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Thromb Haemost 1999; 81(03): 338-344
DOI: 10.1055/s-0037-1614473
Review Article
Schattauer GmbH

Thrombomodulin Gene Defects in Families with Thromboembolic Disease – A Report on Four Families

Ann-Kristin Öhlin
1   From the Institute of Laboratory Medicine, Department of Clinical Chemistry, University Hospital, Lund, Sweden and, Denver, Colorado, USA
,
Richard A. Marlar
2   Department of Pathology, University of Colorado School of Medicine and Laboratory Services, Denver Veterans Affairs Medical Center, Denver, Colorado, USA
› Author AffiliationsThis study was supported by generous grants from the Swedish Medical Research Council (grant B95-03X-11194-01A), the Medical Faculty at the University of Lund, the Heart-Lung Foundation, the M. Bergvall Foundation, the A. Österlund Foundation, the T. Zoega Foundation, the Crafoord Foundation and the research funds of the University Hospital in Lund. This work was supported in part by a grant from the Department of Veterans Affairs (R.A.M.).
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Publication History

Received24 March 1998

Accepted after resubmission17 November 1998

Publication Date:
09 December 2017 (online)

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Summary

It has been suggested that an impaired thrombomodulin (TM) function could constitute an abnormality leading to thromboembolic disease (TED). The TM gene from 51 unrelated American patients with TED and 100 American blood donors was screened for mutations. Four heterozygous point mutations in the TM gene were detected. The mutations are distributed throughout the TM gene and predict amino acid changes 1) Pro483 to Leu, 2) Gly61 to Ala, 3) Asp468 to Tyr (earlier described) and 4) a silent mutation not predicting any amino acid change at Glu163. Family studies reveal that the occurrence of the different TM mutations is associated with a history of TED, but there are indications of multiple risk factors and no perfect co-segregation of the TM defects and TED. Among the controls, three individuals carried heterozygous TM variants predicting either a Pro477-Ser mutation (two cases) or an Asp468-Tyr mutation. Our results thus demonstrate that a previously undocumented abnormality in the protein C anticoagulant pathway, a defect in the TM gene, to a certain extent co-segregates with familial thrombophilia. Further studies are needed to prove the causality of these TM mutations.

 

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