Homozygosity for the protein S Heerlen allele is associated with type IPS deficiency in a thrombophilic pedigree with multiple risk factors

The multifactorial character of thrombotic disease is shown in a Spanish pe digree in which the propositus, with recurrent deep vein thrombosis, inheri ted the factor V R/Q506 mutation, the prothrombin 20210G/A variant and type III Protein S deficiency. Among 14 relatives carrying one or two of these three risk factors, thrombosis is present in a heterozygote for R/Q506 and in another for 20210G/A, who also had slightly positive antiphospholipid an tibodies. Type I PS deficiency was also found in a young asymptomatic woman . PROS1 analysis showed coexistence of type III and type I PS deficiency to be associated with heterozygosity and homozygosity, respectively, for the P460 or PS Heerlen allele of the S/P460 variant. Analysis of PS values in t his and other pedigrees segregating this variant revealed that not only fre e but also mean total PS levels are slightly but significantly lower in the SP360 heterozygotes than in the SS460 homozygotes. These findings strongly suggest a role of the P460 variant in the expression of the PS deficient p henotype.