1/15. sagittal sinus thrombosis associated with transient free protein s deficiency after L-asparaginase treatment: case report and review of the literature.Cerebral sinus thrombosis associated with acquired free protein s deficiency is very rare. We report the case of an adult patient with acute lymphoblastic leukemia who presented with repeated transient ischemic attacks followed by a seizure during consolidation treatment with L-asparaginase. Magnetic resonance of the brain showed a small cortical hemorrhagic infarct. Superior sagittal sinus thrombosis was demonstrated by cerebral angiogram. A marked decrease of the free form of protein S was documented. One month later, when the patient was free of symptoms, the follow-up free protein S antigen level was restored to the normal range. We suggest that the sagittal sinus thrombosis in this patient was caused by acquired, transient free protein s deficiency. This case also extends the clinical spectrum of cerebral sinus thrombosis to include recurrent transient ischemic attacks alternating with seizures.- - - - - - - - - - ranking = 1keywords = antigen (Clic here for more details about this article) |
2/15. Lupus anticoagulant and protein s deficiency in a child who developed disseminated intravascular coagulation in association with varicella.Varicella is not always a benign disease it may cause serious complications. We report a two-year-old boy with disseminated intravascular coagulation in association with varicella. The patient had the lupus anticoagulant, the antiphospholipid antibody, acquired free protein s deficiency, and increased concentrations of the prothrombin F 1 2 fragment. Intravenous immunoglobulin was administered due to its potential antibody-blocking activity, and the patient responded well. We recommend that children with varicella and disseminated intravascular coagulation should be examined for the lupus anticoagulant, the free protein S antigen, the prothrombin fragment F 1 2 and the other coagulation parameters. Intravenous immunoglobulin administration could be useful in such conditions because of its antibody-blocking activity.- - - - - - - - - - ranking = 1keywords = antigen (Clic here for more details about this article) |
3/15. Protein S gene mutation in a young woman with type III protein s deficiency and venous thrombosis during pregnancy.BACKGROUND: We attempted to identify a gene defect in a young woman with type III protein s deficiency and venous thrombosis during pregnancy. methods: Measurements of total and free PS antigen levels in plasma were carried out using an enzyme-linked immunosorbent assay. plasma PS cofactor activity was determined by a clotting assay using activated factor V as the substrate. Genomic dna prepared from peripheral blood was amplified by polymerase chain reaction (PCR) with PROS1-specific oligonucleotide primers. PCR products were sequenced on both strands using specific oligonucleotide primers. RESULTS: plasma PS cofactor activity was undetectable in every measurement at 36 weeks of gestation, as well as at 2 weeks and 4 months after delivery. plasma total PS antigen levels were 70% and 67% at 2 weeks and 4 months after delivery, respectively. Free PS antigen level was 24% at 4 months after delivery. Of all exons analyzed, codon 295 of GGC in exon 10 was substituted for AGC. This missense mutation predicted an amino acid change of glycine to serine. CONCLUSIONS: Measurements of total and free PS antigen levels along with PS activity indicated that this was a case of type III PS deficiency. dna analysis identified a heterozygous missense mutation of codon 295 in the PS gene, substituting glycine for serine.- - - - - - - - - - ranking = 4keywords = antigen (Clic here for more details about this article) |
4/15. Protein S Gla-domain mutations causing impaired Ca(2 )-induced phospholipid binding and severe functional protein s deficiency.We have identified 2 PROS1 missense mutations in the exon that encodes the vitamin k-dependent Gla domain of protein S (Gly11Asp and Thr37Met) in kindred with phenotypic protein s deficiency and thrombosis. In studies using recombinant proteins, substitution of Gly11Asp did not affect production of protein S but resulted in 15.2-fold reduced protein S activity in a factor va inactivation assay. Substitution of Thr37Met reduced expression by 33.2% (P <.001) and activity by 3.6-fold. The Gly11Asp variant had 5.4-fold reduced affinity for anionic phospholipid vesicles (P <.0001) and decreased affinity for an antibody specific for the Ca(2 )-dependent conformation of the protein S Gla domain (HPS21). Examination of a molecular model suggested that this could be due to repositioning of Gla29. In contrast, the Thr37Met variant had only a modest 1.5-fold (P <.001), reduced affinities for phospholipid and HPS21. This mutation seems to disrupt the aromatic stack region. The proposita was a compound heterozygote with free protein S antigen levels just below the lower limit of the normal range, and this is now attributed to the partial expression defect of the Thr37Met mutation. The activity levels were strongly reduced to 15% of normal, probably reflecting the functional deficit of both protein S variants. Her son (who was heterozygous only for Thr37Met) had borderline levels of protein S antigen and activity, reflecting the partial secretion and functional defect associated with this mutation. This first characterization of natural protein S Gla-domain variants highlights the importance of the high affinity protein S-phospholipid interaction for its anticoagulant role.- - - - - - - - - - ranking = 2keywords = antigen (Clic here for more details about this article) |
5/15. A novel G-to-A mutation in the intron-N of the protein S gene leading to abnormal rna splicing in a patient with protein s deficiency.BACKGROUND AND OBJECTIVES: Hereditary protein S (PS) deficiency is a rare autosomal disorder of the coagulation pathway associated with familial thrombophilia. DESIGN AND methods: We investigated a young propositus with recurrent deep vein thrombosis, a positive family history for thrombotic episodes, and low plasma concentrations of free, but not total PS antigen (12% and 70%, respectively). RESULTS: sequence analysis of the PS gene showed a heterozygous G-to-A mutation at the first nucleotide of intron N. The patient's father, who had suffered from deep vein thrombosis and had reduced total and free PS antigen (59% and 28%, respectively) was a heterozygote. The G-to-A change predicts the disappearance of a donor splice site. After transfection with a construct, containing either the wild-type or the mutated sequence, cells with the mutant construct showed an aberrant mRNA, consistent with exclusion of exon 14, but not the expected mRNA. Sequencing of the abnormal mRNA showed the complete absence of exon 14. Exclusion of exon 14 predicts the deletion of the amino acid sequence from residue 508 to residue 582, and the shift of the reading frame of the following 8 amino acids with a premature stop codon within exon 15 at position 591. Thus, the truncated PS gene product would not contain the terminal portion of the sex hormone binding globulin-like domain. INTERPRETATION AND CONCLUSIONS: We have identified a mutation in a highly conserved intronic region of PS gene. The mutation affects in vitro mRNA processing and efficiency of normal splicing.- - - - - - - - - - ranking = 2keywords = antigen (Clic here for more details about this article) |
6/15. Intra-cardial thrombosis with systemic and pulmonary embolism as main symptoms in a patient with protein s deficiency.This report describes the unusual occurrence of both left and right atrial thrombosis with peripheral arterial and pulmonary embolism, respectively, as presenting symptoms of congenital protein s deficiency in a 31-year-old man. The coagulation study performed in the coumarin-treated propositus indicated a heterozygous protein S state. The finding of reduced free protein S antigen and protein S activity levels with normal total protein S and C4B-bp levels in five other family members (father, sister, and three relatives on the paternal side) confirmed the inherited nature of the defect. Since there is an increased frequency of arterial thrombosis in patients suffering from protein s deficiency, any case of idiopathic intra-cardial thrombosis requires careful haemostatic screening. In addition, the possibility of intra-cardial thrombosis should be considered in any thromboembolic event seen in inherited protein s deficiency.- - - - - - - - - - ranking = 1keywords = antigen (Clic here for more details about this article) |
7/15. Combined inherited protein S and heparin co-factor II deficiency in a patient with upper limb thrombosis: a family study.A 42-year-old Italian woman presenting with spontaneous deep vein thrombosis of the right arm, was found to have inherited a deficiency of both protein S (PS) and heparin co-factor II (HC II). The two defects seemed to segregate independently, since her son exhibited only a HC II deficiency while one of her sisters manifested only the PS defect. All affected patients appeared heterozygous for one or other or both deficiency states. The proposita and her sister exhibited a congenital PS deficiency consisting of normal or near normal levels of total PS antigen and C4b-binding protein (C4b-BP) but a moderate reduction both of free PS antigen and of PS functional activity. In addition, the proposita and her son had half normal levels of HC II antigen and activity. Except for the proposita, all were asymptomatic. Inherited deficiencies either of PS or of HC II have been associated with thrombotic manifestations. Since the proposita had an inherited combined defect of the two proteins, severe thrombotic events might be expected. However, this was not found to be the case. The role of HC II deficiency in the pathogenesis of thrombosis whether alone or combined remains to be fully investigated.- - - - - - - - - - ranking = 3keywords = antigen (Clic here for more details about this article) |
8/15. Unusual thromboses associated with protein s deficiency in patients with acquired immunodeficiency syndrome: case reports and review of the literature.Recent reports indicate that patients infected with hiv are at increased risk for the development of thrombosis. Among other possibilities, an acquired deficiency of protein S (PS), one of the plasma's natural anticoagulants, might explain this tendency. PS deficiency can be classified in three types depending on the levels of total and free protein (antigenic assays) as well as anticoagulant activity (functional assay). Although the prevalence of inherited PS deficiency is not known because of its rarity, several conditions can lead to acquired forms of the disease. We report two AIDS patients with coexistent type III PS deficiency and thrombosis. Our first patient presented with bilateral chronic leg ulcers and a skin biopsy revealed dermal microthromboses. On laboratory evaluation he had PS deficiency and was started on anticoagulation, but was lost to follow-up. The second patient presented with hepatic vein thrombosis (budd-chiari syndrome) and was also PS deficient. On long-term anticoagulation, she experienced resolution of the thrombosis. Neither patient had prior personal or family history of venous thrombosis, nor acquired risk factors such as immobility, acute infection, recent surgery, or hormonal therapy. The literature contains a few reports of skin ulcers and budd-chiari syndrome associated with PS deficiency, although none in AIDS patients. While a larger number of studies describe an association between PS deficiency and hiv infection, the causal effect of this deficiency on the thrombophilic tendency in AIDS has not been established. We propose that awareness of the increased risk for thrombosis in hiv infection is important to the understanding of disease pathophysiology and management of these patients.- - - - - - - - - - ranking = 1keywords = antigen (Clic here for more details about this article) |
9/15. Molecular bases of type II protein s deficiency: the I203-D204 deletion in the EGF4 domain alters GLA domain function.OBJECTIVE: To characterize the first type II protein S (PS) deficiency affecting the epidermal growth factor (EGF)4 domain, a calcium-binding module with a poorly defined functional role. patients: The proband suffered from recurrent deep vein thrombosis and showed reduced PS anticoagulant activity (31%), and total, free PS antigen and C4bBP levels in the normal range. RESULTS: reverse transcription-polymerase chain reaction analysis showed the presence of the IVSg-2A/T splicing mutation that, by activating a cryptic splice site, causes the deletion of codons Ile203 and Asp204. Free PS, immunopurified from proband's plasma, showed an altered electrophoretic pattern in native condition or in the presence of Ca2 . The recombinant PS (rPS) mutant showed reduced anticoagulant (<10%) and activated protein c-independent activities (24-38%) when compared with wild-type rPS (rPSwt). Binding of the rPS variant to phospholipid vesicles (Kd 235.7 /- 30.8 nM, rPSwt; Kd 15.2 /- 0.9 nM) as well as to Ca2 -dependent conformation-specific monoclonal antibodies for GLA domain was significantly reduced. CONCLUSIONS: These data aid in the characterization of the functional role of the EGF4 domain in the anticoagulant activities of PS and in defining the thrombophilic nature of type II PS deficiency.- - - - - - - - - - ranking = 1keywords = antigen (Clic here for more details about this article) |
10/15. Identification of a novel PROS1 c.1113T-->GG frameshift mutation in a family with mixed type I/type III protein s deficiency.We report a family with type I and type III protein S (PS) deficiency, which showed to be phenotypic variants of the same genetic disease. Direct sequencing analysis of the PROS1 gene was performed to establish the genotype. The ratio of protein c antigen and total PS antigen levels (protein c/S ratio) was used to classify subjects at risk of venous thromboembolism. All PS deficient subjects had increased protein c/S ratios as well as a novel PROS1 c.1113T-->GG frameshift mutation.- - - - - - - - - - ranking = 2keywords = antigen (Clic here for more details about this article) |
| | Next -> |