FormalPara Highlights

  • Reported incidence of venous thrombotic events in COVID-19 patients

  • Major differences between ISTH and CHEST guidelines in thromboprophylaxis for patients with COVID-19

  • Ongoing RCTs of different anticoagulation strategies in patients with COVID-19

  • A proposal for COVID-19 coagulopathy specific risk factors and dedicated trials

A common and potent consideration has recently entered the landscape of the novel coronavirus disease of 2019 (COVID-19): venous thromboembolism (VTE). COVID-19 has been associated to a distinctive related coagulopathy that shows unique characteristics [1]. The research community has risen to the challenges posed by this « evolving COVID-19 coagulopathy » and has made unprecedented efforts to promptly address its distinct characteristics. However, a key central question that could guide prevention, diagnosis, and treatment strategies of COVID-19 coagulopathy remains under debate: are these haemostatic changes a consequence of severe inflammation or are they a specific effect mediated by the virus? [2]. The immune response to acute SARS-CoV-2 infection and the accompanying surge of cytokines and inflammatory mediators have been accepted as a key pathway triggering thrombogenesis. In this setting, early strategies aimed at reducing inflammation might help prevent thrombosis. The alternative postulate is that the virus directly or indirectly interferes with coagulation pathways. The determinants of both hypotheses seem to stem mostly from host factors such as age, comorbidities, and the prominent role played by the extent of lung injury. Owing to these determinants, the combined use of risk scores to identify high-risk patients for adverse thrombotic events may guide individualized antithrombotic treatment of Covid-19 patients [3]. Another important insight is the recognition of the importance of extravascular fibrinolytic activity in the airway lumen and the alveolar compartment. Extravascular fibrin was demonstrated as a possible mechanism by which inflammatory cells can invade the lung [4]. Breakdown of fibrin as a consequence of high fibrinolytic activity would lead to a marked generation of D-dimers levels independently of thrombotic events. According to this paradigm, high D-dimers levels would not be solely considered as a marker of thrombotic propensity but should be viewed as an integrate marker of disease severity including the extent of lung damage [5].

In the inpatient setting, the prevalence of VTE ranges from 3 to 85%, as detailed in Fig. 1 [6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25].

Fig. 1
figure 1

Reported incidence of venous thrombotic events in COVID-19 patients hospitalized in ICU (a) and non-ICU (b). Covid-19 coronavirus disease 201, ICU intensive care unit

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However, most of studies on coronavirus patients used different design (systematic screening vs D-Dimer threshold vs symptom-driven approach), different intervention (contrasting intensities of thromboprophylaxis regimens), severity (ICU vs wards) and outcome (asymptomatic vs symptomatic VTE) resulting in reduced data comparability across studies (Table 1).

Table 1 Prevalence of venous thrombotic events (acute pulmonary embolism and/or deep vein thrombosis) in COVID-19 patients
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Furthermore, investigations from the outpatients are warranted with high priority, as they represent the vast majority of Covid-19 cases and VTE rate in this specific subset has not been reported yet [26]. Early reports suggested a high incidence of VTE and frequent haemostasis disorders in COVID-19 patients [27, 28]. Though, it remains to be demonstrated that theses frequent «new thrombotic» features at first glance are any different from previous experience from severe viral pneumonia [29,30,31,32,33]. Both intrinsic and extrinsic risk factors for VTE (Fig. 2) together with large number of patients considered at high risk on the basis of current VTE risk scores [34] lead to first interim [35] followed by updated guidance on thromboprophylaxis in hospitalized patients with COVID-19 [36, 37].The first reminder of a beneficial effect of thromboprophylaxis came as early as March 27, 2020 with reduced mortality in critically ills affected by severe COVID-19 and treated with heparin [38]. Of note, only 22.0% of the population analyzed by Tang et al. received anticoagulant therapy for the prevention of VTE and this reinforced the role for routine VTE risk assessment and the initiation of adequate thromboprophylaxis [39]. A substantial 5 to 10% risk of VTE in critically ills is currently reported despite the use of prophylactic anticoagulants [40,41,42,43]. COVID-19 patients presented in later reports with unusual higher rates of VTE despite the use of prophylactic anticoagulants [6,7,8,9, 12, 21].

Fig. 2
figure 2

Intrinsic and extrinsic risk factors for venous thromboembolism in COVID-19. Covid-19 coronavirus disease 2019, CT computed tomography, DVT deep vein thrombosis, ICU intensive care unit, PE pulmonary embolism

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Latest ISTH consensus statement published on May 27, 2020 recommended routine thromboprophylaxis in non-ICU and ICU hospitalized COVID-19 patients with preferably standard-dose LMWH or UFH [37]. Due to time-sensitivity with the pandemic and in the absence of robust evidence, a “stepped therapy” approach in non-ICU patients or treatment-dose heparin in critically ills did not reach full consensus yet. With regards to the rapid deterioration reported in many COVID-19 patients requiring ICU transfer, long half-life and/or reversibility concerns, both fondaparinux and prophylactic dose DOAC were not recommended in critically ill hospitalized COVID-19 patients. Apart from body weight-adjusted dose on extremes cases (< 50 kg or > 120 kg or BMI), the ISTH expert panel recommended against the general use of intermediate dose of LMWH/UFH in non-ICU. Wisely awaiting for some strong evidences, intermediate-dose LMWH was only advocated by 30% of ISTH respondent in non-ICU and up to 50% in ICU patients (Table 2).

Table 2 Major differences between ISTH and CHEST guidelines in thromboprophylaxis for patients with COVID-19
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No more that 6 days after the ISTH guidance had been released, an American College of Chest Physicians (CHEST) panel of experts provided a conflicting set of guidelines on June 2, 2020 [44]. CHEST experts recommended (i) standard dose anticoagulant thromboprophylaxis in non-ICU and ICU patients, (ii) LMWH or fondaparinux over UFH in non-ICU patients, (iii) suggested against the addition of mechanical prophylaxis (i.e. intermittent pneumatic compression) to pharmacological thromboprophylaxis while 60% of ISTH experts pledged for it. Armed with this two set of guidelines, one being « conservative » and the other much more « liberal» on both stepped-up pharmacological and mechanical approach, how is the physician supposed to react in day use practice? Both guidelines nonetheless advocated for more evidence coming from ongoing randomized trials (Table 3), more extensive description of the « sicker » or « higher risk » patient profile likely to benefit from increased intensity anticoagulant thromboprophylaxis, and finally a call for updated evidences regarding bleeding risk in this population as they are insufficient so far. Identifying very-high-risk patients for VTE is undoubtedly the main issue of reducing both incidence and mortality risk of VTE [45]. The triad of risk seems to essentially rely on marked prothrombotic state, thromboinflammation and the extent of lung injury (Fig. 3).

Table 3 Ongoing RCTs of different anticoagulation strategies in patients with COVID-19
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Fig. 3
figure 3

A proposal for COVID-19 coagulopathy specific risk factors and dedicated trials. Covid-19 coronavirus disease 2019, CT computed tomography, ICU intensive care unit, RCTs randomized controlled trials, VTE venous thromboembolic events

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All studies of haemostasis have identified a prothrombotic state in COVID-19 [46]. Thachil et al. lately proposed a new staging classification characterizing COVID-19 associated hemostatic abnormalities (CAHA) [3]. The authors proposed that the spectrum of CAHA first represents a localized phenomenon of hypercoagulability in the lung, which then becomes extensive and systemic (increased D-Dimer level, reduced platelet count and prolonged PT) if not treated adequately. We promptly confirmed a stepwise increase in VTE rates and excess mortality and/or transfer to ICU for each increment in stage of CAHA among 150 non-ICU patients with COVID-19 [47]. Hence, we proposed a CAHA threshold ≥ 2 to consider early aggressive strategies including early VTE imaging screening, “stepped-up” anticoagulant dose regimens and critical care support. VTE risk stratification scheme and prospective RCTs are needed to determine whether intermediate or treatment-dose anticoagulant confer both survival benefit and decreased VTE incidence according to biomarkers threshold including the use of very elevated D-dimer levels and inflammatory markers in hospitalized patients with COVID-19.

Hyperinflammation has been advocated as a key component triggering thromboinflammation and subsequent increased risk of VTE [48, 49]. The first event after inhalation of SARS coronaviruses is invasion of type II alveolar cells in the lung. Viral cell entry triggers the host’s immune response and an inflammatory cascade. While viral multiplication and localized inflammation in the lung is the norm, severe COVID-19 patients will develop an overproduction of proinflammatory cytokines resulting in a cytokine storm [50]. On top of anti-inflammatory or antiviral effects, current therapeutic strategies (e.g. intravenous immunoglobulin, selective cytokine blockade etc.) [51] may have indirect antithrombotic effects and modulate the risk of VTE.

Lung and pulmonary thrombosis have an intimate relationship in COVID-19. The first hint came from accumulating evidence of published necropsy series with the prominence of clot, widespread micro-thrombi and occlusion of alveolar capillaries [26, 52,53,54]. More evidence followed with proof of pulmonary endotheliitis in the time course of SARS-CoV-2 infection [55]. A distinctive pattern of pulmonary intravascular coagulopathy has finally been proposed [56, 57]. The current consensus puts the lungs as the epicenter for the hemostatic and inflammatory issues in COVID-19. Desborough et al. nicely addressed this issue providing evidence that many of the acute pulmonary embolism are indeed described on CT pulmonary angiograms as segmental or subsegmental and that these thromboses may be immunothromboses due to local inflammation, rather than thromboembolic disease [58]. First localized to the lung, then extensive and finally systemic if not treated, the phenomenon of pulmonary intravascular coagulopathy in COVID-19 pneumonia translates in clinical practice with higher oxygen requirement and extensive lung injuries assessed by chest CT [18, 47, 59].

Several anticoagulant regimens are been currently investigated in patients with COVID-19. Systematic screening for marked prothrombotic state, hyperinflammation and the extent of lung injury as determined by chest CT could be helpful to guide individualized thromboprophylaxis in COVID-19 patients.