Fibrin clot formation properties in patients on treatment with oral anticoagulants correlate with drug concentration and intensity of anticoagulation

O. Königsbrügge1, G. Weigel2, I. Pabinger1, C. Ay1 (1Vienna, Austria, 2Innsbruck, Austria)

Date: 16.02.2017,
Time: 08:00 - 09:15

Objective: Vitamin-K-antagonists (VKA) and direct oral anticoagulants (DOAC) are treatment options for stroke prevention in atrial fibrillation (AF), but there is no global coagulation assay that equally quantifies their anticoagulant effects. Therefore, we investigated the in-vitro properties of fibrin clot formation in AF patients on oral anticoagulation and analyzed the correlation with the INR in patients on VKA and drug concentration in patients on DOACs, respectively.

Methods: Patients with AF on treatment with anticoagulation were recruited into a prospective registry and blood samples were taken in trough or peak levels. DOAC plasma concentrations were measured on a liquid chromatography tandem mass spectrometry platform. Fibrin clot turbidity was read on a photometer after addition of tissue factor (2 pmol/L), phospholipids (4 μmol/L), and CaCl2 (20 mmol/L) to citrate plasma. Clot formation lag-phase corresponds to the time to clot formation onset, maximum rate describes the maximum increase in clot formation over time, and peak clot turbidity corresponds to the maximum density of the clot.

Results: Out of 349 patients, 163 patients (46.7%) were receiving VKA with a median INR of 2.0 (25th to 75th percentile 1.8–2.4), 31 patients (8.9%) were on dabigatran with a median plasma concentration of 140 ng/ml (63.3–290), 82 (23.5%) on rivaroxaban with a median concentration of 111.0 ng/ml (33.6–204.75), 22 (6.3%) on apixaban with a median concentration of 179.5 ng/ml (102.4–268.0 ng/ml), and 26 control AF patients were not anticoagulated. DOAC plasma concentrations as well as INR levels in VKA patients correlated positively and strongly with fibrin clot formation lag-phase (r=0.63 p<0.001 and 0.61 p<0.001, respectively DOAC and VKA), negatively and moderately with the maximum rate of clot formation (r= -0.481 p<0.001 and r=-0.32 p<0.001), and negatively, weakly with peak clot turbidity (r= -0.33 p<0.001 and r=-0.15 p=0.06). DOAC samples in trough levels had significantly longer lag-phases (Mann-Whitney-U p<0.001) and lower clot formation rates (p=0.04), compared to patients in target INR range on VKA treatment (table).

Conclusion: Fibrin clot properties correlate to both DOAC plasma concentrations and INR levels in VKA treatment, thus equally reflecting their anticoagulant effects. The fibrin clot formation assay may allow an in-vitro comparison between the anticoagulant effects of DOACs and VKA.