Free protein S deficiency in a family with venous thrombosis Carl G. Lauer, MID, Thomas J. Reid III, MD, PhD, Carol S. Wideman, BS, Bruce L. Evatt, M D , and Barbara M. Alving, M_D, Washington DC, and Atlanta, Ga. Inherited deficiencies of protein S, an inhibitor of the coagulation system, are now recognized as occurring at least twice as frequently as antithrombin III deficienW in patients with venous thrombosis. Protein S is present in plasma in a complexed form, which is inactive, and in a free or functional form. Free protein S combines with activated protein C to inhibit factors V and VIII. This report describes the evaluation of a family with recurrent deep venous thrombosis and superficial thrombophlebitis. Levels of antithrombin III and protein C as well as plasminogen were normal. The levels of total protein S, which includes the value for the free and complexed forms of protein S, were also normal. However, the free protein S levels were greatly reduced in all symptomatic members who were studied. This report illustrates the importance of obtaining measurement of free protein S levels in patients who are suspected of having inherited venous thrombotic disorders. (J VASC SuRG 1990;12:541-4.)

For the past 25 years, congenital deficiency of the inhibitor antithrombin III (AT-III) has been recognized as a strong risk factor for deep venous thrombosis.l'2 Recently, inherited deficiencies of the inhib~tors protein S and protein C have been found more frequently than AT-HI deficiency in families with venous thrombotic disorders. 3,4 Protein S and protein C are vitamin K-dependent proteins that are produced in the liver; together they inhibit activated factors V and VIII. 5 Plasma protein S circulates in a functional free form and also in an inert form bound to C4b-binding protein. 6,7 Evaluation of some patients with protein S deficiency will show decreased levels of total protein S, which indicates a reduction in both free and bound forms. However, others may have normal levels of total prorein S and a decrease in only the free form. 8,9 The present report, which documents a deficiency of only free protein S among the symptomatic members of a family with recurrent venous thrombosis, emphasizes the importance of measuring free protein S levels in patients suspected of having an inherited tendency for venous thrombosis. From the Department of Vascular Surgery, Walter Reed Army Medical Center, and the Department of Hematology,Walter Reed Army Institute of Research, Washington, DC, and the Division of Immunologic,Oncologic, and HematologicDiseases, Centers for Disease Control, Atlanta, Ga. Reprint requests: Barbara Alving, MD, Department of Hematology, Walter Reed ArmyInstitute of Research, Washington, DC 20307-5100. 24/1/23531

Coagulation studies Blood samples were collected into plastic tubes that contained balanced citrate anticoagulant in a ratio of one part anticoagulant to nine parts blood and centrifuged at 4 ° C and 10,000 g for 20 minutes; plasma was removed and frozen at - 7 0 ° C until tested. The activated partial thromboplastin times (AIrI~), prothrombin times, thrombin times, mad fibrinogen levels were measured as previously described} ° Functional assays were used to measure activities of plasminogen, protein C, and AT-III. 11-13 Total protein S in untreated plasma was measured by Laurell rocket electrophoresis, by use of commercially available plates containing antibody to protein S (American Bioproducts Company, Parsipanny, N.J.). For measurement of free protein S, plasma was first treated with polyethylene glycol (final concentration 3.75%) to precipitate the bound protein S. 8 The free protein S, which remained in the supernarant, was then measured by rocket electrophoresis.

CASE REPORT The index case is a 28-year-old man (Fig. 1), admitted to the Vascular Surgery Service at Walter Reed Army Medical Center for evaluation of postphlebitic syndrome. Four years before admission he sprained his left ankle, which was then wrapped with an Ace bandage. One day later he developed left calf pain and swelling. The patient did not receive anticoagulation and remained symptomatic. A venogram obtained 1 month later demonstrated a left popliteal vein thrombosis. The patient was then treated with intravenous heparin, followed by several months of war541

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Fig. 1. Abbreviated pedigree of a family with protein S deficiency. Open square, Asymptomatic male; open circle, asymptomatic female; square or circle with slash, deceased; shaded circle, history of thrombosis but not studied; black square, history of thrombosis with protein S deficiency; asterisk, patients studied; black arrow denotes the index case.

Table I. Coagulation studies in a family with protein S deficiency APT1~ (seconds) Prothronxbin time (seconds) Thrombin time (seconds) Fibrinogen (mg/dl) Plasminogen* Antithrombin III* Protein C* Total protein S~ Free protein S*

Patient

Brother

23.3 12.2

26.4 11.5

22-34 11-14

12.9

11.7

11-14

230 113 97 124 80 25

Sister

Father

400 > 100 80

Free protein S deficiency in a family with venous thrombosis.

Inherited deficiencies of protein S, an inhibitor of the coagulation system, are now recognized as occurring at least twice as frequently as antithrom...
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