Dear Editor,Previous studies showed that patients with COVID-19 are at high risk for thrombotic events,
even those that receive normal doses of thromboprophylaxis with unfractionated heparin
(UFH).[1-3] Furthermore, in an autopsy series,
pulmonary embolism and microvascular thrombosis was described in patients that had died from
COVID-19. The authors found a high rate of thromboembolic events in such patients treated
with therapeutic anticoagulation, with 56% of venous thromboembolism and 6% pulmonary embolisms.
Moreover, in an observational study examining the thrombotic complications of
patients admitted in the intensive care unit (ICU) with COVID-19, White et
al described a cumulative incidence of 30% for arterial and venous thrombosis in
the ICU for such population.Due to increased incidence of thromboembolism, physicians have been using UFH guided by the
aPTT ratio, to maintain a target between 1.5-2.0. However, some patients need higher doses
of UFH to achieve their coagulation status based on the aPTT ratio.In a narrative review, Iba et al described the mechanism of coagulopathy
in COVID-19 patients. ACE2, the host cellular receptor of SARS-CoV-2, has been identified on
the vascular endothelial surface. SARS-CoV-2 uses ACE2 to invade into the cell through the
fusion of its membrane to the host cell membrane leading to endothelial injury. One of the
unique features of the coagulopathy associated to COVID-19 is the increase in Von Willebrand
Factor (VWF) and factor VIII (FVIII) and it is suggested to be the result of vascular
response to SARS-CoV-2 infection. VWF and FVIII are stored in the Weibel-Palade body of
endothelial cells and released in response to infectious stimulus.The aPTT test is a clotting assay that reflects the function of the intrinsic and common
pathways of the coagulation cascade. The test is potentially affected by changes in the
concentrations of coagulation factors, including FVIII, fibrinogen, and coagulation
inhibitors such as lupus anticoagulant.
Mitsuguro et al evaluated the in vitro effect of increased
concentrations of fibrinogen and FVIII on the assay results of aPTT and anti-Xa activity in
plasma samples with various therapeutic concentrations of UFH. They observed that the aPTT
was shortened by increased concentrations of fibrinogen and FVIII. However, the Anti Xa
activity was not influenced by these concentrations of clotting factors.The anti-Xa assay has been proposed by some experts as a better assay for heparin
monitoring. The main reason is that anti-Xa testing offers the advantages of not being
affected by coagulation factor deficiencies other than antithrombin and not being affected
by higher FVIII activity and higher fibrinogen levels. Consequently, a number of medical
centers have switched to the anti-Xa assay for UFH monitoring.For these reasons, anti–Xa activity seems the more appropriate way to monitor heparin
anticoagulation regimens and to prevent a possible increased bleeding risk, especially when
high dosages of heparin are administered, mainly among heparin resistance conditions.This rare phenomenon is defined as the need for high doses of UFH for more than 35 000
IU/24h to achieve the target aPTT ratio. Heparin resistance can result from increased
heparin-binding protein levels, low ATIII levels, increased heparin clearance levels (due to
splenomegaly in liver disease), high factor VIII and fibrinogen levels and factitious
resistance such as when heparin is not connected to the intravenous line.
Beun et al evaluated 75 patients with COVID-19 in the ICU. Of those,
46% experienced thromboembolic events and four patients needed high doses of UFH. They
observed extremely increased levels of FVIII and fibrinogen that explained heparin
resistance and decreased the in vitro anticoagulant activity of UFH as measured by aPTT.
Based on that, they guided anticoagulation therapy with Anti Xa activity.
Moreover, in a retrospective study, White and collaborators, evaluated 69 patients
with COVID-19 in the ICU. Of 10 patients with UFH, 8 patients presented heparin resistance
due to increased production of FVIII and fibrinogen.Furthermore, in a recent review, Levy and Connors described the mechanisms and causes of
heparin resistance in COVID-19 patients. They mentioned that in patients with COVID-19, the
anti–factor Xa level may more accurately reflect UFH activity, especially in those with
substantial inflammation and elevated levels of fibrinogen and factor VIII.In conclusion, the concept of heparin resistance should be considered in critically ill
COVID-19 patients with thromboembolism diagnosis due to higher levels of FVIII and
fibrinogen that may reduce the in vitro activity of aPTT. Therefore, Anti Xa activity could
be considered to guide anticoagulation therapy with UFH in such population and more reliable
studies would be helpful to address this concern.