Recombinant C1-Inhibitor

Effects on Coagulation and Fibrinolysis in Patients with Hereditary Angioedema

Abstract

Background

Recombinant human C1-inhibitor (rhC1INH; Ruconest®) has been developed for treatment of acute angioedema attacks in patients with hereditary angioedema (HAE) due to heterozygous deficiency of C1INH. Previous reports suggest that administration of plasma-derived C1INH products may be associated with an increased risk for thromboembolic complications.

Objectives

Our aim is to evaluate the effects of rhC1INH on coagulation and fibrinolysis in symptomatic HAE patients.

Methods

Levels of various coagulation and fibrinolytic parameters were determined in pre- and postexposure plasma samples from HAE patients included in a randomized clinical trial. Patients were treated with either saline, or 50 or 100 U/kg rhC1INH for an acute angioedema attack.

Results

Prior to rhC1INH treatment, the majority of patients had low to normal activated partial thromboplastin times (aPTT) and increased levels of prothrombin fragment 1+2, thrombin-antithrombin complexes, D-dimers and plasmin-antiplasmin complexes, all of which indicate activation of both coagulation and fibrinolysis. Infusion of rhC1INH at doses up to 100 U/kg did not affect these parameters except for a dose-dependent prolongation of aPTT, confirming that rhC1INH is an inhibitor of the contact system, and that F1+2 levels decreased.

Conclusion

Coagulation and fibrinolytic systems are activated in HAE patients suffering from an acute angioedema attack. Treatment with rhC1INH at 50 or 100 U/kg had no effect on parameters reflecting activation of these systems except for a significant effect on aPTT, which likely reflects a pharmacodynamic effect of rhC1INH, and a reduction on plasma levels of the prothrombin activation fragment F1+2. We conclude that these results argue against a prothrombotic effect of treatment with this rhC1INH product in HAE patients.

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Acknowledgments

The studies were sponsored by Pharming Technologies BV, Leiden, the Netherlands. The analyses of plasma samples have been conducted at the University of Amsterdam, by K. Bakhtiari and J.C.M. Meijers. A. Relan and E.S. van Amersfoort are both employees of Pharming. C.E. Hack is a consultant, who helped with the interpretation of the data and writing this manuscript. All authors contributed equally to this manuscript.

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Correspondence to Dr Edwin S. van Amersfoort.

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Relan, A., Bakhtiari, K., van Amersfoort, E.S. et al. Recombinant C1-Inhibitor. BioDrugs 26, 43–52 (2012). https://doi.org/10.2165/11599490-000000000-00000

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Keywords

  • Plasmin
  • Tranexamic Acid
  • Thrombin Generation
  • Hereditary Angioedema
  • Supplemental Digital Content