A Novel Thrombomodulin Gene Mutation in a Patient Suffering from Sagittal Sinus Thrombosis

Abstract

SummaryThrombomodulin is an endothelial cell membrane glycoprotein that promotes protein C activation. It has been clearly demonstrated that the anticoagulant functions of the protein C system are important in the prevention of thromboembolic disease. Patients with protein C or protein S deficiency and/or resistance to activated protein C (APC resistance) are at higher risk for developing thromboembolic disease. The first mutation in the thrombomodulin gene was discovered in an American patient suffering from pulmonary embolism at the age of 45 (Öhlin and Marlar 1995). Here we report a case of sagittal sinus thrombosis in a 42-year-old Swedish woman. She was found to carry a heterozygous point mutation changing G127 to A, predicting an Ala25 to a Thr change in the mature thrombomodulin protein. This mutation was also found in her 16-year-old daughter, who so far has not suffered from any thrombotic events. The patient had no other detectable prothrombotic genetic defects associated with the coagulation system. This case supports the hypothesis of an association between mutations in the thrombomodulin gene and venous thrombosis.

Naturally occurring mutations in the thrombomodulin gene leading to impaired expression and function

“…The substitution Ala25Thr (mutation G127A) was identified in a screening program of patients with MI. 20,24 The same mutation has been identified in a patient with venous thrombophilia 19 and in one patient with both venous and arterial thrombosis. 29 Point mutations leading to substitutions Gly61Ala (G236C), Arg385Ser (G1209T), Asp468Tyr (G1456T), Pro477Ser (C1483T), Pro483Leu (C1502T) and to the premature STOP306 (del791-801) have been identified in screening programs involving patients with venous thrombophilia.…”

“…The lack of any identified functional defect with this mutant is compatible with inconsistent relationships between mutation, thromboembolic disease, and plasma levels of soluble TM. [16][17][18][19] This work has demonstrated that certain mutations of the TM gene may have a detrimental effect on the expression and protein C activation cofactor function of the protein. These results suggest a plausible mechanism by which TM gene mutations might influence venous and arterial thrombotic disease.…”

“…Since the first report, 15 a number of mutations have been identified in patients with venous thrombosis and in their families. [16][17][18][19] Furthermore, in a screening investigation of patients with myocardial infarction (MI), 3 mutations of the 5Ј untranslated region of the TM gene were identified. 20 Each of these latter mutations is in proximity to regulatory elements of the promoter.…”

Identification of the Protein C/Activated Protein C Binding Sites on the Endothelial Cell Protein C Receptor

“…APC, in conjunction with its cofactor protein S, degrades factors Va and VIIIa on the phospholipid surface, thereby attenuating the coagulation cascade. Defects in the protein C anticoagulant pathway have been implicated as the underlying risk factors for the development of venous and arterial thrombosis (5)(6)(7)(8)(9)(10)(11).…”

Genetics of Antiphospholipid Syndrome

“…Therefore, a hereditary deficiency of thrombomodulin may very well play a role as a risk factor for thrombotic disease. A number of missense mutations are currently known in the thrombomodulin gene (THMD) of patients with venous thrombosis (Norlund et al, 1997). A particular aminoacid dimorphism, Ala 455 Val, was found with frequencies of 0.81/0.18 in Caucasian patients who suffered from thrombophilia (van der Velden et al, 1991).…”