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Protein C deficiency resulting from possible double heterozygosity and its response to danazol
R A Gruppo1, P Leimer, R B Francis
1Children's Hospital Medical Center, Cincinnati, OH 45229.
Insights
This study describes a unique family with protein C (PC) deficiency, revealing a complex genetic inheritance pattern. The findings suggest double heterozygosity for distinct PC deficiencies, impacting thrombosis risk and treatment strategies.
Area of Science:
- Hematology
- Genetics
- Molecular Biology
Background:
- Protein C (PC) deficiency is a genetic disorder associated with an increased risk of venous thromboembolism.
- Understanding the molecular basis and clinical manifestations of different types of PC deficiency is crucial for effective management.
Observation:
- A family presented with a unique pattern of protein C deficiency, characterized by recurrent thrombosis in the proband.
- The proband exhibited disproportionately low anticoagulant activity compared to amidolytic activity and immunologic levels.
- A sibling showed a similar pattern, while the mother had Type I and the father had Type II PC deficiency.
Findings:
- Genetic analysis suggested the children were doubly heterozygous for two distinct protein C deficiencies inherited from each parent.
- An abnormal protein C molecule was identified in the affected individuals.
- Danazol treatment increased PC antigen levels but did not improve anticoagulant function in the proband.
Implications:
- This case highlights the complexity of inherited thrombophilia and the importance of detailed functional assays for protein C.
- Double heterozygosity for protein C deficiency can lead to severe thrombotic events.
- Further research is needed to elucidate the long-term effects and optimal management of this rare genetic condition.
Abstract:
A unique family with protein C (PC) deficiency is described. The proband had a history of renal vein thrombosis as a newborn and iliofemoral thrombosis at the age of 6 years. After 6 months of heparin treatment, discontinuation of anticoagulation therapy was accompanied by persistent hypofibrinogenemia with increased fibrinogen consumption. With continuous infusion of heparin, fibrinogen turnover normalized, and the child has remained free of thrombosis. Both the immunologic level of PC and the functional activity measured by amidolytic assay were moderately reduced (47% and 34%, respectively). Functional activity of PC measured by its anticoagulant activity was disproportionately lower (14%). A 3-year-old asymptomatic sibling had a similar disproportionate reduction of PC anticoagulant activity compared with the amidolytic activity or immunologic level. The mother demonstrated type I PC deficiency with a proportionate reduction in immunologic protein levels (59%), anticoagulant activity (52%), and amidolytic activity (46%), whereas the father had type II PC deficiency with normal immunologic protein levels (102%), normal amidolytic function (98%), but a low anticoagulant function (50%). An abnormal PC molecule was detected by two-dimensional immunoelectrophoresis in the father and two children. These data are consistent with the hypothesis that the children are doubly heterozygous for two different types of PC deficiency inherited from each of the parents. A 14-day trial of danazol in the proband resulted in a rise in the PC antigen concentration from 66% to 98% but no change in PC anticoagulant function.