Subscribe to RSS
DOI: 10.1055/s-0040-1714273
Pharmacotherapy for Prevention and Management of Thrombosis in COVID-19
- Principles of Pharmacotherapy for Known Thrombotic Disease
- Empiric Use of Antithrombotic Agents in the Absence of Confirmed Thrombosis
- Conclusion
- References
Coronavirus disease-2019 (COVID-19) is an acute viral syndrome caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has resulted in a global pandemic.[1] [2] The disease can affect a multitude of organ systems in the body.[3] Dysregulation of hemostatic pathways, evidenced by laboratory and clinical data, plays an important role in morbidity and mortality related to COVID-19. Various forms of thrombosis, from thrombotic microangiopathy to large-vessel thrombosis in the venous system (deep vein thrombosis, splanchnic vein thrombosis, pulmonary embolism) or the arterial system (including acute myocardial infarction, ischemic stroke, and acute limb ischemia), have been described.[4] However, existing epidemiological studies suggest that venous thromboembolism (VTE) is the predominant form of thrombotic events, with reported rates in the literature being variable between 7% up to more than 80% (upon routine screening of critically ill patients).[5] [6] [7]
In this setting, the optimal strategies for prevention of thrombotic events and choice of antithrombotic agents for management of pre-existing or new thrombotic events in patients with COVID-19 are of utmost importance. Herein, we provide a succinct summary of potential pharmacological options for the treatment and prevention of thrombosis in patients with COVID-19.
Principles of Pharmacotherapy for Known Thrombotic Disease
The main principles of pharmacotherapy for patients diagnosed with venous or arterial thrombotic disease are similar to the eras prior to COVID-19. Longstanding use of antithrombotic agents for guideline-recommended indications should be, in general, continued. Details about diagnostic challenges and optimal diagnosis of thrombosis in patients with COVID-19 have been previously described elsewhere.[4] [8] Some important considerations for the choice and dose of antithrombotic agents are the urgency for need of invasive procedures (e.g., for patients in the intensive care unit [ICU]), considerations for management of acute impairment of renal and liver function, and drug–drug interactions between investigational COVID-19 therapies and antithrombotic agents.
The most prominent drug–drug interactions with investigational COVID-19 therapies and antiplatelet agents include those occurring between lopinavir/ritonavir and agents such as clopidogrel (may need dose increase) or ticagrelor (may need dose reduction). Replacing with prasugrel in patients without contraindications and alternatively utilizing P2Y12 platelet function assay for dose adjustment are potential management alternatives.[4] [7] Cilostazol, which can be used in the management of peripheral arterial disease, may also require dose reduction if coadministered with lopinavir/ritonavir.[7] For the most part, parenteral antiplatelet agents have a safe interaction profile.
For patients with indications for anticoagulation, rivaroxaban and edoxaban should not be coadministered with lopinavir/ritonavir. Additionally, dose adjustment would be necessary for agents such as vitamin K antagonists (VKAs), apixaban, and betrixaban.[4] VKAs potentially have major drug interactions when prescribed with investigatory agents such as ribavirin, interferon, methylprednisolone, and azithromycin, which often necessitates close international normalized ratio (INR) monitoring, dose adjustment, or using alternative options.[4] [9] Parenteral anticoagulants have no established major drug interaction with investigational therapies for COVID-19 ([Fig. 1]).
![](https://www.thieme-connect.de/media/sth/202007/thumbnails/10-1055-s-0040-1714273-i02800-1.jpg)
![Zoom Image](/products/assets/desktop/css/img/icon-figure-zoom.png)
For fibrinolytic agents, which might need to be used for high-risk pulmonary embolism, ischemic stroke, and ST-elevation myocardial infarction (STEMI), there is no known risk of serious drug–drug interaction with the investigational therapies being studied in COVID-19. Although some institutions advocate for upfront use of fibrinolytic therapy to reduce the risk of health care worker exposure in patients presenting with features concerning for STEMI, such exercise must be practiced with caution given that many patients may present with STEMI-mimics and may not, in fact, have plaque-rupture-mediated acute coronary syndromes (ACS).[10] In addition, patients with COVID-19 may be at risk of excess bleeding events, including alveolar hemorrhage.
#
Empiric Use of Antithrombotic Agents in the Absence of Confirmed Thrombosis
Given the frequency of observed thrombotic events in patients with COVID-19, especially those with severe disease, a myriad of antithrombotic regimens are currently being administered as standard practice or are under investigation. Herein, we provide a brief summary about some of these regimens. Additional details are provided in [Table 1] and [Fig. 2].
![](https://www.thieme-connect.de/media/sth/202007/thumbnails/10-1055-s-0040-1714273-i02800-2.jpg)
![Zoom Image](/products/assets/desktop/css/img/icon-figure-zoom.png)
Abbreviations: ACS, acute coronary syndrome; aPTT activated partial thromboplastin time; ARDS, acute respiratory distress syndrome; ASA, acetylsalicylic acid; COVID-19, coronavirus diseases of 2019; DAH, diffuse alveolar hemorrhage; DAPT, dual antiplatelet therapy; DIC, disseminated intravascular coagulation; DOAC, direct-acting oral anticoagulant; FDA, Food and Drug Administration; HIT, heparin-induced thrombocytopenia; ICH, intracerebral hemorrhage; INR, international normalized ratio ; LMWH, low-molecular-weight heparin; NIH, National Institutes of Health; TPA, tissue plasminogen activator; UFH, unfractionated heparin; VKA, vitamin K antagonist.
Parenteral Anticoagulants
Unfractionated heparin and low-molecular-weight heparin (LMWH) are the most common parenteral anticoagulant agents used for prophylaxis and treatment of thrombotic diseases. Besides antithrombotic roles, they have been shown to have anti-inflammatory and antiviral properties,[7] [11] which possibly make them even more attractive in the management of COVID-19. LMWHs have the advantage of obviating the need for activated partial thromboplastin time (aPTT) monitoring, which may be difficult in COVID-19 due to considerable hemostatic derangement.[12]
Various dosing strategies, ranging from prophylactic to escalated dose (intermediate to full dose),[13] have been proposed. Consensus-based recommendations from the Global COVID-19 Thrombosis Collaborative Group as well as those from the National Institute of Health guidelines recommend prophylactic dosage of anticoagulation in the absence of known thrombosis or contraindication to anticoagulation.[4] Generally, high-risk individuals (comorbidities, respiratory failure, ICU admitted, bedridden, etc.) should receive in-hospital VTE prophylaxis unless contraindicated.[4] There are multiple ongoing studies in search of optimum dosage for thromboprophylaxis in COVID-19 (NCT04366960, NCT04367831, and others).
Other parenteral anticoagulants include danaparoid, bivalirudin, fondaparinux, and argatroban. Danaparoid (primarily in Europe) and argatroban (particularly in some North American centers) have gained attention for use in patients with COVID-19, in part because of their favorable drug–drug interaction profile, but also because of anti-inflammatory properties, minor effects on platelets, and safe usage in heparin-induced thrombocytopenia. However, currently, there is no strong evidence to support their routine use for thromboprophylaxis for COVID-19. We are not aware of ongoing randomized trials for these agents in patients with COVID-19.
#
Oral Anticoagulants
While VKAs are readily available and inexpensive, the possibility of food–drug interactions, serious drug–drug interactions with investigational COVID-19 treatments, and the requirement for frequent INR check represent serious challenges.[7] Again, any drug monitoring using routine coagulation tests, including INR, is difficult due to COVID-19-associated hemostatic derangement.[12] Hence, the empiric use of VKAs is not advisable during the COVID-19 pandemic.
Direct oral anticoagulants (DOACs) have been tried as thromboprophylactic agents in patients with ACS, stable coronary artery disease, or peripheral artery disease.[7]
Anti-inflammatory effects of some DOACs such as rivaroxaban[14] and their favorable utility profile for outpatient management make them an attractive option for COVID-19. The main challenges associated with such agents include drug interactions (as noted above) and risk of bleeding. Use of DOACs should be limited in certain conditions such as renal failure, while their use should be avoided in patients with mechanical heart valves, atrial fibrillation in the setting of mitral stenosis, and antiphospholipid syndrome.[7] Clinicians may also consider switching from VKAs to DOACs in quarantined homebound non-COVID-19 patients under thrombosis prophylaxis, as they do not need frequent hospital visits or blood sampling for INR and/or aPTT.[4]
#
Post-Discharge Prophylaxis
Among patients with COVID-19 who are hospitalized, it seems reasonable to individually assess the risk of VTE prior to hospital discharge. High thrombosis risk individuals (including those with heart failure, active cancer, or D-dimer levels higher than two times the upper normal reference limit) with low bleeding tendencies may be considered for post-discharge VTE prophylaxis regimen unless contraindicated.[4] Based on studies prior to the COVID-19 era, rivaroxaban and betrixaban would be reasonable agents for this purpose.[15] [16] LMWHs are also an alternative for this indication.
#
Fibrinolytic Agents
Fibrinolytic agents have been proposed as a theoretical option for selected number of patients with COVID-19, hypothesizing that they might alleviate the deranged intravascular and pulmonary parenchymal fibrinolytic mechanisms.[17] Animal studies and small preclinical human trials have shown that fibrinolytic agents may prevent or modify the course of acute respiratory distress syndrome (ARDS),[18] confer parenchymal lung protection,[19] or improve ventilatory parameters.[20] Nevertheless, there are significant concerns regarding empiric use of fibrinolytic agents in COVID-19. Most important is the risk of bleeding, including intracranial hemorrhage and diffuse alveolar hemorrhage. Overall, based on the current evidence, these agents should not be administrated empirically in COVID-19 patients. Ongoing studies, including a trial which is assessing the safety and efficacy of inhaled fibrinolytic agents, can better define the role of fibrinolytic therapy in the course of COVID-19.[4] [21]
#
Antiplatelet Agents
Dysregulation in immune and coagulation systems, in both of which platelets play a key role, are among the most prominent features of the pathophysiology of COVID-19.[22] The antiplatelet and anti-inflammatory effects of acetyl salicylic acid (aspirin) are well known. Some,[23] but not all,[24] studies propose that aspirin might mitigate the severity of ARDS.[7]
P2Y12 inhibitors may also have anti-inflammatory properties in addition to antiplatelet effects. Particularly, prior studies have suggested a beneficiary response with ticagrelor with the potential to mitigate lung injury[25] seen in pneumonia,[26] although the findings are not conclusive. A recent prospective open-label nonrandomized study compared five patients receiving heparin-based regimens versus five patients who received a combination of aspirin, clopidogrel, tirofiban bolus and infusion, and fondaparinux. This small hypothesis-generating study suggested that the more intense antithrombotic regimen was associated with an improved ventilation/perfusion ratio, which deserves further assessment for efficacy and safety in larger studies.[27] There is at least one ongoing randomized trial where patients are randomized to dual-antiplatelet therapy with aspirin, clopidogrel, and low-dose rivaroxaban (in addition to statin and omeprazole) versus control (NCT 04333407)
Dipyridamole, a phosphodiesterase-3 inhibitor, is a parenteral antithrombotic agent which has no major drug–drug interaction with investigatory COVID-19 agents. On the background of its antiviral effects shown in animal models of influenza[28] as well as the in vitro activity against SARS-CoV-2,[29] a small study in COVID-19 has shown tendencies toward better clinical outcomes, including reduction in length of hospital stay and higher cure rate, with dipyridamole.[30] Additional studies are required before concrete recommendations could be made.
#
Hemostatic Modulating Agents
Antithrombin, thrombomodulin, and recombinant activated protein C are among hemostatic modulating agents that have been proposed for COVID-19, regarding their role in modifying immune responses and thrombosis formation.[7] Some studies suggest lower plasma levels or less functional activity for inherent immunomodulators such as antithrombin and thrombomodulin in severe viral sepsis, including COVID-19.[4] [7] [31] Nevertheless, there is no strong evidence yet to make a conclusive recommendation for the use of these agents and further studies are needed to assess their safety and efficacy.[7] The Thrombo Embolic Events in Hospitalized Patients with Covid-19 Serious Acute Pneumopathy (THROMBCOVID2) study, currently recruiting, is a prospective observational study that plans to assess multiple laboratory coagulation tests including antithrombin in COVID-19 (NCT04377490). Currently, there are no registered randomized trials to test antithrombin, thrombomodulin, or recombinant activated protein C in patients with COVID-19.
The inflammation–coagulation paradigm of COVID-19 has been described earlier.[7] The contact activation system, which includes high-molecular-weight kininogen, prekallikrein, and factors XI and XII, links coagulation and inflammatory pathways. As demonstrated in animal models, modifications in the system may control the inflammatory–coagulation vicious cycle seen in conditions such as sepsis. Further studies are needed to test if modulating this pathway could confer benefit in COVID-19.[7]
#
Anti-inflammatory Agents
Glucocorticoids, by modulating inflammatory response and coagulation factors, can potentially be beneficial in COVID-19. Similar to prior studies in non-COVID ARDS, recent trials on COVID-19–related ARDS have shown conflicting results. The potential benefits must be weighed against well-established adverse effects (e.g., hyperglycemia, risk for infection, poor wound healing, etc.) and possible drug interaction between agents such as methylprednisolone and VKAs.[7] Currently there is no specific recommendation for their use as an antithrombosis medication. Results from ongoing randomized trials will provide relevant data for clinical practice.
Hydroxychloroquine, with its known immunomodulatory and antithrombotic activity, including targeting antiphospholipid antibodies,[32] has been proposed for use in COVID-19.[7] However, hydroxychloroquine is associated with increased risk of arrhythmias, and its widespread use as an antithrombotic agent is not advisable.
Statins have anti-inflammatory, anticoagulant, and antiplatelet activities, all of which can potentially make them a fascinating treatment option for COVID19.[33] Results from several ongoing trials (such as NCT0438040, NCT04343001, NCT04348695, and NCT04333407) can be informative regarding their use in this circumstance ([Table 1]).
Targeted immunomodulatory therapies have been also proposed to manage COVID-19 and associated thrombotic events. For instance, complement inhibitors might be beneficial for treatment of complement-mediated thrombotic microangiopathy, as thought to occur in some patients.[33] [34] Tocilizumab, an interleukin-6 receptor inhibitor, has been shown to cause a reduction in rates of death or life support interventions on moderate to severe COVID-19 pneumonia and has been included in the Chinese National Health Commission guidelines for treating COVID-19.[35] Tocilizumab is thought to have potential antithrombotic properties, as well. Future studies are required to determine whether use of these agents confer net benefit to reduce the rate of thrombotic events in patients with COVID-19.
#
#
Conclusion
The existing body of evidence, consisting of pathophysiological, epidemiologic, and postmortem studies, indicates a prothrombotic state in COVID-19, and suggests there may be a close association between inflammatory and thrombotic pathways. Antithrombotic therapy for known (or incident) thrombotic disease in patients with COVID-19 will be largely similar to pre-COVID-19 era, with specific attention to the risk of pulmonary hemorrhages, acute deterioration of hepatic and renal function, need for invasive procedures, and drug–drug interactions with investigational COVID-19 therapies. However, optimal prevention of thrombotic events in this prothrombotic condition faces multiple unknowns with regards to the right regimen and dose. Additional epidemiological studies and comparative effectiveness studies are required to help identify the highest risk subgroups, and optimal preventive strategies to safely mitigate the risk of thrombotic events.
#
#
Conflicts of Interest
Dr. Bikdeli reports that he is a consulting expert, on behalf of the plaintiff, for litigation related to a specific type of inferior vena cava filters. Dr. Madhavan reports being supported by an institutional grant by the National Institutes of Health/National Heart, Lung, and Blood Institute to Columbia University Irving Medical Center (T32 HL007854).
-
References
- 1 Huang C, Wang Y, Li X. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395 (10223): 497-506
- 2 World Health Organization. WHO Director-General's opening remarks at the media briefing on COVID-19 - 11 March 2020. Available at: https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19—11-march-2020 . Accessed on June 1, 2020
- 3 Gupta A, Madhavan MV, Sehgal K. et al. Extrapulmonary manifestations of COVID-19. Nat Med 2020 (in-press)
- 4 Bikdeli B, Madhavan MV, Jimenez D. et al. COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up. J Am Coll Cardiol 2020; 75 (23) 2950-2973
- 5 Goyal P, Choi JJ, Pinheiro LC. et al. Clinical characteristics of Covid-19 in New York City. N Engl J Med 2020; 382 (24) 2372-2374
- 6 Ren B, Yan F, Deng Z. et al. Extremely high incidence of lower extremity deep venous thrombosis in 48 patients with severe COVID-19 in Wuhan. Circulation 2020; ; (e-pub ahead of print) DOI: 10.1161/CIRCULATIONAHA.120.047407.
- 7 Bikdeli B, Madhavan MV, Gupta A. et al; Global COVID-19 Thrombosis Collaborative Group. Pharmacological agents targeting thromboinflammation in COVID-19: review and implications for future research. Thromb Haemost 2020; ; (e-pub ahead of print) DOI: 10.1055/s-0040-1713152.
- 8 Driggin E, Madhavan MV, Bikdeli B. et al. Cardiovascular considerations for patients, health care workers, and health systems during the COVID-19 pandemic. J Am Coll Cardiol 2020; 75 (18) 2352-2371
- 9 Lippi G, Gosselin R, Favaloro EJ. Current and emerging direct oral anticoagulants: state-of-the-art. Semin Thromb Hemost 2019; 45 (05) 490-501
- 10 Bangalore S, Sharma A, Slotwiner A. et al. ST-segment elevation in patients with Covid-19—a case series. N Engl J Med 2020; ; (e-pub ahead of print) DOI: 10.1056/nejmc2009020.
- 11 Poterucha TJ, Libby P, Goldhaber SZ. More than an anticoagulant: do heparins have direct anti-inflammatory effects?. Thromb Haemost 2017; 117 (03) 437-444
- 12 Favaloro EJ, Lippi G. Recommendations for minimal laboratory testing panels in patients with COVID-19: potential for prognostic monitoring. Semin Thromb Hemost 2020; 46 (03) 379-382
- 13 Klok FA, Kruip MJHA, van der Meer NJM. et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res 2020; 191: 145-147
- 14 Jose RJ, Manuel A. COVID-19 cytokine storm: the interplay between inflammation and coagulation. Lancet Respir Med 2019; 2019 (00) 2019-2020
- 15 Cohen AT, Spiro TE, Büller HR. et al; MAGELLAN Investigators. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med 2013; 368 (06) 513-523
- 16 Spyropoulos AC, Lipardi C, Xu J. et al. Improved benefit risk profile of rivaroxaban in a subpopulation of the MAGELLAN study. Clin Appl Thromb Hemost 2019; 25: 1076029619886022 (e-pub ahead of print) DOI: 10.1177/1076029619886022.
- 17 Moore HB, Barrett CD, Moore EE. et al. Is there a role for tissue plasminogen activator as a novel treatment for refractory COVID-19 associated acute respiratory distress syndrome?. J Trauma Acute Care Surg 2020; 88 (06) 713-714
- 18 Hardaway RM, Williams CH, Marvasti M. et al. Prevention of adult respiratory distress syndrome with plasminogen activator in pigs. Crit Care Med 1990; 18 (12) 1413-1418
- 19 Stringer KA, Hybertson BM, Cho OJ, Cohen Z, Repine JE. Tissue plasminogen activator (tPA) inhibits interleukin-1 induced acute lung leak. Free Radic Biol Med 1998; 25 (02) 184-188
- 20 Hardaway RM, Harke H, Tyroch AH, Williams CH, Vazquez Y, Krause GF. Treatment of severe acute respiratory distress syndrome: a final report on a phase I study. Am Surg 2001; 67 (04) 377-382
- 21 Liu C, Ma Y, Su Z. et al. Meta-analysis of preclinical studies of fibrinolytic therapy for acute lung injury. Front Immunol 2018; 9: 1898
- 22 Li H, Liu L, Zhang D. et al. SARS-CoV-2 and viral sepsis: observations and hypotheses. Lancet 2020; 395 (10235): 1517-1520
- 23 Boyle AJ, Di Gangi S, Hamid UI. et al. Aspirin therapy in patients with acute respiratory distress syndrome (ARDS) is associated with reduced intensive care unit mortality: a prospective analysis. Crit Care 2015; 19 (01) 109
- 24 Kor DJ, Carter RE, Park PK. et al; US Critical Illness and Injury Trials Group: Lung Injury Prevention with Aspirin Study Group (USCIITG: LIPS-A). Effect of aspirin on development of ARDS in at-risk patients presenting to the emergency department the LIPS-a randomized clinical trial. JAMA 2016; 315 (22) 2406-2414
- 25 Sexton TR, Zhang G, Macaulay TE. et al. Ticagrelor reduces thromboinflammatory markers in patients with pneumonia. JACC Basic Transl Sci 2018; 3 (04) 435-449
- 26 Aungraheeta R, Conibear A, Butler M. et al. Inverse agonism at the P2Y12 receptor and ENT1 transporter blockade contribute to platelet inhibition by ticagrelor. Blood 2016; 128 (23) 2717-2728
- 27 Viecca M, Radovanovic D, Forleo GB, Santus P. Enhanced platelet inhibition treatment improves hypoxemia in patients with severe Covid-19 and hypercoagulability. A case control, proof of concept study. Pharmacol Res 2020; 158: 104950
- 28 Tonew E, Indulen MK, Dzeguze DR. Antiviral action of dipyridamole and its derivatives against influenza virus A. Acta Virol 1982; 26 (03) 125-129
- 29 Li Z, Li X, Huang Y-Y. et al. FEP-based screening prompts drug repositioning against COVID-19. bioRxiv 2020; DOI: 10.1101/2020.03.23.004580.
- 30 Liu X, Li Z, Liu S. et al. Potential therapeutic effects of dipyridamole in the severely ill patients with COVID-19. Acta Pharm Sin B 2020; ; (e-pub ahead of print) DOI: 10.1016/j.apsb.2020.04.008.
- 31 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 (04) 844-847 Doi: 10.1111/jth.14768
- 32 Schreiber K, Breen K, Parmar K, Rand JH, Wu XX, Hunt BJ. The effect of hydroxychloroquine on haemostasis, complement, inflammation and angiogenesis in patients with antiphospholipid antibodies. Rheumatology (Oxford) 2018; 57 (01) 120-124
- 33 Magro C, Mulvey JJ, Berlin D. et al. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases. Transl Res 2020; (e-pub ahead of print) DOI: 10.1016/j.trsl.2020.04.007.
- 34 Coronavirus Disease. 2019 (COVID-19) Treatment Guidelines. Available at: https://www.covid19treatmentguidelines.nih.gov/ . Accessed June 3, 2020
- 35 Genentech's arthritis drug tocilizumab shows promise in Covid-19 trial. Available at: https://www.clinicaltrialsarena.com/news/french-early-trial-tocilizumab-covid-19/ . Accessed June 3, 2020
Address for correspondence
Publication History
Article published online:
20 August 2020
© 2020. Thieme. All rights reserved.
Thieme Medical Publishers
333 Seventh Avenue, New York, NY 10001, USA.
-
References
- 1 Huang C, Wang Y, Li X. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395 (10223): 497-506
- 2 World Health Organization. WHO Director-General's opening remarks at the media briefing on COVID-19 - 11 March 2020. Available at: https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19—11-march-2020 . Accessed on June 1, 2020
- 3 Gupta A, Madhavan MV, Sehgal K. et al. Extrapulmonary manifestations of COVID-19. Nat Med 2020 (in-press)
- 4 Bikdeli B, Madhavan MV, Jimenez D. et al. COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up. J Am Coll Cardiol 2020; 75 (23) 2950-2973
- 5 Goyal P, Choi JJ, Pinheiro LC. et al. Clinical characteristics of Covid-19 in New York City. N Engl J Med 2020; 382 (24) 2372-2374
- 6 Ren B, Yan F, Deng Z. et al. Extremely high incidence of lower extremity deep venous thrombosis in 48 patients with severe COVID-19 in Wuhan. Circulation 2020; ; (e-pub ahead of print) DOI: 10.1161/CIRCULATIONAHA.120.047407.
- 7 Bikdeli B, Madhavan MV, Gupta A. et al; Global COVID-19 Thrombosis Collaborative Group. Pharmacological agents targeting thromboinflammation in COVID-19: review and implications for future research. Thromb Haemost 2020; ; (e-pub ahead of print) DOI: 10.1055/s-0040-1713152.
- 8 Driggin E, Madhavan MV, Bikdeli B. et al. Cardiovascular considerations for patients, health care workers, and health systems during the COVID-19 pandemic. J Am Coll Cardiol 2020; 75 (18) 2352-2371
- 9 Lippi G, Gosselin R, Favaloro EJ. Current and emerging direct oral anticoagulants: state-of-the-art. Semin Thromb Hemost 2019; 45 (05) 490-501
- 10 Bangalore S, Sharma A, Slotwiner A. et al. ST-segment elevation in patients with Covid-19—a case series. N Engl J Med 2020; ; (e-pub ahead of print) DOI: 10.1056/nejmc2009020.
- 11 Poterucha TJ, Libby P, Goldhaber SZ. More than an anticoagulant: do heparins have direct anti-inflammatory effects?. Thromb Haemost 2017; 117 (03) 437-444
- 12 Favaloro EJ, Lippi G. Recommendations for minimal laboratory testing panels in patients with COVID-19: potential for prognostic monitoring. Semin Thromb Hemost 2020; 46 (03) 379-382
- 13 Klok FA, Kruip MJHA, van der Meer NJM. et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res 2020; 191: 145-147
- 14 Jose RJ, Manuel A. COVID-19 cytokine storm: the interplay between inflammation and coagulation. Lancet Respir Med 2019; 2019 (00) 2019-2020
- 15 Cohen AT, Spiro TE, Büller HR. et al; MAGELLAN Investigators. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med 2013; 368 (06) 513-523
- 16 Spyropoulos AC, Lipardi C, Xu J. et al. Improved benefit risk profile of rivaroxaban in a subpopulation of the MAGELLAN study. Clin Appl Thromb Hemost 2019; 25: 1076029619886022 (e-pub ahead of print) DOI: 10.1177/1076029619886022.
- 17 Moore HB, Barrett CD, Moore EE. et al. Is there a role for tissue plasminogen activator as a novel treatment for refractory COVID-19 associated acute respiratory distress syndrome?. J Trauma Acute Care Surg 2020; 88 (06) 713-714
- 18 Hardaway RM, Williams CH, Marvasti M. et al. Prevention of adult respiratory distress syndrome with plasminogen activator in pigs. Crit Care Med 1990; 18 (12) 1413-1418
- 19 Stringer KA, Hybertson BM, Cho OJ, Cohen Z, Repine JE. Tissue plasminogen activator (tPA) inhibits interleukin-1 induced acute lung leak. Free Radic Biol Med 1998; 25 (02) 184-188
- 20 Hardaway RM, Harke H, Tyroch AH, Williams CH, Vazquez Y, Krause GF. Treatment of severe acute respiratory distress syndrome: a final report on a phase I study. Am Surg 2001; 67 (04) 377-382
- 21 Liu C, Ma Y, Su Z. et al. Meta-analysis of preclinical studies of fibrinolytic therapy for acute lung injury. Front Immunol 2018; 9: 1898
- 22 Li H, Liu L, Zhang D. et al. SARS-CoV-2 and viral sepsis: observations and hypotheses. Lancet 2020; 395 (10235): 1517-1520
- 23 Boyle AJ, Di Gangi S, Hamid UI. et al. Aspirin therapy in patients with acute respiratory distress syndrome (ARDS) is associated with reduced intensive care unit mortality: a prospective analysis. Crit Care 2015; 19 (01) 109
- 24 Kor DJ, Carter RE, Park PK. et al; US Critical Illness and Injury Trials Group: Lung Injury Prevention with Aspirin Study Group (USCIITG: LIPS-A). Effect of aspirin on development of ARDS in at-risk patients presenting to the emergency department the LIPS-a randomized clinical trial. JAMA 2016; 315 (22) 2406-2414
- 25 Sexton TR, Zhang G, Macaulay TE. et al. Ticagrelor reduces thromboinflammatory markers in patients with pneumonia. JACC Basic Transl Sci 2018; 3 (04) 435-449
- 26 Aungraheeta R, Conibear A, Butler M. et al. Inverse agonism at the P2Y12 receptor and ENT1 transporter blockade contribute to platelet inhibition by ticagrelor. Blood 2016; 128 (23) 2717-2728
- 27 Viecca M, Radovanovic D, Forleo GB, Santus P. Enhanced platelet inhibition treatment improves hypoxemia in patients with severe Covid-19 and hypercoagulability. A case control, proof of concept study. Pharmacol Res 2020; 158: 104950
- 28 Tonew E, Indulen MK, Dzeguze DR. Antiviral action of dipyridamole and its derivatives against influenza virus A. Acta Virol 1982; 26 (03) 125-129
- 29 Li Z, Li X, Huang Y-Y. et al. FEP-based screening prompts drug repositioning against COVID-19. bioRxiv 2020; DOI: 10.1101/2020.03.23.004580.
- 30 Liu X, Li Z, Liu S. et al. Potential therapeutic effects of dipyridamole in the severely ill patients with COVID-19. Acta Pharm Sin B 2020; ; (e-pub ahead of print) DOI: 10.1016/j.apsb.2020.04.008.
- 31 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 (04) 844-847 Doi: 10.1111/jth.14768
- 32 Schreiber K, Breen K, Parmar K, Rand JH, Wu XX, Hunt BJ. The effect of hydroxychloroquine on haemostasis, complement, inflammation and angiogenesis in patients with antiphospholipid antibodies. Rheumatology (Oxford) 2018; 57 (01) 120-124
- 33 Magro C, Mulvey JJ, Berlin D. et al. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases. Transl Res 2020; (e-pub ahead of print) DOI: 10.1016/j.trsl.2020.04.007.
- 34 Coronavirus Disease. 2019 (COVID-19) Treatment Guidelines. Available at: https://www.covid19treatmentguidelines.nih.gov/ . Accessed June 3, 2020
- 35 Genentech's arthritis drug tocilizumab shows promise in Covid-19 trial. Available at: https://www.clinicaltrialsarena.com/news/french-early-trial-tocilizumab-covid-19/ . Accessed June 3, 2020
![](https://www.thieme-connect.de/media/sth/202007/thumbnails/10-1055-s-0040-1714273-i02800-1.jpg)
![Zoom Image](/products/assets/desktop/css/img/icon-figure-zoom.png)
![](https://www.thieme-connect.de/media/sth/202007/thumbnails/10-1055-s-0040-1714273-i02800-2.jpg)
![Zoom Image](/products/assets/desktop/css/img/icon-figure-zoom.png)