[Post-varicella cerebral thrombophlebitis with anti-protein S: report of a pediatric case]. / Thrombophlébite cérébrale post-varicelle avec anticorps anti-protéine S : à propos d'un cas pédiatrique.

Purpura fulminans and venous thrombosis are rare complications of chickenpox. We report the case of a 6 year old with no history individuals who experienced cerebral thrombophlebitis, 3 weeks after varicella. MRI, performed at admission, has objectified longitudinal sinus thrombosis and a frontal parenchymal hematoma law. Meanwhile, a recent varicella seroconversion was demonstrated. The assessment of thrombophilia, meanwhile, has objectified a significant decrease in free protein S and activity, without associated DIC. Origin acquired this deficit was confirmed by the detection of antibodies (IgG and IgM) against the total protein S by ELISA. After evaluation of the benefit/risk only anticoagulation was initiated. The clinical and biological evolution was favorable, with rapid normalization of the S protein and decrease of anti-protein S. Many studies report the presence of anti-protein S in young children at the waning of chickenpox, without their exact frequency is determined. The decrease in protein S they cause leads to a transient hypercoagulable state may result in different clinical pictures. Cases of purpura fulminans seem more frequent when venous thrombosis isolated post chickenpox, sometimes atypical, appear rare.

Venous thrombosis and pulmonary embolism in a child with pneumonia due to Mycoplasma pneumoniae.

A 13-year-old boy with Mycoplasma pneumoniae pulmonary infection developed deep vein thrombosis and pulmonary embolism. He was found to have protein S deficiency and transient antiphospholipid antibodies. Though uncommon, it is important to consider venous thromboembolic disease in children whose clinical course is atypically severe.

[Spontaneous skin necrosis from acquired protein S deficiency in a renal transplant recipient]. / Nécrose cutanée spontanée par déficit auto-immun en protéine S chez un transplanté rénal.

INTRODUCTION: Spontaneous skin necrosis revealed acquired protein S deficiency due to isotype G autoantibodies. CASE: This 31-year-old male renal transplant recipient, receiving immunosuppressive treatment, was hospitalized for necrotic purpural lesions. We were not able to detect any triggering factor. Sustained anticoagulant therapy remained essential to prevent new skin lesions and perhaps more thrombotic events. COMMENTS: This condition is rare in adulthood, but is well described in children's purpura fulminans, especially the post-varicella form. Its mechanism remains unclear.

Acquired free protein S deficiency is associated with antiphospholipid antibodies and increased thrombin generation in patients with systemic lupus erythematosus.

In order to determine whether there is a relationship between acquired free protein S deficiency and increased thrombin generation, we performed a cross-sectional study of patients with systemic lupus erythematosus (SLE). Plasma samples were assayed for free protein S and were correlated to levels of prothrombin fragments (F1 + 2); an elevated level of F1 + 2 was used as a surrogate marker for a prothrombotic state. Assays for anticardiolipin antibodies (ACA) and lupus anticoagulant (LA) were performed on two separate blood samples taken at least 3 months apart in order to detect the presence of antiphospholipid antibodies. Of the 36 subjects, 9 had reduced free protein S levels compared to 0 of 21 controls (P = 0.01) and the mean free protein S level was significantly lower in the SLE population than in controls (0.30 +/- 0.08 U/mL versus 0.43 +/- 0.10 U/mL, P < 0.001). Of the 24 subjects with antiphospholipid antibodies, 9 had reduced free protein S levels, compared to 0 of 12 subjects without antiphospholipid antibodies (P = .01). The mean F1 + 2 level was significantly higher in study subjects with reduced free protein S levels than in those with normal free protein S levels (1.22 +/- 0.50 nmol/L versus 0.78 +/- 0.27 nmol/L, P = 0.05). This study confirms an association between antiphospholipid antibodies and reduced free protein S levels and demonstrates that patients with SLE and acquired free protein S deficiency generate more thrombin than patients with SLE and normal free protein S levels. Further studies are needed to determine whether the thrombotic diathesis associated with the presence of antiphospholipid antibodies is directly caused by the concomitant presence of acquired free protein S deficiency.

Inhibition of protein S by autoantibodies in patients with acquired protein S deficiency.

This study was undertaken to analyze antibodies to protein S (PS) in patients with an acquired PS deficiency. Plasma from symptomatic patients with acquired (n = 14) or congenital (n = 10) PS deficiency and 10 healthy donors was screened for PS antibodies by immunoblotting and for anti-phospholipid antibodies. PS antibodies (IgG) were detected in five of the patients with acquired PS deficiency. These antibodies belonged to the G1 and G4 immunoglobulin subclasses. IgG fractions from the same 5 patients were shown to inhibit PS activity. The inhibition of PS activity by the 5 IgG fractions was shown to be time- and dose-dependent and was abolished following incubation with purified PS, while no effect was found after absorption with cardiolipin micelles. In addition, anticardiolipin monoclonal or human purified antibodies, failed to exert significant PS inhibition. These findings demonstrate that anti-PS antibodies are able to inhibit PS activity and that this is independent of anti-phospholipid antibodies. Given the clinical features of the patients, these antibodies should be regarded as an expression of the broad autoimmune syndrome involving the phospholipid-binding plasma proteins.

The relationship between plasma microparticles, protein S and anticardiolipin antibodies in patients with human immunodeficiency virus infection.

The high prevalence of free protein S deficiency in human immunodeficiency virus (HIV)-infected patients is poorly understood. We studied 38 HIV seropositive patients. Free protein S antigen values assayed using the polyethylene-glycol precipitation technique (PEG-fS) were statistically lower in patients than in controls. These values using a specific monoclonal antibody-based ELISA (MoAb-fS) and the values of protein S activity (S-act) were not statistically different between patients and controls. C4b-binding protein values were not different from control values. In patients, PEG-fS values were lower than MoAb-fS values. Ten patients had a PEG-fS deficiency, 4 patients had a MoAb-fS deficiency and 8 had a S-act deficiency. Protein S activity and MoAb-fS were lower in clinical groups with poor prognosis and in patients with AIDS but PEG-fS was not. A trend for reduced S-act/MoAb-fS ratios was observed in patients. PEG-fS was negatively correlated with anticardiolipin antibody titers whereas MoAb-fS was not. The plasma of PEG-fS deficient HIV-patients contained high amounts of flow cytometry detectable microparticles which were depleted from plasma by PEG precipitation. The microparticles were partly CD42b and CD4 positive but CD8 negative. These micro-particles were labelled by an anti free protein S monoclonal antibody. The observed differences between MoAb-fS and PEG-fS values were correlated with the amount of detectable plasma microparticles, just like the differences between MoAb-fS and S-act. Plasma microparticles correlated with anticardiolipin antibody titers. In summary, free protein S antigen in HIV infected patients is underestimated when the PEG precipitation technique is used due to the presence of elevated levels of microparticles that bind protein S. The activity of free protein S is also impaired by high levels of microparticles. The prevalence of free protein S deficiency in HIV positive patients is lower than previously published (4/38, approximately 10%) and is correlated with poor prognosis. By implication, use of a PEG precipitation technique might give artefactually low free protein S antigen values in other patient groups if high numbers of microparticles are present. In HIV patients, high titers of anticardiolipin antibodies are associated with high concentrations of cell-derived plasma microparticles.

Free protein S deficiency may be found in patients with antiphospholipid antibodies who do not have systemic lupus erythematosus.

In order to determine if there is a relationship between antiphospholipid antibodies and reduced free protein S levels, we evaluated 21 patients who had an antiphospholipid antibody but had neither a history of venous thromboembolism nor systemic lupus erythematosus (cases) and 55 matched controls, who did not have an antiphospholipid antibody, a history of thrombosis or systemic lupus erythematosus. Cases and controls had similar protein C and antithrombin levels. Six of 21 cases had reduced free protein S antigen levels, compared to 5 of 55 controls (chi 2 = 5.823 p < 0.025). In addition, the mean free protein S level was significantly lower in cases than in controls (0.30 +/- 0.09 units vs 0.39 +/- 0.13 units, p < 0.01, two-tailed Student's t-test). We conclude that antiphospholipid antibodies are associated with a significant decrease in free protein S levels, and that this acquired free protein S deficiency may contribute to the thrombotic diathesis seen in patients with antiphospholipid antibodies.

Coagulation activation and fibrinolytic imbalance in subjects with idiopathic antiphospholipid antibodies--a crucial role for acquired free protein S deficiency.

To explore the coagulation/fibrinolytic balance and its relation with free protein S (f-PS) in subjects with antiphospholipid antibodies (aPLs) outside the setting of autoimmune inflammatory disorders, we carried out a cross-sectional study on 18 thrombotic patients with primary antiphospholipid syndrome and 18 apparently healthy subjects with persistence of idiopathic aPLs. Prothrombin fragment 1 + 2 (F1 + 2), thrombin-antithrombin complex (TAT) and D-Dimer (D-D) were taken as markers of thrombin generation and fibrin turnover. Mean F1 + 2 levels were higher in thrombotic (p = 0.006) and non-thrombotic subjects (p = 0.0001) than in controls as were those of D-D (p < 0.0001 and p = 0.003 respectively). TAT levels did not differ. Lower mean levels of f-PS were found in thrombotic (p = 0.0006) and non-thrombotic subjects (p = 0.002) than in controls. Within both groups, mean F1 + 2 levels were higher in subjects who had low f-PS levels compared to those with normal f-PS levels (p = 0.01). Gender analysed data revealed blunted tPA release (venous occlusion test) in thrombotic females (from 16.80 +/- 0.79 to 21.3 +/- 3.9 ng/nl, NS) but not in thrombotic males (from 18.2 +/- 2.0 to 33.7 +/- 4.9 ng/ml, p=0.01) nor in asymptomatic subjects of either sex. Also, in both patient groups females had higher mean PAI than males (p < 0.0002) and than control females (p < 0.02). Low free protein S was found in 100% of non-thrombotic and in 90% of thrombotic patients with defective fibrinolysis. These data are consistent with increased thrombin generation, accelerated fibrin turnover and fibrinolysis abnormalities also in asymptomatic carriers of aPLs and highlight a central role for acquired f-PS deficiency in the thrombotic tendency of the antiphospholipid syndrome.

Protein S deficiency and antibodies to protein S in patients with Behçet's disease.

Thrombosis occurs in 20 to 30% of patients with Behçet's disease (BD). Most of the reported hemostatic abnormalities are related to the inflammatory syndrome. We have assessed the activity of antithrombin III, protein C and protein S (PS), in 30 patients with BD and in 30 healthy controls. Thrombosis antecedents were found in 16 patients. Antithrombin III and protein C were within the normal range, however free PS and PSactivity were significantly decreased in patients as compared to control group. PS deficiency detected in eight patients, was associated to thrombosis in 6 of them. No correlation was found between free PS/total PS ratio and C4bBP levels. Antibodies to PS were screened by ELISA and were present in 6 patients, associated to PS deficiency in 4, and to thrombosis antecedents in 5 cases. PS deficiency was transient in two patients, associated to a persistent antiPS in one of them. These findings suggest that auto-immune acquired PS deficiency may be involved in the pathogenesis of thrombotic events in BD.

Further evidence for the presence of anti-protein S autoantibodies in patients with systemic lupus erythematosus.

Acquired protein S (PS) deficiency in systemic lupus erythematosus (SLE) has been previously reported, but its mechanism and its possible thrombotic role have not been established. The aim of our study was to provide further evidence for auto-immune PS deficiency in 27 Tunisian SLE patients, using PS-specific enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance technology (SPR). PS deficiencies for PS activity, free PS or total PS, respectively, were found in 19, 18 and 12 patients. A significant correlation (r= -0.475, P< 0.016) was found between free/total PS ratio and C4bBP levels, suggesting a role of inflammation in free PS deficiency. Immunoglobulin IgG antibodies to PS were detected in four patients by both ELISA and SPR, in six patients only by ELISA, and in two patients only by SPR. Signals for anti-PS IgG by ELISA and SPR were, however, significantly correlated (r = 0.549, P = 0.003). These results suggest that an auto-immune mechanism could account for low PS activity in patients with SLE. Auto-antibodies to PS may form immune complexes, inducing increased clearance of PS or interfering with the protein C-protein S system.

Sneddon syndrome associated with Protein S deficiency.

Sneddon syndrome (SS) is rare, arterio-occlusive disorder characterized by generalized livedo racemosa of the skin and various central nervous symptoms due to occlusion of medium-sized arteries of unknown. Seizure, cognitive impairment, hypertension, and history of repetitive miscarriages are the other symptoms seen in this disease. Livedo racemosa involves persisting irreversible skin lesions red or blue in color with irregular margins. Usually, SS occurs in women of childbearing age. Protein S deficiency is an inherited or acquired disorder associated with an increased risk of thrombosis. We present a 33-year-old woman with SS with diffuse livedo racemosa, recurrent cerebrovascular diseases, migraine-type headache, sinus vein thrombosis, and protein S deficiency. Protein S deficiency and with Sneddon syndrome rarely encountered in the literature.

[Acute illness following chicken pox: spleen infarction as a complication of varicella zoster infection]. / Acuut ziek na waterpokken: miltinfarcten als complicatie van varicella-zosterinfectie.

BACKGROUND: Varicella zoster virus (VZV) infection can cause temporary acquired protein S or C deficiency via cross reacting antibodies and consequently inducing a hypercoagulable state. CASE DESCRIPTION: A 6-year-old girl with a history of congenital cardiac disease was seen at an Emergency Department with acute chest pain, dyspnoea and fever, seven days after developing chicken pox. Diagnostic tests revealed massive infarction of the spleen, and a protein S and C deficiency. In addition, blood cultures revealed a Lancefield group A ß-haemolytic streptococcus (GABHS). The patient recovered fully after treatment with low molecular weight heparin and antibiotics. CONCLUSION: In this patient, septic emboli caused splenic infarction. Thromboembolic complications should be suspected in children with VZV who present with acute symptoms, in particular if bacterial superinfection is found.

[Purpura fulminans]. / Purpura fulminans.

Varicella-associated purpura fulminans (PF) is a rare complication to varicella infection. The condition is due to autoantibodies directed against protein S which forms part of the anticoagulation system. Lack of protein S leads to disseminated intravascular coagulation in the small vessels, which causes thrombosis and ischemia. Despite early treatment, amputation and skin-grafting is often necessary. In this case story, we give a brief review of the pathogenesis and possible modes of treatment. Knowledge of PF is necessary since early treatment may be life-saving.

Acute renal cortical necrosis due to acquired antiprotein S antibodies.

Although varicella is a common disease of childhood, renal complications are quite rare. We report here the interesting case of a-22 month-old boy exhibiting renal cortical necrosis related to an acquired protein S deficiency following varicella. Ten days after the vesicle eruption appearance, he presented with ecchymosed heels, oligoanuric kidney failure, anemia [hemoglobin (Hb) 78 g/L], schizocytosis (2.5%), but normal platelet count. Kidney sonography and magnetic resonance imaging evoked renal cortical necrosis. All together, these features suggested acquired protein S deficiency secondary to varicella. Strikingly, it was confirmed by a dramatic decrease in protein S plasma activity and a huge increase in immunoglobulin (Ig)G antibodies against protein S in the plasma. Anticoagulation therapy in addition with plasmapheresis and steroid pulses allowed a dramatic decrease in the antibodies against protein S and recovery of normal protein S activity. Undelayed diagnosis and treatment did not avoid kidney insufficiency but prevented life-threatening complications. In the light of this case report, protein S deficiency due to antibody inhibition should be carefully monitored anytime in the context of varicella when kidney insufficiency or necrosis occurs.

Acquired protein S deficiency leads to obliterative portal venopathy and to compensatory nodular regenerative hyperplasia in HIV-infected patients.

OBJECTIVE: To identify the mechanism of nodular regenerative hyperplasia in HIV-infected patients. DESIGN: Case-control study. SETTING: The hepatology and the infectious disease units of two tertiary care centers in France. PATIENTS: We compared 13 consecutive HIV-positive patients with unexplained nodular regenerative hyperplasia to 16 consecutive HIV-positive patients without nodular regenerative hyperplasia, to eight HIV-negative patients with nodular regenerative hyperplasia from an identified cause and to 10 anonymous healthy blood donors. MAIN OUTCOME MEASURE: Patients and controls were screened for diminished protein S activity and antiprotein S immunoglobulin G (IgG) antibodies. The antiprotein S activity of purified IgG from patients and controls was assessed in a functional test of activation of protein C in which protein S serves as a cofactor. A full liver CT portography was realized on the liver explant of a case patient. RESULTS: The CT portography disclosed diffuse obliterative portal venopathy. Levels of protein S activity were lower among patients with HIV-associated nodular regenerative hyperplasia when compared with HIV-positive patients without nodular regenerative hyperplasia and when compared with HIV-negative patients with nodular regenerative hyperplasia (P < 0.005 for all comparisons). HIV-positive patients with nodular regenerative hyperplasia had significantly higher levels of antiprotein S IgG than HIV-positive patients without nodular regenerative hyperplasia and healthy controls. Purified IgG from patients with HIV-associated nodular regenerative hyperplasia specifically inhibited the protein S-dependent protein C activation. CONCLUSION: Acquired autoimmune protein S paucity and secondary thrombophilia appear to be causes of obliterative portal venopathy and compensatory nodular regenerative hyperplasia in HIV-positive patients.

Anticardiolipin and acquired protein S deficiency in early childhood.

A 27 month old child presented with left hemiplegia and was found to have deep cerebral venous thrombosis. The deep cerebral venous thrombosis resolved on warfarin. Elevated and fluctuating anticardiolipin antibodies as well as protein S deficiency were detected.

Acquired free protein S deficiency associated with multiple myeloma: a case report.

Investigation of recurrent venous thromboembolic events in a 46-year-old man with progressive IgG kappa (total serum IgG, 74.3 mg/ml) multiple myeloma revealed profound reductions in free protein S (PS) antigen (<0.l U/ml) and PS activity (0.33 U/ml). Total PS antigen, protein C, antithrombin III, and C4b-binding protein levels were within normal limits. The patient had no family history suggestive of a congenital PS deficiency and no history of thrombosis predating the diagnosis of his plasma cell dyscrasia. Patient IgG was isolated from serum using a protein A-sepharose affinity column and characterized. PS-dependent clotting assays (Staclot Protein S, Diagnostica Stago, Asnieres sur-Seine, France) performed on normal pooled plasma mixed with dilutions of patient IgG (0.0-33.0 mg/ml) revealed a dose-dependent neutralization of PS activity by 43%. Total and free PS antigen levels were measured using Laurell rocket electroimmunodiffusion (Assera-Plate Protein S, Diagnostica Stago), which revealed a similar dose-dependent reduction in free PS antigen but preserved normal total PS antigen. Free PS antigen was reduced by 77% to 0.23 U/ml using an IgG concentration (16.5 mg/ml) less than one-fourth of that of the patient at time of serum collection. Specific binding of the patient IgG to commercially available purified human PS was demonstrated by Western immunoblot analysis. Whereas acquired free PS deficiency has been previously reported in association with nephrotic syndrome, inflammatory bowel disease, HIV infection, and varicella infection, this is the first reported case of a hypercoagulable syndrome associated with acquired free PS deficiency and multiple myeloma.