The protein C (PC) pathway, with its cofactor protein S (PS), is an important natural antithrombotic mechanism. Patients with phenotypic PS deficiency may develop recurrent thrombosis during adulthood, with a probability of remaining free of thrombosis of about 50% at age 45. The molecular basis for hereditary PS deficiencies is highly heterogeneous, with a large spectrum of mutations that have various effects on the expression of the relevant allele.