Correspondence

Autoimmune Protein S Deficiency

N Engl J Med 1993; 329:1898December 16, 1993

Article

To the Editor:

We were interested in the report by D'Angelo et al. of autoimmune protein S deficiency in a boy with severe thromboembolic disease (June 17 issue)1 and believe that the transient presence of anticardiolipin antibodies warrants more comment.

Recently, we described a 30-year-old man with deep-vein thrombosis and anticardiolipin antibodies in whom protein S activity was decreased and protein S antigen levels were normal2. Three months later, the patient had no detectable anticardiolipin antibodies and protein S activity and antigen were normal. Two other cases of anticardiolipin antibodies in association with acquired protein S deficiency have been reported3.

Although we found no direct evidence that anticardiolipin antibodies caused the decrease in protein S, the transient presence of these antibodies in conjunction with the transient disturbances in protein S activity is striking. It is interesting that the anti-protein S antibodies in the report by D'Angelo et al. were not neutralizing antibodies1. In contrast, in earlier reports,2,3 the antibodies were neutralizing, since the patients had normal levels of protein S antigen but decreased protein S activity. Thus, anti-protein S autoantibodies can lower protein S antigen levels or cause low levels of protein S activity with normal protein S antigen levels.

Furthermore, protein S is produced and secreted by endothelial cells,4 which have been reported to be the target of some anticardiolipin antibodies5. We suggest that anticardiolipin antibodies, which can be detected transiently after viral infections, may be the pathogenic anti-protein S autoantibodies.

S.D.H. Malnick, M.A., M.Sc., M.B., B.S.
Z.M. Sthoeger, M.D.
Kaplan Hospital, 76100 Rehovot, Israel

5 References

1. 1

   D'Angelo A, Della Valle P, Crippa L, Pattarini E, Grimaldi LME, D'Angelo SV. Autoimmune protein S deficiency in a boy with severe thromboembolic disease. N Engl J Med 1993;328:1753-1757
   Full Text | Web of Science | Medline

2. 2

   Sthoeger ZM, Sthoeger D, Mellnick SD, Steen D, Berrebi A. Transient anticardiolipin antibodies, functional protein S deficiency, and deep vein thrombosis. Am J Hematol 1991;36:206-207
   CrossRef | Web of Science | Medline

3. 3

   Moreb J, Kitchens CS. Acquired functional protein S deficiency, cerebral venous thrombosis, and coumarin skin necrosis in association with antiphospholipid syndrome: report of two cases. Am J Med 1989;87:207-210
   CrossRef | Web of Science | Medline

4. 4

   Fair DS, Marlar RA, Levin EG. Human endothelial cells synthesize protein S. Blood 1986;67:1168-1171
   Web of Science | Medline

5. 5

   Vismara A, Meroni PL, Tincani A, et al. Relationship between anti-cardiolipin and anti-endothelial cell antibodies in systemic lupus erythematosus. Clin Exp Immunol 1988;74:247-253
   Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Malnick and Sthoeger suggest that the anticardiolipin antibodies and anti-protein S autoantibodies described in our case report of transient protein S deficiency are identical. Antiphospholipid antibodies, defined on the basis of either lupus anticoagulant activity or anticardiolipin reactivity, are a heterogeneous family of antibodies with varying affinities for protein-phospholipid complexes1. Antibodies that bind to phospholipids without any requirement for protein cofactors have been described after infectious disease, especially in children. These antibodies are mostly transient and are not associated with an increased risk of thrombosis2. On the other hand, in 3 of 42 patients with antiphospholipid antibodies, the antibodies bound to prothrombin, leading to severe hypoprothrombinemia3. Thus, our patient with severe protein S deficiency and thrombosis may be the counterpart of the three patients with severe autoimmune hypoprothrombinemia with bleeding diathesis. The prevalence of anti-protein S antibodies that lead to protein S deficiency in patients with antiphospholipid antibodies is not high: among the more than 40 cases we have investigated, we found a similar antibody transiently in one boy with purpura fulminans associated with an episode of streptococcal pharyngitis.

Antibodies that neutralize the activity of protein S, but do not lead to a reduction in plasma protein S antigen concentration, may be more frequent in patients with antiphospholipid antibodies4. Malnick and Sthoeger suggest the presence of neutralizing anti-protein S antibodies in previously described patients with antiphospholipid antibodies and thrombosis. Their suggestion is misleading because plasma free and total protein S antigens, but not protein S activity, were measured in the studies cited. Reduced levels of free protein S and normal total protein S concentrations were also found in patients with antiphospholipid antibodies and fetal wastage; however, no anti-protein S antibodies could be detected by immunoblotting5. The possibility should not be overlooked that, in patients with antiphospholipid antibodies, reduced levels of free protein S may result from excessive binding of protein S to C4b-binding protein rather than from the presence of autoantibodies.

Armando D'Angelo, M.D.
Luciano Crippa, M.D.
Silvana Vigano D'Angelo, M.D.
Istituto Scientifico H.S. Raffaele, 20132 Milano, Italy

5 References

1. 1

   Vermylen J, Arnout J. Is the antiphospholipid syndrome caused by antibodies directed against physiologically relevant phospholipid-protein complexes? J Lab Clin Med 1992;120:10-12
   Medline

2. 2

   Lechner K. Lupus anticoagulant and thrombosis. In: Verstraete M, Vermylen J, Lijnene HR, Arnout J, eds. Thrombosis and haemostasis. Leuven, Belgium: Leuven University Press, 1987:525-47.
   

3. 3

   Fleck RA, Rapaport SI, Rao LV. Anti-prothrombin antibodies and the lupus anticoagulant. Blood 1988;72:512-519
   Web of Science | Medline

4. 4

   Oosting JD, Derksen RH, Bobbink IW, Hackeng TM, Bouma BN, de Groot PG. Antiphospholipid antibodies directed against a combination of phospholipids with prothrombin, protein C, or protein S: an explanation for their pathogenic mechanism? Blood 1993;81:2618-2625
   Web of Science | Medline

5. 5

   Parke AL, Weinstein RE, Bona RD, Maier DB, Walker FJ. The thrombotic diathesis associated with the presence of phospholipid antibodies may be due to low levels of free protein S. Am J Med 1992;93:49-56
   CrossRef | Web of Science | Medline

Citing Articles (2)

Citing Articles

1. 1

   Takayuki NAKAYAMA, Tetsuhito KOJIMA. (2001) Japanese Journal of Thrombosis and Hemostasis 12:3, 235-239
   CrossRef

2. 2

   F. Bergmann, P. F. Hoyer, S. Vigano' D' ANGELO, G. Mazzola, C. Oestereich, M. Barthels, A. D'Angelo. (1995) Severe autoimmune protein S deficiency in a boy with idiopathic purpura fulminans. British Journal of Haematology 89:3, 610-614
   CrossRef