FAMILIAL PROTEIN S DEFICIENCY WITH A VARIANT PROTEIN S MOLECULE IN PLASMA AND PLATELETS

Deficiency of protein S (PS), the cofactor for the antithrombotic protease, activated protein C (APC), was first described in 1984 in families with venous thrombotic disease. We describe here a PS deficient family with venous thrombotic disease presenting an abnormal PS molecule in plasma and platelets. The propositus, 20 years old, and two older siblings suffered from severe venous thrombosis and pulmonary emboli documented by imaging techniques. All laboratory studies were normal except for PS. The propositus while taking oral anticoagulant had a PS antigen (ag) level of 17% and PS functional activity of > 5% as measured by the ability of APC to prolong the clotting time of a modified APTT assay using PS-immunodepleted plasma. One brother had PS ag of 42% and PS activity of 7%. As demonstrated by immunoblotting using SDS gels, both the propositus and this brother presented an abnormal PS molecule in plasma at 65,000 apparent MW versus normal PS at 70,000 apparent MW. The mother had normal PS levels (93% ag/100% activity) but had both normal (70,000 MW) and variant (65,000 MW) forms of the PS molecule in plasma as well as in platelet lysates. One clinically affected PS heterozygous deficient brother (64% ag/11% activity), two asymptomatic siblings (68% ag/9% activity and 104% ag/114% activity) and the asymptomatic PS heterozygous deficient father (59% ag/10% activity) had only normal PS molecules (70,000 MW) on PS immunoblots. Two dimensional immunoelectrophoresis studies showed that the variant PS bound to C4b-binding protein in plasma. Since PS is in platelets and megakaryocytes and synthesized by the latter cells, immunoblotting analysis of platelet lysates was done and showed that platelets of each family member contained the same pattern of normal and variant PS forms as found in plasma. This is consistent with the hypothesis that PS gene expression is similar in those cells, presumably megakaryocytes, hepatocytes and endothelial cells, that control the synthesis of both platelet and plasma forms of PS.