Normal reference ranges of antithrombin, protein C and protein S: effect of sex, age and hormonal status.
BACKGROUND
Antithrombin (AT), protein C (PC) and protein S (PS) deficiencies are risk factors for venous thromboembolism. Overlapping values between heterozygous carriers and normal individuals often make a correct classification of a deficiency difficult. The aim of this study was to investigate the effect of sex, age, menopause and hormone therapy on natural anticoagulant plasma levels in a large group of healthy individuals, and to evaluate the need of separate reference ranges.


METHODS
AT and PC were measured with a chromogenic assay, antigenic free PS with an ELISA test. To evaluate the effect of sex, age, oral contraception, hormonal status (and their interaction) on AT, PC and PS levels, linear regression models were used. Biological relevance and the value of the normal deviate z were chosen as rules to decide for separate reference ranges.


RESULTS
The study population consisted of 1837 healthy adult individuals (741 men, 1096 women), aged 18-85 years (median age: 44 years). In men AT levels decreased after the age of 50 years. Men had higher levels of PS than women, particularly at young ages. In women, after correction for menopause, only PC levels increased with age. Menopause affected AT and PS, but not PC levels. Oral contraceptive intake was associated with a decrease of AT and PS, and an increase of PC levels.


CONCLUSIONS
For AT, PC and PS, sex- and age-specific normal reference ranges can be useful, in order to better discriminate true carriers of a natural anticoagulant deficiency.
A. Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Medicine and Medical Specialties, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milan, Italy.
Franca
F
Franchi
Eugenia
E
Biguzzi
Ida
I
Martinelli
Paolo
P
Bucciarelli
Claudia
C
Palmucci
Simona
S
D'Agostino
Flora
F
Peyvandi
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D058833:Antithrombin Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011486:Protein C / Q000378:metabolism*; D017293:Protein S / Q000378:metabolism*; D012016:Reference Values; D012307:Risk Factors; D012737:Sex Factors; D020246:Venous Thrombosis / Q000097:blood*; D055815:Young Adult
D058833:Antithrombin Proteins; D011486:Protein C; D017293:Protein S
AT; Antithrombin; HRT; OC; PNP; PS; hormonal replacement therapy; oral contraceptives; pooling citrated plasma; protein C; protein S; reference values; venous thrombosis