key: cord-326272-ya3r0h1t authors: Dobesh, Paul P.; Trujillo, Toby C. title: Coagulopathy, Venous Thromboembolism, and Anticoagulation in Patients with COVID‐19 date: 2020-10-01 journal: Pharmacotherapy DOI: 10.1002/phar.2465 sha: doc_id: 326272 cord_uid: ya3r0h1t Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2)has led to a world‐wide pandemic, and patients with the infection are referred to as having COVID‐19. Although COVID‐19 is commonly considered a respiratory disease, there is clearly a thrombotic potential that was not expected. The pathophysiology of the disease and subsequent coagulopathy produce an inflammatory, hypercoagulable, and hypofibrinolytic state. Several observational studies have demonstrated surprisingly high rates of venous thromboembolism (VTE) in both general ward and intensive care patients with COVID‐19. Many of these observational studies demonstrate high rates of VTE despite patients being on standard, or even higher intensity, pharmacologic VTE prophylaxis. Fibrinolytic therapy has also been used in patients with acute respiratory distress syndrome. Unfortunately, high quality randomized controlled trials are lacking. A literature search was performed to provide the most up‐to‐date information on the pathophysiology, coagulopathy, risk of VTE, and prevention and treatment of VTE in patients with COVID‐19. These topics are reviewed in detail, along with practical issues of anticoagulant selection and duration. Although a number of international organizations have produced guideline or consensus statements, they do not all cover the same issues regarding anticoagulant therapy for patients with COVID‐19, and they do not all agree. These statements and the most recent literature are combined into a list of clinical considerations that clinicians can use for the prevention and treatment of VTE in patients with COVID‐19. impairs the adaptive immune response through inadequate T-cell help to virus-specific CD8+ cytotoxic T-cells and β-cells. The impaired INF defense, enhanced monocyte/macrophage and neutrophils response producing excessive cytokine and chemokine levels, along with the impaired lymphocyte response produces a hyperinflammatory state that consequentially produces alveolar tissue damage initiating multiple thrombotic processes. This connection between the immune response inflammation and thrombosis has been termed immunothrombosis or thromboinflammation. 23 The clotting cascade is stimulated through both the extrinsic and intrinsic pathways. The extrinsic pathway is initiated by release of tissue factor from cytokine-damaged alveolar endothelial cells. In the setting of significant inflammation, monocytes and macrophages can also express circulating tissue factor. 23 The intrinsic cascade is activated through neutrophil release of neutrophil extracellular traps (NETs). 24 These NETs contain various bioactive molecules in a process called NETosis, which have the ability to stimulate activation of factor XII. NETs also contain proteases that are able to inactivate endogenous anticoagulants, and therefore worsen the procoagulant state. The dual activation of the extrinsic and intrinsic clotting cascade leads to significant thrombin generation and thrombosis. 23 The immune function of platelets has been well documented over the last decade. 25 Platelets are attracted to the area of cytokine-induced endothelial injury and become activated. Through the process of platelet activation, molecules such as platelet factor 4 and neutrophil-activating peptide-2 are released from platelet α-granules, which are involved in the recruitment and activation of monocytes/macrophages and neutrophils. 25 Additional immune actions of activated platelets include being an important source of proinflammatory IL-1β, as well as the further recruitment of neutrophils Accepted Article through interaction of platelet surface P-selectin. The impact of platelet on immune function and thrombosis has been specifically documented in patients with Patients with COVID-19 also have significant hypoxia, especially in severe disease. Hypoxemia triggers expression of hypoxia inducible factors. 27 Hypoxia inducible factors can promote thrombosis by directly activating coagulation proteins and platelets and increasing tissue factor expression, as well as inhibiting endogenous protective functions such as increasing plasminogen activator inhibitor-1 (PAI-1) and inhibiting anticoagulant protein S. Hypercoagulability is further induced by hypoxia inducible factors due to their ability to promote further inflammation and augmenting blood viscosity. 27 An inflammatory response and activation of thrombotic pathways occurs in a number of severe infections, and is not unique to SARS-CoV-2. Normal coagulation responses are often balanced with a fibrinolytic response to prevent fibrin deposition within alveolar tissues. This natural defense mechanism is initiated by the endogenous plasminogen activators, tissue plasminogen activator (t-PA) and urokinase plasminogen activator (u-PA). These are responsible for the conversion of plasminogen to the proteolytic enzyme plasmin, which controls the breakdown of fibrinogen and fibrin deposits into the breakdown products D-dimer and other fibrin degradation products. The increased thrombotic potential in patients with COVID-19 is potentially a result of its interaction with ACE2. 12 The binding of SARS-CoV-2 to ACE2 produces a downregulation of the enzyme and consequentially an increase in AT II. Angiotensin II induces expression of PAI-1 in endothelial cells, which directly inhibits the actions of t-PA and u-PA. 28 Therefore, in patients with SARS and COVID-19, the balance between fibrinolysis with t-PA and u-PA is shifted to more hypofibrinolysis and thrombosis due to the excessive AT II and subsequent increase in PAI-1. The inability to breakdown and remove these fibrin deposits corresponds with poor clinical patient outcome as these deposits reduce normal gas exchange. 12 Although most of the direct tissue damage and inflammation occurs in the lung, the impact of thromboinflammation can be systemic. Many institutions have reported an uncharacteristically high rate of VTE events in both medical ward and ICU COVID-19 patients. [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] Although there is a significant risk of deep vein thrombosis (DVT) in patients with COVID-19, some evaluations have identified a higher number of pulmonary emboli (PE) than DVT. 34.35.43,44 This discrepancy between Accepted Article the frequencies of PE and DVT is unusual, since PE without DVT typically occurs in only about 20% of cases. 45 Therefore, in patients with COVID-19 many of the pulmonary thrombotic cases are likely pulmonary thrombi and not pulmonary embolism. This would be consistent with the pulmonary inflammation, alveolar tissue damage, and alveolar fibrin deposits found on autopsy in patients with COVID-19. [46] [47] [48] [49] Similar to autopsy findings from SARS and MERS, the primary finding associated with the cause of death is respiratory failure due to diffuse alveolar damage. [46] [47] [48] [49] [50] [51] In contrast to patients with SARS and MERS, the morphological damage in the lungs and other organs is less severe in COVID-19, explaining the lower mortality rate. Whereas autopsies from cases of SARS and MERS did demonstrate fibrin deposits in the lungs, this seems to be amplified in cases of COVID-19. In a series of 10 autopsy cases of patients with severe COVID-19 from Brazil, 80% had a variable number of fibrinous thrombi in small pulmonary arterioles. 46 These thrombi were found in areas of both damaged and more preserved lung parenchyma. In a series of seven COVID-19 cases from Belgium, all had intraalveolar fibrin deposits and widespread vascular thrombosis with microangiopathy and occlusion of alveolar capillaries. 47 Finally, a series of 11 COVID-19 autopsy cases from Austria reported that the most striking finding was obstruction of pulmonary arteries by thrombotic material found at both the microscopic and macroscopic level in all cases. 48 Interestingly, 10 of these 11 cases had received pharmacologic VTE prophylaxis, and VTE was not clinically suspected in any cases before autopsy as a contributor of death. The clinical spectrum of SARS-CoV-2 infection has broad presentation including asymptomatic infection, mild upper respiratory tract symptoms, up to severe viral pneumonia requiring mechanical ventilation, and even death (Table 1) . 52 A number of studies have evaluated characteristics of patients with COVID-19, as well as those who progress to worse outcomes, such as ICU admission, acute respiratory distress syndrome (ARDS), or death (Table 2) . 7, [15] [16] [17] [18] [19] [53] [54] [55] [56] Although most patients have a favorable prognosis, patients with worse outcomes have a pronounced increase in inflammatory markers, referred to as a "cytokine storm", approximately 7-14 days from the onset of initial symptoms. 57 This can coincide with the development of pulmonary thrombosis or PE, which may explain the rapid pulmonary collapse observed in patients suddenly progressing to ARDS. In general, patients progressing to worse outcome are about 10 to 15 years older and have more This article is protected by copyright. All rights reserved comorbidities such as hypertension, diabetes mellitus, and cardiovascular disease (Table 2 ). Laboratory findings demonstrate that patients with worse outcomes typically have more liver and renal dysfunction, and significantly lower lymphocyte counts. The sickest patients may also develop elevated procalcitonin and white blood cell counts, but these more likely represent acquired secondary bacterial infection versus caused by SARS-CoV-2 itself. Patients with COVID-19 often have elevated markers of inflammation. 20, 58 One study in China reported that IL-6 was elevated in 52%, ferritin in 63%, erythrocyte sedimentation rate in 85%, and C-reactive protein (CRP) in 86% of patients. 20 These numbers are even higher in sicker patients ( Table 2) . Markers of coagulopathy are also present in patients with COVID-19. Although the SARS-CoV-2 virus itself does not seem to have intrinsic procoagulant activity, the induced coagulopathy and thromboinflammation extend systemically and impact other organs, such as the kidney, and may eventually lead to multiorgan dysfunction and potentially death. 59 Patients with COVID-19 typically have elevated fibrinogen levels, but the extent of increase does not differ based on the severity of disease. 53 Antithrombin activity can also be decreased in patients with COVID-19, but as demonstrated in a study from China, the significantly lower activity (85% in COVID-19 vs. 99% in healthy volunteers; p<0.001) still falls within the normal range (>80%). 53 Prolongation of the prothrombin time (PT) or activated partial thromboplastin time (aPTT) has been demonstrated, but is not a common finding. [53] [54] [55] [56] Tang N and colleagues found that in patients who died of COVID-19, their PT was prolonged by about 2 seconds compared to those who survived (Table 2) . 56 A meta-analysis of 11 studies reported an average increase in the PT of about 14% in patients with Although antiphospholipid antibodies have been reported in patients with COVID-19, and thought to promote the hypercoagulable state, these data should be interpreted with caution. [60] [61] [62] There is a high risk of false positive lupus anticoagulant testing in patients with COVID-19 due to the elevated levels of CRP. Many assays for lupus anticoagulant are sensitive to CRP and give a false positive finding. 63 Although most patients with COVID-19 have normal platelet counts, thrombocytopenia has been reported in 20% to 35%, and is usually mild. 57, 64 In a meta-analysis of nine studies, the platelet count was lower by about 31,000 x 10 9 /L in severe cases compared to nonsevere cases, and about 48,000 x 10 9 /L lower in nonsurvivors compared to survivors. 65 These lower platelet counts may not be enough to register as marked thrombocytopenia, but do likely represent platelet recruitment into pulmonary or systemic thrombi. Although not as common as other severe infectious diseases, the Accepted Article occurrence and severity of thrombocytopenia is associated with higher mortality in patients with 66 In a study of 380 patients with COVID-19, platelet counts of less than 10 x 10 9 /L occurred in 49% of patients with critical disease, 14% in severe disease, and 9% in those with moderate disease. 17 The odds of death in patients with thrombocytopenia was 8.33 (95% CI 2. 56 -27.15 ). Another study of 1476 patients with COVID-19 demonstrated increasing mortality in patients with thrombocytopenia, as well as increasing mortality with decreasing platelet counts. 66 Nonsurvivors (16%) were significantly more likely to have thrombocytopenia compared to survivors (72.7% vs. 10.7%; p<0.001), as well as lower nadir platelet counts (76 vs . 204 x 10 9 /L; p<0.001), respectively. Patients with nadir platelet counts 150 x 10 9 /L or more had a mortality rate of 4.7%, whereas mortality was 17.5% in those with 100-150 x 10 9 /L, 61.2% in those with 50-100 x 10 9 /L, and 92.1% in those with 0-50 x 10 9 /L. The incidence of a nadir platelet count of 0-50 x 10 9 /L was relatively rare (5%) compared to those with a platelet count of 150 x 10 9 /L or more (68%). Breakdown of fibrin or fibrinogen by u-PA or t-PA produces fibrin degradation products, one of which is D-dimer. An elevated D-dimer is typically a sign of excessive coagulation activation and hyperfibrinolysis. Therefore, D-dimer is often used to detect active thrombus with high sensitivity but low specificity. 67 The low specificity is due to other conditions, such as inflammation and infection that can also increase D-dimer in the absence of thrombosis, and are associated with COVID-19. D-dimer is elevated in 36% to 43% of patients with COVID-19, but is commonly elevated in hospitalized patients. 62 Elevations of D-dimer are higher in ICU patients and those with worse outcomes by 2.5 to 9-fold (Table 2 ). 60, 67 Han H and colleagues found that D-dimer levels were elevated with increasing severity of disease, with levels at 2140 ng/mL for patients classified with ordinary disease, 19,110 ng/mL in those with severe disease, and 20,040 ng/mL in those considered critical, compared to 260 ng/mL in healthy controls. 53 Since values are higher in patients with severe disease, D-dimer measurement may be associated with evolution toward worse clinical picture. As would be expected, D-dimer is also elevated in patients with COVID-19 who develop VTE. 36, 38, 39, [43] [44] [45] [46] It has been suggested that D-dimer levels above a certain cut off could be used to predict those with VTE if appropriate diagnostic testing is not feasible. 29, 30, 36, 38, 39 Caution should be exercised in this myopic interpretation of elevated D-dimer levels. If elevated D-dimer is mainly due to coagulopathy and increased fibrinolysis of thrombi, this would suggest a consumption coagulopathy. This is supported by a study conducted by Tang N and colleagues, where disseminated intravascular coagulation (DIC) was more common in nonsurvivors compared to survivors (71.4% vs. 0.6%). 56 DIC is considered a consumption coagulopathy, with elevated D-dimer levels due to significant fibrinolysis and breakdown of fibrin and fibrinogen. Most patients with COVID-19 have elevated fibrinogen levels that is inconsistent with a consumption coagulopathy. The lack of consistent moderate to severe thrombocytopenia and inconsistent prolongation of the PT also are not supportive of DIC being a common complication in patients with COVID-19. Therefore, most of the elevations of D-dimer are likely due to the excessive inflammatory state, similar to the elevations in erythrocyte sedimentation rate, CRP, and ferritin, and should not be considered to be solely from fibrinolysis. 68 This is supported by data demonstrating that a D-dimer 2-fold above the upper limit of normal has been used in patients without VTE to predict those at highest risk of development of VTE. 69 When DIC does occur, it is likely in the last stage of COVID pneumonia, when there may be increased systemic fibrinolysis and multiorgan failure. 70 Hypercoagulability, but not a consumption coagulopathy, is also supported by findings in two thromboelastography studies that evaluated patients with COVID-19 compared to healthy volunteers. 54, 55 Patients with COVID-19 had significantly higher D-dimer and fibrinogen levels compared to healthy controls ( Table 2 ), but normal PT and aPTT. The first study demonstrated that patients with COVID-19 had significantly shorter clot formation time and higher maximum clot firmness. 54 The shorter clot formation time is reflective of the excessive thrombin generation and higher clot firmness reflects the increased fibrin and fibrinogen in these patients. The other study evaluated 24 intubated ICU patients with COVID-19, most of who were on VTE prophylaxis, compared to 40 health volunteers. 55 Similar to the previous findings, patients with COVID-19 had a shorter clotting times and firmer clots. All patients with COVID-19 also had reduced clot lysis at 30 minutes. The lack of clot lysis at 30 minutes does not support a hyperfibrinolytic state, which matches the pathophysiologic mechanism of impaired fibrinolysis from ACE2 binding of SARS-CoV-2. 9, 10, 12, 13 In summary, the coagulopathy associated with SARS-CoV-2 infection typically presents with elevated D-dimer and fibrinogen levels with normal to slightly lower platelet counts, and normal to slightly elevated PT and aPTT. With worsening disease severity, patients will have higher D-dimer levels, lower platelet counts, and eventually elevated PT and aPTT. These coincide with increased Accepted Article markers of inflammation, such as IL-6 and CRP, as well as infection (lymphopenia and potentially leukocytosis), and organ dysfunction (renal and liver dysfunction). Hospitalized patients with acute medical illness, such as infection, are at increased risk of VTE. 71 In general ward patients the rate of VTE without prophylaxis ranges from 5% to 15% depending on the method of assessment. The use of pharmacologic prophylaxis lowers the rate to 2.8% to 5%. 71 In ICU patients, the risk of VTE is higher. Rates from one meta-analysis ranged from 10% to 30%. 72 Another meta-analysis reported a rate of 12.7% for ICU patients mainly assessed by compression ultrasound (CUS). 73 Use of pharmacologic prophylaxis lowers this rate to 5.1% to 7.7%. 74, 75 A number of studies have reported a higher rate of VTE than would be expected in general ward and ICU patients with COVID-19 (Table 3) . [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] Increased thromboembolic events were also documented with the SARS, MERS, and influenza A H1N1 viruses. [76] [77] [78] [79] [80] [81] The true risk of VTE in patients with COVID-19 is difficult to determine since no placebo-controlled randomized trials have been conducted. Rates of VTE in general medical ward patients with COVID-19 have been reported to be around 4% in clinically evaluated patients and as high as almost 15% in patients screened with CUS (Table 3) . [38] [39] [40] In the early phase of the outbreak, before the thrombotic potential of COVID-19 was appreciated, patients in China did not commonly received VTE prophylaxis based on the assumption that they are a lower risk population. In this setting, Cui and colleagues screened 81 COVID-19 ICU patients for VTE with CUS, none of which were receiving VTE prophylaxis. 29 The rate of DVT was 25%, which is at the high end of the range for an ICU population. Another study from China in which only about one-third of screened ICU patients received VTE prophylaxis had a rate of DVT of 46%. 30 Other trials have evaluated VTE rates in CUS screened ICU patients with COVID-19 receiving pharmacologic prophylaxis with rates as high as 69% to 85%, which are higher than reported in typical ICU patients (Table 3) . 31, 32 Most institutions do not routinely screen patients for VTE, even in the ICU. Observational studies on the rates of VTE in ICU patients with COVID-19 when CUS is only done based on clinical suspicion has also been conducted. In patients receiving prophylaxis the rate of VTE ranges from 13% to 28%, which is 2-to 4-fold the rate demonstrated in typical ICU patients (Table 3) . [34] [35] [36] [37] 40, [42] [43] [44] 74, 75 Accepted Article This article is protected by copyright. All rights reserved There have also been observational trials that have compared rates of VTE in COVID-19 patients to historical controls without COVID-19 (Table 3) . [42] [43] [44] Marone and colleagues evaluated general ward patients all receiving CUS for clinical suspicion of DVT with COVID-19 to those without COVID-19 at the same time the previous year. 42 The rate of DVT was more than 2-fold higher in the patients with COVID-19. Poissy and colleagues conducted a similar time frame comparison, but only evaluated patients with clinical suspicion and all received prophylaxis. 43 The rate of PE was 3-fold higher in COVID-19 patients compared to those without, but was also more than 2-fold higher than influenza patients specifically during the same time frame. Finally, Helms and colleagues conduced a matched case control study of ARDS patients with COVID-19 compared to ARDS patients in the same ICU between 2014 and 2019. 44 Patients were evaluated based on clinical suspicion and the use of anticoagulation was similar between the groups. Patients with COVID-19 had over a 2-fold higher rate of thrombotic events and more than a 5-fold higher rate of PE, with no difference in DVT, compared to patients without COVID-19. Most hospitalized patients with COVID-19 are over age 40 years and have a number of risk factors for VTE, such as pneumonia, obesity, immobility, respiratory disease, elevated D-dimer levels, as well as potentially underlying heart failure, smoking, varicose veins, cancer, and previous VTE. intensity may likely be the best approach. Ultimately the optimal approach will depend on the results from several ongoing randomized, controlled clinical trials that will serve to inform clinicians on the best approach (NCT04345848, NCT04359277, NCT04344756, NCT04360824, NCT04354155, NCT04359212, NCT04362085). Until results from these trials are available, clinicians must rely on currently available evidence to craft treatment approaches for both the individual patient, as well as over-arching institutional guidelines to help the bedside clinician. Typically, hospitalized medically ill patients should be evaluated with a validated risk assessment tool to determine if pharmacologic VTE prophylaxis is needed (Table 4 ). 77, 78 Hospitalized patients with COVID-19, whether on the medical ward or ICU, do not need to undergo the step of risk assessment. Both medical ward and ICU patients with COVID-19 have several VTE risk factors, known thromboinflammation, and unacceptable high rates of VTE despite some form of pharmacologic prophylaxis (Table 3) . [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] 43, 44 Consequentially, all hospitalized patients with COVID-19 should receive pharmacologic VTE prophylaxis regardless of any risk assessment predictors unless the risk of bleeding is considered high. Risk assessment should be performed with symptomatic patients with COVID-19 treated at home, since a number of them may still have several VTE risk factors, including immobility, and are at risk of thromboembolic events. 52, [79] [80] [81] Support for the paradigm that a higher intensity of anticoagulation than standard prophylactic doses of heparin comes from previously published evidence from the H1N1 influenza pandemic in 2009. 82 An observational cohort study of critically ill patients with severe ARDS from H1N1 viral pneumonia demonstrated that empiric systemic heparinization titrated to a goal heparin level of 0.3 -0.7 anti-Xa units/mL was significantly better at reducing VTE rates than standard prophylactic doses of either UFH or LMWH. Although these data were obtained only in critically ill patients with ARDS, they do support the idea that higher intensity anticoagulation may be needed in order to improve outcomes in patients with COVID-19. The first report evaluating the use of VTE prophylaxis (UFH or LMWH) and the impact on mortality came from a retrospective review of 449 patients from Wuhan, China. 83 Patients with severe COVID-19 in the ICU received VTE prophylaxis for at least seven days with UFH 5000 units two to three times daily (n=5), enoxaparin 40-60 mg daily (n=94), or no anticoagulation prophylaxis (n=350). Overall, there was no difference in 28-day mortality between the 22% of patients that received either UFH or LMWH compared to patients who received no anticoagulation (30.3% vs. 29.7%; p=0.910, respectively). However, when looking at the subset of patients with significant hypercoagulability as defined by a D-dimer level of at least six-fold above the upper limit of normal (> 3.000 ng/mL), there was a significant decrease in mortality with the use of heparin compared with no anticoagulation (32.8% vs. 52.4%; p=0.017, respectively). When stratifying patients by a sepsis-induced coagulopathy score of > 4, there was also a significant reduction in mortality with the use of heparin versus no anticoagulation (40.0% vs. 64.2%; p=0.029, respectively). These same authors compared these 449 patients with COVID-19 in the ICU to 107 patients in the ICU with non-COVID-19 pneumonia, of which 21.2% received heparin prophylaxis. 84 Although there was still no overall reduction in mortality in patients receiving heparin prophylaxis compared with no anticoagulation (13.6% vs. 15.9%; p=0.798, respectively), mortality is half what was seen in the COVID-19 patients. Interestingly, there was no difference in mortality between heparin users and non-users even when stratified for D-dimer and sepsis-induced coagulopathy in patients without COVID-19. Although this report was the first to suggest that the use of UFH or LMWH could improve outcomes in severely ill patients with COVID-19, there are a number of limitations that should be considered. First, the benefit seen with prophylaxis was only demonstrated in a subgroup of the sickest patients evaluated. The observational nature of the study cannot account for potential confounding variables between the groups. In fact, the authors noted that during the time of the study medical resources were strained and mortality rates may have been higher than other parts of the world. 83 The decision of whether to give LMWH or UFH, as well as doses used, were at the discretion of the clinician and were not controlled in the study. There is no information of the impact of actual VTE events, as this is also an important endpoint. A second observational study from New York sought to identify the value of full therapeutic anticoagulation in patients hospitalized with COVID-19. 85 This single center retrospective study evaluated 2773 patients with COVID-19, of which 786 (28%) received therapeutic anticoagulation. Overall, in-hospital mortality was not different between patients who received therapeutic anticoagulation vs those that did not (22.5% vs. 22.8%, respectively). Patients who received therapeutic anticoagulation were more likely to require invasive mechanical ventilation (29.8% therapeutic anticoagulation vs. 8.1% no therapeutic anticoagulation; p<0.001). Consequentially, patients who were receiving mechanical ventilation (n=395) had a reduction of in hospital mortality by Accepted Article over 50% with the use of therapeutic anticoagulation compared with those who received no therapeutic anticoagulation (29% vs. 63%, median survival 21 days vs. 9 days; p<0.01, respectively). Interestingly, major bleeding was not significantly increased in patients receiving therapeutic anticoagulation (3% therapeutic anticoagulation vs. 1.9% no therapeutic anticoagulation; p=0.2). In a multi-variate Cox proportional hazards model, mortality risk was reduced with longer durations of anticoagulation. Similar to the previous study, this report suffers from several limitations such as unaccounted for confounding variables. Specific anticoagulant agents used for therapeutic anticoagulation were not specified, the indication for anticoagulation was not provided, and it is unclear if non-anticoagulated patients received prophylaxis dose anticoagulation or nothing. The median length of hospitalization was 5 days and the median duration of anticoagulation was only 3 days. Despite these limitations, this report provides at least some insight into the role of higher levels of anticoagulation in the most severe patients with COVID-19, and support evaluating various levels of anticoagulation intensity in ongoing randomized controlled trials. A number of smaller reports also provide partial insight to the appropriate level of VTE prophylaxis needed in patients with COVID-19. A retrospective observational study of 16 ICU patients with COVID-19 evaluated coagulopathy parameters after a nadroparin dose of 4000 IU twice daily for VTE prophylaxis, and then again after a 6000 IU twice daily dose (8000 IU twice daily in patients with body mass index >35). 86 The increase in dose provided a significant reduction in fibrinogen and Ddimer levels and an increase in antithrombin activity. An additional report in 26 patients with severe COVID-19 admitted to the ICU reported a higher frequency of VTE in patients receiving prophylactic compared to therapeutic anticoagulation (100% prophylactic vs. 56% therapeutic; p=0.03), although all 6 patients (23%) with PE were receiving therapeutic anticoagulation. 32 As discussed previously, a number of observational studies have reported higher than expected rates of VTE in critically ill patients with COVID-19, despite the use of standard dose anticoagulant prophylaxis. [31] [32] [33] [34] [35] [36] 40, 41, 44 An important consideration within this area may be augmented renal clearance. Augmented renal clearance is a process whereby renal clearance of medications is increased in the setting of critical illness. A report in 47 ICU patients with COVID-19 identified 18 patients (38.3%) with augmented renal clearance. 87 Patients with augmented renal clearance had numerically more DVT (44% vs. 31%; p=0.352) and significantly more PE (33% vs. 10%; p=0.025) compared to those without, respectively. These data, although from a small group of patients, speaks Accepted Article to the potential need for higher doses of anticoagulant prophylaxis to address both significant hypercoagulability as well as augmented renal clearance. Lastly, there is emerging information that standard doses of prophylaxis may be adequate to prevent DVT and PE, but higher doses may be need to prevent primary pulmonary thrombosis. 45 This is consistent with a number of observations that demonstrated a higher rate of pulmonary events than DVT. 34, 35, 43, 44 Ultimately data from larger randomized controlled trials will help clarify many of these clinical questions. Risk of VTE in patients with COVID-19 is unlikely to disappear at the time of hospital discharge. Studies in medially ill non-COVID-19 patients have demonstrated a high rate of VTE in the 30 days immediately after discharge. 88 This is likely due to patients still recovering and continued immobility. Two agents, betrixaban and rivaroxaban, are approved by the United States Food and Drug Administration for extended VTE prophylaxis in medically ill patients although betrixaban has recently been removed from the market due to a company acquisition. Assuming the appropriate inclusion and exclusion criteria are met (Table 5) , both agents provided a significant reduction in VTE events without significantly increasing major bleeding when used for approximately 30 days post discharge. [89] [90] [91] Despite the lack of ability to get betrixaban, applying the criteria from the trial still has merit in appropriate patient selection for extended prophylaxis. If these agents cannot be used due to significant drug interaction or other reason, enoxaparin 40 once daily can be used. Although enoxaparin has also demonstrated the ability to significantly reduce VTE events in the 30 days post discharge, there is significantly more major bleeding with this regimen. 92 Apixaban should not be used since the trial with this agent did not demonstrate efficacy over placebo for thromboprophylaxis in medically ill patients, and it also had significantly more major bleeding. 93 Although none of these trials included patients with COVID-19, VTE after hospital discharge has been reported in these patients. 94 Patients with COVID-19 have prolonged hospital stays with significant deconditioning, immobility during recovery, high D-dimer levels, and additional risk factors. It is likely that a number of hospitalized patients with COVID-19 would have met criteria to be included in the trials and should realize similar benefit from extended VTE prophylaxis (Table 5) . Regardless of the underlying cause, ARDS has been associated with fibrin deposition in the airspaces along with fibrin-platelet microthrombi at the level of the pulmonary vasculature. These observations have also been noted in the lung microvasculature of patient with COVID-19. [46] [47] [48] [49] Accepted Article conjunction with these findings, patients with COVID-19 can demonstrate hypercoagulable and hypofibrinolysis findings on thrombelastography. 54, 55 These findings have prompted the hypothesis that fibrinolytic therapy may have a role in managing patients with ARDS, and more specifically in patients with COVID-19 who develop ARDS in the setting of a hypofibrinolytic thrombotic coagulopathy. Data supporting the role of fibrinolytic therapy in the management of patients with COVID-19 are limited at best. In a case series of three patients on mechanical ventilation, systemic t-PA at a dose of 25 mg over 2 hours followed by another 25 mg administered over the subsequent 22 hours has been evaluated. 95 All three patients were experiencing ARDS related respiratory failure, and had improvements in their ventilatory parameters and oxygenation following t-PA therapy, however the effects were transient. A second case series of three patients with significantly worsening ventilatory parameters and oxygenation were administered t-PA. One patient received 30 mg over 15 hours (2 mg/hr), while the over two received 50 mg over 3 hours 96 . All patients experienced improvement in ventilatory parameters and oxygenation and were discharged alive. 97 A final case series assessed the effects or aerosolized freeze-dried plasminogen in hospitalized patients with COVID-19. 97 Oxygenation and ventilatory parameters were also improved, but only transiently. A report using a Markov decision analysis approach to evaluate whether t-PA may improve outcomes in patients with COVID-19 demonstrated the use of fibrinolytic therapy in ARDS patients was associated with a mortality benefit, although this can be considered hypothesis generating only. 98 Given that systemic administration of fibrinolytics in the setting of PE is associated with a 10% risk of major bleeding and a 1-2% risk of intracranial hemorrhage, additional information from randomized clinical trials is needed to validate whether t-PA has any role in the management of patients with COVID-19 and ARDS. 99 Several trials are underway to address this clinical question (NCT04356833, NCT04357730). Based on the level of evidence currently available, routine fibrinolytic administration to patients with COVID-19 ARDS cannot be recommended at this time. Several clinical guidance and consensus statements have been developed and disseminated by international organizations to help guide clinicians in the management of the thromboembolic risks associated with COVID-19 (Table 6 ). 52,79,100-103 These guidance statements have been developed in the absence of randomized controlled trials in patients with COVID-19, and hence are largely based This article is protected by copyright. All rights reserved on knowledge regarding the prophylaxis and treatment of VTE in patients without COVID-19, as well as the initial observational publications. As such, some of the recommendations should be considered expert consensus. Although these guidance statements attempt to include the most upto-date information, data regarding VTE risk, prevention, and treatment in patients with COVID-19 is rapidly evolving. At the time of this writing, data presented in this manuscript cannot be found in many of these guidance documents. Also, each of the guidance documents do not address all the clinical issues, and not all of these organizations agree. Therefore, a table of clinical considerations has been provided that considers these different guidance documents together, as well as incorporates the most recent published data ( Table 7) (Table 3 ) in the ICU setting. For example, a study using standard doses of LMWH prophylaxis in ICU patients with COVID-19 reported a failure rate of 27%, which is 3-fold higher than prior reports in ICU patients without COVID-19 that documented a failure rate of 7.7%. 34, 75 Evidence is also beginning to emerge that escalating the dose of VTE prophylaxis in patients who have evidence of thromboinflammation due to a heightened inflammatory state (increased IL-6, D-dimer, fibrinogen, or TEG findings) results in a significant decrease in inflammation and hypercoagulability. 86 In-hospital VTE prophylaxis and treatment should be provided with LMWH or UFH instead of a direct oral anticoagulant (DOAC). Both LMWH and UFH have potential anti-inflammatory properties that Accepted Article may make them beneficial in patients with COVID-19. [104] [105] [106] These agents also may prevent splitting of the S proteins of SARS-CoV-2, which is necessary for incorporation into the host via ACE2. The impact of DOACs on these properties is unknown. 13 Besides patients requiring dialysis, the use of a LMWH is preferred to UFH for both prevention and treatment of VTE. Prophylaxis with LMWH requires fewer injections per day compared to UFH, and treatment with LMWH can be give once or twice daily, with no need for the frequent monitoring and dose adjustments as is necessary with UFH. Use of LMWH instead of UFH will reduce exposure of health care professionals to patients with COVID-19, as well as preserving personal protective equipment. The preference for LMWH over UFH for prophylaxis is also based on benefit of LMWH over UFH in other high risk patients, such as those with trauma, cancer, and high risk medically ill patients. [107] [108] [109] [110] [111] [112] Patients receiving LMWH for VTE prophylaxis should have dose adjustments for obesity and renal function. 113 In patients with a BMI of 30 to 40 kg/m 2 or greater, or weighing more than 100 to 120 kg, increased doses of LMWH, such as enoxaparin 40 mg twice daily, 60 mg once daily, or 0.5 mg/kg have demonstrated improved efficacy and similar safety to standard doses. 114, 115 Date also is available in patients undergoing bariatric surgery, as well as pregnancy, supporting the notion that doses of prophylaxis should be adjusted upwards based on the presence of elevated body weight. 116, 117 If UFH is used for VTE treatment, monitoring must be done with an anti-Xa assay instead of the aPTT. 62 The aPTT can be elevated or become elevated in patients with COVID-19, and therefore is unreliable for monitoring UFH. Even though bleeding is rare in patients with COVID-19, the current evidence does not support the use of therapeutic LMWH or UFH for prevention of VTE. The use of fibrinolysis outside of patients with hemodynamically compromised PE should also be avoided. The use of DOACs in hospitalized patients, especially ICU patients with COVID-19, can be problematic if invasive procedures are needed, requiring longer hold times that may delay procedures. The use of DOACs may also be limited by drug interactions with certain antiviral therapies, such as lopinavir/ritonavir. If the perceived need for invasive procedures is low, and no drug interactions exist, DOACs could be considered as initial therapy for treatment of VTE in non-ICU patients. After discharge, patients initiated on injectable therapy in the hospital should be considered for transition to a DOAC if possible, or warfarin. This article is protected by copyright. All rights reserved As all hospitalized patients with COIVD-19 should receive VTE prophylaxis, thrombocytopenia presents a conundrum. Platelet count drops to less than 100 x 10 9 /L may represent the transition of the patient into a consumption coagulopathy, where withdrawal of anticoagulant therapy may worsen the patient's thrombotic potential. It is not uncommon to continue VTE prophylaxis until platelet counts get below 50 x 10 9 /L or even 20 x 10 9 /L. With the high use of anticoagulation in patients with COVID-19, heparin-induced thrombocytopenia must also be considered, especially in patients receiving UFH. Special attention to the timing and rate of platelet drop needs be considered. Since a consumption coagulopathy occurs fairly late in the course of SARS-CoV-2 infection in the most severe cases, it is relatively rare, but also difficult to distinguish from the timing of heparin-induced thrombocytopenia. In these cases, switching to an alternative agent such as argatroban or fondaparinux seems prudent. Patients with COVID-19 should not only be considered to have a respiratory illness, but a thrombotic condition as well. SARS-CoV-2 not only produces an inflammatory and hypercoagulable state, but also a hypofibrinolytic state not seen with most other types of coagulopathy. The rate of VTE observed is higher than expected for general ward and ICU patients, especially for those receiving prophylaxis. All hospitalized patients with COVID-19 should be considered high risk and receive anticoagulants for VTE prophylaxis. Although a number of approaches have been observed in the literature, there is unfortunately no high-quality data to help make more definitive recommendations at this time. Although guideline statements differ on a number of the clinical issues, such as the best dose of anticoagulant for VTE prophylaxis, duration of prophylaxis, and use of fibrinolytics in patients with ARDS, a number of randomized controlled trials are ongoing to answer these questions. Until these randomized controlled trials become available, an understanding of the pathophysiology, coagulopathy, current guideline and consensus statements, and these clinical considerations (Table 7) are key resources to help clinicians care for patients with COVID-19. IU once daily to 5000 IU BID or 7500 IU (or even 10,000 IU QD in obese patients) can be considered if dalteparin is the formulary LMWH. Adjust doses based on clinical trial data and equal potent anti-Xa units. 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Table 4 . VTE risk assessment models 77, 78 Padua Score † VTE=venous thromboembolism; BMI=body mass index † A score of 4 or higher demonstrates high risk of VTE and pharmacologic prophylaxis should be used. ‡ Patients with local or distant metastases and/or in whom chemotherapy or radiotherapy had been performed in the previous 6 months. § Anticipated bed rest with bathroom privileges (either because of patient's limitations or on physician's order) for at least 3 days. ¶ Carriage of defects of antithrombin, protein C or S, factor V Leiden, G20210A prothrombin mutation, antiphospholipid syndrome.