key: cord-0909119-s0l43bfg authors: McBane, Robert D.; Torres Roldan, Victor D.; Niven, Alexander S.; Pruthi, Rajiv K.; Franco, Pablo Moreno; Linderbaum, Jane A.; Casanegra, Ana I.; Oyen, Lance J.; Houghton, Damon E.; Marshall, Ariela L.; Ou, Narith N.; Siegel, Jason L.; Wysokinski, Waldemar E.; Padrnos, Leslie J.; Rivera, Candido E.; Flo, Gayle L.; Shamoun, Fadi E.; Silvers, Scott M.; Nayfeh, Tarek; Suarez, Meritxell Urtecho; Shah, Sahrish; Benkhadra, Raed; Saadi, Samer Mohir; Firwana, Mohamed; Jawaid, Tabinda; Amin, Mustapha; Prokop, Larry J.; Murad, M. Hassan title: Anticoagulation in COVID-19: A Systematic Review, Meta-Analysis and Rapid Guidance From The Mayo Clinic date: 2020-08-31 journal: Mayo Clin Proc DOI: 10.1016/j.mayocp.2020.08.030 sha: 7ee77746b121a009eb939d9860a98cf4227a10b2 doc_id: 909119 cord_uid: s0l43bfg A higher risk of thrombosis has been described as a prominent feature of COVID-19. This systematic review synthesizes current data on thrombosis risk, prognostic implications, and anticoagulation effects in COVID-19. We included 37 studies from 4,070 unique citations. Meta-analysis was performed when feasible. Coagulopathy and thrombotic events were frequent among patients with COVID-19, and further increased in those with more severe forms of the disease. We also present guidance on the prevention and management of thrombosis from a multidisciplinary panel of specialists from the Mayo Clinic. The current certainty of evidence is generally very low, and continues to evolve. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) has infected more than 5.5 million individuals worldwide with more than 350,000 deaths 1 . In the United States, there have been nearly 1.7 million confirmed cases with nearly 100 thousand deaths. 1,2 A prominently described feature of this disease has been its hematologic manifestations and high risk of thrombosis. The 4 While our understanding of the hematologic manifestations of COVID-19 remains in its early stages, this systematic review aims to provide a summary of current estimates of VTE risk, review of anticipated laboratory values and their association with poor outcomes, benefits and harms of anticoagulation, and suggestions for the prevention and management of patients with this infection who require hospitalization. The present review follows the recommendations by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement 10 and was designed to provide a description of coagulopathy and the role of anticoagulants in patients with COVID-19. The analytical framework is described in Figure 1 . The review was conducted by the Mayo Clinic Evidence-Based Practice Center. Based on the evidence summarized in the systematic review, experts in thrombosis, pulmonary and critical care medicine, hematology, and cardiovascular medicine developed guidance for clinical practice. The guidance was achieved via consensus of this multidisciplinary group following critical review of the literature, available clinical experience and serial discussions. This guidance is intended to help clinicians managing COVID-19 patients in a large multi-state health system. We included primary studies -prospective and retrospective-in patients with that reported on at least one of the following: (a) frequency of coagulation abnormalities, We extracted study characteristics (e.g. study design, setting) and population description (e.g. target population, age range, number of hospitalized vs. ICU). Laboratory data were extracted as either binary (e.g. presence of thrombocytopenia) or continuous using means and standard deviations. If not available, standard deviations were imputed from interquartile ranges. The number of reported VTE and DIC events was also extracted. Severity of disease was categorized as mild, moderate, severe or critical according to the description provided in each publication. Mild Published series were largely drawn from COVID-19 patients admitted to the ICU. Venous thromboembolism rates ranged from 2% to 69% based on three published studies at the time of this analysis. This wide range reflects differing detection strategies, potentially limited by personal protection equipment (PPE) conservation tactics. In studies where ultrasound imaging was prompted by clinical suspicion alone, reported VTE rates were low at 2% to 4%. 14,29 In the only study where surveillance ultrasound was mandated, VTE rate was 69%. 15 The latter study pursued mandatory ultrasound on admission and repeated on day 7 and reported a DVT rate of 50% of which the majority had bilateral lower extremity DVTs, however, the rates of proximal and distal thromboses were not reported. 15 (Table 3) . In two studies where >50% of patients received prophylaxis, rates of VTE ranged 1.6-4.1%, 14,29 and PE, 1. 4-20.6% 14,18,29 whereas in studies with less prophylaxis, VTE was 69%, 15 and PE ranged 23.1-30.2%. 15,26 Meta-analyses of the frequency of thrombotic events are summarized in Table 3 ranging from 1% (myocardial infarction) to 17% (pulmonary embolism). Each pooled analysis included 2-6 studies with sample sizes 598-1362. Overall heterogeneity was moderate to high. An overall VTE rate was not pooled across studies due to high heterogeneity. Six retrospective studies (4 comparatives 15,30,33,45 and 2 uncontrolled 14,29 ) reported patient important outcomes in patients who received anticoagulation ( Table 4) . Two of the comparative studies reported data from the same cohort. 33,45 Mortality was assessed by two comparative studies, 30,33,45 meta-analysis of which did not show statistically significant difference when using anticoagulation (OR: 0.99; 95% CI: 0.82 to 1.19; I 2 =0%). In one cohort study, 45 patients with D-dimer >3.0 mg/mL treated with unfractionated heparin had lower mortality than those not receiving unfractionated heparin (32.8% vs 52.4%, P=.02). Higher risk of VTE was also associated with the need for mechanical ventilation 30 in patients receiving anticoagulants. In one study, 15 VTE rates were significantly higher for patients receiving prophylaxis dosed anticoagulants compared to therapeutic dosed anticoagulation (100% vs. 56%, P=.03). The small sample size of this study however limits the interpretation of these findings. Indeed, the certainty of evidence in all outcomes of J o u r n a l P r e -p r o o f anticoagulation is rated as very low, considering the observational nature of the studies and their small size leading to important imprecision. 53 Risk of bias is described in Supplemental tables 2 and 3. The following approach to patients requiring hospitalization for COVID-19 related complications is suggested (Figure 2 ). First, it should be determined whether the patient is already taking therapeutic anticoagulation for a well-defined indication. For such patients, transitioning to parenteral anticoagulation, such as unfractionated or low molecular weight heparin, should be considered particularly if an invasive procedure is anticipated. This transition will facilitate prompt and efficient scheduling with timely pursuit of these procedures in an otherwise ill patient. Second, for patients not receiving therapeutic anticoagulants, it is then important to determine which form of VTE prophylaxis is most appropriate. This determination will require an assessment of bleeding risk. For patients with active bleeding, severe thrombocytopenia (< 25x10 9 /L), or underlying congenital bleeding disorder, nonpharmacologic prophylaxis with sequential compression devices should be initiated. Once bleeding resolves with certainty, platelet counts recover, or the appropriate management of the underlying congenital bleeding disorder is addressed, pharmacologic prophylaxis can again be re-considered. Guideline recommendations state a preference for enoxaparin (a LMWH) prophylaxis at a dose of 40 mg subcutaneously (SC) daily for all hospitalized 12 patients provided there are no contraindications. 54 Third, baseline laboratory assessment should include complete blood count with differential, PT/aPTT, fibrinogen and D-dimer assessment. As trends in platelet counts, and fibrin D-dimer have prognostic implications, repeating these measures periodically, particularly for the ICU patient can be informative. 22 For younger patients with preserved renal function, in particular, there may be increased metabolic clearance of LMWH, dabigatran, and edoxaban. 63, 64 Drug interactions such as the concomitant use of strong CYP 3A4 and P-glycoprotein inducers should be assessed. Attention to requirements of specific anticoagulants is needed; for example, adequate absorption of rivaroxaban necessitates concomitant meals enriched in fat . 65 Additionally, drug absorption may be compromised by such conditions as disturbances in gastrointestinal motility, gastrointestinal resection, or gastric. 66, 67 Third, medication adherence in the outpatient setting is an important variable regardless of which anticoagulant is prescribed. [68] [69] [70] Fourth, temporary anticoagulant interruptions for invasive procedures may promote thrombosis for several reasons. Invasive procedures, 71-73 blood product transfusions and central venous catheters all increase the thrombotic risk. Fifth, heparin induced thrombocytopenia may complicate anticoagulation delivery for both unfractionated or low molecular weight heparin therapy. Lastly, there is growing evidence that the outcomes of antiphospholipid syndrome treatment are improved with warfarin compared to DOACs. 74, 75 Whether this recommendation should be extended to COVID-19 associated 391 antiphospholipid syndrome is not clear. Between 10% and 20% of patients infected with COVID 19 require hospitalization at a current overall rate of 29.2/100,000 individuals. 2 Of these, nearly 60% do not entail ICU admissions. There is currently limited data of VTE prevalence for patients hospitalized on the medicine ward, apart from the ICU setting. Without these numbers, it is difficult to inform decision making for VTE prophylaxis of this sizeable patient population. Ideally, these rates would be compared to rates for patients in hospital for non-COVID disease receiving prophylaxis. While randomized trials of different antithrombotic prophylaxis strategies are underway, data to inform decision making may not be available for some time. 2. There are no estimates of VTE rates in the ambulatory patient with COVID 19 recovering at home. Whether these patients should receive some form of DVT prophylaxis is not known. 3. A few reports exist regarding bleeding outcomes for these hospitalized patients receiving either prophylaxis or therapeutic anticoagulation. Lastly, the precise mechanism driving the COVID-19 coagulopathy requires further study. There are several intriguing hypotheses including complement mediated thrombogenesis. In this model, membrane attack complex mediated endothelial injury with subsequent coagulation activation has been postulated as the driving mechanism for small vessel thrombosis, end organ damage and associated fibrin D-dimer production. 76, 77 A second hypothesis focuses on the central role of neutrophil activation with neutrophil extracellular traps (NETS) formation resulting in widespread organ injury. [78] [79] [80] Severe COVID 19 infection has been associated with a "cytokine storm" including interleukin, interferon gamma, tumor necrosis factor, and G-CSF release leading to an uncontrolled positive signaling loop between macrophages and neutrophils. In this model, endothelial infection with SARS-COV-2 leads to endothelial activation promoting neutrophil recruitment. Activated neutrophils then release of neutrophil extracellular traps, large extracellular weblike structures containing cytosolic and granular proteins within a scaffold of decondensed nuclear chromatin. NETosis is a highly regulated process which serves as a robust mechanism for thrombus initiation by promoting platelet aggregation and coagulation activation. A third mechanism suggests that the coagulopathy is primarily driven by hypoxia. [81] [82] [83] [84] Severe COVID-19 infections result in bilateral pneumonia, thick secretions, extensive lung parenchyma damage, hypoxia and ARDS. Hypoxic conditions are known to stimulate platelet and neutrophil adhesion to endothelial cells, tissue factor expression while suppressing tissue factor pathway inhibitor and fibrinolytic pathways. It is likely that the pathophysiology of SARS-COV-2 related coagulopathy cannot be easily parsed into systems, and that each mechanism described above plays a role perhaps in tandem or in sequence. J o u r n a l P r e -p r o o f • What laboratory abnormalities occur in patients with COVID-19? • What is the frequency of these abnormalities? • Are these abnormalities predictive of poor outcomes? • Are there any differences in outcomes in patients receiving thromboprophylaxis compared to not receiving it? • Are there any differences in outcomes in patients receiving therapeutic anticoagulation compared to not receiving it? Question 3. What can we learn from patients already on long-term anticoagulation? • Are there any differences in outcomes in patients on longterm anticoagulation? The Coronavirus Disease 2019 (COVID-19)-Associated Hospitalization Surveillance Network (COVID-NET) Characterization of a novel coronavirus associated with severe acute respiratory syndrome Severe acute respiratory syndrome Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia Haematological manifestations in patients with severe acute respiratory syndrome: retrospective analysis Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report Impact of Renal Function on Outcomes With Edoxaban in Real-World Patients With Atrial Fibrillation Dabigatran Versus Warfarin in Relation to Renal Function in Patients With Atrial Fibrillation The effect of food on the absorption and pharmacokinetics of rivaroxaban The effect of bariatric surgery on direct-acting oral anticoagulant drug levels Oral Anticoagulant Use After Bariatric Surgery: A Literature Review and Clinical Guidance Self-reported adherence to anticoagulation and its determinants using the Morisky medication adherence scale Association between medication adherence and illness perceptions in atrial fibrillation patients treated with direct oral anticoagulants: An observational cross-sectional pilot study European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation Cancer effect on periprocedural thromboembolism and bleeding in anticoagulated patients Predictors of major bleeding in periprocedural anticoagulation management Periprocedural anticoagulation management of patients with venous thromboembolism. Arteriosclerosis, thrombosis, and vascular biology Rivaroxaban Versus Vitamin K Antagonist in Antiphospholipid Syndrome Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases Will Complement Inhibition be the New Target in Treating COVID-19 Related Systemic Thrombosis? Targeting potential drivers of COVID-19: Neutrophil extracellular traps Neutrophil extracellular traps in immunity and disease Thrombosis: tangled up in NETs The stimulation of thrombosis by hypoxia Some of the content of this manuscript is adapted for use in an electronic module as a part of AskMayoExpert resource. We thank Lubna Daraz, PhD for assistance with grey literature search. 7 Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale. Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched. 8 Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated. Supplemental table 1 Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis). Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators. 8 Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made. Risk of bias in individual studies 12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis. Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram. Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.