key: cord-0771304-eb2uvdsa
authors: Bristogiannis, Sotirios; Swan, Dawn; Thachil, Jecko
title: Thromboprophylaxis in COVID-19 – Rationale and considerations
date: 2021-07-23
journal: Adv Biol Regul
DOI: 10.1016/j.jbior.2021.100819
sha: 14e54d80780970bbd591c7db78de146c4ad7952b
doc_id: 771304
cord_uid: eb2uvdsa

The Corona Virus Disease-2019 (COVID-19) pandemic is associated with a very high incidence of thrombotic complications. The exact mechanisms for this excess risk for clots have not been elucidated although one of the often-quoted pathophysiological entity is immunothrombosis. Recognition of thrombotic complications early on in this pandemic led to an over-explosion of studies which looked at the benefits of anticoagulation to mitigate this risk. In this review, we examine the rationale for thromboprophylaxis in COVID-19 with particular reference to dosing and discuss what may guide the decision-making process to consider anticoagulation. In addition, we explore the rationale for thrombosis prevention measures in special populations including outpatient setting, pregnant females, children, those with high body mass index and those on extracorporeal membrane oxygenation.

Nearly a year since the emergence of the new Severe Acute Respiratory Syndrome Corona Virus (SARS-CoV-2), the Corona Virus Disease-2019 (COVID- 19) pandemic is still carrying devastating implications for human health and socio-economic welfare. What has now become clear is rather than being an isolated respiratory infection, COVID-19 disease constitutes a syndrome of multi-system manifestations which mandates a multi-disciplinary approach [1, 2] . Coagulopathy has emerged as an integral component of the disease's pathogenesis and has been associated with poor prognosis [3] .

Thus, research has focused on elucidating the elements of haemostatic disturbance in this context, which has translated into clinical interventions to mitigate their effects. These interventions among others have contributed to a considerable improvement in morbidity and mortality [4] .

Thrombosis has unequivocally been recognised as a frequent complication of COVID-19 disease with crucial prognostic implications. Both venous thromboembolic[ (ITU) IR:28%, 95% CI: 22-34%, I 2 :89.5;

(non-ITU) IR: 10% , 95% CI: 6-14%, I 2 :96 ] and less commonly arterial events [ (ITU) IR:3%, 95% CI: 2-5%, I 2 :4.1; (non-ITU) IR: 2% , 95% CI: 0-3%, I 2 :0] [5] have been reported at a much higher frequency than in similar viral infections [6] [7] [8] . Incidence varies in relation to disease severity, the diagnostic approach used (routine asymptomatic screening versus on-demand investigation of symptoms), intensity of anticoagulation used and the definition of outcomes (e.g. Myocardial Infarction versus ST-elevation) ( Table 1) . Patients with COVID-19 disease who develop a thromboembolic event carry an increased risk of death of 74% (OR: 1.74; 95% CI: 1.01-2.98; p: 0.04) [9] .

Following inhalation, SARS-CoV-2 infects host type II pneumocytes provoking initially an innate and subsequently an adaptive immune response [10] . The juxtaposed microvascular endothelial cells are also trans-infected by SARS-CoV-2 which compromises their homeostatic control of local inflammation and facilitates the entry of SARS-CoV-2 in the systemic circulation culminating in pyroptosis of other distant cells [11] . For the majority of patients the immune system manages to control the infection through various cell-, humoral-, cytokine-and complement-mediated responses [11, 12] .Nevertheless, some patients [13] develop a maladaptive immune response triggered by cytokine overproduction or macrophage activation syndrome [10] . At the same time, inflammation and the related tissue injury activates the haemostatic mechanism through various means: a) apoptotic endothelial cells, (alveolar) epithelial cells, fibroblasts and innate immune cells release TF (Tissue Factor) which activates the extrinsic coagulation pathway [14, 15] ; b) enhanced vascular permeability secondary to endothelial dysfunction facilitates the secretion of thrombin into pulmonary capillaries which can activate platelets and the coagulation cascade; c) microparticles secreted by neutrophils (e.g., Neutrophil Extracellular Traps; Cathelicidins) activate platelets and J o u r n a l P r e -p r o o f Factor XII resulting in the stimulation of the intrinsic coagulation pathway; d) endothelial cell damage results in the release of ultra-large vWF and exposure of the extracellular matrix proteins (e.g. Pselectin, collagen) but, also, diminishes the secretion of Thrombomodulin disturbing the haemostatic balance; e) cytokine-stimulated increased hepatic Thrombopoietin production increases the number of the circulating pro-thrombotic megakaryocytes; and f) complement stimulation catalyses further factor II,I and XIII activation [15] . As a consequence of haemostatic system activation, COVID-19 disease can be complicated at early stages by microvascular thrombosis [16] which aggravate hypoxia due to ventilation/perfusion mismatch. In turn, hypoxia can exacerbate tissue injury and inflammation [17, 18] as can the triggered haemostatic system itself through several mechanisms [15] . In conclusion, the pathogenesis of COVID-19 disease-related coagulopathy encompasses activation of both the immune and the haemostatic systems with endothelial dysfunction playing a key role in this process [19] .

[ Figure 1 ]

Thromboprophylaxis has been associated with a statistically significant reduction in mortality (OR: 0.374; 95% CI: 0.154-0.901; p: 0.029) in patients with severe (SIC score≥ 4) COVID-19 disease as was noted early on in the pandemic [3] . Nevertheless, the benefit remains for all hospitalised patients [20] , although evidence is limited [21] .Thus, considering at least the lack of harmful effect of prophylactic doses of anticoagulation [22, 23] , guidelines suggest thromboprophylaxis for all (but only) hospitalised patients in the absence of any contraindications (e.g. active bleeding) [24] [25] [26] [27] [28] [29] [30] [31] [32] .Thromboembolic disease is associated with considerable morbidity that affects patients' quality of life [33]but rarely necessitates on its own hospital re-admission since the risk can be mitigated with anticoagulation [34] .Possible long sequelae of thromboembolic disease are pulmonary hypertension and pulmonary fibrosis secondary to chronic thromboembolic disease [35] , neurological deficits and occasionally ischemic cardiomyopathy as well as chronic kidney injury [36] .

Acknowledging the impact of thromboprophylaxis on the prognosis of COVID-19 disease, clinicians have trialled variable doses, types and periods of anticoagulation-indeed frequently adjusting their strategy according to patients' comorbidities as well as to clinical and/ or laboratory evidence of disease severity.

Low molecular weight heparin has been the mainstay of prophylactic anticoagulation in COVID-19 disease in view of its predictable bioavailability and the ability to adjust dosing in critically ill patients, as well as its anti-inflammatory and immunomodulatory properties [37] [38] [39] . Guidelines suggest the use of low molecular weight heparins (LMWHs) unless CrCl≤ 30 ml/min or there is a high risk of requiring rapid reversal of anticoagulant effect -when Unfractioned Heparin (UFH) can be used instead. UFH J o u r n a l P r e -p r o o f has been suggested in lieu of LMWHs in patients with severe COVID-19 disease who can exhibit heparin resistance [40] due to Antithrombin deficiency [41] and/or markedly raised acute phase reactants such as Fibrinogen [42] .Heparin resistance has, indeed, been documented occasionally in this subset of patients [43] [44] but this cannot be bypassed by UFH [45] and actually the clinical outcomes are worse with UFH than with LMWHs even in this context [46] . Fondaparinux has been advocated as non-inferior to LMWHs in terms of thromboprophylaxis, bleeding complications and survival, but none of these outcomes have met the criteria of statistical significance [47, 48] .

Thrombin Inhibitors can, except from their known anti-thrombotic effect, exhibit invaluable antiinflammatory,anti-viral and anti-apoptotic actions. Their anticoagulation effect isindependent of Anti-Thrombin (AT), which distinguishes them as an appealing choice in patients with critical disease which can be complicated with AT deficiency. No interactions with standard of care medications for SARS-CoV-2 have been identified [49] .Encouraging but limited data exist for the use of Argatroban as thromboprophylaxis in these patients [50] . Head-to-head randomized trials comparing Thrombin Inhibitors to Heparin are under way.

Acknowledging the key role of the endothelial glycocalyx destruction for the escalation of COVID-19 disease [51, 52] , a composite medication of heparin and dermatan sulphate called Sulodexide has been trialled in patients with early-stage disease. Thromboprophylaxis with Sulodexide reduced hospital admissions and the need for oxygen support but failed to show any statistically significant improvement in survival compared to placebo [53] .

Thromboprophylaxis with Vitamin K antagonists and Direct Oral Anticoagulants (DOACs) is generally discouraged due to the disease-related hepatic and/or renal dysfunction [54] , unpredictable bioavailability secondary to potential drug interactions with treatments for SARS-CoV-2 [55] , nutritionrelated effects and absorption issues, and delayed onset but also long half-life of anticoagulation effect [56, 57] .Interestingly, Vitamin K deficiency has also been associated with worse outcomes in COVID-19 disease, which may be due to an induced coagulation imbalance and/or reduction of the protective effect of Vitamin K against arterial calcification as well as lung fibrosis and/or the loss of its immunomodulatory effect [58] .In contrast, DOACs exhibit additional anti-inflammatory, endothelial protective effects [59] and can even directly prevent the infection of host cells by SARS-CoV-2 [60] .Thromboprophylaxis with DOACs has shown improved efficacy without any statistically significant safety compromise compared to LMWH in medical inpatients without COVID-19 disease [61] . With regards to patients with COVID-19 disease Billett et.al. has shown equivalence of survival with prophylactic doses of either Apixaban or Enoxaparin [62] but more clinical trials (NCT0434377, NCT04416048, NCT04504032, NCT04508023, NCT04542408, NCT04505774, NCT04640181, NCT04736901) assessing DOACs, in various doses and settings, in comparison to LMWH are currently underway.

As regards the optimal dose of pharmacological thromboprophylaxis, this depends on co-existing comorbidities and the individual bleeding risk of the patient and as well as the severity of the disease so that timely dose adjustments are made [32, 63, 64] . Therefore, for patients that already receive anticoagulation for another indication on admission (e.g. previous thrombosis or atrial fibrillation), a switch to a similar intensity LMWH regimen should be considered since oral anticoagulants may run the risk of drug interactions [32, 65] . Contrary to initial hopes [66] , these patients are not protected from requiring intensive care for COVID-19 disease [67] .Albeit rare and unrelated to intensity of anticoagulation [68] , the bleeding risk of patients should be considered in decisions about thromboprophylaxis. Although none of the widely used bleeding scores has been validated in COVID-19 patients [69] , a HAS-BLED score ≥ 3 has been associated with a higher risk of major bleeding in this context [70] . For these patients and those with active bleeding, severe thrombocytopaenia (<25 x 10 9 / L) and/or an underlying bleeding disorder, mechanical thromboprophylaxis should be applied [64] .

Such patients should be given pharmacological thromboprophylaxis as soon as the contraindications are resolved.

Provided the patient has no other indications for anticoagulation and is not at high risk of bleeding, the dose of LMWH is determined currently by the severity of the disease. Relevant guidelines have recently been updated in response to the preliminary data published by the National Institutes of Health (NIH) multiplatform randomized controlled trial which incorporates three international studies (REMAP-CAP, ATTACC, and ACTIV-4A) [71, 72] . For hospitalised patients that do not require HDU/ITU organ support (which includes high flow nasal oxygen and non-invasive mechanical ventilation) therapeutic dose of LMWH appears superior to non-therapeutic dose (Table 1 ). In contrast, for patients requiring ITU-level organ support, therapeutic dose LMWH does not show a survival benefit compared with non-therapeutic dose, despite significantly reducing thrombotic events ( Table   2 ). The latter comes as no surprise, as pulmonary embolism events do not seem to increase the risk of death in patients with COVID-19 disease at critical condition [73] . Of note, retrospective studies in ITU patients have shown contradicting results regarding the effect of therapeutic anticoagulation on survival [74, 75] .Although preliminary results from the NIH trial show trends, none of the outcomes other than thrombotic events in the subset of patients with severe COVID-19 disease met criteria for statistical significance. Furthermore, the causes of increased mortality among patients receiving therapeutic dose of LMWH need to be elucidated, as the incidence of major bleeding is comparable between patients with moderate and severe disease and the severity of COVID-19 disease can be a confounding factor. One further limitation of NIH trial is that the comparator arm (non-therapeutic dose Several other studies have shown a survival advantage of therapeutic to prophylactic anticoagulation compromised by a statistically significant increase in major bleeding complications [76, 77] .Nevertheless, these studies lack adjustment of outcomes based on the severity of COVID-19 disease. Indeed, Paranjpe [78] has shown similar survival in ITU patients regardless of the intensity of anticoagulation with exponential increase in the bleeding risk. Intermediate dose anticoagulation has, also, failed to exhibit any survival benefit (OR: 1.09; 95% CI: 0.78-1.53, p:0.5) [79] or reduction in VTE incidence [80] in unselected patients admitted to ITU compared to prophylactic dose and was associated with increased rate of major bleeding( OR: 1.83; 95% CI: 0.53-5.93, p:0.33) [79] . suggested) reduced mortality compared to the group that received standard thromboprophylaxis (or therapeutic only when a VTE event was identified) [87] . As regards patients requiring no ITU support, REMAP-CAP, ATTACC, and ACTIV-4A multiplatform RCT interim results suggest that they benefit the most from therapeutic dose anticoagulation regardless of D-Dimers levels [71] . Thus, D-dimer levels appear to have a role in guiding the escalation of thromboprophylaxis, but it is less clear whether they can safely mandate dose reductions in patients transferred to ITU and/or patients with long-admissions due to COVID-19 complications. Thromboprophylaxis dose adjustment based on Anti-Xa levels in patients with COVID-19 disease has, also, been investigated. Escalating the thromboprophylaxis dose in ITU patients, who frequently exhibit suboptimal anti-Xa levels, has been J o u r n a l P r e -p r o o f associated with improved survival (OR: 0.18; 95% CI: 0.033-0.95; p: 0.031) [88] but this may be beneficial for ward-level patients [44] as well. In patients that are critically ill, D-Dimers-guided thromboprophylaxis should be monitored by anti-Xa levels [89] .Nevertheless, concerns have been expressed about the reliability of anti-Xa monitoring in patients with severe COVID-19 disease [90] .

Patients with COVID-19 infection may be at increased risk for VTE (30-42 days) post discharge although not statistically different to non-COVID-19 medical inpatients [91] . Patients with COVID-19 disease that required ITU support during their admission and/or patients with cardiovascular and/or renal comorbidities exhibit persistent endothelial activation, especially if there is sustained cytokine production [92] .Classical risk factors such as age, restricted mobility (which can be expected post prolonged/premature discharges) and underlying prothrombotic conditions (e.g. malignancy; thrombophilia)are also expected to increase the risk of post-discharge VTE [93] .A score of ≥4 in the modified IMPROVE-VTE score or ≥2 plus D-Dimer level>2 ULN(Upper Limit of Normal) at discharge has been extrapolated from historical studies on medical inpatients and used alternatively to guide decisions about extended thromboprophylaxis. Prophylactic anticoagulation with either LMWH or a DOAC for this subset of patients has been variably advocated for 2-6 weeks post discharge provided the bleeding risk is low [94] and has been shown to reduce the risk of VTE (OR: 0.54; 95% CI: 0.47-0.81) [93] .

[ Figure 2 ]

Thromboprophylaxis in certain special populations with COVID-19 disease such as ambulatory patients, in pregnancy (antepartum and postpartum), in children, morbidly obese patients and patients on Extra Corporeal Membrane Oxygenation (ECMO) needs to take into consideration their particularities.

Although the heightened risk for thromboembolic events in patients with COVID-19 disease requiring hospital admission is well documented and thromboprophylaxis strategies have been extensively studied, the data for those who remain outpatients are scarce and the guidance is largely opinionbased. The incidence of thrombosis in this setting varies in relation to individual's underlying cardiovascular risk factors, level of mobility and severity of COVID-19 disease from 0 to 1.09% [95, 96] .Thus, standard dose thromboprophylaxis for (at least) 14 days with heparin (LMWH or UFH) or even DOACS should be considered for patients with additional thrombotic risk factors [83, 84, [97] [98] [99] [100] .As peak D-Dimers levels that are above 6 times the upper limit of normal [101, 102] can predict J o u r n a l P r e -p r o o f thromboembolic events in this context, it would be of interest to explore the potential benefit [100] of repeating D-Dimers levels 10-12 days after diagnosis [103] and initiating thromboprophylaxis if raisedeven if these patients remain ambulatory [104] .Some researchers have advocated the use of antiplatelet agents instead of anticoagulation in low risk ambulatory patients [97, 105] .Although we acknowledge the scientific basis [106] of this recommendation and the survival benefit of people that acquire a COVID-19 disease while already being on antiplatelet agents [107] [108] [109] , we cannot support this practice in the absence of any randomised controlled trial evidence and in view of their inferior efficacy in preventing venous thromboembolism in similar settings [110] .

Pregnancy COVID-19 infection in pregnancy is associated with a substantially increased risk of complications including maternal VTE (OR: 3.43; 95% CI: 2.01-5.82), ITU admission and death [111] but also possible placental insufficiency [112] . Also, the reference ranges of coagulation parameters differ to those of the normal population and vary according to the trimester so that the usefulness of D-Dimers to adjust thromboprophylaxis is limited [113] .Society guidelines for thromboprophylaxis in pregnancy with COVID-19 disease vary. Provided the bleeding risk is low and labour is not due within 12 hours, thromboprophylaxis with LMWH is generally advocated for all hospitalised antepartum and postpartum patients and patients discharged home who have increased (≥3) VTE risk score at booking. In view of the lack of randomised controlled trials, there is lack of expert consensus whether the intensity of thromboprophylaxis should be escalated to intermediate dosing in patients with moderate-severe disease and/or thromboembolic risk factors. Thromboprophylaxis should be continued for 10-42 days post-discharge with more prolonged duration favoured for patients with a severe presentation [114] .The use of low-dose aspirin for the prevention of pre-eclampsia in high-risk pregnant women after the 12 weeks of gestation is controversial and should take into consideration the risk of bleeding and possibility of an emergency caesarean section if indicated by maternal condition [115, 116] .

Children and adolescents generally (74.1% of the cases) experience a mild course of COVID-19 disease [117] . Nevertheless, depending on the severity of the presentation (and the development of multisystem inflammatory syndrome) children risk developing VTE in 1.25%-26% of cases [118, 119] .Thromboprophylaxis in this subgroup is guided by expert opinion until further data becomes Dimers>500 ng/ml along with Ferritin>500 ng/ml and to treatment dose if D-Dimers>2500 ng/ml, Platelets>450 x10 9 and C-reactive protein(CRP)>100mg/dL [121] .Extended (30 days) post-discharge thromboprophylaxis should be considered for children with COVID-19 disease with markedly elevated (≥ 2 times the upper normal limit) D-Dimer levels on discharge or pre-existing prothrombotic risk factors [120] .Should children develop multisystem inflammatory syndrome in the context of COVID-19 disease, antiplatelet agents and/or therapeutic anticoagulation should be instituted as well [122] .

Obesity (BMI ≥ 30kg/m 2 ) has been recognized as an independent (to metabolic syndrome comorbidities) risk factor of VTE and death for patients with COVID-19 disease [123, 124] .As in non-COVID-19 patients [125] ,LMWH (or UFH) is the anticoagulant of choice but there is no consensus regarding the need to dose-adjust based on either the weight or the BMI of the patient [29, 126] .Weight-based thromboprophylaxis has been shown to be superior to standard dose thromboprophylaxis in preventing VTE events and (possibly, though not statistically significantly) death [86] .Anti-Xa monitoring of anticoagulation effect might also be useful in this subgroup of patients [44] .

ECMO, which has been used as life-rescue therapy in patients with severe COVID-19 disease, can significantly influence the haemostatic balance. To further complicate matters, patients on ECMO are frequently (20%) thrombocytopaenic, require anticoagulation to avoid clotting of the extracorporeal circuits and may develop Heparin-Induced Thrombocytopaenia (HIT) [127] .UFH is usually used but strict monitoring with either aPTT ratio (target range: 1.5-2.5) or anti-Xa (target range: 0.3-0.7 IU/ml) [128] is essential to limit the increased risk of bleeding (Major haemorrhage in 42% of the patients) [129] .Should patients develop recurrent clotting within extracorporeal circuits (or any other VTE), the possibility of HIT must be considered and the intensity of anticoagulation can be increased acknowledging the bleeding risk of the patient [27] .

CoV-2, the immune system and the endothelium of the host. Without doubt, thromboprophylaxis has substantially improved outcomes of patients, but further improvements could perhaps be achieved by specifically targeting the underlying pathogenic processes underpinning coagulopathy in COVID-19.

Thankfully, markers of haemostasis can safely be used to stage the disease, adjust treatment accordingly and to determine patients' prognosis. [43] ; [44] ; [45] ; [46] ; [47] ; [48] VTE: 9.3-50%; PE: 6.2-16.7 %; DVT: 2-50% Non-ITU [42] ; [43] ; [45] ; [49] ; [50] ; [51] VTE: 0-10%; PE: 2.2-10%; DVT: 2-21% Outpatients [52] ; [6] a VTE: 3.8; PE: 2.5-18%; DVT: 1.3% Arterial thrombosis ITU [44] ; [45] ; [48] ; [53] AT: 2-5%; Stroke: 1.3-6.3%; MI: 0-22.2%; Other: 1.4-2.2% Non-ITU [42] AT: 0-3%; Stroke: 0.9%; MI: 7.3%; Other: 0.6% Outpatients [6] a Stroke: 1.9%; MI: 1%; Variation of coagulation factors in severe SARS-CoV-2 infection. *Not statistically significant changes. [1] [2] [3] [4] [5] Variation of coagulation factors in severe SARS-CoV-2 infection. *Not statistically significant changes. [1] [2] [3] [4] [5] J o u r n a l P r e -p r o o f 

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D-Dimer Concentrations and Covid-19 Severity: A Systematic Review and Meta-analysis. frontiers in Public Health

How to Build the Plane While Flying: VTE/PE Thromboprophylaxis Clinical Guidelines for COVID-19

Megakaryocytes and platelet-rich thrombi characterize mutli-organ thrombosis at autopsy in COVID-19: A case series

Association of mortality and aspirin prevention for COVID-19 patients at the Veterans Health Administration

Mortality and pre-hospital use of low-dose aspirin in COVID-19 patients with coronary artery diseaes

The use of aspirin for primary prevention of cardiovascular disease is associated with a lower likelihood of COVID-19 infection

Does aspirin prevent venous thromboembolism? Hematology American Society of Haematology Education Program

COVID-19) Infection in Pregnancy-guidance for health professionals

Placental pathology in COVID-19

Haemostatic and thrombo-embolic complications in pregnant women with COVID-19: a systematic review and critical analysis

A critical review of the pathophysiology of thrombotic complications and clinical practice recommendations for thromboprophylaxis in pregnant patients with COVID-19

Why we should not stop giving aspirin to pregnant women during the COVID-19 pandemic

Should we stop aspirin prophylaxis in pregnant women diagnosed with COVID-19? Ultrasound Obstetric Gynecology

The severity and atypical presentations of COVID-19 infection in pediatrics

Multisystem inflammatory syndrome in U.S. children and adolescents

Children and young adults hospitalized for severe COVID-19 exhibit thrombotic coagulopathy. Pediatric Blood & Cancer

Consensus-based clinical recommendations and research priorities for anticoagulant thromboprophylaxis in children hospitalized for COVID-19-related illness

Antithrombotic prophylaxis in children and adolescent patients with SARS-CoV-2 (COVID-19) infection: A practical guidance for clinicians

Diagnosis,Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association

Obesity and Mortality Among Patients Diagnosed With COVID-19: Results From an Integrated Health Care Organization

Association of Body Mass Index and Index With Morbidity and Mortality in Patients Hospitalized with COVID-19. Circulation

Evaluation of unmet clinical needs in prophylaxis and treatment of venous thromboembolism in at-risk patient groups: pregnancy, elderly and obese patients

Hypercoagulable state in COVID-19 with diabetes mellitus and obesity: Is therapeutic-dose or higher-dose anticoagulant thromboprophylaxis necessary? Diabetes Metabolic Syndrome

COVID-19 and ECMO: the interplay between coagulation and inflammation-a narrative review

Monitoring of Unfractioned Heparin in Severe COVID-19: An Observational Study of Patients on CRRT and ECMO. TH Open

Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome associated with COVID-19: a retrospective cohort study