Peculiar laboratory phenotype/ genotype relationship due to compound inherited protein C defects in a child with severe venous thromboembolism

Abstract

Summary A 7-years-old child who developed unprovoked deep vein thrombosis (DVT) and pulmonary embolism (PE) was tested for inherited thrombophilia. Protein C (PC) antigen level (87 %) and PC coagulometric and amidolytic activities (12 % and 11 %, respectively) were consistent with a homozygous PC type IIA phenotype. The patient was carrier of two heterozygous missense mutations causing p.Arg32Cys substitution associated with a type I PC defect (null allele, from the paternal side) and p.Gly433Ser substitution responsible for a type IIA PC defect (from the maternal side). Thus, the apparently normal PC antigen level in the proband was misleading in the interpretation of phenotype/genotype relationship of this compound PC defect. The child was also carrier of heterozygous prothrombin G20210A variant. Severe venous thromboembolism can occur in otherwise healthy children with complex inherited thrombophilia. Careful laboratory characterization of the phenotype/genotype relationship can be crucial to correctly classify PC defects and for their management with anticoagulants or replacement therapy.