Thrombomodulin gene variations and thromboembolic disease.

Thrombomodulin (TM) is the endothelial cell cofactor for protein C activation. Since deficiencies of other protein C system proteins are known to cause thrombotic disease, then defects in the gene coding for TM could be responsible for inherited thrombophilia. We have searched for mutations in the TM gene among healthy controls as well as patients with thrombophilia and identified eight patients heterozygous for TM mutations that are distributed throughout the TM gene. We have shown that the respective TM mutation co-segregates with thromboembolic disease (TED) in four families. Moreover, we have demonstrated that the C allele in a common C/T dimorphism in the TM gene is significantly more frequent among survivors of premature myocardial infarction (MI) than in matched controls. We suggest that TM defects should be added to the list of risk factors in TED, and after further evaluation possibly be included in a routine laboratory evaluation of thrombophilia.