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Protein S levels during Normal Pregnancy

Guest hhk

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This is in reference to my earlier post about Diagnosis of PSD during Pregnancy. Apart from the article which was posted by James earlier, I also found following references on Protein S levels during normal Pregnancy which I thought may be of interest:

Paper 1


Am J Obstet Gynecol. 1995 Jan;172(1 Pt 1):147-50. Changes in protein C and protein S levels in normal pregnancy. Faught W, Garner P, Jones G, Ivey B.

Department of Obstetrics and Gynecology, University of Ottawa, Ontario, Canada.

OBJECTIVE: The objective of the study was to determine the normal changes in the plasma concentrations of protein C and protein S that occur during each trimester of pregnancy. STUDY DESIGN: The study was a prospective cross-sectional study of 91 normal pregnant women who had plasma concentrations of protein C and protein S measured during the first, second, and third trimesters. RESULTS: There was no statistically significant change in antigenic or functional protein C levels during normal pregnancy. Total protein S levels also remained unchanged. Free protein S levels fell significantly from first to second trimesters (0.45 U/ml mean to 0.26 U/ml mean, p < 0.001), but no further fall occurred during the third trimester. CONCLUSIONS: The second-trimester fall in free protein S levels is a physiologic pregnancy adaptation. Women with a thromboembolic event appearing for the first time during pregnancy should have investigations for protein S deficiency delayed until the postpartum period, to avoid misdiagnosis and treatment.

(MY NOTE: Detilaed study of the paper indicated the patients who were in second trimester were in 26-28 weeks which is begining of third trimester, so the abstract is slightly mis leading in that respect. Also the range of levels reported in the table were as follows:

Protein S free Potein S total

8-16 weeks 0.43 +/- 0.09 0.89 +/- 0.14

26-28 wks 0.26 +/- 0.07 0.81 +/- 0.13

36-38 wks 0.25 +/- 0.05 0.86 +/- 0.15

If any one wants the complete paper I would be happy to fax the same to you)

Paper 2


Am J Obstet Gynecol. 1996 Sep;175(3 Pt 1):657-60. Comparison of protein S functional and antigenic assays in normal pregnancy. Lefkowitz JB, Clarke SH, Barbour LA.

Department of Pathology, University of Colorado Health Sciences Center, Denver 80262, USA.

OBJECTIVE: Our purpose was to determine the effect of pregnancy on the protein S functional assay (clot based), which is used to screen for all subtypes of protein S deficiency states, and to compare its behavior in pregnancy with antigenic assays. STUDY DESIGN: This was a cross-sectional study of 37 normal pregnant women without thromboembolic risks who were tested by both functional and antigenic protein S assays during the first, second, and third trimesters. RESULTS: Mean protein S functional levels decline strikingly from the first to the third trimester, all 10 third-trimester patients had functional protein S levels well below the lower limit of the reference range. In contrast, only 3 of 10 third-trimester and none of the second-trimester patients had free protein S antigenic levels below the reference range. CONCLUSIONS: The protein S functional assay should not be used in pregnancy to screen for the subtypes of protein S deficiency; misdiagnosis and inappropriate treatment could result.

( MY NOTE: I got the entire article from my library and that has a table which shows:

Protein S free antigen level:

non-pregnant 0.5-1.5, in 1st trimester 0.8-1.33 , 2nd trimester 0.65-1.03, 3rd trimester 0.45-0.64

Protein S functional activity :

non-pregnant 0.62-1.42, in 1st trimester 0.57-0.95 , 2nd trimester 0.42-0.68, 3rd trimester 0.16-0.42

Protein S total antigen level:

non-pregnant 0.7-1.34, in 1st trimester 0.77-1.15, 2nd trimester 0.65-0.101, 3rd trimester 0.58-0.80

If any one wants the complete paper I would be happy to fax the same to you)


Original Spanish Version


Google Translated Version



Free protein S (PS) in normal pregnancy: A comparison between two analytical methods

Patricia Fardella B, Mauro Parra C, Guillermo Conte L, Claudio Flores P, Hern?n Mu?oz S, Lilian Soto S, Marianela Cuneo Va, Carmen Mallea Pa, Mar?a Beatriz Retamales Mb, Sof?a Pe?a Rb, Constanza Ojeda Hb.

Secci?n Hematolog?a y Unidad de Medicina Fetal del Departamento de Ginecolog?a y Obstetricia, Hospital Cl?nico de la Universidad de Chile. Laboratorio de Hematolog?a, Cl?nica Alemana. Santiago, Chile.

aTecn?logo M?dico.

bEstudiante, Facultad de Medicina de la Universidad de Chile.

Direcci?n para correspondencia


Background: Pregnancy is a physiological hypercoagulable state with an increased incidence of thromboembolic phenomena. There is an increase in the concentrations of most clotting factors, a decrease in concentration of some of the natural anticoagulants and reduced fibrinolytic activity. Changes in PS levels have also been reported. Aim: To establish referral range values of functional PS and free PS antigen, during the second (2nd T) and third trimester (3rd T) of normal gestation. Patients and methods: Forty one normal pregnant women were included in our study, 20 during the 2nd T (22-24 weeks) and 21 during the 3rd T (29-38 weeks). Functional PS was measured by a clot based test and free PS antigen by ELISA. Results: Free PS Antigen was 65.8?18.3% during the 2nd T and 62.3?16.5% during the 3rd T. The figures for normal controls were 106?6.5%. Functional PS was 43.8?13.3 and 25.9?14.6% during the 2nd T and 3rd T, respectively. The figures for normal controls were 97?24% (p <0.001 compared with pregnant women). Free PS antigen did not change from the 2nd to the 3rd T (p=NS), however functional PS fell significantly from the 2nd to the 3rd T (p <0.001) and was significantly lower than free PS antigen in both trimesters (p <0.001). Conclusions: Pregnancy is associated to a decrease in PS. This abnormality is more pronounced for functional PS than free PS antigen and functional PS falls progressively during pregnancy. These assays should not be used to screen for PS deficiency during pregnancy because they could lead to a misdiagnosis.

(Key Words: Pregnancy trimesters; Protein S; Protein S deficiency)

Paper 4


Aust N Z J Obstet Gynaecol. 2000 Nov;40(4):448-50. Changes in the plasma activities of protein C and protein S during pregnancy. Oruc S, Saruc M, Koyuncu FM, Ozdemir E. Department of Obstetrics and Gynecology, Celal Bayar University Medical School, Manisa, Turkey.

The objective of the study was to determine the changes in the plasma activities of protein C and protein S that occur during normal pregnancy In this prospective cross-sectional study, plasma activities of protein C and protein S were measured in 32 normal pregnant women in the first, second and third trimester and 6 weeks after delivery There was a significant fall in protein C and protein S activities during normal pregnancy compared with the post-puerperal period. The activities of protein C and protein S also gradually decreased throughout pregnancy (p < 0.01). Increasing plasma volume during normal pregnancy and its dilutional effect might play some role in the low activities of protein S observed. The normal falls in protein S and protein C activities make it difficult to diagnose protein S and C deficiency during pregnancy. Based on our findings, if a woman has a thromboembolic event during pregnancy, testing for a definitive diagnosis of protein C or protein S deficiency or functional failure should be delayed until at least 6 weeks postpartum.

(My Note: I was not able to get the full text version of this article but if any one can - it should report the levels detected by them)

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Reduction in protein S activity during normal pregnancy

Authors: KURASAWA, Gotaro1; KOTANI, Kazuhiko2; ITO, Yuji1; SAIGA, Kyoko2; IIJIMA, Kenji3

Source: Australian and New Zealand Journal of Obstetrics and Gynaecology, Volume 47, Number 3, June 2007 , pp. 213-215(3)

Publisher: Blackwell Publishing


We investigated the serial changes in blood protein S (PS) and related proteins in 11 normal pregnant women. The PS activity decreased significantly in the third trimester and reached minimum levels (23.3%) one hour after delivery. Although the PS activity was reduced markedly below the normal limits, all the women delivered safely. The mechanisms that cause the reduction in PS activity and the clinically dangerous conditions involving PS activity during pregnancy warrant further investigation.

Keywords: C4bp; delivery; pregnancy; protein C; protein S

Document Type: Short communication

DOI: 10.1111/j.1479-828X.2007.00720.x

Affiliations: 1: Departments of Obstetrics and Gynecology, Nishiagatsuma Welfare Hospital, Naganohara, Gunma, 2: Division of Health Administration and Promotion, Faculty of Medicine, Tottori University, Yonago, 3: Department of Pathobiological Science and Technology, School of Health Science, Faculty of Medicine, Tottori University, Yonago, Tottori, Japan

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Protein S functional activity (plasma)

Units % of normal

Nonpregnant Adult 65-140

First Trimester 57-95

Second Trimester 42-68

Third Trimester 16-42

Protein S, free (plasma)

Units %

Nonpregnant Adult 70-140

First Trimester 34-133

Second Trimester 19-113

Third Trimester 20-65

Protein S, total (plasma)

Units %

Nonpregnant Adult 70-140

First Trimester 39-105

Second Trimester 27-101

Third Trimester 33-101

Protein S is a vitamin K dependent protein that is a cofactor for activated protein C (APC)-mediated degradation of coagulation factors Va and VIIIa, It also appears to act as a cofactor for tissue factor pathway inhibitor (TFPI), inhibiting tissue factor?mediated factor X activation. Protein S binds with high affinity to C4b binding protein (C4bBP) in plasma, with the excess circulating as free protein S (the predominantly active form).

Protein S deficiency is defined by its decreased APC-cofactor activity. Protein S deficiency has been associated with a increased lifetime risk of venous and possibly arterial thrombosis. Protein S deficiency may be inherited or acquired.

Inherited protein S deficiency is an autosomal dominant disease characterized by low protein S activity and is of three types:

* Type I protein S deficiency has a decrease in the level of free and total protein S.

* Type II (also called IIb) deficiency is uncommon and has a normal total and free antigen levels.

* Type III (also called IIa) deficiency is characterized by low free protein S levels and normal total protein S

Type I and type III account for 95% of inherited cases.

Acquired deficiencies of protein S are more common than inherited protein S deficiency. Some causes of acquired protein S deficiency include vitamin K deficiency, consumption from thrombosis, DIC, or invasive procedures, decreased hepatic synthesis, pregnancy, estrogen, sickle cell anemia, HIV infection, varicella infection, nephrotic syndrome, and acute phase reactions (due to elevated C4b-binding protein).


1. Abbassi-Ghanavati M, Greer LG, Cunningham FG. Pregnancy and laboratory studies: a reference table for clinicians. Obstet Gynecol. 2009 Dec;114(6):1326-31. PMID:19935037

2. Khor B, Van Cott EM.Laboratory evaluation of hypercoagulability. Clin Lab Med. 2009 Jun;29(2):339-66.>PMID:19665682

3.Elizabeth M. Van Cott, M.D., and Michael Laposata, M.D., Ph.D., "Coagulation." In: Jacobs DS et al, ed. The Laboratory Test Handbook, 5th Edition. Lexi-Comp, Cleveland, 2001; 327-358.

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