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 Table of Contents  
LETTER TO EDITOR
Year : 2020  |  Volume : 4  |  Issue : 2  |  Page : 84-87

Prevention of thrombosis in patients with severe COVID-19


College of Medicine, King Saud bin Abdulaziz University for Health Sciences; King Abdullah International Medical Research Center; Intensive Care Department, King Abdulaziz Medical City, Riyadh, Saudi Arabia

Date of Submission07-May-2020
Date of Decision08-Jun-2020
Date of Acceptance13-Jun-2020
Date of Web Publication1-Jul-2020

Correspondence Address:
Hasan M Al Dorzi
ICU2, Mail Code 1425, King Abdulaziz Medical City, PO Box 22490, Riyadh 11426
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/sccj.sccj_21_20

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How to cite this article:
Al Dorzi HM, Arabi Y. Prevention of thrombosis in patients with severe COVID-19. Saudi Crit Care J 2020;4:84-7

How to cite this URL:
Al Dorzi HM, Arabi Y. Prevention of thrombosis in patients with severe COVID-19. Saudi Crit Care J [serial online] 2020 [cited 2020 Aug 6];4:84-7. Available from: http://www.sccj-sa.org/text.asp?2020/4/2/84/288732




  Introduction Top


Coronavirus disease 2019 (COVID-19), which is caused by a novel coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]), has led to a pandemic resulting in 5,817,385 cases and 362,705 (6.2%) fatalities as of May 30, 2020.[1] It has been associated with high morbidity and mortality, especially when it leads to critical illness and respiratory failure. Severe disease is characterized by a severe hyperinflammatory process[2] and hemostatic derangements that include thrombocytopenia, prolongation of prothrombin time (PT) and partial thromboplastin time (PTT), and elevation of D-Dimer and fibrinogen levels.[3] These findings suggest a pathophysiologic relationship between severe inflammation and a procoagulant state, which could be in the form of disseminated intravascular coagulation (DIC) and less likely thrombotic microangiopathy. Actually, in situ microvascular thrombosis in the lungs and other organs has been observed in multiple autopsy studies.[4],[5],[6],[7] The procoagulant state COVID-19 has been associated with worse outcomes. One study of 183 consecutive patients with severe SARS-CoV-2 pneumonia in China found an overall mortality rate of 11.5% with 71.4% of nonsurvivors having overt-DIC (≥5 points on the International Society on Thrombosis and Hemostasis diagnostic criteria) in the later stages of illness compared with 0.6% of survivors.[3] These findings raise questions about the role of anticoagulation in COVID-19.


  The Epidemiology of Venous Thrombosis in Covid-19 Top


The apparent procoagulant state, together with factors such as antecedent comorbidities, immobility, sedation, central venous lines, and mechanical ventilation, increases the risk of venous thromboembolism (VTE) in severe COVID-19. In one retrospective study from China, VTE occurred in 3 of 15 (20%) critically ill COVID-19 patients.[8] Another study of 184 intensive care unit (ICU) patients with COVID-19 pneumonia in three Dutch hospitals found that the cumulative incidence of a composite outcome of symptomatic acute pulmonary embolism, deep-vein thrombosis, ischemic stroke, myocardial infarction, or systemic arterial embolism was 49% (95% confidence interval, 41%–57%) after adjustment for competing risk of death.[9] Pulmonary embolism represented 87% of thrombotic complications.[9] Predictors of thrombosis were age and coagulopathy, defined as spontaneous prolongation PT >3 s or PTT >5 s.[10] A report from an Italian hospital found that 22.2% of 54 ICU patients with COVID-19 pneumonia had thrombotic events (14.8% had deep-vein thrombosis; most [75%] were related to central lines) despite prophylactic low-molecular-weight heparin.[11] However, the VTE rates were lower in a study from Milan (3.8% of 314 patients with COVID-19 in general wards and 8.3% of 48 patients in the ICU).[12] Central line-associated deep-vein thrombosis accounted for approximately one-fourth of VTE events in the ICU where pharmacologic prophylaxis was provided for all patients.[12] A French study of 100 COVID-19 patients who underwent pulmonary computed tomography (CT) angiography found pulmonary embolism in 23 patients (95% confidence interval, 15%–33%).[13] In a cohort of 109 ICU patients with severe COVID 19 in 3 hospitals in the United States, VTE occurred in 28% of patients 8 ± 7 days after hospital admission even though all patients received pharmacologic prophylaxis.[14] D-dimer >2600 ng/mL predicted VTE (area under the receiver operating characteristic curve, 0.760; 95% confidence interval, 0.661–0.858) with a sensitivity of 89.7% and specificity of 59.5%.[14] Whether COVID-19 has higher VTE rates than other severe infections is nevertheless unclear. In critically ill patients with severe sepsis or septic shock, VTE incidence was as high as 37% in one prospective study where 80.5% of patients received pharmacologic prophylaxis and 19.5% sequential compression devices because of a contraindication for anticoagulants.[15]


  Role of Anticoagulants in Covid-19 Top


A retrospective study from China evaluated the role of anticoagulants in COVID-19 and found that 99 of 449 (22%) patients with severe COVID-19 received heparin (94 received low-molecular-weight heparin [40–60 mg enoxaparin/day]) and 5 received unfractionated heparin (10,000–15,000 units/day) for ≥7 days.[16] There was no statistically significant difference in 28-day mortality between the heparin group and nonheparin group (30.3% vs. 29.7%, P = 0.91).[16] However, the 28-day mortality of heparin users was lower than nonusers in patients with sepsis-induced coagulopathy score ≥4 (40.0% vs. 64.2%, P = 0.03) and when D-dimer was >6 fold of upper limit of normal (32.8% vs. 52.4%, P = 0.017).[16] Chronic anticoagulation therapy at admission was associated with a lower risk for developing venous thrombosis (hazard ratio, 0.29, 95% confidence interval, 0.091–0.92) in a study in three Dutch hospitals.[9] However, the use of therapeutic anticoagulation was not associated with all-cause death (hazard ratio, 0.79, 95% confidence, 0.35–1.8).[9] Whether the potential decrease in mortality associated with heparin use is caused by the anticoagulation effect or through other anti-inflammatory or antiviral mechanisms is unclear. A recent meta-analysis of 24 trials that evaluated the effect of different anticoagulants in sepsis found no significant differences in mortality in the overall sepsis population.[17] There were significant reductions in mortality (risk ratio 0.72, 95% confidence interval 0.62–0.85) in patients with sepsis-induced DIC.[17] However, bleeding risk tended to increase with anticoagulant therapy.[17]


  Recommendation for Thromboprophylaxis in Covid-19 Top


Thromboprophylaxis should be a standard of care in severe and critically ill COVID-19 patients. Suggested thromboprophylaxis recommendations are presented in [Table 1]. Pharmacologic prophylaxis is the modality of choice and should be started on admission if the bleeding risk is not increased. Factors such as thrombocytopenia (<30 × 109/L) and prolonged PT (up to 1.5 × upper limit of normal or international normalized ratio up to 1.5) and PTT (up to 1.5 × upper limit of normal) should not be considered as absolute contraindications, especially when these derangements reflect DIC and the patient does not have active bleeding does have not active bleeding.[18] However, careful monitoring of bleeding should be done. Mechanical prophylaxis is an alternative if pharmacologic prophylaxis cannot be provided. When added to pharmacologic prophylaxis, pneumatic compression devices did not further reduce VTE incidence in the multicenter Pneumatic Compression for Preventing Venous Thromboembolism (PREVENT) trial.[19] This is likely to be valid to COVID-19 patients in the ICU, and hence, the combined use is not advised. Extended thromboprophylaxis is needed in COVID-19 patients, especially those with elevated D-dimer (i.e., ≥2 times the upper limit of normal). The International Medical Prevention Registry on Venous Thromboembolism VTE risk score with elevated D-dimer can be used to identify patients that may benefit from extended prophylaxis.[20]
Table 1: Recommendations for thromboprophylaxis in hospitalized and critically ill patients with severe coronavirus disease-19

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  Systemic Anticoagulation in Covid-19 Top


Systemic anticoagulation for diseases such as atrial fibrillation and venous thrombosis before acquiring COVID-19 should be continued during hospitalization.[20] Hypoxia that is not adequately explained by chest X-ray findings should trigger imaging with pulmonary CT angiography. Empirical anticoagulation should be considered when this imaging is not feasible. D-dimer and echocardiography may help to guide the decision. On the other hand, the optimal management of microvascular thrombosis/DIC without VTE in COVID-19 remains unknown at present. Some clinicians have advocated the administration of intermediate or therapeutic doses of heparins and even thrombolysis in patients with increasing D-dimers and worsening hepatic, renal, or respiratory function.[5],[11],[21],[22] This remains controversial and may not be justified for many COVID-19 patients.[23] In acute thrombotic microangiopathy, which results from hyperinflammation and endothelial damage, treatment should be directed against the underlying disease and anticoagulation has a limited role.[23],[24] Further evidence on this topic is awaited. At least two randomized controlled trials that evaluate higher versus lower doses of low-molecular-weight heparin are underway (ClinicalTrials.gov Identifier: NCT04359277 and NCT04366960).[25],[26]


  Screening for Venous Thrombosis in Covid-19 Top


Whether surveillance ultrasound for deep-vein thrombosis is indicated in patients with severe COVID-19 is unknown. This approach has been advocated[11] and seems to be reasonable. A recently published preplanned analysis of the PREVENT trial showed that surveillance was associated with earlier VTE diagnosis (median, 4 days; interquartile range, 2–10 for deep-vein thrombosis) and lower 90-day mortality.[27]


  Conclusions Top


In conclusion, severe COVID-19 has been associated with hyperinflammation and a procoagulant state with high rates of thrombotic events. Pharmacologic prophylaxis should be routinely provided to hospitalized and critically ill patients with COVID-19 in the absence of active bleeding. Hemostatic derangements, such as prolonged PT or PTT and thrombocytopenia, are not absolute contraindications for pharmacologic prophylaxis. Routine full anticoagulation in the absence of clinical evidence thrombosis is not warranted at present.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
World Health Organization. Coronavirus Disease 2019 (↱COVID-19): Situation Report 131. 2020.  Back to cited text no. 1
    
2.
Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ, et al. COVID-19: Consider cytokine storm syndromes and immunosuppression. Lancet 2020;395:1033-4.  Back to cited text no. 2
    
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Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 2020;18:844-7.  Back to cited text no. 3
    
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Luo W, Yu H, Gou J, Li X, Sun Y, Li J, et al. Clinical pathology of critical patient with novel coronavirus pneumonia (COVID-19). Preprints 2020;2020:2020020407.  Back to cited text no. 4
    
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Campbell CM, Kahwash R. Will complement inhibition be the new target in treating COVID-19-related systemic thrombosis? Circulation 2020;141:1739-41.  Back to cited text no. 5
    
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Zhang Y, Xiao M, Zhang S, Xia P, Cao W, Jiang W, et al. Coagulopathy and antiphospholipid antibodies in patients with Covid-19. N Engl J Med 2020;382:e38.  Back to cited text no. 6
    
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Dolhnikoff M, Duarte-Neto AN, de Almeida Monteiro RA, da Silva LF, de Oliveira EP, Saldiva PH, et al. Pathological evidence of pulmonary thrombotic phenomena in severe COVID-19. J Thromb Haemost 2020;18:1517-9.  Back to cited text no. 7
    
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Xu J, Wang L, Zhao L, et al. Risk assessment of venous thromboembolism and bleeding in COVID-19 patients. Research Square; 2020.  Back to cited text no. 8
    
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Kaplan D, Casper TC, Elliott CG, Men S, Pendleton RC, Kraiss LW, et al. VTE incidence and risk factors in patients with severe sepsis and septic shock. Chest 2015;148:1224-30.  Back to cited text no. 15
    
16.
Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost 2020;18:1094-9.  Back to cited text no. 16
    
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Barnes GD, Burnett A, Allen A, Blumenstein M, Clark NP, Cuker A, et al. Thromboembolism and anticoagulant therapy during the COVID-19 pandemic: interim clinical guidance from the anticoagulation forum. Journal of Thrombosis and Thrombolysis 2020; 50:72  Back to cited text no. 18
    
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21.
Wang J, Hajizadeh N, Moore E, McIntyre R, Moore P, Veress L, et al. Tissue Plasminogen Activator (tPA) Treatment for COVID-19 Associated Acute Respiratory Distress Syndrome (ARDS): A Case Series. Journal of thrombosis and haemostasis 2020:1-4..  Back to cited text no. 21
    
22.
Casini A, Alberio L, Angelillo-Scherrer A, Fontana P, Gerber B, Graf L, et al. Thromboprophylaxis and laboratory monitoring for in-hospital patients with COVID-19-a Swiss consensus statement by the Working Party Hemostasis. Swiss Med Wkly 2020;150:w20247.  Back to cited text no. 22
    
23.
Bikdeli B, Madhavan MV, Jimenez D, Chuich T, Dreyfus I, Driggin E, et al. COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-up. Journal of the American College of Cardiology 2020;75:2950-73.  Back to cited text no. 23
    
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25.
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26.
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27.
Arabi YM, Burns KEA, Alsolamy SJ, Alshahrani MS, Al-Hameed FM, Arshad Z, et al. Surveillance or no surveillance ultrasonography for deep vein thrombosis and outcomes of critically ill patients: A pre-planned sub-study of the PREVENT trial. Intensive Care Med 2020;46:737-46.  Back to cited text no. 27
    



 
 
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