key: cord-0970954-lxfl31ro authors: Weeks, Lachelle D.; Sylvester, Katelyn W.; Connors, Jean M.; Connell, Nathan T. title: Management of therapeutic unfractionated heparin in COVID‐19 patients: A retrospective cohort study date: 2021-05-07 journal: Res Pract Thromb Haemost DOI: 10.1002/rth2.12521 sha: 1d493d1840ada61dcfc4dea9bcaf9e8d65a41c45 doc_id: 970954 cord_uid: lxfl31ro BACKGROUND: Patients hospitalized with severe acute respiratory syndrome coronavirus 2 infection are at risk for thrombotic complications necessitating use of therapeutic unfractionated heparin (UFH). Full‐dose anticoagulation limits requirements for organ support interventions in moderately ill patients with coronavirus disease 2019 (COVID‐19). Given this benefit, it is important to evaluate response to therapeutic anticoagulation in this population. OBJECTIVES: The aim of this study was to assess therapeutic UFH infusions and associated bleeding risk in patients with COVID‐19. PATIENTS/METHODS: This retrospective cohort study includes patients at Brigham and Women’s Hospital, Boston, Massachusetts, receiving weight‐based nursing‐nomogram titrated UFH infusion during a 10‐week surge in COVID‐19 hospitalizations. Of 358 patients on therapeutic UFH during this interval, 97 (27.1%) had confirmed COVID‐19. Patient characteristics, laboratory values, and information regarding UFH infusion and bleeding events were obtained from the electronic medical record. RESULTS: Patients who were COVID‐19 positive had fewer therapeutic activatrd partial thromboplastin times (aPTTs) compared to COVID‐19–negative patients (median rate, 40.0% vs 53.1%; P < .0005). Both major and clinically relevant nonmajor bleeding were increased in COVID‐19–positive patients, with major bleeding observed in 10.3% (95% confidence interval [CI], 5.7%‐17.9%) of patients who were COVID‐19 positive and 3.1% (95% CI, 1.6%‐5.9%) of patients who were COVID‐19 negative (P < .005). In logistic regression, bleeding events were associated with receiving UFH for longer than 7 days, but not platelet count, coagulation, or inflammatory measurements. CONCLUSIONS: Our data indicate a higher incidence of bleeding complications in patients with COVID‐19 receiving weight‐based nursing‐nomogram titrated UFH infusions despite a higher prevalence of subtherapeutic aPTTs in this population. These data underscore the need for prospective studies aimed at improving the quality and safety of therapeutic anticoagulation in patients with COVID‐19. • Intravenous blood thinners may be required in patients with coronavirus disease 2019 (COVID- 19) who develop blood clots. • We evaluated 358 patients receiving blood thinners during the COVID-19 surge in our hospital. • Anticoagulant effect was often outside the therapeutic range in patients with COVID-19. • Bleeding typically occurred in the first 3 days of anticoagulation or after 7 days of treatment. Coronavirus disease 2019 , caused by the highly contagious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), manifests as acute respiratory illness and is linked to significant coagulopathy and thrombosis. [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] While a recent report suggested that patients with COVID- 19 have similar rates of thrombosis as patients with comparable degrees of severe illness and inflammation, 12 others have noted distinctions between coagulation profiles in COVID-19 and other severe pneumonias. 13 In addition to venous thromboembolic disease, autopsies have demonstrated diffuse microthrombi in lung vasculature, 14, 15 offering a possible explanation for the severely reduced lung compliance in COVID-19 compared to other viral pneumonias. 16 Early reports indicated a survival benefit with the use of prophylactic anticoagulation, 17 signaling an important contribution of thrombotic complications to COVID-19 mortality. It is hypothesized that hypercoagulability and enhanced thrombotic risk, reflected by a need for enhanced thromboprophylaxis, is related to a profound inflammatory syndrome in COVID-19 infections that underlies dramatic procoagulant profiles, 18, 19 presence of antiphospholipid antibodies, [20] [21] [22] complement activation, 23 hyperviscocity, 24 and enhanced endothelial activation by overexpression of tissue factor in platelets, monocytes, and macrophages. [25] [26] [27] As there is increased incidence of thromboembolic complications-some of which occur despite appropriately dosed thromboprophylaxis 5 clinical trial data has shown that full-dose anticoagulation may limit need for mechanical ventilator support in moderately ill patients with COVID-19, 28 evaluating whether this population has a typical response to heparin-based anticoagulation is important. Parenteral anticoagulation with heparins-both unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH)-have advantages over oral anticoagulants for in-hospital use due to fewer drug-drug interactions with antivirals and other therapeutics. While LMWH use obviates the need for frequent monitoring and dosing adjustments, UFH remains a common anticoagulant for treating thromboembolic disease in hospitalized patients. UFH is relatively inexpensive, can be used in renal impairment, and is the predominant agent used in critical care indications such as extracorporeal membrane oxygenation (ECMO) due to its short half-life and reversibility. 29 However, known challenges with therapeutic UFH infusions include significant interindividual dose-response variability 30 driven by differences in clot burden, degrees of inflammation, and the presence of antiphospholipid antibodies. Nursing-driven-nomogram dosing of UFH is superior to individual dosing but requires familiarity with and adherence to the nomogram parameters. 31 The ability to safely administer and monitor UFH infusions may be further compromised by reports of heparin resistance [32] [33] [34] in patients with COVID-19 as well as health system stresses during surges in COVID-19 hospitalizations. We evaluated the safety of UFH infusions during the 10-week surge in COVID-19 hospitalizations at our academic medical institution and report the real-world management and complications of weight-based nomogram titration of UFH infusions by nursing staff in hospitalized patients with and without COVID-19. This study was approved by the Institutional Review Board of Partners Healthcare. All patients with an active order for therapeutic UFH infusion between March 1, 2020, and May 15, 2020, were reviewed. bleeding, coronavirus, coronavirus 2019, COVID-19, SARS-CoV-2, therapeutic anticoagulation, thromboembolism, thrombosis, unfractionated heparin thrombosis (DVT) or pulmonary embolism (PE), we recorded whether the diagnosis was empiric or supported by radiographic confirmation. Patients received UFH infusion according to a weight-based nomogram titrated by nursing staff. 35 Our institutional protocol for therapeutic intensity or full-dose anticoagulation with UFH uses a goal activated partial thromboplastin time (aPTT) range of 60 to 80 seconds (1.5-2.0× baseline) based on our laboratory criteria. Low-intensity UFH infusions had a goal aPTT of 50 to 70 seconds and were used to treat acute coronary syndrome or when patients were deemed to have increased bleeding risk by providers, such as We used the Scientific and Standardization Committee of the ISTH criteria to classify patients who bled (identified from manual review of the EMR) while receiving an UFH infusion. Patients with suspected bleeding without an identified source were counted as having a bleeding event only if there was a documented drop in hemoglobin that was not explained by hemodilution or hemolysis. Major and clinically relevant nonmajor bleeding (CRNMB) was determined according to ISTH definitions. 36, 37 Clinical factors associated with the number of supratherapeutic aPTTs, length of time receiving UFH and degree of inflammation were hypothesized to be associated with bleeding, and we evaluated the association of these parameters with bleeding in patients with and without COVID-19. The data are displayed in forest plots as odds ratios and 95% confidence intervals. Among patients who were COVID-19 positive, we observed significantly higher baseline aPTT (P = .007) as well as marked elevations in d-dimer (P = .0002), fibrinogen (P < .0001) and C-reactive protein (CRP; P < 0.001) compared to patients who were COVID-19 negative. No difference was observed in baseline platelet count for patients who were COVID-19 positive and patients who were COVID-19 negative (Table 1 ). When analysis was restricted to include only the subset of patients in the ICU at the time of UFH initiation, d-dimer, fibrinogen, and CRP remained significantly higher in patients who were COVID-19 positive compared to patients who were COVID-19 negative (Table S1 ). UFH infusion indication and timing (hospital day on which infusion began) are summarized in Table 2 . UFH infusions were initiated later in the hospital course for patients who were COVID-19 positive Figure 2C ). We next evaluated whether patients in our cohort who had subtherapeutic index aPTT values could be classified as heparin resistant. Subtherapeutic index aPTT values were documented for 34 patients (9.5% of the total cohort). This included 12 patients who were COVID-19 positive (12.4%) and 21 patients who were COVID-19 negative (8.0%) (Table S2) A description of all bleeding events is provided in Table S3 negative (0.57 vs 0.34; P = 0.006; Figure 3B ). Patients who bled were more commonly in the ICU (100% of patients who were COVID-19 positive and 60% of patients who were COVID-19 negative with bleeding) and were predominantly receiving UFH for DVT/PE (Table S3 ). Importantly, significantly higher 15-day cumulative incidence was observed for patients who were COVID-19 positive compared to patients who were COVID-19 negative (0.65 vs 0.41; P = .01; were associated with the ECMO cannulation insertion site (Table S3) . We next evaluated clinical parameters associated with bleeding. Importantly, a higher incidence of bleeding was observed in patients who were COVID-19 positive even when patients receiving low-intensity heparin infusions were excluded from the analysis. We hypothesized that a higher percentage of supratherapeutic aPTT values, a longer time exposed to heparin, and higher levels of systemic inflammation would be associated with bleeding while patients were receiving UFH infusion. In multivariable regression analysis, stratified by COVID-19 status and adjusted for age and patient location (ICU vs floor) as a proxy for illness severity, we observed that bleeding was associated with receiving UFH for >7 days in both patients who were COVID-19 positive and patients who were COVID-19 negative (Figure 4 and Table S5 ). Interestingly, CRP values >100 mg/L were not associated with bleeding in patients who were COVID-19 positive or patients who were COVID-19 negative, and having ≥60% supratherapeutic aPTT values was associated with bleeding in patients who were COVID-19 negative but not patients who were COVID-19 positive (Figure 4 and Table S5 ). Upon further review, all patients who were COVID-19 positive who bled were documented as having therapeutic-range aPTTs at the time of bleeding (Table S4 ) and only 1 of the patients who were 20 COVID-19 positive with ≥60% supratherapeutic aPTT values bled. We observed similar associations in multivariable regression analysis restricted to only ICU patients stratified by COVID-19 status (Table S5) . positive and the 1 patient tested who was COVID-19 negative. Anti-Xa levels were used for UFH monitoring in 24 (9.3%) of 358 patients in our cohort, including 6 patients who were COVID-19 positive and 3 patients who were COVID-19 negative with >60% supratherapeutic aPTTs (Table S6 ). In this retrospective analysis of therapeutic anticoagulation in patients receiving weight-based nursing-nomogram titrated UFH infusions, we report our observation of high incidence of bleeding and atypical difficulty using aPTT monitoring to titrate UFH in patients who were COVID-19 positive. Patients who were COVID-19 positive were infrequently within goal range for aPTT. The correlation between aPTT, UFH concentration, and antithrombotic effect may be less reliable in the context of COVID-19 infection. 19, 27, 38, 39 Our data indicate a mild increase in Patients who were COVID-19 positive bled in the absence of thrombocytopenia, hypofibrinogenemia, or DIC, contrary to earlier reports 17 but consistent with recent data. 12 Bleeding was not explained by supratherapeutic aPTT in patients who were COVID-19 positive, but was in patients who were COVID-19 negative. We do not interpret our data to suggest that prolonged aPTT is in any way protective against bleeding in COVID-19 infection. Rather, these data add credence to the unreliability of aPTT as a marker for bleeding risk in this population. Before COVID-19, reports indicated that a number of bleeding events may occur in the absence of critically high aPTT values. 50 Moreover, use of LMWH rather than UFH may decrease bleeding risk due to predictable pharmacologic doseresponse properties 51 and a direct comparison of bleeding complications using full-dose LMWH and UFH in patients with COVID-19 is warranted. Interim reports of clinical trials evaluating full-dose anticoagulation with heparin/LMWH compared to prophylaxis in patients with COVID-19 offer conflicting results. In moderately ill patients, full-dose heparin/LMWH was superior to prophylactic dose with a higher number of days free of organ support. However, in severely ill ICU patients, full-dose heparin/LMWH met predefined futility criteria, although there were fewer thrombotic events with the intervention in a secondary analysis. 28 Further results from these trials are needed to know how to apply this information to patients; however, management of therapeutic-dose UFH will not change. Two major bleeding events observed in patients who were COVID-19 positive and Pfizer, and research funding to her institution from CSL Behring. 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