RESISTANCE TO ACTIVATED PROTEIN-C AND LOW-LEVELS OF PROTEIN-S ACTIVITY IN 9 THROMBOPHILIC FAMILIES - A CORRECT DIAGNOSIS

In order to define the thrombophilic conditions related to activated p rotein C resistance (APC-R) and protein S (PS) deficiency and to detec t the possible combination of these defects, we studied nine unrelated patients selected because of low anticoagulant response to APC and re duced PS activity with at least one first degree relative having the s ame coagulation feature. The mean APC ratio was 0.64 (normal values > 0.80) and range 0.35-0.80. Three of the patients were heterozygous and two were homozygous for the Leiden mutation (FVR506Q); in the remaini ng four there was no mutation. The mean PS activity was 41.6% and rang e 32-54 (normal 65-150%). Five of the patients had low PS activity des pite normal total and free antigenic levels, and normal activity when measured at higher plasma dilution; these were carrying at least one g ene for the Leiden mutation. In the remaining four patients the crosse d-immunoelectrophoresis and the Western-blotting analysis showed a typ e I PS deficiency confirmed by the familial restriction fragment lengt h polymorphism analysis. Thus, four families were diagnosed with the t ype I PS defect and five with congenital APC-R. No combined PS/FV Leid en or type II PS defect was found. The only defect found was in the an ticoagulant PC pathway. We therefore designed a procedure to diagnose thrombophilic conditions related to this pathway. This study indicates that a specific methodological approach must be used to accurately ch aracterize APC-R and PS deficiency and that care is necessary to avoid the possibility of misdiagnosis.