key: cord-0904739-4gjg9a7v authors: Lawlor, Matthew; Gupta, Aakriti; Ranard, Lauren S.; Madhavan, Mahesh V.; Li, Jianhua; Eisenberger, Andrew; Parikh, Sahil A.; Sethi, Sanjum S.; Masoumi, Amirali title: Discordance In Activated Partial Thromboplastin Time and Anti-factor Xa Levels in COVID-19 Patients on Heparin Therapy date: 2020-11-28 journal: Thromb Res DOI: 10.1016/j.thromres.2020.11.030 sha: d8fc7393b5406f2f9123640b1659e1e8d4621beb doc_id: 904739 cord_uid: 4gjg9a7v • Activated partial thromboplastin time correlates poorly with anti-factor Xa assay in COVID-19 patients receiving intravenous unfractionated heparin. • Activated partial thromboplastin potentially underestimates heparin activity compared with anti-factor Xa in COVID-19 patients receiving intravenous unfractionated heparin. • Elevated fibrinogen levels did not correlate with refractory activated partial thromboplastin time in COVID-19 patients. Abnormal coagulation parameters, including prothrombin time, D-dimer, and fibrinogen degradation products, are common in coronavirus disease 2019 (COVID-19) and are associated with poor outcomes. 1, 2 Moreover, thrombotic complications are common in COVID-19 [2] [3] [4] [5] , often resulting in the use of systemic anticoagulation such as intravenous unfractionated heparin (UFH), which requires frequent monitoring and dose adjustment often guided by activated partial thromboplastin time (aPTT) levels. In addition, perturbation of the aPTT has been shown to be common in this population, with aPTT prolongation frequently associated with lupus anticoagulant and decrease in the assay seen with elevated levels of fibrinogen and factor VIII 6, 7 , making aPTT guided UFH dose adjustment particularly challenging in patients with COVID-19. Anti-factor Xa, a functional assay that facilitates the measurement of antithrombin (AT)catalyzed inhibition of factor Xa by unfractionated heparin (UFH), is used to guide the determination of therapeutic APTT ranges in the clinical management of UFH. 8 Previous studies in non-COVID hospitalized patients have shown moderate correlation between aPTT levels and anti-Xa levels. [9] [10] [11] Here, we examined the correlation of aPTT and anti-Xa assays in patients with COVID-19 receiving intravenous UFH. Patients with COVID-19 were retrospectively identified in the electronic medical record by means of positive SARS-CoV-2 RT-PCR assay codes at the NewYork-Presbyterian Hospital/Columbia University Irving Medical Center between March 18, 2020 and April 25, 2020 through the institution's clinical data warehouse. This study was conducted with approval from the Institutional Review Board. A total of 88 consecutive adult patients aged 18 years and older with COVID-19 who received therapeutic intravenous UFH, and in whom aPTT and anti-Xa were simultaneously measured yielding 579 paired observations. Baseline characteristics, medications, indication for anticoagulation, laboratory parameters, and intensive care unit utilization were automatedly extracted from the electronic health record. Simultaneous anti-Xa and aPTT measurements were abstracted by manual chart review. aPTT and anti-Xa assay reagents were manufactured by Stago Diagnostica, Inc., Parsippany, New Jersey. The standard of care for monitoring heparin activity in our hospital via aPTT assay unless patient has abnormal aPTT at baseline or documented antiphospholipid syndrome, in which case anti-Xa assay is preferred. Therapeutic range for aPTT is 80 to 121 seconds and 0.3 to 0.7 IU/ml for anti-Xa level in our hematology lab. Results were plotted on a scatterplot (X-axis, anti-Xa; Y-axis, aPTT) and linear regression analysis was performed. The best-fit line and its correlation coefficient (R 2 value) were calculated. Each paired observation was classified as subtherapeutic, therapeutic, and supratherapeutic. Statistical analysis was performed using R version 3.5.1. Medical Center. AG performed data analysis and all authors had access to the primary data. Original data will be made available upon request to the corresponding author. Our study included high-acuity patients, a large majority of whom had abnormal baseline coagulation parameters, elevated inflammatory biomarkers, and elevated cardiac biomarkers, and required admission to the intensive care unit. Linear regression modeling in this patient population reveals poor correlation between the aPTT and anti-Xa levels in patients treated with intravenous UFH. Historical comparison with non-COVID-19 patients receiving intravenous UFH has shown moderate correlation between these two assays (R 2 =0.46 reported by Byun et al) [9] [10] [11] , suggesting diminished aPTT reliability in COVID-19 patients, in particular. Discordance between the therapeutic strata of the two assays suggest that the aPTT underestimated heparin activity compared with anti-Xa assay in a majority of discordant observations. Previous data have shown high fibrinogen associated with apparent heparin resistance; though in this study the aPTT appears refractory to the degree of heparin activity demonstrated by the anti-Xa assay, this correlation was not found in our data. Importantly, corresponding fibrinogen levels were drawn within 24 hours and not necessarily concomitantly with aPTT and anti-Xa, which limit this evaluation. In conclusion, our study suggests that there is poor correlation of anti-Xa and aPTT in patients with COVID-19 receiving intravenous UFH, and aPTT alone may be an unreliable measure of heparin activity. COVID-19 patients have a complex coagulopathy, with dysregulated components that can either shorten or prolong the aPTT, reducing its reliability. Additional research may prospectively explore the utility of measuring fibrinogen, Factor VIII activity and lupus anticoagulant in conjunction with the aPTT and anti-Xa in order to more accurately assess heparin activity to guide therapeutic anticoagulation in COVID-19 patients This study was partially supported by an American Heart Association (AHA) COVID-19 Rapid Response Award (grant number pending).. Dr. Madhavan has received support from an institutional grant by the National Institutes of Health/National Heart, Lung, and Blood Institute to Columbia University Irving Medical Center (T32 HL007854). Dr. Parikh reports institutional research support from Abbott Vascular, J o u r n a l P r e -p r o o f Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-up High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients Lupus Anticoagulant and Abnormal Coagulation Tests in Patients with Covid-19 Thromboembolic events and apparent heparin resistance in patients infected with SARS-CoV-2 Anti-factor Xa (anti-Xa) assay Establishing the heparin therapeutic range using aPTT and anti-Xa measurements for monitoring unfractionated heparin therapy Performance of Anti-Factor Xa Versus Activated Partial Thromboplastin Time for Heparin Monitoring Using Multiple Nomograms Antifactor Xa levels vs. activated partial thromboplastin time for monitoring unfractionated heparin. A pilot study