Hematology and Coagulation
Yuko Mishima, PhD (she/her/hers)
University of Oklahoma Health Sciences Center, Oklahoma, United States
Plasma experiments modeled patients who received 600–800 U/Kg of heparin following a dose of 800 mg of andexanet. Heparinized normal pooled plasma (n=6) was spiked with 4 µM GDXa. Tissue factor (TF)-activated thrombin generation was used to assess heparin reversal effects of GDXa and restoration of anticoagulation with AT (1.5, 3.0, and 4.5 µM). In platelet-poor plasma obtained from cardiac surgery patients (CPB plasma) (n=6), TG assay of GDXa-spiked plasma was conducted. Then additional heparin with/without 3.0 µM AT supplementation were assessed. Serum thrombin-AT complex, AT activity and tissue factor pathway inhibitor (TFPI) were also measured in TF-activated, recalcified CPB plasma spiked with GDXa.
Results/Findings:
In normal pooled plasma, the addition of GDXa to plasma containing a high concentration heparin (12 U/ml) restored the peak and velocity to 28.8% and 26.5% of those in the non-heparinized control. TG peak and velocity were mildly reduced in GDXa-spiked plasma supplemented with heparin and 1.5 μM AT, but they were significantly reduced when heparin was supplemented with either 3.0 or 4.5 μM AT (Figure 1). Heparin reversal by GDXa was also demonstrated in CPB plasma, but supplementing both heparin (8 U/ml) and AT (3 µM) attenuated GDXa-induced changes in peak and velocity by 72.5% and 72.2%, respectively. High heparin and AT levels attenuated thrombin-AT complex formation in TF-activated, GDXa-spiked CPB plasma by 85.7%. In the presence of GDXa, TFPI and AT activity were reduced by 88.6% and 26.0%, respectively. TFPI depletion by GDXa was not prevented by the addition of heparin, either alone or in combination with AT.
Conclusions:
Combining heparin and AT supplementation provided more effective than heparin alone in mitigating GDXa-induced heparin resistance by compensating for the loss of TFPI.