Current evidence demonstrates that COVID-19 patients are at high risk for thrombosis, even those receiving standard or intensified thromboprophylaxis doses with low molecular weight heparin (LMWH) or unfractionated heparin (UFH). Novelli et al. mentioned that about 75.7% of patients (28/37 patients) receiving UFH/LMWH might be considered heparin resistant, and 51.3% experienced thromboembolic events, suggesting prophylactic heparin insufficiently down-regulates coagulation.
In the intensive care unit (ICU), heparin resistance is expected, particularly in critically ill patients with more severe systemic inflammation. A previous study by White et al. also demonstrated failure to achieve therapeutic anticoagulation levels as measured by APTT or anti-Xa assays in COVID-19 ICU patients. Novelli et al. and White et al. have offered some possible insights into why the high failure rate of thromboprophylaxis is seen in COVID-19 when standard thromboprophylaxis doses are used.
Heparin resistance is generally defined as high doses of UFH greater than 35,000 IU/day required to achieve anticoagulation. A weight-based definition of resistance (IU/kg/hr) may be more appropriate; however, the consensus is lacking. A study by Weeks et al. defined resistance as requiring ≥21 IU/kg/hr of heparin. Because similar criteria were also lacking for LMWH, Novelli et al. arbitrarily defined LMWH resistance as not achieving the expected anti-Xa range.
Two different strategies are commonly used to monitor the therapeutic effects of UFH: APTT and anti-Xa assay. APTT is usually performed for UFH monitoring because it is a widely available and inexpensive parameter. Despite that, the laboratory method used in evaluating the APTT greatly influences the therapeutic range because of the significant reagent-to-reagent variability. Several guidelines recommend that each institution define its own APTT therapeutic range (corresponding to 0.3–0.7 IU/ml anti-Xa) used in the laboratory rather than a usual fixed APTT therapeutic range of 1.5–2.5 times control. APTT can also be affected by increased FVIII or FIB levels, causing pseudo heparin resistance. Conversely, monitoring heparin using anti-Xa takes advantage of a narrower reagent variability and was not affected by FVIII or FIB. The overall superiority of anti-Xa over APTT in monitoring heparin therapy is controversial; however, the current evidence signifies better anti-Xa reliability for clinical monitoring of critically ill patients.11 Lawlor et al. showed APTT potentially underestimate heparin activity in COVID-19 patients receiving UFH compared with anti-Xa, and APTT alone may be an unreliable measure of heparin activity. In addition, the anti-Xa assay is a reliable determinant of blood LMWH concentrations, especially in particular populations, such as severe obesity or renal failure patients, where dose-finding studies have not been carried out.
Consistent with previous results, Novelli et al. demonstrated that anti-Xa was a more potentially reliable method in heparin monitoring than APTT in acute COVID-19 patients. While the anti-Xa vastly underestimates heparin levels, the thrombin generation test shows that heparins effectively down-regulate coagulation. Based on these limited COVID-19 data, we agree with Novelli et al. to suggest monitoring the heparin activity based on anti-Xa with a target value of 0.3–0.7 IU/ml in all COVID-19 patients, instead of based on APTT levels; and specifically add thrombin generation test in patients with liver disorder.
High-dose UFH may be received by critical COVID-19 patients, such as for extracorporeal membrane oxygenation (ECMO) or hemodialysis, where activated clotting time (ACT) can be a monitoring option. In these settings, the APTT and anti-Xa may not be helpful because the doses of heparin administered often result in a plasma heparin concentration >1 IU/ml, exceeding APTT and anti-Xa analytical range limits. We still recommend using ACT as a rapid bedside test for monitoring high-dose UFH since the ACT shows a dose-response to heparin concentrations in the range of 1–5 IU/ml.
In conclusion, identifying clinical heparin resistance in COVID-19 may become a challenge for physicians, especially in the ICU setting. When clinical resistance is suspected, physicians must ensure sufficient heparin activity in the patient, ideally by checking anti-Xa and activated prothrombin time ratio (APR). APR is a modification of the APTT result: the patient’s APTT divided by the mean of the normal range. APR has unique advantages in that it reflects the hypercoagulable state and the particular importance of the contact activation inhibition, which is not reflected in the anti-Xa assay.18 A clinical decision must be made on whether there is a risk of excessive bleeding and whether a dose increase is recommended. Proper modalities in heparin monitoring can define the desired therapeutic anticoagulation level.
Author: dr. Mochamad Yusuf Alsagaff, Sp.JP(K), PhD
Detail information can be viewed on:
https://doi.org/10.1111/ijlh.13778
Alsagaff, MY, Mulia, EPB. Resistance or pitfall in heparin monitoring: An ongoing issue in COVID-19 anticoagulation. International Journal of Laboratory Hematology. 2022; 44(4): e135-e137. doi:10.1111/ijlh.13778
