Abstract

In 2019, a completely unique pneumonia, called coronavirus disease 2019 (COVID-19), spread rapidly throughout the planet. This novel global pandemic severely threatened public respiratory health and medical services. To date, apart from the common respiratory symptoms, coagulation disorders, especially Pulmonary Thromboembolism (PTE), has been proven as a crucial complication in severe COVID-19 patients, and therefore the incidence of PTE causes poor clinical outcome and increased fatality. Therefore, it’s important that healthcare providers, including respiratory physicians, medicine specialists, hematologists, cardiologists, communicable disease specialists, and other specialists, recognize that patients with COVID-19 are at increased risk of PTE, and make sure that appropriate prophylaxis is run to the acceptable patients, which they effectively manage PTE when it does occur. The mechanism of PTE in patients with coronavirus pneumonia consists of endothelial injury, activated platelet, cytokine storm, and a suppressed fibrinolytic system. Early prophylaxis, antiviral therapy, anticoagulation, and supportive treatment are beneficial to COVID-19 patients. In this review, we summarize the harm that coronavirus pneumonia wreaks and highlight the clinical relationship between PTE and coronavirus infection. The potential mechanism and therefore the prophylaxis and therapeutic measures also are discussed to involve more effort and research to research the strategies for PTE in COVID-19.

Keywords: coronavirus; COVID-19; pulmonary thromboembolism.

Citation: Shojaee R, Matloub SK, Matloub RK. Prophylaxis and treatment of pulmonary thromboembolism in COVID-19 patients. J Clin Images Med Case Rep. 2021; 2(5): 1367.

Introduction

Several reports have described significant procoagulant events, including life-threatening Pulmonary Embolism (PE), in covid-19 patients. The incidence of PE is reported to be around 2.6–8.9% of COVID-19 in hospitalized patients and up to one-third of these requiring medical Care Unit (ICU) admission, despite standard prophylactic anticoagulation. This may be explained by direct and indirect pathologic consequences of COVID-19, complement activation, cytokine release, endothelial dysfunction, and interactions between differing types of blood cells [1-45].

Evidence of PE may found in patients who underwent CTA imaging. Interestingly, comorbid conditions were similar in patients with PE and people without [29,30]. The incidence of PE in hospitalized patients with COVID-19 has been reported to be around 1.9-8.9% [29,33,43,44].

Infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is associated with coagulation abnormalities which predispose to considerable procoagulant effects [56-60].

The onset of PTE varied from 2-4 weeks after the occurrence of the initial symptoms of SARSCoV-2 infection and led to deterioration of the clinical picture altogether cases. In 100 hospitalized patients with COVID-19, Grillet et al. found radiologic evidence of PTE in 23% of cases in CTA, performed within the typical of 12 days after the onset of symptoms [61]. Coagulation activation has been reported in COVID-19, determining pathological changes specifically involving the lung microvasculature, and an increased risk of DVT, PE, and DIC in severe phase. The use of anticoagulants, especially heparin, is suggested by expert consensus for patients with severe COVID-19, although a final guidance can’t be implemented yet. There are several ways in which probably heparin administration can benefit patients with COVID-19, beyond the anticoagulant effect [65].

Discussion

PTE is defined as a thrombus that blocks the circulation and it can cause acute rises of pulmonary vascular resistance and therefore the afterload of the proper ventricle which will finally induce right coronary failure and shock. PTE and deep phlebothrombosis (DVT) are collectively mentioned as venous thromboembolisms (VTEs) and that they are considered because the different clinical manifestation of VTEs in several time and at different locations [66].

PTE may be a potential life-threatening complication, which occurs frequently in patients with COVID-19. Intermediate therapeutic dose of anticoagulants are often considered in patients with COVID-19 with risk factors for VTE, especially those requiring ICU admission. Extending thromboprophylaxis after hospital discharge or during home self-isolation may be reasonable after meticulous riskbenefit assessment, especially in patients with high risk of VTE [62].

The ISTH and therefore the American Society of Hematology (ASH) [46-49] have recently recommended that a prophylactic dose of LMWH (40 mg qd) [50] or subcutaneous unfractionated heparin (5000 IU tid)-should be started altogether suspected or confirmed COVID-19 patients admitted to the hospital. In patients with known heparin-induced thrombocytopenia, fondaparinux [50,51], which was found to be effective in reducing sepsis-derived coagulopathy in an animal model [52], should be used. If pharmacological prophylaxis is contraindicated, mechanical VTE prophylaxis (e.g., intermittent pneumatic compression) should be considered in immobilized patients [46]; combined pharmacologic and mechanical prophylaxis is not generally recommended [51]. Although limited data are available, it’s reasonable to think about pharmacological thromboprophylaxis in patients admitted to hospital with COVID-19 infection, even in pregnant women, since they’re likely to be at an increased risk of VTE [46]. The use of and intermediate dose of LMWH (e.g., enoxaparin 4000 IU subcutaneously every 12 h) are often considered on a private basis in patients with multiple risk factors for VTE [53] and in critically ill patients thanks to the upper incidence of PE during this population [29-41]. In obese patients, higher weight-based doses could also be needed, with doses of 7500 IU UFH 3 times daily or enoxaparin 40 mg twice daily [54,55]. While the sort of therapeutic anticoagulant wasn’t described in 4 included studies, heparin-based anticoagulants (UFH and LMWH) were the foremost frequent sort of anticoagulants reported within the other studies. These findings may reflect current supposition among physicians that heparin may have therapeutic effect in COVID-19 beyond its anticoagulant properties. Heparin is postulated to wield both antiviral and anti-inflammatory effects through inhibition of viral entry and dampening of pro-inflammatory signals, respectively [63]. Even though these theoretical hypotheses are biologically plausible, it still lacks strong evidence in supporting these effects. Furthermore, whether heparin-based anticoagulants are superior to DOAC or VKA in terms of clinical outcome in patients with COVID-19 requires further study [64]. A meta-analysis by Lippi et al. revealed that thrombocytopenia was a standard feature in critically ill COVID-19 patients [weighted mean difference –31 × 109 /L; 95% confidence interval (CI), from –35 to –29 × 109 /L] and the decrease of platelet count was associated with the increased risk of severe disease and deaths in COVID-19 patients [67]. In contrast, some studies have reported that no significant difference of platelet count existed between the severe COVID-19 patients and moderate patients [68-70]. Lastly, a study also showed that the platelet count in COVID-19 patients with DVT wasn’t significantly different from those without DVT [71]. Moreover, Qu et al. found platelet peaks and Plateletto-Lymphocyte (PLR) at the platelet peak were associated with the severity and duration of COVID-19 patients [72]. However, some cases reported an elevated platelet count in severe COVID-19 patients and this phenomenon was considered because the over-activation of platelets resulting from the over-production of proinflammatory factors and the formation of a cytokine storm [72,73]. Therefore, the platelet count can vary with each individual and therefore the specific relation between platelets and COVID-19 needs more research to reveal it.

Anticoagulant treatment is significant for all patients with PTE, which may effectively prevent the thrombosis from forming and relapsing and activating the human fibrinolytic system. Tang et al. reported that the utilization of heparin, mainly LMWH, achieved good clinical outcomes and notably decreased the 28-day mortality in severe COVID-19 patients with coagulation disorders compared with those not receiving heparin treatment (40.0% versus 64.2%, p = 0.029) [74]. Moreover, heparin can inhibit the inflammatory response in body and protect the endothelium of the microvessels [75], which suggests that heparin plays an important role in treating COVID-19 patients with PTE in various ways. However, the concrete dose of heparin should be carefully administered by clinical doctors on the idea of specific conditions and therefore the risks of anticoagulation treatment, especially the threat of uncontrolled massive hemorrhage, should be weighed and considered in detail [66].

Conclusion

Patients with COVID-19 are at increased risk of developing PE which can occur in up to one-third of critically ill COVID-19 patients requiring ICU admission. Thromboprophylaxis should therefore be started in COVID-19 patients admitted to the hospital and intermediate therapeutic doses of anticoagulants are often considered in patients requiring ICU admission or those with multiple risk factors for VTE. Extending thromboprophylaxis after hospital discharge or within the prehospital phase during home self isolation should be done consistent with a meticulous risk/benefit assessment, balancing the reduced risk of VTE with the risk of increased bleeding events. Therapeutic anticoagulation is that the cornerstone within the management of patients with PE. Selection of an appropriate agent and proper dosage requires consideration of underlying comorbidities and organ dysfunction. Based on the findings, it seems that thromboembolic events should be considered as a possible explanation for clinical deterioration in COVID-19 cases and in-charge physicians should consider PTE as a medical diagnosis for worsening of dyspnea in these cases. In conclusion, the infection of CoVs, especially SARSCoV-2, can frequently induce coagulation disorders and PTE, which can cause the deterioration of the patient, organ failure, and mortality in those with coronavirus pneumonia. The mechanism of PTE in coronavirus pneumonia patients, including pulmonary thromboembolism and therefore the formation of primary thrombosis in pulmonary vessels, contains four aspects: The damage of the pulmonary vessel endothelium, the assembly of excessive proinflammatory factors and a cytokine storm, the aggregation and adhesion of platelets, and therefore the suppression of the human fibrinolytic system. Advanced assessment and prophylaxis, including both pharmacological and mechanical prophylaxis, could even be beneficial to decrease the occurrence of PTE. For coronavirus pneumonia patients with PTE, antiviral treatment, anticoagulation treatment, and symptomatic and supportive treatment can effectively promote the clinical outcome and reduce the deathrate. To date, the interdisciplinary communication and integration among academia, industry, government organizations and clinical medicine are applied within the outbreak of COVID-19 to know the suitable methods for diagnosis and therapeutics. With the assistance of multidisciplinary cooperation and research, scientists can find better strategies for diagnosis, prophylaxis, and therapy for PTE in patients with coronavirus pneumonia.

Declarations

Conflicts of interest: The authors declare no conflict of interest.

References

1. SAKR, Yasser, et al. Pulmonary embolism in patients with coronavirus disease-2019 (COVID-19) pneumonia: A narrative review. Annals of intensive care, 2020, 10.1: 1-13.
2. Danzi GB, Loffi M, Galeazzi G, Gherbesi E. Acute pulmonary embolism and COVID-19 pneumonia: a random association? Eur Heart J. 2020; 41: 1858.
3. Cellina M, Oliva G. Acute pulmonary embolism in a patient with COVID-19 pneumonia. Diagn Interv Imaging. 2020; 101: 325–6.
4. Ullah W, Saeed R, Sarwar U, Patel R, Fischman DL. COVID-19 complicated by acute pulmonary embolism and right-sided heart failure. JACC Case Rep. 2020; 2: 1379–82.
5. Casey K, Iteen A, Nicolini R, Auten J. COVID-19 pneumonia with hemoptysis: acute segmental pulmonary emboli associated with novel coronavirus infection. Am J Emerg Med. 2020; 38: 1544.e1–3.
6. Foch E, Allou N, Vitry T, Masse L, Allyn J, et al. Pulmonary embolism in returning traveler with COVID-19 pneumonia. J Travel Med. 2020; 27: taaa63.
7. Rotzinger DC, Beigelman-Aubry C, von Garnier C, Qanadli SD. Pulmonary embolism in patients with COVID-19: time to change the paradigm of computed tomography. Thromb Res. 2020; 190: 58–9.
8. Fabre O, Rebet O, Carjaliu I, Radutoiu M, Gautier L, Hysi I. Severe acute proximal pulmonary embolism and COVID-19: a word of caution. Ann Thorac Surg. 2020.
9. Sulemane S, Baltabaeva A, Barron AJ, Chester R, Rahman-Haley S. Acute pulmonary embolism in conjunction with intramural right ventricular thrombus in a SARS-CoV-2-positive patient. Eur Heart J Cardiovasc Imaging. 2020; 21: 1054.
10. Audo A, Bonato V, Cavozza C, Maj G, Pistis G, et al. Acute pulmonary embolism in SARS-CoV-2 infection treated with surgical embolectomy. Ann Thorac Surg. 2020.
11. Le Berre A, Marteau V, Emmerich J, Zins M. Concomitant acute aortic thrombosis and pulmonary embolism complicating COVID-19 pneumonia. Diagn Interv Imaging. 2020; 101: 321–2.
12. Jafari R, Cegolon L, Jafari A, Kashaki M, Otoukesh B, Ghahderijani BH, et al. Large saddle pulmonary embolism in a woman infected by COVID-19 pneumonia. Eur Heart J. 2020; 41: 2133.
13. Griffin DO, Jensen A, Khan M, Chin J, Chin K, Saad J, et al. Pulmonary embolism and increased levels of D-dimer in patients with coronavirus disease. Emerg Infect Dis. 2020; 26: 1941.
14. Martinelli I, Ferrazzi E, Ciavarella A, Erra R, Iurlaro E, et al. Pulmonary embolism in a young pregnant woman with COVID-19. Thromb Res. 2020; 191: 36–7.
15. Lushina N, Kuo JS, Shaikh HA. Pulmonary, cerebral, and renal thromboembolic disease associated with COVID-19 infection. Radiology. 2020; 289: E181–3.
16. Harsch IA, Skiba M, Konturek PC. SARS-CoV-2 pneumonia and pulmonary embolism in a 66-year-old female. Pol Arch Intern Med. 2020; 130: 438–9.
17. Ueki Y, Otsuka T, Windecker S, Raber L. ST-elevation myocardial infarction and pulmonary embolism in a patient with COVID-19 acute respiratory distress syndrome. Eur Heart J. 2020; 41: 2134.
18. Ioan AM, Durante-Lopez A, Martinez-Milla J, Perez-Calvo C, Santos A. Pulmonary embolism in COVID-19. When nothing is what it seems. Rev Esp Cardiol. 2020; 73: 665–7.
19. Bruggemann R, Gietema H, Jallah B, Ten Cate H, Stehouwer C, Spaetgens B. Arterial and venous thromboembolic disease in a patient with COVID-19: A case report. Thromb Res. 2020; 191: 153–5.
20. Perez-Girbes A. Acute pulmonary embolism and Covid-19: a common association in seriously ill patients? Arch Bronconeumol. 2020; 56: 34.
21. Khodamoradi Z, Boogar SS, Shirazi FKH, Kouhi P. COVID-19 and Acute pulmonary embolism in postpartum patient. Emerg Infect Dis. 2020; 26: 1937–9.
22. Poggiali E, Bastoni D, Ioannilli E, Vercelli A, Magnacavallo A. Deep vein thrombosis and pulmonary embolism: two complications of COVID-19 pneumonia? Eur J Case Rep Intern Med. 2020; 7: 001646.
23. Marsico S, Espallargas Gimenez I, Carbullanca Toledo SJ, et al. Pulmonary infarction secondary to pulmonary thromboembolism in COVID-19 diagnosed with dual-energy CT pulmonary angiography. Rev Esp Cardiol. 2020; 73: 672–4.
24. Schmiady MO, Sromicki J, Kucher N, Ouda A. Successful percutaneous thrombectomy in a patient with COVID-19 pneumonia and acute pulmonary embolism supported by extracorporeal membrane oxygenation. Eur Heart J. 2020; 41: 3107.
25. Polat V, Bostanci GI. Sudden death due to acute pulmonary embolism in a young woman with COVID-19. J Thromb Thrombolysis. 2020.
26. Ahmed I, Azhar A, Eltaweel N, Tan BK. First Covid-19 maternal mortality in the UK associated with thrombotic complications. Br J Haematol. 2020; 190: e37–8.
27. Molina MF, Al Saud AA, Al Mulhim AA, Liteplo AS, Shokoohi H. Nitrous oxide inhalant abuse and massive pulmonary embolism in COVID-19. Am J Emerg Med. 2020; 38: 1549.e1–2.
28. Vitali C, Minniti A, Caporali R, Del Papa N. Occurrence of pulmonary embolism in a patient with mild clinical expression of COVID-19. Thromb Res. 2020; 192: 21–2.
29. Grillet F, Behr J, Calame P, Aubry S, Delabrousse E. Acute pulmonary embolism associated with COVID-19 pneumonia detected by pulmonary CT angiography. Radiology. 2020; 296: E186–8.
30. Leonard-Lorant I, Delabranche X, Severac F, Helms J, Pauzet C, Collange O, et al. Acute pulmonary embolism in COVID-19 patients on CT angiography and relationship to D-dimer levels. Radiology. 2020; 296: E189–91.
31. Helms J, Tacquard C, Severac F, Leonard-Lorant I, Ohana M, Delabranche X, et al. High risk of thrombosis in patients with severe SARS-CoV-2 infection: A multicenter prospective cohort study. Intensive Care Med. 2020.
32. Klok FA, Kruip M, van der Meer NJM, Arbous MS, Gommers D, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020; 191: 145–7.
33. Lodigiani C, Iapichino G, Carenzo L, Cecconi M, Ferrazzi P, Sebastian T, et al. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan. Italy. Thromb Res. 2020; 191: 9–14.
34. Llitjos JF, Leclerc M, Chochois C, Monsallier JM, Ramakers M, et al. High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients. J Thromb Haemost. 2020; 18: 1743–6.
35. Poissy J, Goutay J, Caplan M, Parmentier E, Duburcq T, et al. Pulmonary embolism in COVID-19 patients: awareness of an increased prevalence. Circulation. 2020; 14: 184–6.
36. Beun R, Kusadasi N, Sikma M, Westerink J, Huisman A. Thromboembolic events and apparent heparin resistance in patients infected with SARS-CoV-2. Int J Lab Hematol. 2020; 42: 19–20.
37. Middeldorp S, Coppens M, van Haaps TF, Foppen M, Vlaar AP, et al. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost. 2020; 18: 1995–2002.
38. Wichmann D, Sperhake JP, Lutgehetmann M, Steurer S, Edler C, Heinemann A, et al. Autopsy findings and venous thromboembolism in patients with COVID-19: A prospective cohort study. Ann Intern Med. 2020.
39. Klok FA, Kruip M, van der Meer NJM, Arbous MS, Gommers D, et al. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: an updated analysis. Thromb Res. 2020; 191: 148–50.
40. Bompard F, Monnier H, Saab I, Tordjman M, Abdoul H, et al. Pulmonary embolism in patients with Covid-19 pneumonia. Eur Respir J. 2020; 56: 2001365.
41. Thomas W, Varley J, Johnston A, Symington E, Robinson M, et al. Thrombotic complications of patients admitted to intensive care with COVID-19 at a teaching hospital in the United Kingdom. Thromb Res. 2020; 191: 76–7.
42. Poyiadi N, Cormier P, Patel PY, Hadied MO, Bhargava P, et al. Acute pulmonary embolism and COVID-19. Radiology. 2020.
43. Galeano-Valle F, Oblitas CM, Ferreiro-Mazon MM, Alonso-Munoz J, Del Toro-Cervera J. Antiphospholipid antibodies are not elevated in patients with severe COVID-19 pneumonia and venous thromboembolism. Thromb Res. 2020; 192: 113–5.
44. Stoneham SM, Milne KM, Nuttal E, Frew GH, Sturrock BR, Sivaloganathan H, et al. Thrombotic risk in COVID-19: a case series and case-control study. Clin Med. 2020; 20: e76–81.
45. Lax SF, Skok K, Zechner P, Kessler HH, Kaufmann N, Koelblinger C, et al. Pulmonary arterial thrombosis in COVID-19 with fatal outcome: results from a prospective, single-center, clinicopathologic case series. Ann Intern Med. 2020.
46. 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 followup. J Am Coll Cardiol. 2020; 75: 2973.
47. Thachil J, Tang N, Gando S, Falanga A, Cattaneo M, Levi M, et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost. 2020; 18: 1023–6.
48. Kollias A, Kyriakoulis KG, Dimakakos E, Poulakou G, Stergiou GS, Syrigos K. Thromboembolic risk and anticoagulant therapy in COVID-19 patients: emerging evidence and call for action. Br J Haematol. 2020; 189: 846–7.
49. Spyropoulos AC, Levy JH, Ageno W, Connors JM, Hunt BJ, Iba T, et al. Scientific and standardization committee communication: clinical guidance on the diagnosis, prevention and treatment of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost. 2020; 18: 1859–65.
50. Obi AT, Barnes GD, Wakefield TW, Brown Rvt S, Eliason JL, Arndt E, et al. Practical diagnosis and treatment of suspected venous thromboembolism during COVID-19 pandemic. J Vasc Surg Venous Lymphat Disord. 2020; 8: 526–34.
51. Witt DM, Nieuwlaat R, Clark NP, Ansell J, Holbrook A, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy. Blood Adv. 2018; 2: 3257–91.
52. Keshari RS, Silasi R, Popescu NI, Georgescu C, Chaaban H, et al. Fondaparinux pentasaccharide reduces sepsis coagulopathy and promotes survival in the baboon model of Escherichia coli sepsis. J Thromb Haemost. 2020; 18: 180–90.
53. Marietta M, Ageno W, Artoni A, De Candia E, Gresele P, Marchetti M, et al. COVID-19 and haemostasis: A position paper from Italian Society on Thrombosis and Haemostasis (SISET). Blood Transfus. 2020; 18: 167–9.
54. Pannucci CJ, Fleming KI, Holoyda K, Moulton L, Prazak AM,. Enoxaparin 40 mg per day is inadequate for venous thromboembolism prophylaxis after thoracic surgical procedure. Ann Thorac Surg. 2018; 106: 404–11.
55. Wang TF, Milligan PE, Wong CA, Deal EN, Thoelke MS, Gage BF. Efficacy and safety of high-dose thromboprophylaxis in morbidly obese inpatients. Thromb Haemost. 2014; 111: 88–93.
56. Stoneham SM, Milne KM, Nuttall E, Frew GH, Sturrock BR, Sivaloganathan H, et al. Thrombotic risk in COVID-19: a case series and case-control study. Clin Med (Lond) 2020; 20: e76-e81.
57. 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.
58. Rouhezamin MR, Haseli S. Diagnosing Pulmonary Thromboembolism in COVID-19: A Stepwise Clinical and Imaging Approach. Acad Radiol 2020; 27: 896-7.
59. 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: JACC State-of-the-Art Review. J Am Coll Cardiol 2020; 75: 2950-73.
60. Kollias A, Kyriakoulis KG, Dimakakos E, Poulakou G, Stergiou GS, et al. Thromboembolic risk and anticoagulant therapy in COVID-19 patients: emerging evidence and call for action. Br J Haematol. 2020; 189: 846-7.
61. Grillet F, Behr J, Calame P, Aubry S, Delabrousse E. Acute Pulmonary Embolism Associated with COVID-19 Pneumonia Detected by Pulmonary CT Angiography. Radiology 2020: 201544.
62. SAKR, Yasser, et al. The clinical spectrum of pulmonary thromboembolism in patients with coronavirus disease-2019 (COVID-19) pneumonia: A European case series. Journal of critical care. 2021; 61: 39-44.‏
63. Hippensteel, JA, LaRiviere, WB, Colbert, JF, Langouët-Astrié, CJ, Schmidt, EP. Heparin as a therapy for COVID-19: Current evidence and future possibilities. Am J Physiol Lung Cell Mol Physiol. 2020; 319: L211–L217.
64. WIJAYA, Indra; ANDHIKA, Rizky; HUANG, Ian. The use of therapeutic-dose anticoagulation and its effect on mortality in patients with COVID-19: A systematic review. Clinical and Applied Thrombosis/Hemostasis. 2020; 26: 1076029620960797.‏
65. GOZZO, Lucia, et al. The potential role of heparin in patients with COVID-19: Beyond the anticoagulant effect. A review. Frontiers in pharmacology. 2020; 11.‏
66. Essien EO, Rali P, Mathai SC. Pulmonary embolism. Med Clin North Am. 2019; 103: 549–64.
67. Lippi G, Plebani M, Henry BM. Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A meta-analysis. Clinica Chimica Acta. 2020; 506: 145–8.
68. Shi W, Lv J, Lin L. Coagulopathy in COVID-19: focus on vascular thrombotic events [published online ahead of print, 2020 Jul 15]. J Mol Cell Cardiol. 2020; 146: 32–40.
69. Zhang G, Zhang J, Wang B, Zhu X, Wang Q, et al. Analysis of clinical characteristics and laboratory findings of 95 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A retrospective analysis. Respir Res 2020; 21: 74.
70. Mao L, Jin H, Wang M, Hu Y, Chen S, et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. 2020; 77: 1–9.
71. Zhang L, Feng X, Zhang D, Jiang C, Mei H, et al. Deep vein thrombosis in hospitalized patients with COVID-19 in Wuhan, China: Prevalence, risk factors, and outcome [published correction appears in Circulation. 2020; 14; 142: e33. Circulation. 2020; 142: 114–28.
72. Qu R, Ling Y, Zhang YH, Wei LY, Chen X, et al. Platelet-to-lymphocyte ratio is associated with prognosis in patients with coronavirus disease-19. J Med Virol. 2020; 92:1533–41.
73. Conti P, Ronconi G, Caraffa A, Gallenga CE, Ross R, et al. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by coronavirus-19 (COVID-19 or SARS-CoV-2): antiinflammatory strategies. J Biol Regul Homeost Agents. 2020; 34: 1.
74. Tang N, Bai H, Chen X, Gong J, Li D, et al. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thrombosis Haemostasis 2020; 18: 1094–9.
75. Thachil J. The versatile heparin in COVID-19. J Thromb Haemost. 2020; 18: 1020–2.