Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 8  |  Issue : 3  |  Page : 199-204

Venous thromboembolism in COVID 19 infection: Prevalence and practice of prophylaxis - A narrative


Vascular Surgery, Manipal Hospitals, Bengaluru, Karnataka, India

Date of Submission13-Jul-2020
Date of Acceptance09-Oct-2020
Date of Web Publication6-Jul-2021

Correspondence Address:
U Vasudeva Rao
Vascular Surgery, Manipal Hospitals, Bengaluru, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijves.ijves_97_20

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  Abstract 


The aims of this review are to ascertain the true prevalence of venous thromboembolism (VTE) in critically ill COVID 19 patients, to explore the strategy regarding prophylaxis and whether intensified prophylaxis is required for critically ill patients and to review the published guidelines to identify areas where clarity is required. An electronic search of the literature on VTE in COVID patients with reference to prevalence and prophylaxis was made using PubMed as the main search engine. A snowball search was followed to retrieve additional relevant data. The database consisted of prospective and retrospective studies and systematic reviews. The results showed that the reported incidence of VTE varies from <10% to more than 60%. Majority of studies reported a higher incidence of VTE in critically ill COVID 19 patients. Few authors, therefore, suggested a higher dose of low molecular weight heparin (LMWH), but this approach has not been validated. There is also a suggestion to extend the prophylaxis postdischarge. There are also reports of thromboprophylaxis with LMWH improves outcome in critically ill patients. This review confirms the generally held view that the incidence of VTE is higher in COVID 19 patients who are critically ill. However, whether they will benefit from a higher or intensified dose of Heparin is not fully assessed, with opinion equally divided among researchers there are few other grey areas like prophylaxis post discharge and in ambulatory patients.

Keywords: Anticoagulant, COVID 19, heparin, venous thromboembolism prophylaxis, venous thromboembolism


How to cite this article:
Rao U V, Wasim M D. Venous thromboembolism in COVID 19 infection: Prevalence and practice of prophylaxis - A narrative. Indian J Vasc Endovasc Surg 2021;8:199-204

How to cite this URL:
Rao U V, Wasim M D. Venous thromboembolism in COVID 19 infection: Prevalence and practice of prophylaxis - A narrative. Indian J Vasc Endovasc Surg [serial online] 2021 [cited 2021 Jul 25];8:199-204. Available from: https://www.indjvascsurg.org/text.asp?2021/8/3/199/320632




  Background Top


There is sufficient evidence for an increased incidence of venous thromboembolism (henceforth referred to as VTE) in critically ill medical patients compared to those in the wards. Several risk factors come in to play for this increased prevalence – Age, history VTE, obesity, immobilization, sepsis, respiratory and cardiac failure, pregnancy, cancer, stroke, polytrauma, Cetera.

In a review of randomized trials, it was reported that without prophylaxis, the incidence is as high as 31%[1] and this can be significantly reduced by heparin prophylaxis.[2],[3] It was also observed that the frequency might remain high despite prophylaxis and in practice, VTE prophylaxis varies and may be inadequate at some centers.[4] In another observational study, the incidence of VTE in patients receiving prophylaxis was 27% though the presence of VTE did not affect the outcome.[5] Many centers have attempted to find the reasons for such failure, and few of them have indicated specific predictors.[6],[7] Recently, a retrospective cohort study consisting of 37050 patients identified several predictors and suggested an exclusive scoring method for critically ill patients.[8]

All these data suggest that there is a higher incidence of VTE in critically ill medical patients. Both chemical and mechanical prophylaxis helps to reduce this incidence but may fail in certain situations. Approximately 15% of patients with Coronavirus infection become seriously ill, and five per cent become very critical.[9] These patients are also at risk of developing VTE. Whether the incidence among COVID patients is higher than non-COVID patients and what should be the protocol for VTE prophylaxis for this group of patients is not fully assessed.


  Introduction Top


Ever since its discovery in Wuhan China, the COVID 19 virus has rapidly spread all over the world, affecting millions of people. Many sick patients require hospitalization for management. The World Health Organization has declared the infection as a pandemic. Institutions all over the globe are frantically looking for a suitable treatment to contain the disease and a vaccine to prevent further spread.

The virus spreads by aerosols from coughing or sneezing and also contaminated surfaces. Any organ in the body can get involved, but the virus has an affinity to the lung parenchyma, causing severe inflammation. It can also damage cardiac myocytes and vascular endothelium. Patients may remain asymptomatic or show mild symptoms in the form of dry cough, fever, body ache, breathing difficulty, etc., A subset of patients, especially those who are aged and have comorbidities may get a more severe form of the disease, requiring hospitalization. Significant number of these patients may develop more complications, as the disease progresses and may end up in an intensive care unit (ICU) with or without ventilator support.

The epidemiology and pathophysiology of respiratory failure which occurs in COVID 19 are described in detail elsewhere.[10],[11] Suffice to say that there is intense inflammation of the lung alveoli resulting in hypoxia which produces acute respiratory distress. Recent observations suggest that respiratory failure in COVID patients is not just due to ARDS alone. There is some evidence to suggest that microvascular thrombosis and VTE may play a role as well. It was further collaborated by autopsy findings which showed a varying degree of thrombosis both in the main pulmonary artery and its segmental branches.[9],[12],[13],[14] Due to the limitation of conducting frequent imaging for fear of spread among the health-care workers, the true incidence of venous thrombosis and pulmonary embolism was not properly assessed. A review of literature mainly on the cause of death and autopsy findings, found that there is a definite alteration of coagulation system resulting in prothrombotic state and consequent thromboembolism.[15]


  Studies Related to Prevalence Top


The first exercise in this review is to find out if there is truly an increased incidence in patients with COVID 19 infection, especially in those who are critically ill. During the early phase of the disease pandemic, thrombotic complications were not fully recognized, and thromboprophylaxis and antithrombotic therapy were not part of the treatment protocol. Tao Wang and others on behalf of the National Health Commission of People's Republic of China collected data from 1099 patients of which 73 were excluded. VTE risk was evaluated using the Padua Prediction Score. Four hundred and seven (40%) were considered as high risk. Bleeding risk was also assessed in these patients. Only 7% of patients had received prophylaxis. The study concluded that VTE prophylaxis was not adequate in this group of patients.[16] As the virus infection spread not only within China but also in other countries across the globe, more studies regarding the various manifestations of the disease were reported mainly in critically ill patients, and incidence of thromboembolism both arterial and venous became apparent. In a study of 81 patients admitted to the ICU at Union Hospital Wuhan China, 20 patients (25%) were found to have lower limb deep-vein thrombosis (DVT). Patients did not receive any prophylaxis. The study also concluded that D-Dimer testing was a useful index for predicting VTE in patients with severe CoronaVirus infection.[17] In another study from Wuhan 66 out of 143 patients (46.1%) developed DVT. Combination of Confusion Urea Respiratory rate Blood pressure and Age above 65 score of 3–5, Padua prediction score of 4 and above and D Dimer of >1 ug/ml has sensitivity of 88.52% and specificity of 61.43% for screening for DVT. Additional observation was that DVT was present in 18 (34%) of subgroup receiving prophylaxis versus 35 (63.3%) in the nonprophylaxis group (P = 0.010).[18] In a study of 184 patients with proven COVID infection admitted to ICU, Klok et al. reported an incidence of image proven VTE of 27%.[19] All patients received thromboprophylaxis as per the local hospital protocol. Pulmonary embolism was the most frequent complication in this series. An update on this study further confirmed the high incidence of VTE when the same group of patients was followed up to 2 weeks.

In a single-center cohort study involving 198 hospitalized patients of which 75 were admitted to ICU, Middeldorp et al. observed that the proportion of patients with VTE were significantly higher in ICU (47%) compared to those in the wards (3.3%). The cumulative incidence of symptomatic VTE in this series at the end of 3 weeks was 42%.[20] A retrospective study of 388 patients admitted to an academic hospital in Milan, Italy reported an incidence of 27.6% for 61 patients admitted in ICU.[21] A retrospective study of two French ICUs involving 26 consecutive patients showed higher incidence, compared to other studies with overall VTE rate of 69%.[22] In a prospective study of 150 consecutive patients admitted to 4 ICUs in 2 tertiary referral hospitals in France 64 patients had clinically relevant thrombotic complications. The incidence of Pulmonary embolism was 16.7% and after matching with historical controls, it was 11.7% versus 2.1%.[23] In another survey of the prevalence from Colorado USA, the frequency of VTE events in 106 patients was 26.1%.[24] Their study also showed no relation of VTE to the outcome. On the contrary Al-Samkari et al. from the USA in a multicenter retrospective study of 400 patients, of which 144 were critically ill, reported an incidence of 7.6% (95% confidence interval 3.9–13.3) for VTE and 5.6% for bleeding.[25] A retrospective study from the UK concluded that some of the patients might have primary immune-thrombosis rather than embolism and this may be one of the reasons thromboprophylaxis may fail in such patients.[26] Finally in a scoping review of the thrombosis risk associated with covid 19 infection Al-Ani et al. from Canada concluded that VTE and stroke occurred in approximately 20% and 3% of patients respectively.[27] The study also found the higher frequency in severely ill patients, in particular, those admitted to ICU. The risk is elevated despite prophylaxis. The study raised a few important issues like the optimal dose of anticoagulation, and the role of D Dimer-optimal cut off value and its prognostic significance.[27]


  Discussion Top


From the above findings, it is apparent that there is a higher incidence of thrombotic complications in critically ill COVID infected patients, though there is wide variation between centers with regards to its frequency. The pathway of coagulation abnormalities in these patients and its relation to disease progression has been the subject of intense research and review. As with other coronavirus infections, the fundamental pathology is one of the systemic inflammatory responses, and the lung appears to be the main target organ. Other organs like the heart kidney gastrointestinal tract may also get involved as the severity of the disease increases. As the severity of inflammation progresses, coagulopathy begins to appear due to endothelial damage and defects in coagulation pathways. This pathological process is often termed as thrombo-inflammation or immune-thrombosis.[28] The autopsy findings of the presence of platelet-rich thrombi both in small and medium-size pulmonary arteries support this hypothesis.[13] Various proinflammatory cytokines are found to be elevated in critically ill patients, which causes extensive endothelial damage as evidenced by the high level of Von Willebrand factor. These and other pathological processes are reviewed in detail by Iba et al.[29] The abnormal laboratory findings associated with inflammation and coagulation are evaluated in detail by many authors.[30],[31] The primary hematological abnormalities are low lymphocyte count, moderately low platelet count, and increased leukocyte count. Lymphocytopenia is the first one to appear and is a more consistent finding. There may be a drastic fall in platelet count in more severely ill patients. High platelet to lymphocyte ratio may indicate a more pronounced cytokine storm. Elevated leukocyte count may occur in those with myocardial injury along with raised troponins. Biomarkers of inflammation are elevated in critically ill patients– C Reactive Protein, Ferritin, Procalcitonin, Lactic Dehydrogenase, and raising levels may indicate a worse outcome. Other markers of increased cytokine activity are also altered (interleukin [IL]-1, IL-6, tumor necrosis factor).

Coagulation indices that indicate the presence of coagulopathy are increased D Dimer, increased Fibrinogen, prolonged prothrombin time, and activated partial thromboplastin time. These values keep changing as the severity of the disease increases, but the clinical picture is not precisely that of conventional disseminated intravascular coagulation (DIC), where both thrombosis and bleeding may occur. Connors and Levy suggested the term COVID-induced Coagulopathy (CAC) to differentiate the condition from both DIC and sepsis-induced coagulopathy (SIC).[32] In sepsis, thrombocytopenia is more profound, and D Dimer concentration does not reach high values seen in COVID 19 patients. Bleeding in comparison to thrombosis is not an issue in COVID patients, unlike in other forms of DIC although it may complicate matters just before the death. Thrombocytopenia is not a significant predictor of disease prognosis or adverse outcome.[33] The inflammation-induced endothelial injury could result in a massive release of plasminogen activators which affect the natural anticoagulant mechanism. This defective imbalance between procoagulant and anticoagulant pathways could result in micro thrombosis and DIC not only in the lungs but in many other organs. The plasma concentrations of physiological anticoagulants like antithrombin III and protein C are reduced due to decreased production and increased consumption. Antithrombin and anti-Xa oral agents have been suggested for containing the disease progression.[34] Overall, the limited evidence currently available indicates that Coronavirus infection can rapidly develop into a severe condition with pulmonary renal and hepatic complications, potentially increasing both thrombotic and hemorrhagic risk.[35] The exact mechanisms behind such hemostatic imbalance among severely ill patients are still not clear, and there is an urgent need for specifically designed studies which may throw more light on the subject.[35]


  Prophylaxis Top


VTE is a potentially preventable complication in hospitalized patients. There is sufficient evidence to suggest a significant reduction in VTE events in those receiving prophylaxis in moderate and high-risk patients. Several guidelines exist both for prevention and treatment of patients with VTE. As mentioned earlier, a large proportion of patients who are critically ill with COVID 19 have more than one risk factor, and they are exposed to even higher risk as the disease progresses. Because of the potentially higher risk of both arterial and venous thrombotic events in these patients, many critical care centers and other researchers have suggested modification of existing strategy and add COVID as an additional risk factor. Since the outbreak of this disease began only from the beginning of this year and more and more population is getting affected in many countries, the current guidelines meant specifically to address the issue of the prevention and management of VTE is still evolving. However, based on the understanding of the pathophysiology of the disease in general and associated coagulopathy in particular and results of many studies both prospective randomized and retrospective, carried out at many centers, researchers have come out with specific recommendations. First consensus statement came from a group of experts from China and Europe[36] followed by North America[37],[38] and other European nations.[39],[40],[41],[42] Recently, a position paper on VTE guidelines has come from Brazil.[43] International Society on Thrombosis and Hemostasis (ISTH) published its guidelines and recommendations.[44]

There appears to be a consensus among most recommendations about the need to assess each patient admitted to the hospital with COVID 19 infection with regards to the risk of developing venous thrombosis. The patient may have preexisting risk factors, and few of them may be on anticoagulant or antithrombotic agents before admission. These patients will be exposed to additional risk once they are hospitalized, and the risk assessment using one of the risk assessment models (RAM) is very crucial while adopting the prophylaxis strategy. One can choose any of the established RAM (Caprini, Padua, Wells, International Medical Prevention Registry on VTE-IMPROVE) either in its original version or with modifications. As far as critically ill patients there is no debate about the need for prophylaxis and heparin, either unfractionated (UFH) or low molecular weight heparin (LMWH) is the agent of choice, provided there is no bleeding risk. The advantage with UFH is that the effects can easily be reversed if need be, but the disadvantage is that it needs to be given more frequently in ICU settings dealing with a contagious patient. On balance, many guidelines suggest LMWH to be given, in one or two divided doses as per the body weight. In patients with renal impairment, unfractionated heparin is preferable. In patients who develop heparin-induced thrombocytopenia, Fondaparinux is given instead of heparin though some prefer non-heparin anticoagulants over Fondaparinux[36] Direct-acting oral anticoagulants (DOAC) are not recommended for critically ill patients as a prophylactic agent because of possible drug interaction with other antiviral agents[37],[40] In patients with moderate to high risk of bleeding, mechanical prophylaxis with intermittent pneumatic compression is recommended. The patient is closely monitored both clinically and with laboratory tests for any signs of worsening of the condition.

There are a few grey areas and differences among various guidelines. These controversial issues are discussed below.

Because a large proportion of patients are elderly and have comorbidities, it is suggested by a few authors that VTE prophylaxis should be given to all hospitalized patients with COVID 19.[42] The reason given for adopting this approach is that in patients with less severe disease the risk from failure to reassess and provide timely thromboprophylaxis for a large pool of hospitalized population is much more likely to outweigh the risk of bleeding.[45] However, others are not in favor of this approach and recommend risk assessment first.[37],[43],[46] The role of D Dimer in deciding whether a patient should receive prophylaxis is not well established. Artifoni et al. have suggested aggressive prophylaxis for patients with high D Dimer levels on admission.[45] A major teaching hospital in London UK suggested D Dimer based anticoagulation for ICU patients.[47] However, there is no uniformity as to the optimal level at which anticoagulation is recommended. There is even suggestion to investigate the efficacy and safety of thromboprophylaxis in ambulatory patients with COVID 19 infection.[21]

Another debatable issue is a higher dose of prophylaxis as recommended by some.[48] The reason is the fact that even after standard dose prophylaxis there are significant failures with rates of VTE much higher compared to non COVID patients. Many other authors suggest a cautious approach as there is not enough evidence to suggest a higher dose of prophylaxis is more effective and safe.[35] In patients with worsening clinical status (increasing hypoxia due to respiratory failure) hepatic and renal impairment and raising D Dimer levels, the recommendation is to consider intermediate or therapeutic anticoagulation if the bleeding risk is ruled out (low platelet count renal and hepatic impairment and signs of over bleeding).[38] ISTH guidelines recommend higher prophylactic dose (50%) for obese patients.[44] Intensified prophylaxis is also recommended for patients with additional risk factors and raising D Dimer levels by Langer et al.[28] One of the clinical guidelines from North America recommends escalation of dose to critically ill patients, but the decision is not based on elevated D Dimer levels.[49] A clinical trial is underway comparing the efficacy and safety of high versus low doses of LMWH in hospitalized COVID 19 patients, and the results are awaited.[50]

Finally, whether to continue prophylaxis postdischarge is not very clear. It is felt that the threat of VTE may continue even after the patient has recovered from the illness. Therefore, it is safer to maintain the prophylaxis either by LMWH or one of the oral anticoagulants for up to 4–6 weeks.[42],[47] Recent systematic review of current guidelines concluded that there is consensus regarding the need for thromboprophylaxis for all hospitalized patients with COVID 19 infection and suggested randomized control studies to confirm the beneficial or harmful effects of intensified prophylaxis.[51] Another review of clinical guidelines highlighted the limitations of many of the studies which are highly heterogeneous in reporting anticoagulant management.[52] There are still many unanswered questions, like prevalence in hospitalized patients, the need for a dedicated scoring system, screening for DVT on admission and during hospitalization, the optimal dose for prophylaxis, diagnosis of Pulmonary Embolism with computed tomographic pulmonary angiography and prophylaxis for patient being treated at home.[53] Further studies are required to answer these questions.

Despite reports of treatment failures with prophylaxis, the benefit of heparin in reducing the mortality in critically ill patients is proven by a few studies. In a study from Wuhan involving 449 patients, 99 patients received LMWH for 7 days or more the 28 days mortality was found to be lower for those receiving heparin with SIC score of 4 and above or D Dimer of six-fold of an upper limit of normal.[54] Hippensteel reviewed different actions of heparin both on the coagulation system and also on cellular inflammation and opined that it might be a useful agent not only as an anticoagulant but also part of antiviral therapy.[55]


  Conclusion Top


From the review of the available evidence, it is fairly clear that there is a definitely higher incidence of thromboembolic events in patients with COVID 19 infection, especially when they become critically ill. The incidence seems to remain high despite prophylaxis. Many theories have been proposed, which include the effect of intense inflammation of endothelium caused by the cytokine storm on the coagulation mechanism. In view of this association of inflammation and thrombosis and its consequences, it is advisable for all hospitalized patients to receive prophylaxis in the form of either LMWH or UFH (in case of renal impairment) provided there is no bleeding risk. There is no concrete evidence to suggest higher dose (intermediate or intensified) for critically ill patients and this approach should be individualized till the results of randomized trial is available. Majority of the guidelines suggest continuing the prophylaxis post discharge, particularly if any of the risk factors persist. It can be either DOAC or LMWH depending on the patient preferences and availability. The opinion is divided regarding thromboprophylaxis for ambulatory and outpatients and screening ultrasound for patients on admission.

Financial support and sponsorship

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Conflicts of interest

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