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Resistance to activated protein C and Legg-Perthes disease
C J Glueck1, G Brandt, R Gruppo
1Cholesterol Center, Jewish Hospital.
Insights
Resistance to activated protein C, a common thrombophilia, is a significant cause of Legg-Perthes disease in children. This coagulation defect was found more frequently in children with Legg-Perthes disease than in healthy controls.
Area of Science:
- Hematology
- Pediatric Orthopedics
- Genetics
Background:
- Thrombophilia can lead to femoral head venous occlusion, causing Legg-Perthes disease.
- Resistance to activated protein C is the most prevalent thrombophilic trait.
Purpose of the Study:
- To investigate the association between resistance to activated protein C and Legg-Perthes disease in children.
- To determine the prevalence of Factor V Leiden mutation in pediatric patients with Legg-Perthes disease.
Main Methods:
- Measured activated protein C resistance in 64 children with Legg-Perthes disease and 160 pediatric controls.
- Analyzed genomic DNA for the Factor V Leiden gene mutation (CGA to CAA substitution at position 1691).
- Calculated the activated protein C ratio using clotting times.
Main Results:
- Resistance to activated protein C was the most common coagulation defect in children with Legg-Perthes disease (23/64) compared to controls (7/160).
- The Factor V Leiden mutation was present in 8/64 children with Legg-Perthes disease (7 heterozygotes, 1 homozygote) versus 1/101 controls.
- Only 22% of children with Legg-Perthes disease had normal coagulation measures.
Conclusions:
- Resistance to activated protein C is a likely pathogenetic factor in Legg-Perthes disease.
- The Factor V Leiden mutation contributes to the development of Legg-Perthes disease in a subset of affected children.
Abstract:
Thrombophilia may cause thrombotic venous occlusion in the femoral head, with venous hypertension and hypoxic bone death, leading to Legg-Perthes disease. Resistance to activated protein C, the most common thrombophilic trait, was measured in 64 children with Legg-Perthes disease. Genomic deoxyribonucleic acid was studied to delineate the CGA-->CAA substitution at position 1691 of the Factor V Leiden gene responsible for resistance to activated protein C. The activated protein C ratio was calculated by dividing clotting time obtained with activated protein C-calcium chloride by clotting time obtained with calcium chloride alone. Resistance to activated protein C, with a low activated protein C ratio (less than 2.19, the 5th percentile for 160 normal pediatric controls) was the most common coagulation defect, found in 23 of 64 children with Legg-Perthes disease versus 7 of 160 pediatric controls. Eight of 64 children with Legg-Perthes disease had a low activated protein C ratio and the mutant Factor V gene (7 heterozygotes, 1 homozygote) versus 1 of 101 normal pediatric controls. Two or 3 generation vertical and horizontal transmission of heterozygosity for the mutant Factor V gene was found in 4 of the 8 kindreds. Of 64 children with Legg-Perthes disease, only 14 (22%) had entirely normal coagulation measures. Resistance to activated protein C appears to be a pathogenetic cause of Legg-Perthes disease.