Resistance to activated protein C and low levels of protein S activity in nine thrombophilic families: a correct diagnosis.
In order to define the thrombophilic conditions related to activated protein C resistance (APC-R) and protein S (PS) deficiency and to detect the possible combination of these defects, we studied nine unrelated patients selected because of low anticoagulant response to APC and reduced PS activity with at least one first degree relative having the same 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 remaining four there was no mutation. The mean PS activity was 41.6% and range 32-54 (normal 65-150%). Five of the patients had low PS activity despite normal total and free antigenic levels, and normal activity when measured at higher plasma dilution; these were carrying at least one gene for the Leiden mutation. In the remaining four patients the crossed-immunoelectrophoresis and the Western-blotting analysis showed a type I PS deficiency confirmed by the familial restriction fragment length polymorphism analysis. Thus, four families were diagnosed with the type I PS defect and five with congenital APC-R. No combined PS/FV Leiden or type II PS defect was found. The only defect found was in the anticoagulant 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 characterize APC-R and PS deficiency and that care is necessary to avoid the possibility of misdiagnosis.
Gemmati
D
D
Center for the Study of Haemostasis and Thrombosis, University of Ferrara, Italy.
Serino
M L
ML
Verzola
I
I
Mari
R
R
Moratelli
S
S
Ballerini
G
G
D015153:Blotting, Western; D004351:Drug Resistance; D005165:Factor V / Q000032:analysis; D005260:Female; D005787:Gene Frequency; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D012150:Polymorphism, Restriction Fragment Length; D011486:Protein C / Q000502:physiology*; D017293:Protein S / Q000032:analysis*; D019851:Thrombophilia / Q000175:diagnosis* / Q000235:genetics
D011486:Protein C; D017293:Protein S; C095381:factor V Leiden; D005165:Factor V