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Association of Protein S Deficiency with Thrombosis in a Kindred with Increased Levels of Plasminogen Activator Inhibitor-1

Charles D. Bolan, MD; Chitra Krishnamurti, PhD; Douglas B. Tang, PhD; Leonthena R. Carrington, BS; and Barbara M. Alving, MD
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From the Walter Reed Army Institute of Research and the Walter Reed Army Medical Center, Washington, D.C. Requests for Reprints: Charles D. Bolan, MD, Department of Hematology Oncology, Ward 78, Walter Reed Army Medical Center, Washington, DC 20307. Acknowledgments: The authors thank Dr. Jose-Antonio Fernandez for measuring the plasma chain-C4BP concentration in the laboratory of Dr. John H. Griffin at the Scripps Research Institute in La Jolla, California.

Copyright 2004 by the American College of Physicians

Ann Intern Med. 1993;119(8):779-785. doi:10.7326/0003-4819-119-8-199310150-00002
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Objective: A single kindred in North America with venous thrombosis was described as having defective fibrinolysis because of increased levels of plasminogen activator inhibitor-1 (PAI-1). Our study describes the discovery of protein S deficiency in this kindred and its association with venous thromboembolism.

Design: A family study.

Setting: Community.

Participants: Twenty-eight adults (ages 21 to 71 years) from three generations of the kindred; seven had a history of venous thromboembolism.

Measurements: Plasma levels of total and free protein S antigen, as well as the activities of protein S, protein C, PAI-1, and antithrombin III.

Results: Six of 7 persons (86%) with a history of venous thromboembolism were deficient in total and free protein S; of 21 asymptomatic members, 9 were deficient in protein S (P = 0.08). When compared with these 9 asymptomatic family members, the 6 persons with protein S deficiency and a history of thrombosis tended to smoke (P = 0.01) and to have higher triglyceride levels (P = 0.001). Overall, the mean PAI-1 activity in the 7 persons who had thrombosis was 7.9 kAU/L (AU/mL) and was 9.3 kAU/L (AU/mL) in the 21 persons who did not have thrombosis (95% CI, 9.9 to 7.0).

Conclusions: In this kindred, a deficiency of total and free or functional protein S is the cause of thrombosis. Measurement of PAI-1 activity was not useful in the evaluation of familial thrombosis. The utility of the routine measurement of PAI-1 activity in the evaluation of familial thrombosis has not been established.


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Figure 1.
Family pedigree.

Generations are in roman numerals, and persons within generations are in arabic numerals. Striped symbols represent persons with a history of thrombosis; black symbols represent persons with protein S deficiency; and white symbols represent persons with no known history of thrombosis. Squares and circles represent men and women, respectively, who were interviewed; diamonds represent living family members not personally interviewed but with no known history of thrombosis according to other members interviewed. Diagonally slashed lines represent deceased persons, and small hash marks represent persons available for laboratory testing.

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Figure 2.
Functional and free protein S levels in normal and deficient patients related and not related to the pedigree.Panel APanel B

Patients unrelated to this pedigree. Functional protein S activity and free protein S antigen levels measured by enzyme-linked immunosorbent assay in 45 healthy volunteers (23 men and 22 women) and in 14 patients unrelated to this pedigree with protein S deficiency (10 men and 4 women). The dotted lines are the lower limits of the reference ranges for functional and free protein S for both women and men. Functional and free protein S levels in the adult pedigree members. Functional protein S activity and free protein S antigen levels measured by enzyme-linked immunosorbent assay in 27 adult family members. The conversion factor for protein S to SI units is 0.01.

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Figure 3.
Plasma plasminogen activator inhibitor-1 activity (PAI-1) in the adult pedigree members.n[18]

Plasminogen activator inhibitor-1 activity levels in adult men (squares) and women (circles) pedigree members ( = 25) expressed as arbitrary units (AU). Black and white symbols indicate persons with and without a history of thrombosis. Values for the reference population are also given. The conversion factor to SI units for PAI-1 (kAU/L) is 1.

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