID-19 patients Most of the series of necropsies conducted on patients in an ICU present a high risk of VTE. Middeldorp et al. who died from COVID-19 have shown signs of diffuse studied 198 patients with COVID-19, 74 (37%) of whom alveolar damage with atypical pneumocytes, as well as signs had been admitted to an ICU. The accumulated incidence of diffuse microthrombosis on a peripheral level (4,37,38). of VTE at 14 days was higher in those patients in an ICU These findings could explain the severe hypoxemia (48%; 95% CI: 33–61%) than in those in a hospital ward characteristic of SDRA in COVID-19 patients, the result (10%; 95% CI: 3–24%) (53). One study that analyzed the of the ventilation-perfusion disorder and loss of the results of all the computerized tomographies of pulmonary hypoxic vasoconstriction reflex; they would also support arteries performed on COVID-19 patients due to clinical the hypothesis proposed by some authors that severe forms suspicion of PE or an elevation in D-dimer found an of COVID-19 are linked to endothelial dysfunction and accumulated incidence of PE of 24%. The incidence was microvascular thrombosis. Accordingly, the concept of significantly higher in patients in an ICU (50%; 95% CI: MicroCLOTS (microvascular COVID-19 lung vessels 30–70%) than in those in a hospital ward (18%; 95% CI: obstructive thrombo-inflammatory syndrome) has been put 12–27%) (58). forward as a pathophysiological hypothesis for the atypical The prevalence of VTE in other studies that included SDRA associated with COVID-19 (39). critically ill COVID-19 patients varied from 9% to 54%, However, although this phenomenon of microthrombosis depending on methodological differences and the use of is characteristic of ARDS from COVID-19, it is not thromboprophylaxis and systematic screening for VTE exclusive to it, as it is also frequently found in the (45,48,49,51,52,54,56,57,62). In one study by Cui et al. (45), intermediate evolutionary and proliferative phases of acute the patients did not receive thromboprophylaxis and alveolar damage of any etiology, along with hyperplasia, the prevalence of VTE was 25%. However, the highest atypia and mitosis of type II pneumocytes (40). incidence of VTE (54%) was found in a study by Llitjos As regards acute coronary syndrome (ACS) in et al., even though up to 69% of the patients had received COVID-19 patients, plaque rupture has previously been full doses of anti-coagulants. These results can be partially reported in patients with viral disease and explained by explained by the disease’s severity in the cohort, the state vascular or plaque inflammation (41,42). On the one hand, of hypercoagulability and the performance of systematic none of the currently available data indicate any greater risk screening for DVT in the lower limbs via sonography (54). of thrombotic ACS; on the other hand, higher troponin A French prospective study compared the incidence levels in COVID-19 (a biomarker of myocardial injury) of thrombotic events in COVID-19 patients in an ICU have been associated with greater severity (43,44). (n=150) with non-COVID-19 patients in an ICU (n=150). By using propensity analysis, the authors found that patients with ARDS due to COVID-19 presented a higher risk of Risk of acute VTE in COVID-19 patients thrombotic events than the non-COVID-19 control group Seventeen studies have been published to date on the (12% vs. 5%; OR 2.6; 95% CI: 1.1–6.1%) (53). incidence of VTE in COVID-19 patients (Table 1) The incidence rates of VTE in patients hospitalized (45-60,62). Most of these works have included patients for COVID-19 are therefore similar to those published in admitted to an ICU and were receiving thromboprophylaxis series investigating other diseases. Although COVID-19 © Journal of Thoracic Disease. All rights reserved. J Thorac Dis 2021;13(2):1239-1255 | http://dx.doi.org/10.21037/jtd-20-3062 Journal of Thoracic Disease, Vol 13, No 2 February 2021 1244 Table 1 Frequency of VTE in patients with COVID-19 and related risk factors First author, journal Study design and country of its N, % males Mean age Patients in ICU Criteria for inclusion Use of thromboprophylaxis Indication for VTE imaging study Rate of VTE Risk factors related to VTE (reference) population (%) Cui et al., J Thromb Retrospective single-centre, China 81, 46% 60 yrs 100% COVID-19 pneumonia, No use of thromboprophylaxis Not specified 25%, all as DVT Aged, lymphopenia, prolonged aPTT, DD Haemost (45) admission to ICU Maatman et al., Crit Retrospective, multi-centre, USA 109, 57% 61 yrs 100% Confirmed COVID-19 All patients received thromboprophylaxis: enoxaparin Clinical suspicion 28% Values at admission: Platelet count, Care Med (46) pneumonia requiring ICU 40 mg daily, enoxaparin 30 mg b/d or UFH 5,000 IU aspartate aminotransferase lactate subcutaneous heparin every 8 h dehydrogenase, DD and troponin Al-Samkari et al., Retrospective, multi-centre, USA 400, 57% 62 yrs 36% Confirmed COVID-19 requiring 97% received thromboprophylaxis: standard dose: Not specified 4.8% DD, fibrinogen, C-reactive protein, ferritin, Blood (47) hospitalization 88.5%; intermediate- or full-dose: 8.8% and procalcitonin Klok et al., Thromb Retrospective, multi-centre, 184, 76% 64 yrs 100% COVID-19 pneumonia, All patients with TP at standard dose with Nadroparin Clinical suspicion (according to criteria 15%. Accumulated Age, coagulopathy (PT >3 seconds and/or Res (48) Netherlands admission to ICU (regime varied according to centre) of the clinician responsible) incidence 7 days of aPTT >5 seconds) 27% (95% CI: 17– 37%) Klok et al., Thromb Retrospective, multi-centre, 184, 76% 64 yrs 100% COVID-19 pneumonia, All patients with TP at standard dose with Nadroparin Clinical suspicion 37%. Accumulated Long-term anticoagulation was a protective Res (49) Netherlands admission to ICU (regime varied according to centre) incidence 14 days factor of 49% (95% CI: 41–57%) Alonso-Fernández Prospective, single-centre, Spain 30, 63% 64 yrs 38% Hospitalized for COVID-19 Enoxaparin 40 mg daily: 27 (90%) Elevated DD (>1,000 ng/ml) 15% Age, DD, platelet count, C-reactive protein et al., PLoS One (50) pneumonia and DD >1,000 ng/mL Helms et al., Intensive Study of prospective cohort of 150, 81% 63 yrs 100% COVID-19 pneumonia, LMWH: prophylactic dose: 105 (70%); therapeutic Clinical suspicion or rapid rise in DD 18% Not studied Care Medicine, consecutive patients, multi-centre, admission to ICU dose: 45 (30%) preprint version (51) France Longchamp et al., Retrospective, single-centre, France 25, 64% 68 yrs 100% COVID-19 pneumonia, 24/25 (96%) patients were prescribed TP: UFH or Lower-limb CCUS was systematically 32% Not studied Res Pract Thromb admission to ICU enoxaparin at standard prophylactic dose performed in all patients between days 5 Haemost (52) and 10 after admission to the ICU. CTPA performed for clinical suspicion Middeldorp et al., J Retrospective study of cohort of 198, 66% 61 yrs 37% Hospitalized for probable or All with nadroparin: <100 kg: 2,850/12 h; ≥100 kg: CTPA for clinical suspicion; CCUS by 17%. Accumulated UCI Thromb Haemost, consecutive patients, single-centre, confirmed COVID-19 5,700/12 h randomized selection incidence 14 days of version preprint (53) Netherlands 34% Llitjos et al., J Retrospective study of cohort of 26, 77% 68 yrs 100% COVID-19, admission to ICU Heparin: prophylactic dose: 18 (69%); therapeutic CCUS in all patients (day 1-3 and day 7). 54% Anticoagulation at prophylactic vs. Thromb Haemost (54) consecutive patients, multi-centre, dose: 8 (31%) Study for PE if there is clinical suspicion therapeutic doses France Lodigiani et al., Retrospective study of cohort of 388, 68% 66 yrs 16% Hospitalized for confirmed TP in all patients in ICU and in 75% of those in a Clinical suspicion or rapid rise in DD 7.7%. Accumulated Not studied Thromb Res (55) consecutive patients, single-centre, COVID-19 hospital ward incidence 21% Italy Thomas et al., Retrospective, single-centre, United 63, 69% 59 yrs 100% COVID-19, admission to ICU All with Dalteparin adjusted to weight and renal Clinical suspicion 9.5%. Accumulated Not studied Thromb Res (56) Kingdom function incidence 27% Poissy et al., Retrospective, single-centre, France 107, Unspecified 100% COVID-19, admission to ICU Antithrombotic prophylaxis with LMWH or UFH, Clinical suspicion due to respiratory and/ 20.6%. Accumulated DD, activity of factor VIII, levels of VWF Circulation (57) unspecified with no specified dose or percentage of use in the or acute hemodynamic deterioration incidence at 15 days complete cohort of 20.4% Bompard et al., Eur Retrospective, multi-centre, France 135, 70% 64 yrs 18% COVID-19 with pneumonia, TP with enoxaparin 40 mg/d in all hospitalized Clinical suspicion and/or elevated DD 24% DD, ICU, MV Respir J (58) with CTPA performed patients (53% of total) Table 1 (continued) © Journal of Thoracic Disease. All rights reserved. J Thorac Dis 2021;13(2):1239-1255 | http://dx.doi.org/10.21037/jtd-20-3062 Journal of Thoracic Disease, Vol 13, No 2 February 2021 1245 Table 1 (continued) First author, journal Study design and country of its N, % males Mean age Patients in ICU Criteria for inclusion Use of thromboprophylaxis Indication for VTE imaging study Rate of VTE Risk factors related to VTE (reference) population (%) Demelos et al., Prospective observational, single- 156, 65% 68 yrs 10% Hospitalized for COVID-19 TP with enoxaparin 40 mg/d or bemiparin 3,500 UI/d CCUS in all patients 15%. All as DVT: 1 DD Thromb Res (59) centre, Spain transferred from ≥2 days, >18 years, DD in 153 patients (98%) proximal DVT proximal ICU >1,000 ng/mL and 22 distal DVT Poyiadi et al., Retrospective observational, multi- 328, 46% 61 yrs 25% ICU Confirmed COVID-19 (PCR Not studied CTPA in all patients 22% BMI >30 kg/m2, DD ×6 times ULN, history Radiology (60) centre, USA of nasopharyngeal swab) and adequate CTPA Mouhat et al., Eur Retrospective, observational, single- 162, 67% 66 yrs 42% ICU Hospitalized for COVID-19 and Anticoagulants in 87% (preventive dose in 74%, All included patients underwent a CTPA 27% DD >2,590 ng/mL. Lack of any anticoagulant Respir J (61) centre, France CTPA performed for severe therapeutic doses in 13%): LMWH in 85%; UFH in for clinical signs of severe disease. therapy disease (SpO2 <94% in room 8%; oral anticoagulant: 7% air or BR >29/min) aPTT, activated partial thromboplastin time; BMI, body mass index; CCUS, compression Doppler ultrasound; BR, breathing rate; COVID-19, coronavirus disease 2019; CTPA, computed tomography pulmonary angiogram; DD, D-dimer; DVT, deep venous thrombosis; ICU, intensive care unit; LMWH, low molecular weight heparin; MV, mechanical ventilation; PE, pulmonary embolism; PT, prothrombin time; RCP, polymerase chain reaction; SpO2, oxygen saturation; TP, thromboprophylaxis; UFH, unfractionated heparin; ULN, upper limit of normal; USA, United States of America; VTE, venous thromboembolism; VWF, von Willebrand factor. © Journal of Thoracic Disease. All rights reserved. J Thorac Dis 2021;13(2):1239-1255 | http://dx.doi.org/10.21037/jtd-20-3062 1246 García-Ortega et al. PE in COVID-19 Figure 2 Rates of VTE in patients with COVID-19 infection according to admission to ICU or not (right) or use of pharmacological thromboprophylaxis or not (left). VTE, venous thromboembolism; COVID-19, coronavirus disease 2019; ICU, intensive care unit. patients in an ICU did present an increased risk of VTE, it work of Tang et al., a cohort of 449 patients hospitalized is not completely clear whether this is greater than the risk for severe COVID-19 showed that the use of heparin at a to patients who are critically ill with other diseases (65-67). prophylactic dosage for at least 7 days was associated with reduced mortality in a subgroup of patients with criteria for sepsis-induced coagulopathy (sepsis-induced coagulopathy VTE prophylaxis in COVID-19 patients score ≥4) or with very elevated D-dimer (>3 mg/L) (78). The prevalence of VTE in patients hospitalized for acute Table 2 summarizes the main recommendations of diseases is approximately 10-20%, and consequently the international organizations and scientific societies for guidelines for clinical practice recommend the use of thromboprophylaxis in COVID-19 patients (79-85). pharmacological thromboprophylaxis in those patients On the basis of the evidence currently available, the with a high thrombotic risk, as identified by means of various consensual documents that have been published well validated scales [e.g., Caprini score, Padua model, propose the early use of VTE prophylaxis, unless there IMPROVE (International Medical Prevention Registry are contraindications, in COVID-19 patients requiring on Venous Thromboembolism)] (24,68-72). The use of admission to a hospital and, more especially, an ICU. prophylactic anticoagulation has been shown to reduce the Some authors and scientific societies have proposed the risk of VTE in acutely ill hospitalized patients, including use of intermediate- or full-dose parenteral anticoagulation those hospitalized for infections (e.g., pneumonia). Similarly, for the routine care of ICU COVID-19 patients, even VTE risk stratification and in-hospital pharmacological if VTE has not been confirmed, according to the (as yet VTE prophylaxis should be applicable for hospitalized undemonstrated) hypothesis of a potential benefit in the COVID-19 patients (71-75). However, some publications prevention of microvascular thrombosis (48,78,83,85). have reported that anticoagulant therapy at prophylactic Besides, it has been proposed that anticoagulants could help doses may be inadequate for controlling the increased risk to reduce not only procoagulant effects in inflammatory of VTE in patients hospitalized for COVID-19 (76). conditions but could also reduce proinflammatory stimuli The authors of a study including 1,026 patients via reduced expression of cytokines and chemokines (86). hospitalized for COVID-19 evaluated the baseline One study of critically ill (non-COVID) patients with thrombotic risk by means of the Padua prediction model sepsis found that prophylactic anticoagulation at a standard and they found that up to 40% of the patients presented dose fails in 12% of patients. It also observed a beneficial a high risk of VTE (Padua score >4) (77). Moreover, in a effect from the use of high doses of LMWH on gas © Journal of Thoracic Disease. All rights reserved. J Thorac Dis 2021;13(2):1239-1255 | http://dx.doi.org/10.21037/jtd-20-3062 Journal of Thoracic Disease, Vol 13, No 2 February 2021 1247 Table 2 Guidelines and recommendations for thromboprophylaxis in COVID-19 patients Organization/scientific society COVID-19 patients Recommendations of thromboprophylaxis World Health Organization (WHO) (75) Severe, acute respiratory LMWH (preferably); unfractionated heparin 5,000 UI/12 h; intermittent pneumatic compression if pharmacological anticoagulation is contraindicated infection International Society on Thrombosis and Out-patient mild disease Encouragement of greater mobility; individualized stratification of the thrombotic and hemorrhagic risk Haemostasia (ISTH) (74) Hospitalized moderate or severe Individualized stratification of the thrombotic and hemorrhagic risk; prophylactic doses of LMWH (preferably) or UFH; mechanical thromboprophylaxis (intermittent pneumatic compression) if pharmacological anticoagulation disease with no DIC is contraindicated; therapeutic anticoagulation or intermediate doses not recommended in the absence of confirmed VTE Hospitalized moderate or severe Every patient must receive prophylactic anticoagulation unless there are contraindications (active bleeding and platelet count <25×109/L); therapeutic anticoagulation or intermediate doses not recommended in the absence disease with DIC of confirmed VTE; pharmacological thromboprophylaxis considered at discharge for up to 45 days American Sociedad Americana de Hospitalized All patients must receive pharmacological thromboprophylaxis with LMWH or Fondaparinux (preferable to UFH to reduce contact), unless there is a major risk of hemorrhage; fondaparinux in cases of heparin-induced Hematología (ASH) (76) thrombocytopenia; mechanical thromboprophylaxis if pharmacological anticoagulation is contraindicated; anticoagulation at therapeutic doses not recommended in the absence of confirmed VTE Sociedad Española de Hemostasia y Infection without major risk LMWH with adjustment of dose to weight and kidney function Trombosis (SETH) (79) factors for thrombosis Creatinine clearance >30mL/min Creatinine clearance <30 mL/min Enoxaparin <80 kg: 40 mg/24 h; 80–100 kg: 60 mg/24 h; >100 kg: 40 mg/12 h <80 kg: 20 mg/24 h; >80 kg: 40 mg/24 h Tinzaparin <60 kg: 3,500 UI/24 h; >60 kg: 4,500 UI/24 h <60 kg: 3,500 UI/24 h; >60 kg: 4,500 UI/24 h Bemiparin 3500 UI/24 h 2,500 UI/24 h Nadroparin 0.3 mL/24 h – Dalteparin 5,000 UI/24 h – Fondaparinux if there is allergy to heparin or heparin-induced thrombocytopenia Creatinine clearance >50 mL/min 2.5 mg/24 h Creatinine clearance <50 and >20 mL/min 2.5 mg/24 h Creatinine clearance <20 mL/min Contraindicated Infection with major risk factors LMWH with adjustment of dose to kidney function for thrombosis Creatinine clearance >30 mL/min Creatinine clearance <30 mL/min Enoxaparin 1 mg/kg/24 h 0.5 mg/kg/24 h Tinzaparin 75 UI/kg/24 h 75 UI/kg/24 h Bemiparin 5,000 UI/24 h 3,500 UI/24 h Nadroparin <70 kg: 0.4 mL/24 h; >70 kg: 0.6 mL/24 h – Dalteparin 5,000 UI/24 h – Fondaparinux if there is allergy to heparin or heparin-induced thrombocytopenia: Creatinine clearance >50 mL/min 5 mg/24 h Creatinine clearance <50 and >20 mL/min 2.5 mg/24 h Creatinine clearance <20 mL/min Contraindicated Thrombosis UK (77) Hospitalized Evaluation of thrombotic risk in all the patients (NICE/ ASH). LMWH, unless contraindicated, if there is immobilization and criteria of severity: Creatinine clearance >30: LMWH or Fondaparinux s.c. Creatinine clearance <30: UFH 5000 UI s.c. or low dose of LMWH. All patients with complete immobilization are recommended intermittent pneumatic compression, as well as pharmacological thromboprophylaxis. Mechanical thromboprophylaxis exclusively if platelets <30,000 or bleeding Working Group on Cardiovascular Hospitalized All hospitalized patients must receive LMWH; adjustment of the dose is recommended inBMI>35 and after evaluating the hemorrhagic risk and the platelet count. In patients with criteria of severity and high thrombotic risk, Thrombosis of the Sociedad Española de LMWH is recommended at intermediate/extended or therapeutic doses, following an evaluation of the hemorrhagic risk. Prolongation of LMWH at prophylactic doses for 7–10 days after the hospital discharge Cardiología (77) British Thorax Society (BTS) (80) Low risk Weight-adjusted prophylactic dose (e.g., 70 kg with creatinine clearance >30 mL/min: Dalteparin 5,000 UI/day, enoxaparin 40 mg/day) High risk LMWH at intermediate doses (e.g., 70 kg with creatinine clearance >30 mL/min: Dalteparin 5,000 UI/12h, enoxaparin 40 mg/12h) COVID-19, coronavirus disease 2019; BMI, body mass index; DIC, disseminated intravascular coagulation; LMWH, low molecular weight heparin; NICE, National Institute for Health and Care Excellence; UFH, unfractionated heparin; VTE, venous thromboembolism. © Journal of Thoracic Disease. All rights reserved. J Thorac Dis 2021;13(2):1239-1255 | http://dx.doi.org/10.21037/jtd-20-3062 1248 García-Ortega et al. PE in COVID-19 exchange (PaO2/FiO2) in a subgroup of patients with ARDS for COVID-19 (144 critically ill), all receiving standard- who received high doses of LMWH (87). The existing data dose prophylactic anticoagulation. The authors found that are still very limited, however, and the optimal anticoagulant the overall and major bleeding rates were 5% (95% CI, dose in patients with severe COVID-19 remains unknown, 2.9–7.3%) and 2% (95% CI, 1.0–4.2%), respectively, almost and so further prospective investigation is required. all in critically ill patients (47). Similarly, further research needs to be conducted on the In any case, there are no reliable data at present on use of weight-adjusted thromboprophylaxis in COVID-19 the real rate of thrombotic and hemorrhagic events patients, as there have been no studies on this topic to in COVID-19 patients, and neither do we know the date. Its use has probably been justified by the fact that efficacy and safety of the various strategies used for overweight patients were underrepresented in the pivotal thromboprophylaxis, or the risk profiles involved. We clinical trials (63-65,88,89) and in the data obtained in a therefore need results from well-designed clinical studies systematic review of obese patients who underwent bariatric that would show the benefits of different strategies of surgery, which showed a (not statistically significant) trend anticoagulants in COVID-19 patients (clinicaltrials.org), towards a reduction in VTE events in individuals who although this could vary according to patients’ specific received weight-adjusted thromboprophylaxis (0.5% vs. individual characteristics (e.g., thrombotic risk factors, 2.0%), without any increase in the risk of hemorrhage (1.6% disease severity) (Table 3). vs. 2.3%) (90). Another point of controversy is the use of extended Diagnosis of acute VTE in COVID-19 patients thromboprophylaxis after hospitalization in COVID-19 patients (91). Studies of extended thromboprophylaxis VTE is diagnosed via well-validated algorithms that in patients with acute diseases have not demonstrated combine scales of clinical probability (e.g., Wells, Geneva, any net beneficial effect, and the current guidelines YEARS), D-dimer results and imaging tests (29). A normal for clinical practice only recommend its use during a D-dimer value rules out a diagnosis of VTE in patients with patient’s hospitalization (61,92). In the case of COVID-19 a low or intermediate clinical suspicion. An imaging test is patients, although there is no still evidence about the required to confirm the diagnosis in patients with a high risk of post-discharge VTE and major bleeding rates in clinical probability (due to the low negative predictive value COVID-19, some experts have suggested the possibility of D-dimer in this subgroup) or a positive D-dimer value of individualizing the use of extended VTE prophylaxis (due to the low specificity of D-dimer for the diagnosis of (for a month, or even 45 days) considering the net benefit VTE) (24,93). between risk factors for VTE (e.g., reduced mobility, However, as mentioned above, an elevated D-dimer level obesity, previous VTE, active cancer, etc.) and low risk of is a common finding in COVID-19 patients (2-4,6,7,14) hemorrhage (24,93). and the classic cut-off point (0.5 mg/L) excludes very few At the moment, there is evidence available on the role of patients from the need for a confirmatory imaging test, thromboprophylaxis in a patient who presents concomitant computed tomography pulmonary angiogram (CTPA) mild COVID-19 and significant comorbidities but has not and/or lower-limb ultrasound (in the case of clinical been hospitalized. The consensus document by Bikdeli suspicion of PE and/or DVT, respectively). Moreover, et al. on patients confined with mild COVID-19 without bedside cardiac ultrasound could be worth considering in requiring hospital admission recommends encouraging patients with hemodynamic instability, to assess for signs mobility and considering individualized pharmacological of right ventricular dysfunction and, in exceptional cases, prophylaxis in those with a high risk of VTE and a low risk the presence of a clot in transit (24,95). Given the lack of hemorrhage (27). of specificity of the respiratory symptoms in COVID-19 Mechanical prophylaxis with intermittent pneumatic patients (particularly the most seriously ill), experts compression should only be used in immobilized patients if have recommended a high degree of clinical suspicion, pharmacological prophylaxis is contraindicated (94). particularly when there is any deterioration on a respiratory Furthermore, it must be remembered that the main (e.g., hypoxemia disproportionate to lung involvement) or complication associated with anticoagulant treatment is hemodynamic level (acute unexplained right ventricular bleeding. A recent multicentre retrospective study has dysfunction) (25,96). assessed the rate of bleeding in 400 patients hospitalized Furthermore, it must be borne in mind the risk of © Journal of Thoracic Disease. All rights reserved. J Thorac Dis 2021;13(2):1239-1255 | http://dx.doi.org/10.21037/jtd-20-3062 Journal of Thoracic Disease, Vol 13, No 2 February 2021 1249 Table 3 Future challenges for the study of thrombotic risk in COVID-19 patients Variable Challenges Pathophysiology To assess which elements of coagulation and other biomarkers (mainly inflammatory biomarkers) are associated with the development of VTE, as well as factors that modulate this association To find the best biomarkers for predicting the development of VTE complications Epidemiology To prospectively determine the real incidence of VTE in population-based studies, in out-patient vs. hospitalized patients, and according to the severity of COVID-19 Follow-up studies of international registers of COVID-19 patients to evaluate their risk of VTE To determine the risk of VTE in pregnant COVID-19 patients Prevention of VTE To determine the optimal risk stratification for consideration of VTE prophylaxis To assess the efficacy and safety of different anticoagulant doses (prophylactic doses and others) to find the optimal anti-thrombotic strategy, preferably through RCT To assess the efficacy and safety of antiplatelet agents for VTE prevention, preferably through RCT To determine whether the impact of clinical, analytical and/or imaging characteristics should be considered to indicate the dose and time of thromboprophylaxis, preferably through RCT (e.g., weight-adjusted prophylactic dosing) To assess the efficacy and safety of extended (post-discharge) thromboprophylaxis, preferably through RCT To assess the impact of pharmacological thromboprophylaxis in pregnant COVID-19 patients, and during the postpartum period Diagnosis of VTE To determine the most appropriate diagnostic algorithm of incident thrombotic events for patients with suspected VTE and COVID-19 infection To prospectively assess the efficacy of classical predictor scores to identify VTE among COVID-19 patients (e.g., Well score, Geneva score) To develop and validate a novel specific score to predict VTE among hospitalized COVID-19 patients Treatment of VTE To assess the efficacy and safety of anticoagulant therapy through RCT To assess the utility of reperfusion treatments (e.g., systemic thrombolysis, surgical embolectomy) in patients with concomitant COVID-19 and acute PE with hemodynamic instability To assess the potential drug-drug interactions between anticoagulants and routine COVID-19 therapies Outcomes of VTE To assess the impact of acute VTE in outcomes of COVID-19 patients (e.g., survival, post-COVID-19 syndrome) To assess the risk of persistent symptoms of exercise intolerance and dyspnea (post-PE syndrome including CTED and CTEPH) during the follow-up (>3 months of anticoagulant therapy) in COVID-19 patients with concomitant PE vs. without concomitant PE To evaluate the risk of recurrent VTE after stopping anticoagulation COVID-19, coronavirus disease 2019; CTED, chronic thromboembolic disease; CTEPH, chronic thromboembolic pulmonary hypertension; PE, pulmonary embolism; RCT, randomized clinical trials; VTE, venous thromboembolism. transmitting infection to health care workers who perform D-dimer cut-off value of 2.59 mg/L was identified as the best these imaging tests or other patients, with the added for predicting the occurrence of PE (AUC: 0.88, P<0.001, difficulty that some patients could be required to be in a sensitivity 83.3%, specificity 83.8%) and it was associated with prone position for severe ARDS. a 17-fold increase in the adjusted risk of PE (62). One recent retrospective study on 162 patients hospitalized for COVID-19 pneumonia with clinical signs of severity Treatment of acute VTE in COVID-19 patients who underwent CTPA in order to rule out PE analyzed the predictive value of D-dimer for the diagnosis of PE. A Therapeutic anticoagulation is currently the treatment of © Journal of Thoracic Disease. All rights reserved. J Thorac Dis 2021;13(2):1239-1255 | http://dx.doi.org/10.21037/jtd-20-3062 1250 García-Ortega et al. PE in COVID-19 choice for confirmed VTE (24) although, as mentioned who received previous oral anticoagulant treatment above, there is insufficient scientific evidence to support the (atrial fibrillation, valvulopathy, VTE, etc.), a change to use of full-dose anticoagulation in COVID-19 patients. The HBPM at therapeutic doses is recommended, to avoid any choice of agents and dosage for the treatment of incident pharmacological interactions with the drugs used to treat acute VTE in hospitalized COVID-19 patients should COVID-19 and facilitate the hospital management of be based on current guidelines, but the pharmacological patients who are potentially seriously ill or vulnerable. This interactions between some COVID-19 therapies and oral change is proposed until the clinical picture is resolved and/ anticoagulants [both vitamin K antagonists (VKA) and or the pharmacological interaction has finished, bearing in direct oral anticoagulants (DOAC)], and the difficulties mind the half-life of the drugs involved (84). involved in performing regular out-patient controls of the activity of VKAs render LMWHs in monotherapy Future challenges the anticoagulant treatment of choice, at least during the first weeks after the thrombotic episode (72). Parenteral The issue of COVID-19 infection and coagulation anticoagulation has the advantages that it can be withdrawn disorders/ thrombotic risk is one of the most important temporally, does not need to be monitored it and has not aspects that need more extensive and higher-quality data if demonstrated any drug-drug interactions with routine the management of COVID-19 patients is to be improved. COVID-19 therapies. Furthermore, a daily dosing regimen The data currently available is still very limited, and there of LMWH could have the benefit over unfractionated are gaps in our knowledge that require further research. heparin of reducing health care workers’ risk of exposure The challenge now is to adequately fill these gaps. Table 3 (27,97). Using oral anticoagulation with DOACs also may shows some of the studies that will be required for this offer some potential advantages, such as easier out-patient purpose in the future. management, reduced contact between health care workers All these issues provide opportunities for improving and patients and a lack of any need for monitoring (24,27). the management of these patients and for answering One topic of particular interest is the option of questions that are having such an enormous clinical impact. therapeutic anticoagulant management for patients with a Close collaboration will be required between VTE and diagnosis of incidental acute PE with isolated sub-segmental COVID-19 working groups. filling defects in the CTPA. Some recent publications have shown that the incidental acute PE found in COVID-19 Conclusions patients is characterized radiologically by an overall thrombotic load that is low (as assessed by the Qanadli The research now emerging highlights the complex index), less extensive and predominantly peripheral (more interactions between COVID-19 infection and thrombotic frequently involving only sub-segmental branches), so this disease. COVID-19 infection induces a pro-thrombotic issue acquires a special significance in the handling of these state, secondary to the organism’s hyper-inflammatory patients (98,99). The current guidelines, mostly based response and to hypoxia, which can predispose to on expert opinions due to limited data, indicate that the an increased incidence of venous thrombotic events, clinical relevance of the CTPA diagnosis of sub-segmental particularly in the most severely ill patients. The PE remains unknown, although anticoagulant treatment results presented in recent scientific publications on the is recommended in cases of single sub-segmental PE in a coagulopathy associated with COVID-19 and the risk of hospitalized patient and/or multiple sub-segmental PE (29). thrombotic events have triggered debate and controversy Invasive treatment for acute VTE in COVID-19 patients about the optimal strategy for the prophylaxis, diagnosis (e.g., catheter-directed therapies, surgical embolectomy) and anti-thrombotic treatment of VTE, as reflected by must be restricted to situations backed by more evidence, the divergences in the recommendations published by due to the risk of contagion to both other patients and various scientific organizations and societies. It is still health care workers, and the prevailing guidelines must be not clear whether the failure rate of pharmacological followed. For example, the placement of an inferior vena thromboprophylaxis is higher in critically ill COVID-19 cava filter is an adequate treatment for VTE in a setting patients than in others who are critically ill from other with absolute contraindications (24). diseases; this doubt has led some authors to recommend As regards those patients hospitalized for COVID-19 the use of thromboprophylaxis at intermediate doses © Journal of Thoracic Disease. All rights reserved. J Thorac Dis 2021;13(2):1239-1255 | http://dx.doi.org/10.21037/jtd-20-3062 Journal of Thoracic Disease, Vol 13, No 2 February 2021 1251 or therapeutic anticoagulation in this patient profile, Open Access Statement: This is an Open Access article although we would need to have results from the clinical distributed in accordance with the Creative Commons trials current underway to endorse these proposals. The Attribution-NonCommercial-NoDerivs 4.0 International diagnosis of VTE in COVID-19 patients presents certain License (CC BY-NC-ND 4.0), which permits the non- difficulties and traits that must be taken into account, such commercial replication and distribution of the article with as the risk of contagion of other patients and of health the strict proviso that no changes or edits are made and the care workers and the overlap of respiratory symptoms original work is properly cited (including links to both the that can be explained by both respiratory infection and formal publication through the relevant DOI and the license). the presence of acute PE. While we await the definition See: https://creativecommons.org/licenses/by-nc-nd/4.0/. of the diagnostic algorithm for VTE most suited to patients hospitalized for COVID-19, it seems reasonable References to maintain a high degree of clinical suspicion of PE and/or DVT in these patients, in order to determine 1. 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Stratified meta-analysis of intermittent different phenotype of thrombotic disease? Thromb Res pneumatic compression of the lower limbs to prevent 2020;193:86-89. Cite this article as: García-Ortega A, de la Rosa D, Oscullo G, Castillo-Villegas D, López-Reyes R, Martínez-García MÁ. Coagulation disorders and thromboembolic disease in COVID-19: review of current evidence in search of a better approach. J Thorac Dis 2021;13(2):1239-1255. doi: 10.21037/ jtd-20-3062 © Journal of Thoracic Disease. All rights reserved. J Thorac Dis 2021;13(2):1239-1255 | http://dx.doi.org/10.21037/jtd-20-3062