key: cord-0945992-9b5cuyae authors: Bikdeli, Behnood; Madhavan, Mahesh V.; Gupta, Aakriti; Jimenez, David; Burton, John R.; Der Nigoghossian, Caroline; Chuich, Taylor; Nouri, Shayan Nabavi; Dreyfus, Isaac; Driggin, Elissa; Sethi, Sanjum; Sehgal, Kartik; Chatterjee, Saurav; Ageno, Walter; Madjid, Mohammad; Guo, Yutao; Tang, Liang V.; Hu, Yu; Bertoletti, Laurent; Giri, Jay; Cushman, Mary; Quéré, Isabelle; Dimakakos, Evangelos P.; Gibson, C. Michael; Lippi, Giuseppe; Favaloro, Emmanuel J.; Fareed, Jawed; Tafur, Alfonso J.; Francese, Dominic P.; Batra, Jaya; Falanga, Anna; Clerkin, Kevin J.; Uriel, Nir; Kirtane, Ajay; McLintock, Claire; Hunt, Beverley J.; Spyropoulos, Alex C.; Barnes, Geoffrey D.; Eikelboom, John W.; Weinberg, Ido; Schulman, Sam; Carrier, Marc; Piazza, Gregory; Beckman, Joshua A.; Leon, Martin B.; Stone, Gregg W.; Rosenkranz, Stephan; Goldhaber, Samuel Z.; Parikh, Sahil A.; Monreal, Manuel; Krumholz, Harlan M.; Konstantinides, Stavros V.; Weitz, Jeffrey I.; Lip, Gregory Y. H. title: Pharmacological Agents Targeting Thromboinflammation in COVID-19: Review and Implications for Future Research date: 2020-05-30 journal: Thromb Haemost DOI: 10.1055/s-0040-1713152 sha: 95c7adefa9d3a947bdcdea866d54392c18086527 doc_id: 945992 cord_uid: 9b5cuyae Coronavirus disease 2019 (COVID-19), currently a worldwide pandemic, is a viral illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The suspected contribution of thrombotic events to morbidity and mortality in COVID-19 patients has prompted a search for novel potential options for preventing COVID-19-associated thrombotic disease. In this article by the Global COVID-19 Thrombosis Collaborative Group, we describe novel dosing approaches for commonly used antithrombotic agents (especially heparin-based regimens) and the potential use of less widely used antithrombotic drugs in the absence of confirmed thrombosis. Although these therapies may have direct antithrombotic effects, other mechanisms of action, including anti-inflammatory or antiviral effects, have been postulated. Based on survey results from this group of authors, we suggest research priorities for specific agents and subgroups of patients with COVID-19. Further, we review other agents, including immunomodulators, that may have antithrombotic properties. It is our hope that the present document will encourage and stimulate future prospective studies and randomized trials to study the safety, efficacy, and optimal use of these agents for prevention or management of thrombosis in COVID-19. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in a global pandemic. 1,2 SARS-CoV-2, which is responsible for coronavirus disease 2019 (COVID- 19) , can cause pneumonia and acute respiratory distress syndrome (ARDS) as well as several extrapulmonary manifestations. These include cardiovascular, hematologic, and thrombotic sequelae due to direct and indirect effects of the viral illness. [3] [4] [5] Indeed, the limited data available on thrombotic complications in patients with COVID-19 suggest that rates of venous thromboembolic events may be as high as 25 to 30%, particularly in critically ill, mechanically ventilated patients. [6] [7] [8] Thrombotic complications also include stroke, acute limb ischemia, and acute coronary syndromes. [9] [10] [11] Limited data are available to determine the antithrombotic therapy to improve outcomes in patients with COVID-19 who do not have confirmed evidence of thrombosis. The optimal dose and agent for thromboprophylaxis remain unknown. Conservative management has merit based on historical data pertaining to critically ill medical patients 12 as well as for COVID-19-specific escalation of treatment. 13 For interim decision-making, consensus-based guidance has been provided by some groups, 14-18 including the Global COVID-19 Thrombosis Collaborative Group 5 (►Table 1). However, unlike other extensively studied illnesses such as sepsis, 19 a comprehensive assessment of potential options for prevention of thrombosis in various subgroups of patients with COVID-19 has not to date been proposed. In this article, prepared by the Global COVID-19 Thrombosis Collaborative Group, we summarize potential therapeutic options for prevention of thrombosis in COVID-19 patients in the absence of confirmed thrombotic events. Our focus is on novel approaches to dosing commonly used antithrombotic agents (heparin-based regimens and direct oral anticoagulants [DOACs]), considerations for empiric use of less widely used antithrombotic drugs such as danaparoid, and the potential applications of antiplatelet agents. In addition to the direct antithrombotic effects, other mechanisms of action-including anti-inflammatory or antiviral effects-have been postulated. 20, 21 Finally, we discuss other therapies, such as immunomodulators, that may have antithrombotic properties. The goal is not to provide immediately actionable management recommendations (as high-quality data to reliably inform such guidance in patients with COVID-19 are lacking), but rather to summarize potential treatment options and their advantages and limitations for ongoing and future investigations. We outline research priorities for these agents across the relevant clinical subgroups. To provide a thorough assessment for the rationale and potential advantages and limitations of various antithrombotic agents, subcommittees from the collaborative drafted the sections focused on specific agents, and these sections were then reviewed and revised by the entire group. The colead authors searched MEDLINE (with PubMed interface) to ensure that no other high-quality clinical study was missed (date of last search: May 5, 2020) . For research priority setting, a survey was sent to the group of coauthors who were asked to rate the overall priority for investigating each of the discussed agents and to identify the care setting wherein the investigation was most reasonable (outpatients with COVID-19, inpatients on the wards, critically ill patients in the intensive care unit [ICU] , or patients posthospital discharge). In the subsequent sections, we describe various investigational strategies for anticoagulants, antiplatelet agents, hemostatic modulating agents, and immunomodulators that may have potential for further investigation for patients with COVID-19 (►Table 2; ►Fig. 1). In addition, a summary of the survey results for research priorities with these agents is provided in ►Table 3 and ►Figs. 2 and 3. Unfractionated heparin and low-molecular-weight heparins (LMWHs) are the most frequently administered parenteral anticoagulants. 22 In addition to their antithrombotic activity, they have postulated anti-inflammatory and antiviral Table 1 Suggested considerations for prevention and management of thrombosis among hospitalized patients with COVID-19 a Risk stratification for VTE should be performed for all inpatients with COVID-19. In the absence of contraindications, the vast majority of inpatients, including all patients with severe COVID-19 who are critically ill should receive prophylactic anticoagulation The optimal intensity of anticoagulation in patients with COVID-19 remains unknown. Although prophylactic dosing is most widely used, higher intensity of anticoagulation (including intermediate-dose and full-therapeutic anticoagulation) is being used by many clinicians/institutions. Additional studies are required to identify the optimal regimen in various patient groups with COVID-19 For hospitalized patients with COVID-19 who require therapeutic anticoagulation (for prior indications including AF, VTE, mechanical valves, or new incident events such as new VTE or type I myocardial infarction), presence or absence of DIC, and hepatic and renal function should be considered when determining the appropriate choice of anticoagulant agent and dose a Hemostatic derangements, including elevated D-dimer levels, are common among inpatients with COVID-19. The majority of a consensus panel did not find sufficient evidence for routine screening for VTE (e.g., bilateral lower extremity ultrasound, or computed tomography pulmonary angiography) for hospitalized patients with COVID- 19 Therapeutic Targets for COVID-19-Associated Thrombosis Bikdeli et al. properties. Their anti-inflammatory properties may occur through selectin blockade, inhibition of bradykinin and thrombin generation, and binding of inflammatory cytokines. 23, 24 Heparins may also possess antiviral properties. For example, heparin may attenuate viral interaction with the angiotensin-converting enzyme 2 (ACE2) receptor by binding SARS-CoV-2 spike protein. 25 The use of empiric heparin anticoagulation in patients with H1N1 ARDS was associated with reduced risk of thrombotic events without an increase in bleeding complications. 26 With this consideration and the concern for breakthrough rates of thrombotic events despite prophylactic anticoagulation, 7 several randomized trials evaluating varying intensities of heparin-based anticoagulation, ranging from prophylactic, or weight-adjusted prophylactic dose treatment to intermediate to full-dose therapy are underway (NCT04345848, NCT04344756, NCT04373707, NCT04359277, NCT04367831, NCT04362085, NCT04377997). Additionally, several institutions have implemented protocols to initiate therapeutic anti-coagulation empirically, utilizing risk stratification based on an individual's thrombotic and bleeding risk. 27, 28 Future prospective studies are needed to evaluate the use of these strategies on thrombotic and bleeding complications. One potential challenge in the use of unfractionated heparin is the utility of the activated partial thromboplastin time (aPTT) for monitoring heparin. In patients with COVID-19, besides the intensity of heparin-based regimens, substantial heterogeneity in the aPTT response may be driven by high levels of factor VIII and fibrinogen, or the presence of a lupus anticoagulant. 29, 30 Consequently, anti-factor Xa levels may need to be measured to ensure that a therapeutic heparin level is achieved. 31 Trials of inhaled heparin for treatment of COVID-19 are being planned to disrupt SARS-CoV-2 and its ACE2 receptor interaction. Docking of the virus to host cells is mediated by the interaction between the spike (S) protein and heparan sulfate chains of proteoglycans. This facilitates further binding of SARS-CoV-2 to its cell-surface receptor, ACE2, via the surface unit (S1) of its S protein. [32] [33] [34] It is known that heparin can displace surface proteoglycans, and prevent SARS-CoV-2 entry into human cells. 21, 35 Drug-drug interactions between COVD-19 investigational therapies and antithrombotic agents should be also considered. ►Fig. 3 provides a graphical summary of potential interactions. Danaparoid (a mixture of sulfated glycosaminoglycans including heparan sulfate, dermatan sulfate, and chondroitin sulfate) attenuates thrombin generation by catalyzing the inhibition of factor Xa by antithrombin and by inhibition of thrombin by antithrombin and heparin cofactor II. 36 Currently, danaparoid is predominantly used in patients with heparin-induced thrombocytopenia in several countries other than the United States. ARDS is associated with dysregulated inflammation and coagulation. 5, 20, 37 Patients with ARDS have an increased risk of venous thromboembolism (VTE) as well as thrombocytopenia, 38 renal failure, and bleeding. 39 Because of its safety profile in patients with heparin-induced thrombocytopenia, its minor effects on platelet function 40 (particularly in sepsis), and potential for management of disseminated intravascular coagulation (DIC), 36 ,41 danaparoid appears to be an attractive option for research in critically ill patients with COVID-19. Importantly, however, no reversal agent is available in the setting of bleeding complications. Thrombi have been noted in the pulmonary arteries and vessels of other organs including the liver and kidneys in patients having died of COVID-19. The presence of these in situ thrombi raises the possibility that widespread endothelial activation in COVID-19 triggers thrombosis. 42, 43 In animal models of sepsis, danaparoid reduces cytokine levels and attenuates thrombosis. 44, 45 Intra-alveolar deposits of fibrin and activated leukocytes also contribute to the respiratory failure in patients with COVID-19 pneumonia. Danaparoid can be nebulized and has been shown to attenuate pulmonary coagulopathy, systemic coagulation, pulmonary inflammation, and improve survival in a lung injury model. 46 Nebulized danaparoid administration may concentrate its effect on the lungs and decrease the risk of systemic adverse reactions. Although danaparoid is being empirically used in some centers, no published report or registered clinical trials exist for its use in COVID-19. Parenteral anticoagulants such as bivalirudin, argatroban, and fondaparinux have been studied in management of patients with acute coronary syndromes, VTE, and heparin-induced thrombocytopenia. 47, 48 However, these agents are more expensive than unfractionated heparin or LMWH, and there are limited data about their use in COVID-19. Vitamin-K antagonists (VKAs), including warfarin, function by inhibiting vitamin K epoxide reductase, which results in the prevention of the recycling of vitamin K epoxide back to its active form. 49 The active form of vitamin K is essential for synthesis of clotting factors in the coagulation cascade (e.g., II, VII, IX, and X) and anticoagulant factors (proteins C and S), 49 and so VKAs result in reduction of these factors. These drugs are used for treatment of established thrombotic events (e.g., deep venous thrombosis or pulmonary embolism) or for prophylaxis in patients with specific indications (e.g., atrial fibrillation and prosthetic mechanical heart valves). However, in the course of COVID-19 there are several challenges with use of VKAs, including drugdrug interactions, and need for international normalized ratio monitoring, as described previously. 5 There are currently no active studies evaluating the use of VKAs in COVID-19. Beyond their anticoagulant effects, DOACs, especially factor Xa inhibitors, may exert anti-inflammatory effects in COVID- 19. 50 As has been demonstrated with rivaroxaban, DOACs can prevent arterial and venous thrombosis in patients with history of acute coronary syndrome, 51 stable atherosclerotic vascular disease, 52 or peripheral artery disease undergoing revascularization. 53 Rivaroxaban and betrixaban reduce the risk of VTE in medically ill patients. [54] [55] [56] As such, there is interest in administering DOACs to patients with severe COVID-19. These benefits should be weighed against the increased risk of bleeding events. DOACs offer the potential for in-hospital and posthospital VTE prophylaxis. Results of studies with DOACs for extended prophylaxis in medically ill patients without COVID-19 have been mixed. 54, 57 However, recent investigations in patients who are at high risk for VTE and low risk for bleeding (including those with severe infection) have demonstrated a net clinical benefit, especially for extended thromboprophylaxis posthospital discharge with betrixaban or rivaroxaban. 54, 58 There is currently one registered clinical trial (C-19-ACS) assessing low-dose rivaroxaban along with dualantiplatelet therapy, statins, and a proton-pump inhibitor in patients with COVID-19 and a suspected acute coronary syndrome (NCT04333407). A few centers have integrated DOACs into VTE prophylaxis algorithms for both in-hospital and postdischarge care. 28 However, concerns remain about DOAC use in patients with COVID-19-associated complications, including its renal clearance and acute renal insufficiency, need for invasive procedures (e.g., dialysis access), extracorporeal membrane oxygenation, and difficultly in administering reversal agents. 59, 60 Finally, drug-drug interactions need to be considered when using DOACs with some investigational COVID-19 therapies (see ►Fig. 4). 5 A recent small study showed increased absorption with high drug levels of DOACs in patients with COVID-19 who received antiviral agents. 61 DOACs may offer an attractive option to prevent thromboembolic events in the prehospitalization period for high-risk patient groups with COVID-19, such as those with underlying cardiovascular disease or high VTE risk factors. There is at least one planned study with rivaroxaban underway in outpatients with COVID-19 (Prevent HD). In patients with high suspicious for VTE, diagnosis should be sought when possible. For empiric treatment of select patients in whom presumed VTE events cannot be confirmed during the hospitalization period, for logistical reasons, use of DOACs upon hospital discharge offers additional convenience. 62 Challenges with this approach include the uncertainty in the diagnosis of VTE, and that delayed VTE imaging may not have sufficiently high negative predictive value to exclude an earlier event. Some COVID-19 patients will not be candidates for DOACs, such as those with severe renal dysfunction, mechanical heart valves, and antiphospholipid syndrome, or those taking antiviral or immunomodulatory medications that may be associated with drug-drug interactions, and poor medication adherence. Sulodexide is an orally administered purified glycosaminoglycan consisting of heparan sulfate (80%) and dermatan sulfate. 63 It exerts antithrombotic properties through reduction of fibrinogen 64,65 and plasminogen activator inhibitor-1 (PAI-1) 64,66 and is thought to have anti-inflammatory properties. 65, 67, 68 In a recent systematic review of randomized trials across a variety of cardiovascular indications, use of sulodexide compared with control was associated with reduced risk of VTE, myocardial infarction, cardiovascular mortality, and all-cause mortality. 69 Despite the potential interest, limited data exist about the safety and efficacy of sulodexide in patients with COVID-19 and there are currently no registered trials for sulodexide in these patients. Systemic fibrinolytic (thrombolytic) therapy is approved for management of ST-segment elevation myocardial infarction, ischemic stroke, and high-risk pulmonary embolism. Off-label use has been reported for the treatment of a small number of severely ill patients with ARDS secondary to COVID-19. [70] [71] [72] While empiric use of fibrinolytic agents is not based on solid clinical evidence and confers significant bleeding risk, there is precedent for its use in ARDS. As with other causes of ARDS, fibrin-rich hyaline membranes have been reported in lung biopsy specimens from patients with COVID-19. 73 Additionally, D-dimer, prothrombin time, and fibrinogen levels may all be increased in COVID-19 patients with significant lung involvement, 74 suggesting derangement of coagulation. The presence of microthrombi in the pulmonary microcirculation has been implicated as a possible mechanism for clinical deterioration. 75 Fibrinolytic agents such as urokinase and tissue-type plasminogen activator have reduced the risk of ARDS in porcine models. 76 Similarly, lung-protective findings have Therapeutic Targets for COVID-19-Associated Thrombosis Bikdeli et al. been noted in murine models. 77 A meta-analysis of preclinical studies corroborated these findings in various animal models. 78 Anecdotal reports have noted improvement in oxygenation and ventilation parameters. 79 A recent small study (n ¼ 60) study found improvement in surrogate parameters of ventilation and a reduction in ICU mortality in patients with severe non-COVID-19-related ARDS treated with inhaled streptokinase. 80 The bleeding risks of fibrinolysis must be balanced against these preclinical data and small human series. Systemic fibrinolysis has been associated with a 1 to 3% rate of intracranial hemorrhage and notable risk of other forms of major bleeding across a wide span of acute diseases. [81] [82] [83] Additionally, there is concern for diffuse alveolar hemorrhage after fibrinolysis, though reports of this complication have yet to be reported. Prior studies have suggested fibrinolytic agents such as alteplase can be associated with prolonged hypofibrinogenemia. 84 Based on the present evidence utilization of fibrinolysis for COVID-19-associated ARDS, even when severe, cannot uniformly be recommended given its unknown risk-benefit ratio. However, investigational use of fibrinolytic agents in carefully selected patients may be considered. A phase 2a randomized trial is underway to test the hypothesis whether systemic tissue-type plasminogen activator results in an improvement of respiratory function/oxygenation and reduction in mortality (NCT04357730). Further, inhaled fibrinolytic agents are an interesting option, potentially limiting systemic complications. 85 Assessment of their safety and efficacy requires further investigation (NCT04356833). Aspirin Dysregulated immune response and abnormal coagulation are common occurrences in the pathophysiology of viral sepsis, ARDS, and organ failure in COVID-19. 86 Platelets play a key role in the pathogenesis of sepsis and thrombosis, and are a potential target for prevention of the complications. 87 In addition to thrombosis and hemostasis, platelets have immunomodulatory activity, including both inflammatory and anti-inflammatory responses, as well as an effect on antimicrobial host defense. 88, 89 There is evidence that the initial intrinsic defense against infections is mediated by platelet-neutrophil cross-communication that tightly regulates immune and complement responses. 88 These interactions can facilitate a variety of proinflammatory effects such as cytokine release, endothelial cell activation, platelet-leukocyte interaction, formation of neutrophil extracellular traps, and fibrin/microthrombus formation that while potentially harmful 90, 91 can also inhibit macrophage-dependent inflammation and thus may on balance be protective. 87, 92, 93 Acetylsalicylic acid (aspirin) has been extensively studied in ARDS. Aspirin has been associated with ARDS prevention and higher survival rates from acute lung injury in animal models and observational human studies. [94] [95] [96] [97] [98] [99] Aspirin has been associated with reduced mortality in the setting of both prehospital use and use in ICU. 97, 98 These findings, however, were not validated in a phase 2b randomized clinical trial. 100 Some investigators have hypothesized that higher maintenance doses of aspirin (325-650 mg/d) may be required to The role of P2Y 12 receptor inhibitors has also been described in ARDS and sepsis. Adenosine diphosphate-mediated activation of the P2Y 12 receptor may occur in many inflammatory and immune cell types including platelets, leukocytes, and dendritic cells. Among 224 consecutive patients admitted for community-acquired pneumonia, those receiving antiplatelet agents (aspirin and/or thienopyridines) for at least 6 months had lower use of the ICU and shorter stay in the hospital compared with age-matched controls. 103 In a post hoc analysis from the PLATO trial, patients with acute coronary syndromes treated with the potent P2Y 12 inhibitor ticagrelor and aspirin had fewer adverse pulmonary events and sepsis and lower mortality with those events compared with patients treated with the less potent P2Y 12 inhibitor clopidogrel and aspirin. 104 The XANTHIPPE trial (Examining the Effect of Ticagrelor on Platelet Activation, Platelet-Leukocyte Aggregates, and Acute Lung Injury in Pneumonia) was the first double-blind, placebo-controlled, randomized study to evaluate the effect of ticagrelor on inflammation, platelet activation, and lung function in patients with community-or hospital-acquired pneumonia. 105 Among 60 randomized patients, ticagrelor administration within 48 hours of pneumonia diagnosis was associated with an anti-inflammatory effect evidenced by reduced platelet-leukocyte aggregates in the circulation, lowered interleukin (IL)-6 levels, and improved lung function with a decrease in supplemental oxygen requirements. However, given the potential bleeding risks, in the absence of phase III trials demonstrating favorable clinical outcomes, these research findings have not translated into routine clinical practice. With respect to COVID-19 and antiplatelet agents, there are many unknowns as regards their use and utility. First, it is not clear which phase of the disease might best respond. Second, the optimal agent and dose to maximize efficacy while minimizing bleeding risks are unknown. Due to its pleiotropic effects, ticagrelor may have more potent antiinflammatory and even bactericidal characteristics than other agents. 106, 107 Randomized trials evaluating role of aspirin and clopidogrel in COVID-19 patients at increased cardiovascular risk are underway (NCT04333407). Third, antiplatelet therapies may have adverse drug-drug interactions with some investigational COVID-19 therapies such as lopinavir/ritonavir and remdesivir. 5, 108, 109 Fourth, thrombocytopenia (immune-mediated or consumption-related) is associated with increased risk for worse clinical outcomes with COVID-19. 110, 111 Finally, the extent to which bleeding risks are increased, particularly in patients with DIC, is unknown. Dipyridamole is a phosphodiesterase inhibitor that inhibits platelet aggregation by increasing intracellular concentrations of cyclic adenosine monophosphate. 112 In addition to its well-known antithrombotic properties, dipyridamole may have antiviral effects with proposed activity against influenza in animal models. 113 In mouse models of viral pneumonia, dipyridamole administration promoted interferon response and prolonged survival in infected mice. Dipyridamole has antiviral effects in vitro, specifically confirming the affinity of dipyridamole for a SARS-CoV-2 main protease (M pro ). 114 To date, one study has examined dipyridamole in the treatment of COVID-19; 31 patients with COVID-19 were randomized to dipyridamole (150 mg three times a day for 7 days) versus control. In this small study, those treated with dipyridamole showed trends toward higher cure and hospital discharge rates. Increased platelet counts and decreased D-dimer levels were also noted with dipyridamole treatment, attributed to infection resolution. 115 Further high-quality data are needed to evaluate the anti-SARS-CoV-2 therapeutic potential of dipyridamole. Vorapaxar is an antiplatelet agent that exerts its antiplatelet activity through antagonism of the protease-activated receptor 1 (PAR-1) and inhibition of thrombin-induced platelet aggregation. 116 In patients with history of myocardial infarction, or peripheral arterial disease, vorapaxar has been shown to reduce thrombotic cardiovascular events. 117 The main concern associated with vorapaxar is its increased risk of bleeding events and reports of intracranial hemorrhage in patients with a previous history of stroke. PAR-1 is thought to have an important role in thrombin-induced platelet aggregation, and the link between coagulation, inflammation, and the fibrotic response. As such, investigating vorapaxar in patients with COVID-19 has received some attention. 50 However, its terminal half-life of 8 days renders it difficult to use in patients with severe COVID-19. To date, there are no registered randomized trials for use of vorapaxar in patients with COVID-19. The single-chain glycosaminoglycan antithrombin, which is produced in the liver, is modestly decreased in patients hospitalized with COVID-19. 118,119 Thus, reduced antithrombin may be a potential therapeutic target for patients with COVID-19. Furthermore, the β-isoform of antithrombin binds preferentially to vascular heparin sulfate proteoglycans and initiates prostacyclin production and inhibition of nuclear factor kappa B (NF-κB), resulting in anti-inflammatory effects, which might be further pronounced by the binding of β-antithrombin to receptors on monocytes. 120 Limited supporting data exist from patients with severe acute respiratory syndrome (SARS). Compared with healthy individuals such patients had lower levels of the natural inhibitors of coagulation and higher levels of PAI-1. Blood coagulation parameters were investigated in 94 patients with COVID-19 pneumonia, of whom 49 had "ordinary," 35 had severe, and 10 had critical forms of COVID-19. 121 When compared with 40 healthy controls, patients in Thrombosis and Haemostasis Vol. 120 No. 7/2020 Therapeutic Targets for COVID-19-Associated Thrombosis Bikdeli et al. all three categories of COVID-19 had significantly lower levels of antithrombin, and the three subsets of patients had similar levels (86.0, 85.6, and 82.4%). Nebulized antithrombin has resulted in decreased coagulopathy and inflammation in animal models of lung injury. [122] [123] [124] Despite these promising findings, there is to date no clinical evidence to support antithrombin provision to critically ill patients or in those with DIC and COVID-19. In a randomized controlled trial of 2,314 patients with severe sepsis, there was no effect of antithrombin therapy on 28-day mortality. 125 Moreover, in a meta-analysis of 3,019 patients included in 11 trials, antithrombin administration in critically ill patients was associated with more bleeding events (relative risk [RR]: 1.58; 95% confidence interval [CI] 1.35-1.84). 126 Thrombomodulin is an endothelial cell glycoprotein with potent anticoagulant and anti-inflammatory effects mediated through activated protein C (APC)-dependent and APCindependent protein C mechanisms. In inflammatory states, thrombomodulin production is downregulated and surface thrombomodulin is cleaved so that there is reduced activation of protein C. 127 The role of recombinant thrombomodulin as a potential modifier of clinical outcomes in patients with sepsis has been evaluated in clinical trials. The SCARLET study (Sepsis Coagulopathy Asahi Recombinant LE Thrombomodulin) was a randomized placebocontrolled double-blind study of recombinant human soluble thrombomodulin in 800 patients with objective evidence of bacterial infection, sepsis-induced systemic inflammatory response syndrome, and concurrent cardiovascular and/or respiratory dysfunction. 128 There was no significant between-group differences in the 28-day primary mortality outcome or other secondary endpoints. A post hoc subgroup analysis in patients with coagulopathy reported a trend for reduced mortality compared with placebo (risk difference -5.40%; 95% CI À1.68% to 12.48%). A subsequent systematic review and meta-analysis suggested lower mortality among patients with (but not in those without) sepsis-induced coagulopathy treated with thrombomodulin (RR: 0.80; 95% CI, 0.65-0.98). 129 Currently, there is insufficient evidence to recommend the routine use of thrombomodulin in patients with severe COVID-19. However, investigational use is warranted in selected subgroups with evidence of coagulopathy. APC can play a key role in reducing the damage caused by wide variety of triggers, including ischemia/reperfusion injury, gastrointestinal inflammation, sepsis, and Ebola virus infection. 130 In 2002, recombinant human protein C was approved by the U.S. Food and Drug Administration (FDA) for the clinical treatment of severe sepsis and ARDS. Protein C concentrates reduced the risk of mortality in early studies of sepsis and septic shock. However, subsequent clinical trials have reported neutral results. 19 Specifically, a randomized trial of 1,697 patients did not demonstrate a reduction in mortality at 28 or 90 days after APC was administered in the setting of septic shock, 131 and subsequent concerns emerged regarding the risk of serious bleeding and death in individuals with bleeding precautions. 132 A possible explanation is that APC may only benefit septic patients complicated by DIC, which was a minority of patients in these trials. In a study of 27 patients with ARDS (16 treated with recombinant APC and 11 with placebo), the infusion of recombinant APC increased APC levels in the pulmonary compartment and attenuated systemic coagulopathy and pulmonary coagulopathy, providing faster resolution of pulmonary dysfunction without bleeding complications. 133 However, in a subsequent randomized controlled trial of 71 patients, infusion of recombinant APC for infectious or inflammatory ARDS did not improve alveolocapillary permeability nor the clinical course of ARDS patients. 134 It is intuitive that protein C concentrates may be more beneficial in patients with significant protein C reduction. However, in a small study of 11 critically ill COVID-19 patients, protein C levels were overall increased, with only 4 patients having a protein C level lower than normal. 119 The protein C mutant, 3K3A-APC, being developed for acute stroke treatment, was engineered to have low anticoagulant activity (so low bleeding risk) while retaining APCs' antiinflammatory and cytoprotective cell signaling properties that may be important in pneumonia. The potential utility of recombinant APC or 3K3A-APC in patients with COVID-19, including those with DIC, is worthy of prospective investigation. 135 Dysregulation of inflammation and coagulation are hallmarks of COVID-19. The contact activation system, which includes factor XII, factor XI, high-molecular-weight kininogen, and prekallikrein, links inflammation and coagulation by triggering the generation of thrombin and bradykinin. Thrombin promotes clot formation and platelet activation, whereas bradykinin induces the release of proinflammatory cytokines. In nonhuman primate models of bacterial sepsis, inhibition of factor XIIa or blockade of reciprocal factor XI and factor XII activation reduced the levels of inflammatory cytokines, attenuated microvascular thrombosis, and improved survival. [136] [137] [138] [139] Likewise, in murine models of bacterial sepsis, inflammation and coagulation were attenuated, and survival was enhanced in factor XI-deficient mice compared with their wild-type counterparts. 140, 141 Several inhibitors of factor XII and factor XI are currently under investigation. Studies evaluating the efficacy and safety of these agents in COVID-19 are warranted. 142 There is conflicting evidence for the use of corticosteroids in COVID-19-related ARDS. 143 Postulated benefits, including reduction in inflammation and lung injury, must be weighed against the potential risks of delayed viral clearance and increased susceptibility to secondary infections. [144] [145] [146] [147] Thrombosis and Haemostasis Vol. 120 No. 7/2020 Therapeutic Targets for COVID-19-Associated Thrombosis Bikdeli et al. 1017 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Mechanisms as to whether corticosteroids may modulate thrombotic risk in this patient population are not well-established. As the microvascular and macrovascular thrombotic complications observed in COVID-19 may in part be attributable to the inflammatory environment precipitated by the infection, corticosteroids may reduce thrombotic risk through anti-inflammatory activity. Studies of inflammatory states, particularly rheumatologic conditions, have shown a proportional relationship between inflammatory activity, coagulability, and the risk of VTE. Results regarding frequency of thrombosis with disease-modifying therapies, including corticosteroids, are mixed. 148, 149 Possible beneficial 150 mechanisms include reductions in levels of procoagulant factors, including fibrinogen and von Willebrand factor. 151 However, experimental studies have also linked steroid use to increased levels of various clotting factors, and several large-scale studies have shown exogenous glucocorticoids to be a risk factor for thrombosis. [150] [151] [152] Prior studies of corticosteroids in patients with non-COVID-19-related ARDS have shown mixed results with potential benefit limited to only certain subgroups of patients. 153 Further experience and research, including results from a series of ongoing randomized trials, are needed to better understand the balance of pro-and anticoagulant properties of glucocorticoids in the setting of COVID-19. Hydroxychloroquine is a 4-aminoquinoline that has an immunomodulatory effect and antithrombotic activity that have been demonstrated in animal models and in patients with systemic lupus erythematosus, rheumatoid arthritis, and antiphospholipid syndrome. [154] [155] [156] [157] In a mouse model, hydroxychloroquine reversed the thrombogenic properties of antiphospholipid antibodies. 158 Hydroxychloroquine may also have mild antiplatelet effects in patients with antiphospholipid antibodies, and may reduce blood viscosity. 154 An observational prospective study of patients with antiphospholipid antibody syndrome treated with hydroxychloroquine 200 mg daily demonstrated significant reduction in soluble tissue factor levels at 3 months compared with baseline. 159 Other potential antithrombotic mechanisms have led to its limited evaluation as a thromboprophylaxis modality in postoperative patients more than three decades ago. 160, 161 However, the exact mechanisms by which it exerts it antithrombotic effect remain largely unknown. Given the known adverse effects with hydroxychloroquine, including QTc prolongation and risk of arrhythmias, 162 its routine use as an antithrombotic therapy in patients with COVID-19 cannot be recommend until further prospective data emerge. HMG-CoA reductase inhibitors (statins) are widely used as cholesterol-lowering medications in patients with or at increased risk of atherosclerotic cardiovascular disease. 163 The pleiotropic effects of statins include improving endothelial function, decreasing inflammatory markers, and inhibiting thrombogenicity. 164 Because patients with COVID-19 may exhibit increased activation of the inflammatory cascade and are prone to venous and arterial thrombosis, leveraging statins as a component of treatment has been proposed. 5, 165, 166 While no clinical studies have evaluated statin therapy in the management of COVID-19, there is biological plausibility and precedent for such investigation. Through inhibition of the MYD88 stress-response pathway, statins suppress NF-kB-induced proinflammatory cytokines. 167 This may underlie their proposed utility in other viral pneumonias, including those caused by related coronaviruses. [168] [169] [170] Besides mitigating inflammation, antiplatelet and anticoagulant properties can occur via downregulation of tissue factor, upregulation of thrombomodulin, and inhibition of thromboxane A 2 . 171 Prior reports have shown that use of statins is associated with reduced rates of VTE, and statins have stabilizing effects on atherosclerotic plaques. 172, 173 At least three clinical trials (NCT04348695, NCT04333407, and NCT04343001) are recruiting COVID-19 patients in randomized statin investigations. SARS-CoV-2 infection is associated with an inflammatory response marked by increased cytokine levels (e.g., IL-2, IL6, IL-10, tumor necrosis factor-α). 174 To treat the inflammatory response generated by severe COVID-19, some have proposed to repurpose immunomodulatory medications approved for other diseases. One potential target is the complement cascade. A major component of innate immunity, the complement cascade has three independent pathways for activation (classical, lectin, and alternative), each culminating with formation of the lytic membrane attack complex. Eculizumab is an anti-C5 monoclonal antibody that blocks terminal complement activity. One of its clinical applications is complement-mediated thrombotic microangiopathy, namely atypical hemolytic uremic syndrome, which is thought to occur in some patients with 175 In one study of five COVID-19 nonsurvivors, there was evidence of systemic activation of the alternative and lectin-based complement pathways and deposition of the membrane attack complex in both lung and skin. 175 Based on these data and evidence of efficacy of complement inhibition in murine models of SARS-CoV and MERS-CoV, the use of eculizumab in COVID-19 has been proposed. 20,175 Potential barriers include a 1,000 to 2,000 times increased risk of meningococcal disease (requiring prior vaccination or antibiotic prophylaxis) and cost ($20,000-$25,000 per dose). The Janus kinase (JAK)-signal transducer and activator of transcription pathway is another potential therapeutic target. JAK inhibitors target cytokine signaling pathways and have thus been proposed as a candidate to treat COVID-19. Baricitinib, a JAK1/JAK2 inhibitor approved for the treatment of rheumatoid arthritis, mitigates the systemic inflammatory response and has in vitro activity against SARS-CoV-2 through its numb-associated kinase inhibition that has a high affinity for AAK1, a regulator of clathrin-mediated endocytosis. 176 Notably, this therapy does carry a FDA warning for an increased incidence of VTE (6/997 patients with baricitinib vs. 0/1,070 controls), 177 and recent National Institutes of Health (NIH) COVID-19 Treatment Guidelines recommends against the use of baricitinib outside of a clinical trial, such as the NIHsponsored ACTT-2 trial comparing remdesivir AE baricitinib. 178 Ruxolitinib is a JAK2 inhibitor approved for patients with myelofibrosis and polycythemia vera. Similar to baricitinib (NCT04340232, NCT04320277, and NCT04346147), ruxolitinib is presently under investigation as a treatment for COVID- 19 (NCT04334044, NCT04348071, NCT04337359, NCT04331665, NCT04348695, and NCT04338958). Tocilizumab, an IL-6 receptor antagonist approved for the treatment of rheumatoid arthritis and cytokine release syndrome associated with chimeric antigen receptor-T cell therapy, is included in the Chinese National Health commission guidelines for treating COVID-19. While findings are yet to be published, a randomized trial of 129 hospitalized patients with moderate-to-severe COVID-19 pneumonia suggested that tocilizumab administration may significantly reduce rates of death or life support interventions. 179 It is thought that tocilizumab may mitigate the proatherothrombotic profile associated with rheumatoid arthritis. However, no specific data related to use of tocilizumab and VTE events in patients with COVID-19 have been published. Despite the efforts of the international medical and scientific communities and recent declines in hospitalizations, COVID-19 continues to pose an unprecedented challenge. The prognosis for hospitalized patients with COVID-19, especially in the setting of critical illness, continues to be poor. 180, 181 While contributing factors to poor outcomes in patients with COVID-19 are likely multifactorial, thrombotic complications play a major role in the prognosis of these patients. 5 The development of safe and effective thromboprophylaxis and treatment strategies for thrombotic disease is contingent on an improved understanding of the mechanistic and pathophysiologic basis for such complications in COVID-19 patients. In this document, we have outlined several agents and mechanisms of action for potential for use as antithrombotic agents in the setting of COVID-19. Survey results from group of authors may be helpful for research priority settings for various agents and patient subgroups with COVID-19 (►Table 3). High-quality research investigations into the optimal drug, dose, and duration of therapies to prevent and treat thrombotic complications of COVID-19 offer the potential to improve outcomes of infected patients. No specific funding was sought or received for this manuscript. A list of Disclosures for co-authors is available online in the ►Supplementary Material (available in the online version). Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China World Health Organization. WHO Director-General's opening remarks at the media briefing on COVID-19 -11 Cardiovascular considerations for patients, health care workers, and health systems during the coronavirus disease 2019 (COVID-19) pandemic COVID-19 and cardiovascular disease COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia Incidence of thrombotic complications in critically ill ICU patients with COVID-19 High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study Large-vessel stroke as a presenting feature of Covid-19 in the young ST-segment elevation in patients with Covid-19 -a case series Acute limb ischemia in patients with COVID-19 pneumonia RE: ISTH interim guidance to recognition and management of coagulopathy in COVID-19 ISTH interim guidance on recognition and management of coagulopathy in COVID-19: a comment A systematic summary of systematic reviews on anticoagulant therapy in sepsis Will complement inhibition be the new target in treating COVID-19 related systemic thrombosis? Circulation 2020 The versatile heparin in COVID-19 American College of Chest Physicians Evidence-Based Clinical Practice Guidelines More than an anticoagulant: do heparins have direct anti-inflammatory effects? The old but new: can unfractioned heparin and low molecular weight heparins inhibit proteolytic activation and cellular internalization of SARS-CoV2 by inhibition of host cell proteases? Using heparin molecules to manage COVID-2019 Empirical systemic anticoagulation is associated with decreased venous thromboembolism in critically ill influenza A H1N1 acute respiratory distress syndrome patients Practical diagnosis and treatment of suspected venous thromboembolism during COVID-19 pandemic Emergence of institutional antithrombotic protocols for coronavirus Monitoring unfractionated heparin with the aPTT: time for a fresh look Lupus anticoagulant and abnormal coagulation tests in patients with Covid-19 Antifactor Xa levels versus activated partial thromboplastin time for monitoring unfractionated heparin The 2019 coronavirus (SAR-SCoV-2) surface protein (Spike) S1 Receptor Binding Domain undergoes conformational change upon heparin binding SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor Structural basis of receptor recognition by SARS-CoV-2 Inhibition of SARS pseudovirus cell entry by lactoferrin binding to heparan sulfate proteoglycans Heparinoids danaparoid and sulodexide as clinically used drugs Immunothrombosis in acute respiratory distress syndrome: cross talks between inflammation and coagulation Heparin-induced thrombocytopenia in critically ill patients IMPROVE Investigators. Factors at admission associated with bleeding risk in medical patients: findings from the IMPROVE investigators The platelet proaggregating and potentiating effects of unfractionated heparin, low molecular weight heparin and heparinoid in intensive care patients and healthy controls Comparison of danaparoid sodium and synthetic protease inhibitors for the treatment of disseminated intravascular coagulation associated with hematological malignancies: a retrospective analysis Pulmonary thrombosis in 2019-nCoV pneumonia? Autopsy findings and venous thromboembolism in patients with COVID-19: a prospective cohort study Danaparoid sodium inhibits systemic inflammation and prevents endotoxin-induced acute lung injury in rats Danaparoid sodium attenuates the increase in inflammatory cytokines and preserves organ function in endotoxemic rats Nebulized anticoagulants in lung injury in critically ill patients-an updated systematic review of preclinical and clinical studies Individual patient data pooled analysis of randomized trials of bivalirudin versus heparin in acute myocardial infarction: rationale and methodology Heparin-induced thrombocytopenia: a comprehensive clinical review Vitamin K antagonist use: evidence of the difficulty of achieving and maintaining target INR range and subsequent consequences COVID-19 cytokine storm: the interplay between inflammation and coagulation Rivaroxaban in patients with a recent acute coronary syndrome Rivaroxaban with or without aspirin in stable cardiovascular disease Rivaroxaban in peripheral artery disease after revascularization Rivaroxaban for thromboprophylaxis in acutely ill medical patients Rivaroxaban for thromboprophylaxis after hospitalization for medical illness Extended thromboprophylaxis with betrixaban in acutely ill medical patients ADOPT Trial Investigators. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients Improved benefit risk profile of rivaroxaban in a subpopulation of the MAGELLAN study Therapeutic Targets for COVID-19-Associated Thrombosis Bikdeli et al Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study Covid-19 in critically ill patients in the Seattle region -case series Direct oral anticoagulant plasma levels' striking increase in severe COVID-19 respiratory syndrome patients treated with antiviral agents: the Cremona experience Antithrombotic therapy for VTE Disease: CHEST guideline and expert panel report Sulodexide for treating venous leg ulcers Use of sulodexide in patients with peripheral vascular disease Sulodexide: a renewed interest in this glycosaminoglycan Pharmacodynamic effects of single and repeated doses of oral sulodexide in healthy volunteers. A placebo-controlled study with an enteric-coated formulation Recurrent aphthous stomatitis unresponsive to topical corticosteroids: a study of the comparative therapeutic effects of systemic prednisone and systemic sulodexide Antioxidative activity of sulodexide, a glycosaminoglycan, in patients with stable coronary artery disease: a pilot study Sulodexide versus control and the risk of thrombotic and hemorrhagic events: metaanalysis of randomized trials Doctor gambles on clot-busting drug to save virus patients Tissue plasminogen activator (tPA) treatment for COVID-19 associated acute respiratory distress syndrome (ARDS): a case series Fibrinolytic therapy for refractory COVID 19 acute respiratory distress syndrome: scientific rationale and review. Research and practice in Thrombosis and Haemostasis Pathological findings of COVID-19 associated with acute respiratory distress syndrome Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Is there a role for tissue plasminogen activator (tPA) as a novel treatment for refractory COVID-19 associated acute respiratory distress syndrome (ARDS)? Prevention of adult respiratory distress syndrome with plasminogen activator in pigs Tissue plasminogen activator (tPA) inhibits interleukin-1 induced acute lung leak Meta-analysis of preclinical studies of fibrinolytic therapy for acute lung injury Treatment of severe acute respiratory distress syndrome: a final report on a phase I study Streptokinase versus unfractionated heparin nebulization in patients with severe acute respiratory distress syndrome (ARDS): a randomized controlled trial with observational controls Intracranial hemorrhage associated with thrombolytic therapy for elderly patients with acute myocardial infarction: results from the Cooperative Cardiovascular Project SITS-MOST investigators. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study Risk factors for intracranial haemorrhage in patients with pulmonary embolism treated with thrombolytic therapy development of the PE-CH score Coagulation and fibrinolytic activity of tenecteplase and alteplase in acute ischemic stroke Fibrinolytic abnormalities in acute respiratory distress syndrome (ARDS) and versatility of thrombolytic drugs to treat COVID-19 SARS-CoV-2 and viral sepsis: observations and hypotheses The role of platelets in sepsis The role of platelets in mediating a response to human influenza infection Thrombocytopenia impairs host defense in gram-negative pneumonia-derived sepsis in mice Platelets and the immune continuum Platelets in defense against bacterial pathogens Platelets protect from septic shock by inhibiting macrophage-dependent inflammation via the cyclooxygenase 1 signalling pathway Activated platelets enhance IL-10 secretion and reduce TNF-α secretion by monocytes Complete reversal of acid-induced acute lung injury by blocking of platelet-neutrophil aggregation Platelet depletion and aspirin treatment protect mice in a two-event model of transfusion-related acute lung injury Effect of antiplatelet therapy on acute respiratory distress syndrome and mortality in critically ill patients: a meta-analysis Aspirin therapy in patients with acute respiratory distress syndrome (ARDS) is associated with reduced intensive care unit mortality: a prospective analysis Prehospital aspirin use is associated with reduced risk of acute respiratory distress syndrome in critically ill patients: a propensity-adjusted analysis Prevention or treatment of ARDS with aspirin: a review of preclinical models and meta-analysis of clinical studies Effect of aspirin on development of ARDS in atrisk patients presenting to the emergency department: the LIPS-A randomized clinical trial Aspirin and acute respiratory distress syndrome Aspirin for prevention of acute respiratory distress syndrome (ARDS): let's not throw the baby with the water! Clopidogrel treatment and the incidence and severity of community acquired pneumonia in a cohort study and meta-analysis of antiplatelet therapy in pneumonia and critical illness Lower mortality following pulmonary adverse events and sepsis with ticagrelor compared to clopidogrel in the PLATO study Ticagrelor reduces thromboinflammatory markers in patients with pneumonia Inverse agonism at the P2Y12 receptor and ENT1 transporter blockade contribute to platelet inhibition by ticagrelor Antibacterial activity of ticagrelor in conventional antiplatelet dosages against antibiotic-resistant Gram-positive bacteria Clopidogrel increases dasabuvir exposure with or without ritonavir, and ritonavir inhibits the bioactivation of clopidogrel Impact of boosted antiretroviral therapy on the pharmacokinetics and efficacy of clopidogrel and prasugrel active metabolites Hematological findings and complications of COVID-19 Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: a meta-analysis Anti-platelet therapy: phosphodiesterase inhibitors Antiviral action of dipyridamole and its derivatives against influenza virus A FEP-based screening prompts drug repositioning against Potential therapeutic effects of dipyridamole in the severely ill patients with COVID-19 Overview of the 2014 Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee meeting about vorapaxar Steering Committee and Investigators. Vorapaxar in the secondary prevention of atherothrombotic events Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia Hypercoagulability of COVID-19 patients in intensive care unit. A report of thromboelastography findings and other parameters of hemostasis Antithrombin: an anticoagulant, anti-inflammatory and antibacterial serpin Prominent changes in blood coagulation of patients with SARS-CoV-2 infection Nebulized anticoagulants limit pulmonary coagulopathy, but not inflammation, in a model of experimental lung injury Nebulized anticoagulants limit coagulopathy but not inflammation in pseudomonas aeruginosa-induced pneumonia in rats Effects of various doses of antithrombin III on endotoxin-induced endothelial cell injury and coagulation abnormalities in rats Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial Antithrombin III for critically ill patients: a systematic review with meta-analysis and trial sequential analysis Thrombomodulin in disseminated intravascular coagulation and other critical conditions-a multi-faceted anticoagulant protein with therapeutic potential Effect of a recombinant human soluble thrombomodulin on mortality in patients with sepsis-associated coagulopathy: the SCARLET randomized clinical trial Efficacy and safety of recombinant human soluble thrombomodulin in patients with sepsis-associated coagulopathy: a systematic review and metaanalysis Activated protein C: biased for translation Drotrecogin alfa (activated) in adults with septic shock Adverse outcomes associated with the use of drotrecogin alfa (activated) in patients with severe sepsis and baseline bleeding precautions Activated protein C attenuates pulmonary coagulopathy in patients with acute respiratory distress syndrome Recombinant human activated protein C in the treatment of acute respiratory distress Therapeutic Targets for COVID-19-Associated Thrombosis Bikdeli et al. syndrome: a randomized clinical trial Hospital-associated outbreak of Middle East respiratory syndrome coronavirus: a serologic, epidemiologic, and clinical description Blocking activated factor XII with a monoclonal antibody prevents organ failure and saves baboons challenged with heat-inactivated S Inhibition of contact-mediated activation of factor XI protects baboons against S aureus-induced organ damage and death Inhibition of factor XII in septic baboons attenuates the activation of complement and fibrinolytic systems and reduces the release of interleukin-6 and neutrophil elastase The contact system contributes to hypotension but not disseminated intravascular coagulation in lethal bacteremia. In vivo use of a monoclonal anti-factor XII antibody to block contact activation in baboons Inhibition of factor XI activation attenuates inflammation and coagulopathy while improving the survival of mouse polymicrobial sepsis Factor XI-deficient mice display reduced inflammation, coagulopathy, and bacterial growth during listeriosis The contact activation system as a potential therapeutic target in patients with COVID-19 Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease SARS: systematic review of treatment effects Saudi Critical Care Trial Group. Corticosteroid therapy for critically ill patients with middle east respiratory syndrome Corticosteroids as adjunctive therapy in the treatment of influenza A meta-analysis of the risk of venous thromboembolism in inflammatory rheumatic diseases Risk of pulmonary embolism in patients with autoimmune disorders: a nationwide follow-up study from Sweden Use of glucocorticoids and risk of venous thromboembolism: a nationwide population-based case-control study Systematic review on the effect of glucocorticoid use on procoagulant, anti-coagulant and fibrinolytic factors Risk factors and short-term mortality of venous thromboembolism diagnosed in the primary care setting in the United Kingdom Corticosteroids and ARDS: a review of treatment and prevention evidence Hydroxychloroquine reverses platelet activation induced by human IgG antiphospholipid antibodies Use of hydroxychloroquine to prevent thrombosis in systemic lupus erythematosus and in antiphospholipid antibody-positive patients Antiphospholipid syndrome Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review Hydroxychloroquine reverses thrombogenic properties of antiphospholipid antibodies in mice The effect of hydroxychloroquine on haemostasis, complement, inflammation and angiogenesis in patients with antiphospholipid antibodies Clinical and experimental evaluation of the thromboprophylactic effect of hydroxychloroquine sulfate after total hip replacement Hydroxychloroquine and postoperative thromboembolism after total hip replacement Assessment of QT intervals in a case series of patients with coronavirus disease 2019 (COVID-19) infection treated with hydroxychloroquine alone or in combination with azithromycin in an intensive care unit PCNA guideline on the management of blood cholesterol: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines Pleiotropic effects of statins on the cardiovascular system HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression Considerations for statin therapy in patients with COVID-19 Atorvastatin suppresses NLRP3 inflammasome activation via TLR4/MyD88/ NF-κB signaling in PMA-stimulated THP-1 monocytes Association between use of statins and mortality among patients hospitalized with laboratory-confirmed influenza virus infections: a multistate study Statins may decrease the fatality rate of Middle East respiratory syndrome infection Inhibition of NF-κB-mediated inflammation in severe acute respiratory syndrome coronavirus-infected mice increases survival Statins as antithrombotic drugs A randomized trial of rosuvastatin in the prevention of venous thromboembolism Antiatherothrombotic properties of statins: implications for cardiovascular event reduction Clinical and immunological features of severe and moderate coronavirus disease 2019 Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases COVID-19: combining antiviral and anti-inflammatory treatments Cardiovascular safety during treatment with baricitinib in rheumatoid arthritis National Institutes of Health Coronavirus Disease Genentech's arthritis drug tocilizumab shows promise in Covid-19 trial Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study and the Northwell COVID-19 Research Consortium. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the Low-molecular-weight heparin treatment for acute lung injury/acute respiratory distress syndrome: a meta-analysis of randomized controlled trials Heparin prevents Zika virus induced-cytopathic effects in human neural progenitor cells Coronaviridae and SARSassociated coronavirus strain HSR1 Difference of coagulation features between severe pneumonia induced by SARS-CoV2 and non-SARS-CoV2 The 2019 coronavirus (SARS-CoV-2) surface protein (Spike) S1 Receptor Binding Domain undergoes conformational change upon heparin binding Association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with COVID-19 Use of a low-molecularweight heparinoid (danaparoid sodium) for continuous renal replacement therapy in intensive care patients Acute respiratory distress syndrome as an organ phenotype of vascular microthrombotic disease: based on hemostatic theory and endothelial molecular pathogenesis Therapeutic effects of dipyridamole on COVID-19 patients with coagulation dysfunction Activated protein C action in inflammation Adjuvant corticosteroid therapy for critically ill patients with Coagulopathy and antiphospholipid antibodies in patients with Covid-19 Changes in coagulation and fibrinolysis of post-SARS osteonecrosis in a Chinese population The authors would like to acknowledge BioRender for providing templates and the platform that were used for creating ►Fig. 1.