Anti-FXa Activity with Intermediate-Dose Thromboprophylaxis in COVID-19

To the Editor:

We read with interest the article by Dutt and colleagues describing measurement of anti–factor Xa (FXa) activity in ward patients with coronavirus disease (COVID-19) as well as those requiring intensive care (1). The authors suggest that patients admitted to an ICU with COVID-19 may warrant a higher starting dose of pharmacological thromboprophylaxis, although the optimal dose in these patients is uncertain pending upcoming randomized controlled trials. Current guidelines from various medical societies suggest routine pharmacological thromboprophylaxis in patients with COVID-19. However, there is a lack of consensus on whether standard-dose or higher intermediate-dose thromboprophylaxis should be used (2–5). We would like to present our experience with measuring anti-FXa activity using a higher, weight-based dose of enoxaparin for thromboprophylaxis. This retrospective observational study was deemed exempt by our institutional review board.

In early April, we noticed a high rate of thrombosis and thromboembolism among critically ill patients with COVID-19, an observation consistent with those in other institutions (6–8). Therefore, we adopted intermediate-dose thromboprophylaxis for critically ill patients with COVID-19 with enoxaparin (0.5 mg/kg twice daily), as described in Table 1, as our new standard of care. The dosages were selected based on several single-center studies suggesting higher rates of attainment of target anti-FXa activity with higher-dose enoxaparin (9, 10). Importantly, the target anti-FXa activity for pharmacologic prophylaxis is not evidence based, and adjusting doses to provide higher attainment of target activity was not demonstrated to improve clinical outcomes.

Table 1.

Institutional Guidelines

Creatinine Clearance	VTE Prophylaxis Dosing for COVID-19 in Critically Ill
	<50 kg	50–69 kg	70–79 kg	≥80 kg
≥30 ml/min	Enoxaparin 30 mg, s.c., q24h	Enoxaparin 30 mg, s.c., q12h	Enoxaparin 40 mg, s.c., q12h	Enoxaparin 0.5 mg/kg, s.c., q12h, rounded to nearest syringe size
≤30 ml/min but not hemodialysis	Enoxaparin 30 mg, s.c., q24h		Enoxaparin 40 mg, s.c., q24h	Enoxaparin 0.5 mg/kg, s.c., q24h, rounded to nearest syringe size
Hemodialysis	Do not use enoxaparin; use heparin 5,000 U, s.c., q8–12h	Enoxaparin 30 mg, s.c., q24h

Definition of abbreviations: COVID-19 = coronavirus disease; FXa = factor Xa; q24h = once every 24 h; VTE = venous thromboembolism.

Maximum initial enoxaparin dose = 100 mg, subcutaneously, q12h. Target peak anti-FXa 0.2–0.5 U/ml; draw 3–4 hours after third or fourth dose of regimen. If anti-FXa < 0.2 U/ml, increase dose to next syringe size and keep current frequency. If anti-FXa > 0.5 U/ml, decrease dose to next syringe size or consider package labeled prophylaxis dosing.

We monitored anti-FXa activity for the first 40 patients receiving this dosing strategy. Anti-FXa was checked 3–4 hours after the third or fourth dose of the intermediate-dose enoxaparin regimen. The enoxaparin dose was then adjusted as necessary to achieve a target anti-FXa activity of 0.2–0.5 U/ml.

Results are shown in Table 2. Seventy-five percent (n = 33) of patients achieved the targeted anti-FXa activity without further dose adjustment. Twenty-five percent (n = 11) of patients had their dose adjusted from institutional guideline recommended doses at some point in their hospitalization. Only three patients had dose adjustment because of their anti-FXa activity, with decreased dosage for two patients, one of whom later developed venous thromboembolism. Only two patients had enoxaparin decreased or stopped because of bleeding (hematuria in both cases). Four patients had their dosages increased to a therapeutic regimen because of clinically suspected (n = 2) or confirmed (n = 2) clotting events. Both patients with confirmed clotting events and one patient with a suspected clotting event were initially on standard-dose thromboprophylaxis before the institutional transition to intermediate-dose thromboprophylaxis.

Table 2.

Patient Characteristics

	Critically Ill Patients with COVID-19 (n = 40)
Age, yr	64.7 (9.4) [41–90]
Weight, kg	101.1 (31.1) [53.3–186]
Serum creatinine, mg/dl	1.27 (0.64) [0.54–3.37]
Admission D-dimer, μg/ml FEU	3.7 (7.3) [0.43–40.48]
Daily enoxaparin dose, mg, median (IQR) [range]	80 (80–120) [60–160]
Enoxaparin frequency
Daily	2 (5)
Twice daily	38 (95)
Anti-FXa activity (U/ml)*	0.42 (0.14) [0.19–0.69]
Anti-FXa between 0.2 and 0.5 U/ml*	33 (75)
>0.5 U/ml	10 (23)
<0.2 U/ml	1 (2)
Any dose adjustment†	11 (25)
Dose increased†	7 (16)
Change in weight or renal function	1 (2)
Subtherapeutic anti-FXa	1 (2)
Confirmed/suspected clotting event	4 (9)
New-onset atrial fibrillation	1 (2)
Dose decreased or discontinued†	6 (14)
Change in weight or renal function	3 (7)
Supratherapeutic anti-FXa	2 (5)
Bleeding event	2 (5)

Definition of abbreviations: COVID-19 = coronavirus disease; FEU = fibrinogen equivalent units; FXa = factor Xa; IQR = interquartile range.

Continuous variables are presented as mean (SD) [range] unless otherwise noted. Nominal variables are presented as n (%).

^*Of 44 anti-FXa performed in 40 patients.

^†Two patients had doses decreased and increased; one patient had both a dose decrease and a discontinuation of therapy because of elevated anti-FXa and bleeding event, respectively.

We achieved a high rate of the targeted anti-FXa activity using this intermediate dosing scheme. Most patients outside the target anti-FXa range were above rather than below goal concentrations. After reviewing this data, our institution decided to continue intermediate-dose thromboprophylaxis but eliminate routine anti-FXa monitoring because it rarely resulted in dose adjustments. Only 2 of the 10 patients with anti-FXa activity of greater than 0.5 U/ml were decreased because of this monitoring, which was likely due to concern over the high rates of thromboembolic complications in this population. In addition, anti-FXa monitoring for thromboprophylaxis is controversial, especially in intensive care (11–13). There is no clear relationship between anti-FXa activity and the safety or efficacy of thromboprophylaxis. Although low anti-FXa activity has been associated with thromboembolism, there is no proven benefit to adjusting the enoxaparin dose to a “target” anti-FXa activity. Furthermore, the target anti-FXa activity of 0.2–0.5 U/ml has not been rigorously validated.

In conclusion, our results may assist others considering intermediate-dose thromboprophylaxis and anti-FXa monitoring in critically ill patients with COVID-19. Our findings suggest that intermediate-dose thromboprophylaxis led to anti-FXa activity according to predefined criteria in most of the studied patients and may not require routine anti-FXa monitoring. The optimal dose of thromboprophylaxis in critically ill patients with COVID-19 is still unknown pending larger randomized controlled trials.