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What is the preferred therapy and duration for the treatment of acute VTE in COVID-19 patients? Any correlations between COVID-19 associated antiphospholipid antibodies (aPL) and thrombosis risk?

Comment by InpharmD Researcher

For acute VTE management in patients with COVID-19, LMWH has some advantages in the inpatient setting, whereas the DOACs may be preferred in the post-hospital discharge setting due to the ease of use over parenteral anticoagulation and a lack of routine INR monitoring over vitamin K antagonists thus minimizing healthcare worker exposure to potential COVID-19 infection. The recommended duration of anticoagulation therapy for COVID-19 patients with proximal DVT or PE is a minimum of three months. To date, the real prevalence of aPL among COVID-19 patients remains unknown. Whether a transient elevation of aPL noted especially in critically ill COVID-19 patients persists and poses a further thrombosis risk is unknown.
Background

According to the CHEST guidelines and expert panel report on prevention, diagnosis, and treatment of VTE in patients with COVID-19, the initial parenteral anticoagulation with therapeutic weight-adjusted low molecular weight heparin (LMWH) or intravenous (IV) unfractionated heparin (UFH) is recommended for acutely ill hospitalized COVID-19 patients with proximal deep vein thrombosis (DVT) or pulmonary embolism (PE). LMWH or UFH is preferred over oral anticoagulants due to the shorter half-lives, parenteral administration, and fewer drug-drug interactions with concurrent antiviral agents or other immunomodulatory investigational treatments to which the COVID-19 patients are subjected to. The use of LMWH, in particular, will limit staff exposure and avoid the potential for heparin pseudo-resistance. If the perceived need for invasive procedures is low, and no drug-to-drug interactions are evident, apixaban or rivaroxaban can be considered as the initial oral anticoagulation. Dabigatran, edoxaban, and vitamin K antagonist therapy can be used after overlap with initial parenteral anticoagulation. [1]

In critically ill COVID-19 patients with proximal DVT or PE, again parenteral anticoagulation is preferred over oral anticoagulant therapy. Among options for parenteral anticoagulation, LMWH or fondaparinux is recommended over UFH. UFH might be more suitable in patients at high risk of bleeding, severe renal failure, or in those with overt or imminent hemodynamic decompensation secondary to PE, in whom primary reperfusion treatment may be unavoidable. [1]

The recommended duration of anticoagulation therapy for COVID-19 patients with proximal DVT or PE is a minimum of three months. [1]

The National Institutes of Health (NIH) last updated this February, American Society of Hematology (ASH), and International Society on Thrombosis and Haemostasis (ISTH) concur with the CHEST guidelines that LMWH or UFH remain the anticoagulants of choice in hospitalized, critically ill COVID-19 patients with established diagnoses of venous thromboembolism (VTE). [2-4]

For outpatient management of COVID-19 patients with proximal DVT or PE and no drug-to-drug interactions, the CHEST guidelines recommend direct oral anticoagulants (DOACs) such as apixaban, dabigatran, rivaroxaban, or edoxaban. For patients who are not good candidates for DOACs, vitamin K antagonists are preferred over LMWH due to patient convenience and comfort with vitamin K antagonist use. Dabigatran, edoxaban, or vitamin K antagonists needs to be bridged with the parenteral anticoagulation at first. [1]

In contrast to the CHEST guidelines, the Journal of the American College of Cardiology (JACC) State-of-the-Art Review on COVID-19 and thrombotic or thromboembolic disease suggests DOACs or LMWH as the preferred agent for outpatient management due to the lack of routine INR monitoring which may minimize healthcare worker exposure to potential COVID-19 infection. [5]

Given that a substantial proportion of critically ill COVID-19 patients, in particular, have shown antiphospholipid antibodies (aPL) positivity, recent review articles tried to associate thrombotic manifestations to aPL status in COVID-19 patients. However, to date, the real prevalence of aPL among COVID-19 patients remains unknown: a majority of studies evaluating COVID-19-associated aPL assessed aPL at one point only and did not perform a repeat test at least 12 weeks apart which is a criterion for the antiphospholipid syndrome (APS). The ISTH guidelines specify that at least 12 hours of anticoagulant discontinuation is recommended prior to the testing for lupus anticoagulant (LA); however, critically ill COVID-19 patients are often anticoagulated without proper discontinuation. Given a lack of standardization among limited studies, the presence of inter-laboratory variation, and that an elevated level of the acute phase reactant C-reactive protein in COVID-19 patients can interfere with reagents used to test LA, the positive LA or aPL results, especially those at borderline, need to be interpreted with caution. Whether this transient elevation of aPL persists and poses a further thrombosis risk is unknown. A transient elevation of aPL antibodies in critically ill COVID-19 patients may be of no clinical significance and increased thrombosis risk in COVID-19 patients may be secondary to other coagulative processes. Large, prospective randomized control trials are warranted to establish a causal relation between aPL positivity and thrombosis in COVID-19 patients. [6-7]

The gold standard therapy for secondary antithrombotic prophylaxis in APS patients is vitamin K antagonist with a target INR of 2.0-3.0. DOACs may be safe alternatives to warfarin in uncomplicated APS patients with a single prior VTE episode or those with low-risk aPL profiles intolerant of vitamin K antagonists. Acute onset of VTE is treated with LMWH or UFH. The management of APS in the context of COVID-19 is not well studied/discussed. [8]

References:

[1] Moores LK, Tritschler T, Brosnahan S, et al. Prevention, diagnosis, and treatment of VTE in patients with coronavirus disease 2019: CHEST guideline and expert panel report. Chest. 2020;158(3):1143-1163. doi: 10.1016/j.chest.2020.05.559.
[2] The National Institutes of Health (NIH). Antiviral drugs that are approved or under evaluation for the treatment of COVID-19. Available: https://www.covid19treatmentguidelines.nih.gov/antiviral-therapy/. Updated February 11, 2021. Accessed February 16, 2021.
[3] The American Society of Hematology (ASH). COVID-19 and VTE/anticoagulation. Available: https://www.hematology.org/covid-19/covid-19-and-vte-anticoagulation. Updated January 29, 2021. Accessed February 16, 2021.
[4] Spyropoulos AC, Levy JH, Ageno W, et al. Scientific and Standardization Committee communication: clinical guidance on the diagnosis, prevention, and treatment of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost. 2020;18(8):1859-1865. doi:10.1111/jth.14929.
[5] Bikdeli B, Madhavan MV, Jimenez D, et al. COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020;75(23):2950-2973. doi: 10.1016/j.jacc.2020.04.031.
[6] El Hasbani G, Taher AT, Jawad A, et al. COVID-19, antiphospholipid antibodies, and catastrophic antiphospholipid syndrome: a possible association?. Clin Med Insights Arthritis Musculoskelet Disord. 2020;13:1179544120978667. doi:10.1177/1179544120978667.
[7] Kallapur AS, Yen EY, Singh RR. Vascular thrombosis in COVID-19: a potential association with antiphospholipid antibodies. medRxiv. 2020. Preprint. Available: https://www.medrxiv.org/content/10.1101/2020.11.02.20224642v1.full. Accessed February 17, 2021.
[8] Rodziewicz M, D'Cruz DP. An update on the management of antiphospholipid syndrome. Ther Adv Musculoskelet Dis. 2020;12:1759720X20910855. doi:10.1177/1759720X20910855.