Pharmacological Agents Targeting Coagulopathy in COVID-19: A Review

Infection with severe acute respiratory syndrome coronavirus (SARS-CoV-2) and the resultant syndrome COVID-19 has wrecked the entire world. The disease mostly manifests as mild viral pneumonia but in a small proportion of patients it can produce an intense inflammatory and prothrombotic state leading to multiorgan failure and even death. Varying incidences of venous thromboembolism (VTE) have been found in COVID-19 patients. This review describes the role of various pharmacological agents used prophylactically as well as therapeutically for thromboembolism in such patients. The anticoagulants which are administered as antithrombotic therapy can be used parenterally (heparin and direct thrombin inhibitors) or orally (direct oral thrombin inhibitors). The mechanism of action, pharmacology, usage, and adverse effects of such agents has been discussed especially in the context of ongoing COVID-19 pandemic. As a result of various completed and ongoing clinical trials, scientific community has collected promising evidence and formulated guidelines regarding the role of anticoagulants in COVID-19 patients. © The Author(s), under exclusive licence to Springer Nature Singapore Pte Ltd. 2021.

Real-World Management of Pharmacological Thromboprophylactic Strategies for COVID-19 Patients in Japan: From the CLOT-COVID Study.

Background: Data on prophylactic anticoagulation are important in understanding the current issues, unmet needs, and optimal management of Japanese COVID-19 patients. Objectives: This study aimed to investigate the clinical management strategies for prophylactic anticoagulation of COVID-19 patients in Japan. Methods: The CLOT-COVID study was a multicenter observational study that enrolled 2,894 consecutive hospitalized patients with COVID-19. The study population consisted of 2,889 patients (after excluding 5 patients with missing data); it was divided into 2 groups: patients with pharmacological thromboprophylaxis (n = 1,240) and those without (n = 1,649). Furthermore, we evaluated the 1,233 patients who received prophylactic anticoagulation-excluding 7 patients who could not be classified based on the intensity of their anticoagulants-who were then divided into 2 groups: patients receiving prophylactic anticoagulant doses (n = 889) and therapeutic anticoagulant doses (n = 344). Results: The most common pharmacological thromboprophylaxis anticoagulant was unfractionated heparin (68.2%). The severity of COVID-19 at admission was a predictor of the implementation of pharmacological thromboprophylaxis in the multivariable analysis (moderate vs mild: OR: 16.6; 95% CI:13.2-21.0; P < 0.001, severe vs mild: OR: 342.6, 95% CI: 107.7-1090.2; P < 0.001). It was also a predictor of the usage of anticoagulants of therapeutic doses in the multivariable analysis (moderate vs mild: OR: 2.10; 95% CI: 1.46-3.02; P < 0.001, severe vs mild: OR: 5.96; 95% CI: 3.91-9.09; P < 0.001). Conclusions: In the current real-world Japanese registry, pharmacological thromboprophylaxis, especially anticoagulants at therapeutic doses, was selectively implemented in COVID-19 patients with comorbidities and severe COVID-19 status at admission.

Retrospective study of COVID patients diagnosed with VTE

Background: We found that the number of patients diagnosed with PE following COVID began to increase so we wanted to study the trend and triggers In a recent review of our COVID-19 admissions, the incidence of VTE in patients with SARSCoV-2 was 34.5% in imaged patients (119 patients had CT pulmonary angiograms, and 41patients had identified pulmonary thromboembolism (Barnet Hospital, unpublished data, 2020 Kumar el at 2020). Aim(s): To review the number of patients referred to the clinic before and present, make a comparison of number of VTEs before and during COVID pandemic Methods: Retrospective cohort study was conducted from Jan until June 2020. All patients who have confirmed as COVID with VTE were included, suspected COVID were excluded from the study The anticoagulation team all uploaded information to excel and this was analysed and report produced Results: A total of 657 patients were referred to the anticoagulation clinic between Jan to June 2020 Out of them 184 had VTE out of that number 32 were identified as COVID 19. DOAC drug prescribed Total number 32 Apixaban 5 mg BD 20 Rivaroxaban 20 mg 8 Dabigatran 150 mg 0 Edoxaban 60 mg OD 0 LMWH 3 Conclusion(s): Conclusion(s): Most patients did not have any issues related to the VTE but they were still recovering as a result of COVID. They reported feeling tired, short of breath and weak. These are not the usual symptoms reported by VTE patients apart from PE patients We treated them for duration of three months but if these patients were not fully mobile or had on going symptoms we plan to continue the therapy for a total of six months.

Lung perfusion assessed by SPECT/CT after a minimum of three months anticoagulation therapy in patients with SARS-CoV-2-associated acute pulmonary embolism: a retrospective observational study.

BACKGROUND: Anticoagulant treatment is recommended for at least three months after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related acute pulmonary embolism (PE), but the persistent pulmonary clot burden after that time is unknown. METHODS: Lung perfusion was assessed by ventilation-perfusion (V/Q) SPECT/CT in 20 consecutive patients with SARS-CoV-2-associated acute PE after a minimum of three months anticoagulation therapy in a retrospective observational study. RESULTS: Remaining perfusion defects after a median treatment period of six months were observed in only two patients. All patients (13 men, seven women, mean age 55.6 ± 14.5 years) were on non-vitamin K direct oral anticoagulants (DOACs). No recurrent venous thromboembolism or anticoagulant-related bleeding complications were observed. Among patients with partial clinical recovery, high-risk PE and persistent pulmonary infiltrates were significantly more frequent (p < 0.001, respectively). INTERPRETATION: Temporary DOAC treatment seems to be safe and efficacious for resolving pulmonary clot burden in SARS-CoV-2-associated acute PE. Partial clinical recovery is more likely caused by prolonged SARS-CoV-2-related parenchymal lung damage rather than by persistent pulmonary perfusion defects.

Impact of a Pharmacist-Led Warfarin to Direct Oral Anticoagulant Conversion Initiative during the COVID-19 Pandemic.

Purpose: To assess the impact of a pharmacist-led warfarin to DOAC conversion initiative during the COVID-19 pandemic. Methods: Patients who were prescribed warfarin and followed with the anticoagulation clinic for INR monitoring were assessed by outpatient clinical pharmacists as potential candidates for transition to DOACs from March-August 2020. Results: 530 patients were assessed for transition to DOACs, of which 373 (70.4%) were deemed by clinical pharmacists to be candidates for DOACs. Of the patients who were candidates for DOACs, 66 (17.7%) were transitioned from warfarin to a DOAC. Of the patients who transitioned to a DOAC, 59 (89.4%) remained on a DOAC after one year. Conclusion: Outpatient clinical pharmacists are an effective resource to help identify patients who are candidates for DOACs and assist with transition from warfarin. Further, high persistence rates with DOAC therapy after one year demonstrate the positive impact of the clinical pharmacist on medication adherence.

A Case of Renal Vein Thrombosis Associated With COVID-19 Treated With Rivaroxaban.

Renal vein thrombosis (RVT) is a rare form of deep venous thrombosis. It usually involves one or both renal veins and one of their branches. Most cases were reported in patients with nephrotic syndrome or inherited hypercoagulability syndromes. RVT can present with flank pain, hematuria, and acute kidney injury but can also present asymptomatically and be incidentally discovered on abdominal or renal imaging. The management of RVT is usually with warfarin for at least six to 12 months and periodically is continued if the patient is in the nephrotic range. Direct-acting oral anticoagulants (DOACs) have not been well studied in cases of RVT, especially in patients with coronavirus disease 2019 (COVID-19). We present a case of RVT in the setting of COVID-19 that was treated successfully with a DOAC, rivaroxaban, with complete resolution of the thrombus.

Antiphospholipid antibodies: what is new in 2022 / Détection des anticorps antiphospholipides : actualités en 2022

Antiphospholipid syndrome (APS) is a clinicobiological entity defined by the association of thrombotic events and/or obstetric complications and the presence of persistent antiphospholipid antibodies (aPLs) detected by coagulation tests (lupus anticoagulant, LAC) and/or immunological assays (anticardiolipin and anti-glycoprotein-beta-I antibodies). The increased use of direct oral anticoagulants (DOAC) for the treatment of venous thromboembolism (VTE) is now a challenge for hematology laboratories for the diagnosis of APS. DOAC interfere with LAC screening and confirmation tests resulting in a risk of false positive results. To avoid these interferences, several solutions are suggested. Some of them rely on the use of DOAC-reversal systems (activated charcoal tablet, filter system) others on the use of reagents insensitive to DOAC presence in the sample. Detection of anti-phosphatidylserine/prothrombin antibodies may be helpful because they are strongly associated to the presence of LAC and are increasingly recognized as a useful tool in the diagnosis and prognosis of APS. Finally, positivity of LA in the setting of a viral infection is frequent and not specific to APS. During the Covid-19 pandemic, many patients developed arterial and VTE that could suggest testing for aPLs. The association between LAC and a risk of VTE or in-hospital mortality in hospitalized Covid-19 patients was not demonstrated. Moreover, aPLs do not persist after Covid-19. Currently, testing for aPLs in Covid-19 patients is not recommended.

Le syndrome des antiphospholipides (SAPL) est une entité clinico-biologique définie par l'association de manifestations thrombotiques et/ou de complications obstétricales et la présence persistante d'anticorps antiphospholipides (aPLs) détectés par des tests de coagulation (lupus anticoagulant, LA) et/ou par des tests immunologiques (anticorps anti-cardiolipine et anticorps anti-ß2-glycoprotéine-I). L'essor des anticoagulants oraux directs (AOD) dans la prise en charge des évènements thrombotiques veineux (ETV) constitue aujourd'hui un défi pour les laboratoires d'hémostase dans le cadre du diagnostic du SAPL. Les AOD interfèrent avec les tests de dépistage et de confirmation du LA occasionnant des faux positifs. Afin de se soustraire à ces interférences plusieurs solutions sont proposées. Certaines reposent sur l'utilisation de système neutralisant l'AOD (pastille de charbon activé, système de filtre) d'autres sur l'utilisation de réactifs insensibles à la présence d'AOD. On peut également faire appel aux anticorps anti-phosphatidylsérine/prothrombine très corrélés à la présence de LA et constituant un outil de plus en plus reconnu dans le diagnostic biologique du SAPL et son pronostic. Enfin, la positivité des aPLs dans un contexte infectieux est fréquente et non spécifique du SAPL. Au cours de la pandémie Covid-19, de nombreux patients ont présentés des ETV et artériels qui ont pu motiver la recherche d'aPLs. L'association entre LA et le risque d'ETV ou la mortalité hospitalière chez les patients Covid-19 hospitalisés n'a pas été démontrée. De plus, il ne semble pas qu'il y ait de persistance de ces aPLs après la Covid-19. A ce jour, la recherche d'aPLs chez les patients atteint de Covid-19 n'est pas recommandée.

Impact of pharmacist intervention on anticoagulation management and risk for potential COVID-19 exposure during the COVID-19 pandemic.

INTRODUCTION: Patients taking warfarin require frequent international normalized ratio (INR) monitoring in healthcare settings, putting them at increased risk of Coronavirus disease 2019 (COVID-19) exposure during the pandemic. Thus, strategies to limit in-person visits to healthcare facilities were recommended by the Anticoagulation Forum. The objective of this study was to describe the number and types of changes made to anticoagulation therapy as a result of pharmacist intervention during the COVID-19 pandemic. MATERIALS AND METHODS: A retrospective chart review of patients included in a primary care COVID-19 anticoagulation intervention was conducted. During this intervention, pharmacists provided individualized recommendations for anticoagulation changes in patients taking warfarin to limit their healthcare facility exposure while also maintaining safe anticoagulation management practices. RESULTS: As a result of pharmacist intervention, 83 (55.7 %) of the 149 patients included in the intervention had changes in anticoagulation including: switching to a direct oral anticoagulant (n = 12), extending the INR monitoring interval (n = 48), switching to home INR monitoring (n = 21), or stopping anticoagulation (n = 2). For those patients who were taking warfarin for the entire 6 months pre- and post-intervention, the total number of healthcare facility and laboratory visits with an INR completed decreased from 8.8 to 6.4 (p < 0.001) per patient without a statistically significant decrease in time in therapeutic range (p = 0.76). CONCLUSIONS: This study depicts rapid implementation of a population health-based approach to assess all patients taking warfarin for options to minimize healthcare visits and decrease risk for COVID-19 exposure. Methods to reduce healthcare visit burden while maintaining patient safety should be considered as a regular component of anticoagulation management post-pandemic.

Clinically Ambiguous Hemorrhagic Cardiac Tamponade Associated with Apixaban.

Hemorrhagic cardiac tamponade in the setting of direct oral anticoagulants (DOACs) is rare but life-threatening. Presentation in subacute cases can also be nonspecific, which can potentially delay diagnosis. A 60-year-old female with a history of heart failure and chronic obstructive pulmonary disease presented with shortness of breath, chest pain, and cough while on treatment with apixaban after a recent hospitalization for pulmonary embolism. Clinical presentation was consistent with multiple diagnoses, including pneumonia and heart failure exacerbation. However, there were several risk factors for hemopericardium with DOACs such as elevated creatinine, hypertension, elevated international normalized ratio (INR), and concomitant use of medications with similar metabolic pathways as apixaban. In addition, subtle findings on examination such as oximetry paradoxus and electrical alternans were crucial for an early diagnosis and management. In this case, we discuss key characteristics of hemopericardium with DOACs, as well as considerations on its management.

The Effect of Direct Oral Anti-Coagulants on Delayed Traumatic Intracranial Hemorrhage After Mild Traumatic Brain Injury: A Systematic Review.

BACKGROUND: The use of anticoagulant medications leads to a higher risk of developing traumatic intracranial hemorrhage (tICH) after a mild traumatic brain injury (mTBI). The management of anticoagulated patients can be difficult to determine when the initial head computed tomography is negative for tICH. There has been limited research on the risk of delayed tICH in patients taking direct oral anticoagulant (DOAC) medications. OBJECTIVE: Our aim was to determine the risk of delayed tICH for patients anticoagulated with DOACs after mTBI. METHODS: We conducted a systematic review using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and searched several medical databases to examine the risk of delayed tICH in patients on DOACs. RESULTS: There were 1252 nonduplicate studies that were identified through an initial database search, 15 of which met our inclusion and exclusion criteria and were included in our analysis after full-text review. A total of 1375 subjects were combined among the 15 studies, with 20 instances of delayed tICH after mTBI. Nineteen of the 20 patients with a delayed tICH were discharged without any neurosurgical intervention, and 1 patient on apixaban died due to a delayed tICH. CONCLUSIONS: This systematic review confirms that delayed tICH after mTBI in patients on DOACs is uncommon. However, large, multicenter, prospective studies are needed to confirm the true incidence of clinically significant delayed tICH after DOAC use. Due to the limited data, we recommend using shared decision-making for patients who are candidates for discharge.

Outpatient and inpatient anticoagulation therapy and the risk for hospital admission and death among COVID-19 patients.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is associated with a hypercoagulable state. Limited data exist informing the relationship between anticoagulation therapy and risk for COVID-19 related hospitalization and mortality. METHODS: We evaluated all patients over the age of 18 diagnosed with COVID-19 in a prospective cohort study from March 4th to August 27th, 2020 among 12 hospitals and 60 clinics of M Health Fairview system (USA). We investigated the relationship between (1) 90-day anticoagulation therapy among outpatients before COVID-19 diagnosis and the risk for hospitalization and mortality and (2) Inpatient anticoagulation therapy and mortality risk. FINDINGS: Of 6195 patients, 598 were immediately hospitalized and 5597 were treated as outpatients. The overall case-fatality rate was 2•8% (n = 175 deaths). Among the patients who were hospitalized, the inpatient mortality was 13%. Among the 5597 COVID-19 patients initially treated as outpatients, 160 (2.9%) were on anticoagulation and 331 were eventually hospitalized (5.9%). In a multivariable analysis, outpatient anticoagulation use was associated with a 43% reduction in risk for hospital admission, HR (95% CI = 0.57, 0.38-0.86), p = 0.007, but was not associated with mortality, HR (95% CI=0.88, 0.50 - 1.52), p = 0.64. Inpatients who were not on anticoagulation (before or after hospitalization) had an increased risk for mortality, HR (95% CI = 2.26, 1.17-4.37), p = 0.015. INTERPRETATION: Outpatients with COVID-19 who were on outpatient anticoagulation at the time of diagnosis experienced a 43% reduced risk of hospitalization. Failure to initiate anticoagulation upon hospitalization or maintaining outpatient anticoagulation in hospitalized COVID-19 patients was associated with increased mortality risk. FUNDING: No funding was obtained for this study.

Implementation of warfarin to direct oral anticoagulant conversion initiative in pharmacist-run anticoagulation clinics during COVID-19 pandemic.

Due to community transmission of coronavirus disease 2019 (COVID-19), social distancing and stay-at-home orders were implemented statewide in an effort to limit the spread of disease. This posed unique challenges for patients on medications requiring close and continued monitoring by clinic staff, such as anticoagulation clinics. Thus, innovative measures were implemented at Cleveland Clinic Health System (CCHS) to maintain the health and care of ambulatory patients. An initiative to evaluate patients for warfarin to direct oral anticoagulants (DOAC) conversion was used in the pharmacist-run anticoagulation clinics. This article describes how patients were screened for eligibility, the education to pharmacists, the utilization of student learners in the process, and the workflow for provider notification of conversion. Follow up monitoring, challenges encountered, and future directions are also described.

The use of direct acting oral anticoagulants in patients with COVID-19 infection.

The use of direct-acting oral anticoagulants (DOACs) has increased rapidly in the last decade; becoming the mainstay for both the prophylaxis and the treatment of venous thromboembolism in various situations including non-valvular atrial fibrillation, joint replacement surgeries and acute DVT/PE, etc. In the present times, DOACs are possibly one of the most widely prescribed medications in the developed world. The worldwide epidemic caused by COVID-19 caused significant changes in the practice of medicine worldwide. Patients who developed severe respiratory illness caused by COVID-19 were noted to develop a wide range of complications, including both arterial and venous thromboembolic complications including deep vein thrombosis and pulmonary embolism, etc. This review is an attempt to identify the role of DOACs in the treatment and prevention of these complications as well as the safety of continuing therapy with DOACs in the patients who were receiving them before contracting the infection.

Review of Medical Therapies for the Management of Pulmonary Embolism.

Traditionally, the management of patients with pulmonary embolism has been accomplished with anticoagulant treatment with parenteral heparins and oral vitamin K antagonists. Although the administration of heparins and oral vitamin K antagonists still plays a role in pulmonary embolism management, the use of these therapies are limited due to other options now available. This is due to their toxicity profile, clearance limitations, and many interactions with other medications and nutrients. The emergence of direct oral anticoagulation therapies has led to more options now being available to manage pulmonary embolism in inpatient and outpatient settings conveniently. These oral therapeutic options have opened up opportunities for safe and effective pulmonary embolism management, as more evidence and research is now available about reversal agents and monitoring parameters. The evolution of the pharmacological management of pulmonary embolism has provided us with better understanding regarding the selection of anticoagulants. There is also a better understanding and employment of anticoagulants in pulmonary embolism in special populations, such as patients with liver failure, renal failure, malignancy, and COVID-19.

How to Build the Plane While Flying: VTE/PE Thromboprophylaxis Clinical Guidelines for COVID-19 Patients.

Over the years, the practice of medicine has evolved from authority-based to experience-based to evidence-based with the introduction of the scientific process, clinical trials, and outcomes-based data analysis (Tebala GD. Int J Med Sci. 2018;15(12):1397-1405). The time required to perform the necessary randomized controlled trials, a systematic literature review, and meta-analysis of these trials to then create, accept, promulgate, and educate the practicing clinicians to use the evidence-based clinical guidelines is typically measured in years. When the severe acute respiratory syndrome novel coronavirus-2 (SARS-nCoV-2) pandemic commenced in Wuhan, China at the end of 2019, there were few available clinical guidelines to deploy, let alone adapt and adopt to treat the surge of coronavirus disease 2019 (COVID-19) patients. The aim of this study is to first explain how clinical guidelines, on which bedside clinicians have grown accustomed, can be created in the midst of a pandemic, with an evolving scientific understanding of the pathophysiology of the hypercoagulable state. The second is to adapt and adopt current venous thromboembolism diagnostic and treatment guidelines, while relying on the limited available observational reporting of COVID-19 patients to create a comprehensive clinical guideline to treat COVID-19 patients.

Reduction in all-cause mortality in COVID-19 patients on chronic oral anticoagulation: A population-based propensity score matched study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) global pandemic has strikingly high mortality rate with hypercoagulability state being part of the imputed mechanisms. We aimed to compare the rates of in hospital mortality in propensity score matched cohorts of COVID-19 patients in chronic anticoagulation versus those that were not. METHODS: In this population-based study in the Veneto Region, we retrospectively reviewed all patients aged 65 years or older, with a laboratory-confirmed COVID-19 diagnosis. We compared, after propensity score matching, those who received chronic anticoagulation for atrial fibrillation with those who did not. RESULTS: Overall, 4697 COVID-19 patients fulfilled inclusion criteria, and the propensity score matching yielded 559 patients per arm. All-cause mortality rate ratio was significantly higher among non-anticoagulated patients (32.2% vs 26.5%, p = 0.036). On time to event analysis, all-cause mortality was found lower among anticoagulated patients, although the estimate was not statistically significant. (HR 0.81, 95%CI 0.65-1.01, p = 0.054). CONCLUSION: Among elderly patients with COVID-19, those on chronic oral anticoagulant treatment for atrial fibrillation seem to be at lower risk of all-cause mortality compared to their propensity score matched non-anticoagulated counterpart. This finding needs to be confirmed in further studies.

Anticoagulation Options for Coronavirus Disease 2019 (COVID-19)-Induced Coagulopathy.

As the coronavirus disease 2019 (COVID-19) pandemic is evolving, coagulopathy induced by the disease and its severe complications are raising concerns in the medical community. Because coagulopathy caused by COVID-19 has been difficult to control, it is important to have a better understanding of what therapies have been studied thus far and what therapies have demonstrated better outcomes for hospitalized patients. This review is focused on literature, research, and expert clinical judgments published in 2020 with a few references to articles published earlier. The review introduces the interim guidelines of the International Society of Thrombosis and Haemostasis (ISTH) for management of COVID-19-induced coagulopathy, discusses the efficacy of these guidelines in clinical settings, and summarizes the response of the scientific community to these guidelines and their clinical implications. Due to the failure of patients to respond to the prophylactic doses of heparin recommended by ISTH, higher doses of heparin may be necessary to achieve adequate anticoagulation. Patients' resistance to prophylactic doses of heparin could be due to low levels of anti-thrombin and high levels of fibrinogen, which would reinforce the use of therapeutic doses of heparin in the early stages of hospitalization. The review also compares low-molecular-weight heparin (LMWH) and unfractionated heparin (UFH) as anticoagulant choices for COVID-19 patients. Given the complications specific to COVID-19, UFH may be a better choice of anticoagulant. Outpatient anticoagulation options are also reviewed. Changing qualified patients from vitamin K antagonists (VKA) to direct-acting oral anticoagulant (DOAC) for the convenience of less frequent monitoring may be appropriate. New anticoagulant, nafamostat, used in Japan is also discussed as a possible potentiate for heparin therapy.

Managing anticoagulation in the COVID-19 era between lockdown and reopening phases.

Patients on anticoagulant treatment are constantly increasing, with an estimated prevalence in Italy of 2% of the total population. The recent spreadout of the COVID-19 pandemic requires a re-organization of Anticoagulation Clinics to prevent person-to-person viral diffusion and continue to offer the highest possible quality of assistance to patients. In this paper, based on the Italian Federation of Anticoagulation Clinics statements, we offer some advice aimed at improving patient care during COVID-19 pandemic, with particular regard to the lockdown and reopening periods. We give practical guidance regarding the following points: (1) re-thinking the AC organization, (2) managing patients on anticoagulants when they become infected by the virus, (3) managing anticoagulation surveillance in non-infected patients during the lockdown period, and (4) organizing the activities during the reopening phases.

Direct oral anticoagulant plasma levels' striking increase in severe COVID-19 respiratory syndrome patients treated with antiviral agents: The Cremona experience.

BACKGROUND: Antiviral drugs are administered in patients with severe COVID-19 respiratory syndrome, including those treated with direct oral anticoagulants (DOACs). Concomitant administration of antiviral agents has the potential to increase their plasma concentration. A series of patients managed in the Cremona Thrombosis Center were admitted at Cremona Hospital for SARS-CoV-2 and started antiviral drugs without stopping DOAC therapy. DOAC plasma levels were measured in hospital and results compared with those recorded before hospitalization. METHODS: All consecutive patients on DOACs were candidates for administration of antiviral agents (lopinavir, ritonavir, or darunavir). Plasma samples for DOAC measurement were collected 2to 4 days after starting antiviral treatment, at 12 hours from the last dose intake in patients on dabigatran and apixaban, and at 24 hours in those on rivaroxaban and edoxaban. For each patient, C-trough DOAC level, expressed as ng/mL, was compared with the one measured before hospitalization. RESULTS: Of the 1039 patients hospitalized between February 22 and March 15, 2020 with COVID-19 pneumonia and candidates for antiviral therapy, 32 were on treatment with a DOAC. DOAC was stopped in 20 and continued in the remaining 12. On average, C-trough levels were 6.14 times higher during hospitalization than in the pre-hospitalization period. CONCLUSION: DOAC patients treated with antiviral drugs show an alarming increase in DOAC plasma levels. In order to prevent bleeding complications, we believe that physicians should consider withholding DOACs from patients with SARS-CoV-2 and replacing them with alternative parenteral antithrombotic strategies for as long as antiviral agents are deemed necessary and until discharge.

Switch from oral anticoagulants to parenteral heparin in SARS-CoV-2 hospitalized patients.

The development of COVID-19 syndrome in anticoagulated patients, and especially their admission to intensive-care units with acute severe respiratory syndrome (SARS-CoV-2), expose them to specific problems related to their therapy, in addition to those associated with the acute viral infection. Patients on VKA hospitalized with SARS-CoV-2 show high instability of PT INR due to the variability of vitamin K metabolism, diet, fasting, co-medications, liver impairment, and heart failure. Patients on DOAC are exposed to under/over treatment caused by significant pharmacological interferences. In consideration of the pharmacological characteristics of oral anticoagulant drugs, the multiple pharmacological interactions due to the treatment of acute disease and the possible necessity of mechanical ventilation with hospitalization in intensive-care units, we suggest replacing oral anticoagulant therapies (VKA and DOAC) with parenteral heparin to avoid the risk of over/under treatment.