Abstract
Background In factor XI (FXI) deficiency, bleeding cannot be predicted by routine analyses.
Since FXI is involved in tissue factor (TF)-independent propagation loop of coagulation,
we hypothesized that investigating the spatiotemporal separated phases of coagulation
(TF-dependent and -independent) could improve diagnostics.
Objectives This article investigates the correlation of parameters describing TF-dependent and
-independent coagulation with the clinical phenotype of FXI deficiency and their ability
to assess hemostasis after FXI replacement.
Methods We analyzed: (1) plasma from healthy controls (n = 53); (2) normal plasma (n = 4) spiked with increasing concentrations of a specific FXI inhibitor (C7P); (3)
plasma from FXI-deficient patients (n = 24) with different clinical phenotypes (13 bleeders, 8 non-bleeders, 3 prothrombotics);
(4) FXI-deficient plasma spiked with FXI concentrate (n = 6); and (5) plasma from FXI-deficient patients after FXI replacement (n = 7). Thrombin generation was measured with the reference method calibrated automated
thrombogram and with Thrombodynamics (TD), a novel global assay differentiating TF-dependent
and -independent coagulation.
Results C7P dose-dependently decreased FXI activity, prolonged activated partial thromboplastin
time, and hampered TF-independent coagulation. In FXI-deficient bleeders, TD parameters
describing TF-independent propagation of coagulation and fibrin clot formation were
reduced compared with controls and FXI-deficient nonbleeders and increased in FXI-deficient
patients with prothrombotic phenotype. Receiver operating characteristic analysis
indicated that TF-independent parameters were useful for discriminating FXI-deficient
bleeders from non-bleeders. In FXI-deficient plasma spiked with FXI concentrate and
in patients receiving FXI replacement, TD parameters were shifted toward hypercoagulation
already at plasma FXI levels around 20%.
Conclusion TF-independent coagulation parameters assessed by TD have the potential to identify
the clinical phenotype in FXI-deficient patients and to monitor FXI replacement therapy.
Keywords
bleeding - FXI deficiency - global hemostasis assay - Hemoleven - thrombin generation
