Correspondence

Thrombomodulin in Atypical Hemolytic–Uremic Syndrome

N Engl J Med 2009; 361:1511October 8, 2009

Article

To the Editor:

Delvaeye et al. (July 23 issue)1 report the presence of mutations in the gene encoding thrombomodulin in approximately 5% of a cohort of patients with atypical hemolytic–uremic syndrome. Thrombomodulin is synthesized and expressed by vascular endothelial cells.2 Therefore, it would be expected that wild-type thrombomodulin would be present in renal allografts. With this in mind, it is surprising that in one patient, Patient S015, atypical hemolytic–uremic syndrome recurred 3 days after renal transplantation and that in another, Patient S924, the disorder presented for the first time in an allograft. Do the authors have a hypothesis to explain these findings?

Matthew M. Edey, M.B., B.S.
Princess Alexandra Hospital, Brisbane, Australia
mattedey@doctors.org.uk

2 References

1. 1

   Delvaeye M, Noris M, De Vriese A, et al. Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl J Med 2009;361:345-357
   Full Text | Web of Science | Medline

2. 2

   Van de Wouwer M, Collen D, Conway EM. Thrombomodulin-protein C-EPCR system: integrated to regulate coagulation and inflammation. Arterioscler Thromb Vasc Biol 2004;24:1374-1383
   CrossRef | Web of Science | Medline

Author/Editor Response

In addition to being expressed as a membrane-anchored endothelial cell-surface protein, thrombomodulin also exists in a soluble form in plasma. This form is increased during inflammation and vascular injury, and it is generated by enzymatic cleavage of the intact protein.1,2 Soluble thrombomodulin consists of several fragments, some of which have vasculoprotective properties.3 It is possible that endothelial thrombomodulin is down-regulated in kidney allografts, with loss of the anticomplement activity, thus resulting in a greater dependence on the soluble plasma forms of thrombomodulin for renal protection. However, the mutant soluble forms of thrombomodulin may be inadequate in either amount or quality to provide sufficient protection or may actually contribute to the disease. Renal transplantation would not be expected to affect the composition of soluble thrombomodulin, and thus the syndrome might present or recur with an otherwise healthy allograft.

Charles T. Esmon, Ph.D.
Naomi L. Esmon, Ph.D.
Oklahoma Medical Research Foundation, Oklahoma City, OK

Edward M. Conway, M.D., Ph.D.
University of British Columbia, Vancouver, BC, Canada
emconway@interchange.ubc.ca

3 References

1. 1

   Boehme MW, Deng Y, Raeth U, et al. Release of thrombomodulin from endothelial cells by concerted action of TNF-α and neutrophils: in vivo and in vitro studies. Immunology 1996;87:134-140
   Web of Science | Medline

2. 2

   Lohi O, Urban S, Freeman M. Diverse substrate recognition mechanisms for rhomboids: thrombomodulin is cleaved by mammalian rhomboids. Curr Biol 2004;14:236-241
   Web of Science | Medline

3. 3

   Van de Wouwer M, Collen D, Conway EM. Thrombomodulin-protein C-EPCR system: integrated to regulate coagulation and inflammation. Arterioscler Thromb Vasc Biol 2004;24:1374-1383
   CrossRef | Web of Science | Medline