Original Article
Brief Report
Autoimmune Protein S Deficiency in a Boy with Severe Thromboembolic Disease
N Engl J Med 1993; 328:1753-1757June 17, 1993
- Article
Protein S is a vitamin K-dependent plasma protein involved in the regulation of the protein C anticoagulant pathway,1 the system responsible for the inactivation of factors Va and VIIIa2. Protein S functions as a cofactor for activated protein C by increasing its affinity for the cell surface3 and by blocking the capacity of factor Xa to protect factor Va from inactivation by activated protein C4; it also enhances the profibrinolytic effects of activated protein C5-7.
The congenital deficiency of protein S is associated with an increased risk of recurrent juvenile venous and arterial thromboembolism8-10. The association of a thrombotic diathesis with acquired protein S deficiency11-15 is less clear-cut. Experiments conducted in baboons have shown that the reduction in free protein S -- the plasma form of protein S with anticoagulant activity16 -- exacerbates the disseminated intravascular coagulative response to sublethal endotoxinemia and eventually causes death17; however, a clinical counterpart of these studies in animals is lacking.
We describe the occurrence, during recovery from chickenpox, of severe thromboembolic disease in a boy with a transient isolated deficiency of protein S due to the presence of a circulating autoantibody to protein S.
Methods
Protein S Determinations
Crossed immunoelectrophoresis of protein S18 and measurements of the plasma antigen levels of protein S,19 protein C, and C4b-binding protein20 and of the anticoagulant activity of protein S13 and protein C21 were performed as previously described.
The inhibition of protein S anticoagulant activity by goat, mouse, and human antibodies to protein S was assessed with a commercially available kit (IL test protein S, Instrumentation Laboratory) and an ACL 300 coagulometer (Instrumentation Laboratory). A total of 50 microliters of normal pooled plasma or of purified protein S (20 μg per milliliter) was incubated for 60 minutes at 37 °C with 450 microliters of buffer containing increasing concentrations of immunopurified goat polyclonal IgG; the mouse monoclonal antibodies HPS-2,20 5E9E9,22 and 3B10.2522; or the IgG fraction isolated from human plasma and concentrated with a Minicon B15 concentrator (W.R. Grace, Amicon Division). The samples were then tested for residual protein S anticoagulant activity.
Purification Procedures
Human protein S was purified23 and iodinated (125I-labeled sodium, Amersham) according to the Iodogen method (Pierce Chemical)24. Radiolabeled preparations of protein S had a specific activity of 5 to 8 micro Ci per μg of protein. IgG fractions were purified from human plasma on a protein G column (MabTrap G, Pharmacia), with rates of recovery ranging from 25 to 40 percent.
Immunoblotting
The samples were subjected to sodium dodecyl sulfate-polyacrylamide-gel electrophoresis with a linear gradient of 10 to 15 percent (PhastGel and PhastSystem units, Pharmacia), and protein S (0.7 μg of unreduced protein S per lane) was transferred to 0.45-micrometer nitrocellulose membranes (Bio-Rad) for electroblotting at a fixed voltage (33 V) overnight at 4 °C. After blocking,22 the membranes were exposed for three hours to the patient's plasma or the purified IgG fraction (adjusted to a final total concentration of 12.5 to 50 μg of IgG per milliliter), cut into strips, and incubated overnight with either radiolabeled protein S (1,500,000 cpm per strip) or rabbit antihuman IgG at a dilution of 1:1000 (Dakopatts). The strips incubated with protein S were exposed to Kodak safety film AR at -80 °C for 16 to 24 hours. The strips incubated with antihuman IgG were exposed for two hours to peroxidase-labeled, affinity-purified goat antibody to rabbit total IgG at a dilution of 1:1000 (Kirkegaard and Perry Laboratories), followed by the addition of the peroxidase substrate 3-amino-9-ethylcarbazole (Sigma).
Detection of Antihuman Protein S IgG by Polyacrylamide Isoelectric Focusing
Plasma proteins (dilution, 1:2 to 1:16 in 20 microliters of phosphate-buffered saline) were applied to the center of Ampholine PAG plates (LKB Bromma) and separated according to pH (pH range, 3.5 to 9.5) as described previously25. After the proteins were transferred and blocked,25 the nitrocellulose membranes were incubated with radiolabeled protein S (1,000,000 cpm per lane) overnight at 4 °C and then exposed to Kodak safety film at -80 °C for 48 hours. Isoelectric focusing of plasma at higher dilutions (1:500 to 1:1000) was used to detect IgG bands on the basis of peroxidase staining25.
Enzyme-Linked Immunosorbent Assay (ELISA) for the Detection of Antihuman Protein S IgG in Plasma
Serial plasma dilutions (1:250 to 1:32,000) were added to 96-well plates coated with protein S (0.25 μg per well) and incubated for one hour. The samples were washed, rabbit antihuman IgG (total, anti-kappa chain, and anti-lambda chain; dilution, 1:1000 to 1:2000) (Dakopatts) was added, and the plates were incubated for one hour. The samples were washed, and peroxidase-labeled, affinity-purified goat antibody to rabbit total IgG (dilution, 1:1000) was added. All additions were mixed with 50 microliters of TRIS-sodium chloride buffer with bovine serum albumin at 22 °C. After one hour the plates were washed, 50 microliters of peroxidase substrate (2.2-azino-di-(3-ethyl-benzthiaziline sulfonate)) (Kirkegaard and Perry Laboratories) was added, and color development was monitored at an optical density of 405 nm (Titertek Multiskan MCC, Flow Laboratories).
Other Procedures
Vitamin K-dependent clotting factors II, VII, IX, and X (immunoadsorbed plasmas from Instrumentation Laboratory); antithrombin III (Coatest antithrombin, Kabi); plasminogen (Coatest plasminogen, Kabi); and heparin cofactor II (IL test antithrombin III, Instrumentation Laboratory) were measured with a coagulometer. Before heparin cofactor II was measured, plasma samples were depleted of antithrombin III26. The results of these determinations, similar to those for protein C, protein S, and C4b-binding protein, were expressed in conventional units (units per milliliter) based on the values observed in pooled plasma obtained from 30 healthy subjects (15 male and 15 female subjects). Anticardiolipin antibodies (IgM and IgG) were measured by ELISA (Delta Biologicals). The IgG content of samples was determined by nephelometry (Behring).
Case Report
An 11-year-old boy was admitted to the emergency department of our institution because of a painful enlargement of his left testicle that occurred during his recovery from chickenpox, which had been diagnosed 12 days earlier. The patient was febrile (temperature, 38.2 °C), with no evidence of lymphadenopathy or hepatosplenomegaly. The erythrocyte sedimentation rate and concentrations of C-reactive protein and lactate dehydrogenase were elevated. Tests of liver and kidney function were normal. The hemoglobin level and the platelet count were normal, but there was leukocytosis (white-cell count, 25,000 per cubic millimeter; 86 percent neutrophils). The total serum protein level was 7.1 g per deciliter, with a normal electrophoretic profile (1.4 g of gamma globulin per deciliter).
At surgery, there was extensive hemorrhagic necrosis of the left testis epididymis, and the hydatid of Morgagni, with thrombosis of the veins of the pampiniform plexus and of the lower third of the spermatic vein, but no evidence of torsion of the spermatic cord. Intraoperative contrast venography -- performed to rule out backward extension of a thrombus originating in the renal vein -- showed patency of the upper two thirds of the spermatic vein and of the renal vein. After orchiectomy, a subcutaneous infusion of heparin calcium was started (5000 units three times per day). On the third postoperative day, the patient had symptoms of deep venous thrombosis of the left leg. Doppler ultrasonography showed flow reduction in the left popliteal vein. Heparin sodium was given intravenously (25,000 U per day) in an attempt to maintain the activated partial-thromboplastin time (APTT) ratio (Thrombofax, Ortho Diagnostic Systems) in the range of 1.8 to 2.5. On the next day, the dose of heparin was increased to 31,000 U per day. During the night, dyspnea, tachypnea, and pleuritic pain developed. A diagnosis of pulmonary embolism was confirmed by ventilation-perfusion scanning. The heparin dose was increased to 40,000 U per day, resulting in the maintenance of the APTT ratio between 2.0 and 2.5. Doppler ultrasonography suggested thrombosis of the left superficial femoral vein. Venography revealed extension of the thrombus into the left iliac veins and the inferior vena cava, with progression into the right common iliac vein. A temporary caval filter was positioned, and a local infusion of recombinant tissue plasminogen activator was started and continued for four days (1 mg per hour) while the intravenous infusion of heparin was maintained. Repeated venographic examinations showed substantial resolution of the thrombosis in the inferior caval and proximal iliac veins. Thrombosis of the right subclavian and axillary vein followed the removal of the temporary filter after eight days, while the patient was receiving effective treatment with heparin. Nineteen days after orchiectomy, treatment with acenocoumarol was started, and the heparin infusion was interrupted five days later. Oral anticoagulation was continued for one year (target value for the International Normalized Ratio, 2.5). At this time, Doppler ultrasonography and ascending phlebography showed substantial recanalization of the femoropopliteal venous system.
Results
On the third postoperative day, while the boy was being treated with intravenous heparin, the APTT ratio was 1.60, the prothrombin-time ratio was 1.19, the batroxobin (Reptilase)-time ratio was 1.02, the prothrombin-time-derived fibrinogen level was 238 mg per deciliter, and the platelet count was 194,000 per cubic millimeter. Concentrations of antithrombin III (1.01 U per milliliter), plasminogen (1.31 U per milliliter), heparin cofactor II (1.02 U per milliliter), and protein C (antigen, 0.91 U per milliliter; anticoagulant activity, 1.01 U per milliliter) were normal. The patient's protein S levels were markedly reduced, with 0.14 U of total protein S antigen per milliliter and less than 0.06 U of free protein S and protein S anticoagulant activity per milliliter. Crossed immunoelectrophoresis showed a markedly reduced, faint cathodal precipitin arc corresponding to protein S bound by C4b-binding protein, with no precipitation in the area of the free protein S peak. The level of C4b-binding protein was 1.40 U per milliliter. The levels of factors VII (0.84 U per milliliter), IX (1.00 U per milliliter), x(0.98 U per milliliter), and II (1.04 U per milliliter) were normal.
The patient's relatives were investigated to determine whether there was a familial deficiency of protein S. Unexpectedly, unequivocally normal levels of protein S antigen and activity were found (Table 1Table 1
Protein S Status of the Patient and His Family Members.), and there was no family history of thrombosis. The boy's total protein S antigen levels increased gradually to 0.28 U per milliliter on the 8th postoperative day and to 0.47 U per milliliter on the 13th day, and they were normal by the 19th postoperative day (0.84 U per milliliter). Free protein S antigen and activity levels were 0.06, 0.15, and 0.26 U per milliliter and 0.06, 0.17, and 0.24 U per milliliter, respectively, on the 8th, 13th, and 19th postoperative day. The levels of C4b-binding protein increased slightly to 1.50, 1.70, and 1.90 U per milliliter. These changes suggested the presence of an antibody to protein S in the patient's plasma.We objectively demonstrated the binding of IgG antibody to protein S by transferring purified protein S onto nitrocellulose membranes and incubating the membranes with the patient's plasma or IgG fraction. The IgG bound to blotted protein S was detectable by the addition of rabbit antihuman IgG or radiolabeled protein S (Figure 1Figure 1
Detection of IgG Antibody to Protein S by Immunoblotting.). The strength of the reaction with blotted protein S, as reflected by the intensity of staining, was inversely proportional to the dilution of the sample and was absent with normal pooled plasma (Figure 1). Polyacrylamide isoelectric focusing of the patient's plasma proteins permitted the identification of two discrete IgG bands that migrated in the pH range of 6.8 to 7.2 and were absent in normal pooled plasma (Figure 2Figure 2
Polyacrylamide Isoelectric Focusing of Plasma IgG.).A direct ELISA was developed to monitor the changes in the antibody titer. The specificity of the ELISA was proved by the displacement of the antibody from solid-phase protein S after the addition of purified protein S to the patient's plasma (dilution, 1:1000). Half-maximal displacement was observed at a two- to fourfold excess concentration of protein S in solution, indicating the reversibility of binding. The binding of the antibody to solid-phase protein S was not affected by a large excess of varicella-zoster virus antigen preparation (62Ai38, Behring). A sample of varicella-zoster virus hyperimmune human serum (S 82-316, Behring) showed no IgG binding to protein S in the ELISA. The patient's anti-protein S antibody was essentially reactive to anti-lambda chain IgG. Figure 3Figure 3
Change in Total Protein S Antigen Levels and Anti-Protein S Antibody Titer. shows the changes in the antibody titer and in the levels of total plasma protein S antigen in the days after surgery. The increase in plasma protein S levels mirrored the decrease in the antibody titer; clearance of the antibody from the circulation was biphasic; 50 percent of it was cleared in approximately 15 days.Like the IgG fraction of normal pooled plasma, the patient's total IgG fraction (final concentration, 3.5 mg per milliliter) did not inhibit the activated protein C cofactor activity of protein S. Goat polyclonal IgG substantially inhibited protein S activity at a concentration of 12 μg per milliliter (residual protein S activity, 0.12 U per milliliter). There was no inhibition of protein S activity with the mouse monoclonal antibodies HPS-2 and 3B10.25 (100 μg per milliliter); with 5E9E9, maximal inhibition (residual protein S activity, 0.70 U per milliliter) was observed at a concentration of 12 μg per milliliter. Virtually identical results were obtained with the patient's plasma and purified protein S.
A large panel of autoantibodies was assessed to investigate the presence of additional manifestations of autoimmune disease. There was a slightly positive response to anti-smooth-muscle-cell antibodies (1:40) and anticardiolipin (IgG) antibodies (26 IU per milliliter; normal value, <12.5). The levels of complement components C3 and C4 were normal. Anticardiolipin antibodies were negligible (level, 9 IU per milliliter) one year after orchiectomy.
Discussion
Spontaneously occurring antibodies to the natural inhibitors of blood coagulation have been described in two previous reports27,28. In both cases, the presence of an inhibitor to protein C was suspected because of the presence of reduced levels of activity and normal antigen levels of the protein. The observation of inhibitory activity has also been the mainstay of the diagnosis of spontaneous inhibitors to factor VIII, although the autoantibodies involved, which in most instances are of polyclonal origin, may also recognize epitopes at a distance from the active site29.
We describe a novel type of acquired protein S deficiency associated with a circulating antibody to protein S. The antibody was of monooligoclonal origin, belonged to the IgG lambda class, and had an isoelectric point close to pH 7.0. Although present in a relatively low concentration, the antibody was associated with a severe deficiency of total protein S antigen -- but not of the other vitamin K-dependent clotting factors -- and virtually unmeasurable plasma protein S activity. The strict temporal association of the disappearance of the antibody from the circulation with the return of plasma protein S to normal levels strongly suggests a cause-effect relation. Rapid clearance of the circulating immune complex may have resulted in the low levels of protein S antigen. Like some heterologous monoclonal antibodies, the antibody had no direct inhibitory effect on the activity of protein S, a finding indicating interaction with a protein S epitope or epitopes not involved in the expression of activated protein C cofactor activity.
Although it appeared during our patient's recovery from chickenpox, the anti-protein S antibody did not cross-react with antigens of the varicella-zoster virus. The presence of antiphospholipid IgG and the low titer of anti-smooth-muscle-cell antibodies suggest that the anti-protein S antibody originated as part of a transient generalized abnormality of the immune response. Chickenpox represents a form of endotheliitis, protein S is produced and secreted by endothelial cells,30 and endothelial cell and phospholipid-binding antibodies are found in a large proportion of patients with Rocky Mountain spotted fever, a disease associated with a more severe form of vasculitis31.
The patient, an 11-year-old boy, had remarkably severe manifestations of thromboembolic disease. Their association with the presence of a transient autoimmune protein S deficiency confirms the physiologic relevance of protein S and of the entire protein C system in preventing the formation of intravascular clots, providing a clinical counterpart to the studies conducted in animals. In those studies, the infusion of protein S17 or activated protein C32 exerted a protective effect. Since the thrombosis in our patient appeared resistant to heparin therapy, the infusion of protein S or activated protein C concentrates might represent a useful adjunct to anticoagulant treatment in the control of the thrombotic manifestations in patients with autoimmune protein S deficiency.
Supported in part by a grant from the Programma Nazionale di Ricerca Farmaci, Consorzio Antitrombotici.
We are indebted to Gianvito Martino, M.D., and Giuseppina Mazzola, Ph.D., for their assistance and helpful suggestions, to Dr. Aldo Bocciardi and Franco Meschi for referring the patient, and to Francesco Dati, M.D. (Behringwerke, Marburg, Germany), for his kind gift of varicella-zoster virus antigen preparation and hyperimmune serum.
Source Information
From the Servizio di Coagulazione, Istituto Scientifico H.S. Raffaele (A.D., P.D.V., L.C., E.P., S.V.D.) and Unita di Neuroimmunologia -- Dipartimento Biotecnologie, Clinica Neurologica, Universita degli Studi di Milano (L.M.E.G.), Milan, Italy.
Address reprint requests to Dr. A. D'Angelo at the Servizio di Coagulazione, Istituto Scientifico H.S. Raffaele, Via Olgettina 60, 20132 Milan, Italy.
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