Tissue Factor-Independent Coagulation Correlates with Clinical Phenotype in Factor XI Deficiency and Replacement TherapyFunding This study was supported by the annual research grant of Swiss Hemophilia Network (Switzerland), unrestricted research grants from CSL-Behring AG (Switzerland), Novo Nordisk Pharma SA (Switzerland), Roche Pharma SA (Switzerland), Swedish Orphan Biovitrum AG (Switzerland), and an investigator initiated research grant from Shire International GmbH, Switzerland, now a Takeda company (grant id # IIR-CHE-001695). The authors confirm that all the indicated funders were used to support the current study.
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.
D.B.C. contributed to the design and the implementation of the research, performed research, analyzed results, wrote and edited the manuscript; M.G.Z. performed research and critically revised the manuscript. A.A. and A.-P.B.M.S. contributed to research and critically revised the manuscript. V.C. and C.H. developed and made available for this study the specific FXI inhibitor and critically revised the manuscript. L.A. conceived the original idea, supervised the research, wrote and edited the manuscript.
Received: 17 April 2020
Accepted: 23 July 2020
13 September 2020 (online)
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