Thrombomodulin gene defects in families with thromboembolic disease - A report on four families

It has been suggested that an impaired thrombomodulin (TM) function could c onstitute an abnormality leading to thromboembolic disease (TED). The TM ge ne from 51 unrelated American patients with TED and 100 American blood dono rs was screened for mutations. Four heterozygous point mutations in the TM gene were detected. The mutations are distributed throughout the TM gene an d predict amino acid changes 1) pro(483) to Leu, 2) Gly(61) to Ala, 3) Asp( 468) to Tyr (earlier described) and 4) a silent mutation not predicting any amino acid change at Glu(163). Family studies reveal that the occurrence o f 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 heter ozygous TM variants predicting either a pro(477)-Ser mutation (two cases) o r an Asp(468)-Tyr mutation. Our results thus demonstrate that a previously undocumented abnormality in the protein C anticoagulant pathway, a defect i n the TM gene, to a certain extent co-segregates with familial thrombophili a. Further studies are needed to prove the causality of these TM mutations.