A rare case of protein C mutation causing neonatal purpura fulminans

Congenital protein C deficiency presenting as purpura fulminans is a rare condition in neonates. It is a disorder with autosomal recessive inheritance and is caused by homozygous or compound heterozygous mutations in PROC gene. The authors report a case of autosomal homozygous PROC gene transversion mutation in a newborn baby born to third degree consanguineous parents who presented as purpura fulminans at birth. She had almost undetectable protein C levels. As protein C concentrate was not readily available, she was managed with low molecular weight heparin along with fresh frozen plasma. Despite our best efforts, baby succumbed to her illness on day 21 of life. Autosomal recessive protein C deficiency should always be sought as an explanation for thrombotic disorders in the newborn with manifestations of disseminated intravascular coagulation.

Genotype–Phenotype Relationships in a Large French Cohort of Subjects with Inherited Protein C Deficiency

Inherited protein C (PC) deficiency caused by mutations in the PROC gene is a well-known risk factor for venous thromboembolism. Few studies have investigated the relationship between PROC genotype and plasma or clinical phenotypes. We addressed this issue in a large retrospective cohort of 1,115 heterozygous carriers of 226 PROC pathogenic or likely pathogenic mutations. Mutations were classified in three categories according to their observed or presumed association with type I, type IIa, or type IIb PC deficiency. The study population comprised 876 carriers of type I category mutations, 55 carriers of type IIa category mutations, and 184 carriers of type IIb category mutations. PC anticoagulant activity significantly influenced risk of first venous thrombosis (p trend < 10−4). No influence of mutation category on risk of whole or unprovoked thrombotic events was observed. Both PC anticoagulant activity and genotype significantly influenced risk of venous thrombosis. Effect of detrimental mutations on plasma phenotype was ambiguous in several carriers, whatever the mutation category. Altogether, our findings confirm that diagnosing PC inherited deficiency based on plasma measurement may be difficult but show that diagnosis can be improved by PROC genotyping.

Laboratory Limitations of Excluding Hereditary Protein C Deficiency by Chromogenic Assay: Discrepancies of Phenotype and Genotype

Protein C (PC) deficiency is associated with an increased risk for venous thromboembolism (VTE). In daily practice, exclusion of a hereditary PC deficiency is often based on a single determination of PC activity, by either clotting time–based or mostly chromogenic assay. However, diagnosis of hereditary PC deficiency is challenging due to several laboratory and clinical limitations. We compared the potential of PC activity values measured by either chromogenic or clotting time–based assay to predict a variation in the PROC gene. One hundred one (35%) of 287 patients carried variations within the PROC gene, including 2 previously not published variations. In 20 (20%) patients with identified variation, PC activity, determined by chromogenic assay, was within the reference range. For prediction of an underlying genetic defect determined by chromogenic and clotting time–based assay, sensitivity was 80% versus 99%, specificity 75% versus 18%, positive predictive value 64% versus 39%, and negative predictive value (NPV) 88% versus 97%. The lower NPV of chromogenic versus clotting time–based PC assay can be mainly explained by the presence of PC deficiency type IIb. Following our proposed diagnostic algorithm, additional measurement of PC activity by clotting time–based assay in case of a positive VTE history improves detection of this subtype of PC deficiency. Considering potential therapeutic consequences for primary and especially for secondary VTE prophylaxis, genetic analysis is required not only for confirmation but also for clarification of PC deficiency.

PROC Promoter Single Nucleotide Polymorphisms Associated With Low Protein C Activity But Not Increased Risk of Thromboembolism in Pediatric Population

Protein C (PC) deficiency, caused by mutations of the PROC gene, is a common inherited risk factor of thromboembolism (TE) among Thai people. This study aimed to investigate the association of 3 single nucleotide polymorphisms (SNPs; −1654 C/T, −1641 A/G, −1461A/T) at the PROC promoter region with PC activity and the risk of developing TE. A total of 216 patient s with TE, diagnosed at aged 0 to 20 years, and 102 healthy adults were enrolled. The SNPs were identified by Sanger sequencing. Protein C activity was measured using an automated functional clotting assay. Linear and logistic regression analyses were used to determine the association of SNPs with PC activity and the risk of TE. Patients and controls with homozygous TAA (119.6% ± 26.1%) and CGT haplotypes (102.7% ± 22.6%) had significantly lower PC activity than those with a homozygous CAA haplotype (140.4% ± 44.9%); P = .027 and .016, respectively. However, none of these haplotypes increased the risk of TE. This study suggested that the 3 PROC promoter SNPs were shown to be associated with lower PC activity but did not increase the risk of TE.