Analysis of PROS1 mutations and clinical characteristics in three Chinese families with hereditary protein S deficiency.

We report three heterozygous PROS1 mutations that caused type I protein S deficiency in three unrelated Chinese families. We measured protein S activity and antigen levels for all participants, screened them for mutations in the PROS1 gene. And we employed the calibrated automated thrombin generation (CAT) method to investigate thrombin generation. Numerous bioinformatics tools were utilized to analyze the conservation, pathogenicity of mutation, and spatial structure of the protein S. Phenotyping analysis indicated that all three probands exhibited simultaneous reduced levels of PS:A, TPS:Ag, and FPS:Ag. Genetic testing revealed that proband A harbored a heterozygous c.458_458delA (p.Lys153Serfs*6) mutation in exon 5, proband B carried a heterozygous c.1687C>T (p.Gln563stop) mutation in exon 14, and proband C exhibited a heterozygous c.200A>C (p.Glu67Ala) mutation in exon 2. Bioinformatic analysis predicted that the p.Lys153Serfs*6 frameshift mutation and the p.Gln563stop nonsense mutation in the protein S were classified as "disease-causing." The identification of the novel mutation p.Lys153Serfs*6 in PROS1 enriches the Human Genome Database. Our research suggests that these three mutations (p.Lys153Serfs*6, p.Gln563stop, and p.Glu67Ala) are possibly responsible for the decreased level of protein S in the three families. Furthermore, the evidence also supports the notion that individuals who are asymptomatic but have a family history of PSD can benefit from genetic analysis of the PROS1 gene.

New plasma protein C and protein S concentrate: A synergy for therapeutic purposes.

BACKGROUND AND OBJECTIVES: Deficiencies of protein C (PC) or protein S (PS) are rare diseases, characterized by mutations in the PC or PS genes, which encode plasma serine proteases with anti-coagulant activity. Severe PC or PS deficiencies manifest in early life as neonatal purpura fulminans, a life-threatening heamorrhagic condition requiring immediate treatment. First-line treatment involves replacement therapy, followed by maintenance with anti-coagulants. Replacement therapy with specific protein concentrates is currently only limited to PC, and therefore, a PC + PS concentrate represents a useful addition to therapeutic options, particularly for severe PS deficiency. Further, the production of a PC + PS concentrate from unused plasma fractionation intermediates would impact favourably on manufacturing costs, and consequently therapy prices for patients and health systems. MATERIALS AND METHODS: Several chromatographic runs were performed on the same unused plasma fractionation intermediates using different supports to obtain a PC/PS concentrate. The best chromatographic mediums were chosen, in terms of specific activity and recovery. A full process of purification including virus inactivation/removal and lyophilization steps was set up. RESULTS: The final freeze-dried product had a mean PC concentration of 47.75 IU/mL with 11% of PS, and a mean specific activity of 202.5 IU/mg protein, corresponding to over 12,000-fold purification from plasma. CONCLUSION: The development of a novel concentrated PC/PS mixture obtained from a waste fraction of other commercial products could be used for its potential therapeutic role in the management of neonatal purpura fulminans pathology.

Thrombosis-related characteristics of pregnant women with antithrombin deficiency, protein C deficiency and protein S deficiency in Japan.

BACKGROUND:  We previously conducted a primary survey of pregnant women with hereditary thrombophilia based on national surveillance in Japan, but did not examine their thrombosis-related characteristics. Antithrombin (AT) deficiency, protein C (PC) deficiency and protein S (PS) deficiency are the major types of hereditary thrombophilia in Japan. METHODS: We examined their detailed information related to thrombosis, and evaluated peripartum outcomes in comparison with control data obtained from the Japan Society of Obstetrics and Gynecology. RESULTS: Definite or probable AT deficiency, PC deficiency and PS deficiency were observed in 80, 50, and 317 pregnancies, respectively, from 2014 to 2018 in Japan, with prevalence rates among total deliveries of 0.011%, 0.007%, 0.044%. The number of pregnancies with AT, PC and PS deficiency might have been as many as 27, 17 and 108 every year if complete answers had been provided. In the peripartum period of current pregnancies, 27.5% of women with AT deficiency, 28.0% with PC deficiency and 13.2% with PS deficiency developed thrombosis (p < 0.001 vs. control). Pregnant women with AT and PC deficiency were more susceptible to thrombosis than those with PS deficiency (P < 0.01). Of the thromboses, 92.3% occurred during pregnancy, 62.8% at less than 15 gestational weeks. The earliest onset of thrombosis was 5 gestational weeks. Prophylactic anticoagulation significantly prevented the onset of both antepartum and postpartum thrombosis (p < 0.0001). The rate of recurrent pregnancy loss in women with low PC or PS activities was significantly higher than in controls (p < 0.0001); however, it is unknown whether recurrent pregnancy loss is related to hereditary PS deficiency. There seem to have been few serious maternal or fetal/neonatal complications due to placental insufficiency related to a hypercoagulable state other than growth restriction. CONCLUSIONS: This survey revealed the thrombosis-related characteristics of pregnant women with hereditary thrombophilia in Japan. We suggest prophylactic anticoagulation to prevent maternal or fetal/neonatal complications.

Use of thrombomodulin-modified thrombin generation in uncomplicated pregnancy: the normal range and prothrombotic phenotype.

Pregnancy is a hypercoagulable state associated with an increased risk of venous thrombosis. Thrombomodulin(TM)-modified thrombin generation is a promising laboratory method to detect the thrombotic tendency and prothrombotic phenotype. 141 women were enrolled: 30 healthy non-pregnant controls, 85 healthy pregnant women (26 in 1st trimester, 28 in 2nd trimester, 31 in 3rd trimester), and 26 patients with gestational diabetes mellitus (GDM). Thrombin generation was measured using platelet poor plasma (PPP) TM + and PPP TM- reagents. The parameters were endogenous thrombin potential (ETP), Lagtime, Peak Height, time to peak and ETP ratio(ETP(TM+)/ETP(TM-)). Protein S-depleted plasma samples with different activity were prepared and measured. Pregnancy was associated with a significant decrease of ETP in the presence of TM, compared with that found in the absence of TM. This was observed in all trimesters (1st trimester 1185.67 ± 284.95 nM*min vs.1510.39 ± 281.90 nM*min, p < .001; 2nd trimester 1458.96 ± 349.65 nM*min vs. 1929.10 ± 316.98 nM*min, p < .001; 3rd trimester 1391.60 ± 317.05 nM*min vs. 1854.88 ± 327.60 nM*min, p < .001). The ETP ratio was also markedly increased in all trimesters (0.78 ± 0.10, 0.76 ± 0.11 and 0.74 ± 0.12) compared with that of non-pregnant controls (0.51 ± 0.17, p < .001). The results of ETP ratio in protein S-depleted plasmas were 0.986, 0.943 and 0.880 with 0%, 16% and 40% of protein S activity, which indirect represented the thrombotic phenotype of PS deficiency in pregnancy. TM-modified thrombin generation serves as a useful test for hypercoagulation in pregnant women. The ETP ratio and the reference range of ETP in the presence of TM could provide the basis to predict the risk of thrombotic complications during pregnancy.

A case of ischemic stroke associated with protein-losing gastroenteropathy and protein S deficiency.

Protein-losing gastroenteropathies are characterized by an excessive loss of serum proteins into the gastrointestinal tract, resulting in hypoalbuminemia. Some rare cases are complicated with ischemic stroke. We report a 24-year-old woman who developed acute dysarthria and right hemiplegia 4 months after delivering her first baby by cesarean section. Diffusion-weighted magnetic resonance imaging showed a high-intensity signal in the left anterior cerebral artery territory and middle cerebral artery territory. She had marked hypoalbuminemia and decreased protein S activity. We identified protein-losing gastroenteropathy as the cause of the hypoalbuminemia, and she had a missense mutation of the PROS 1 gene, which was associated with decreased protein S activity. We speculated that the development of protein-losing gastroenteropathy accelerated the decline in protein S activity and caused cerebral infarction.

[PROSI Mutation With Clinical Heterogeneity in Protein S Deficiency:Report of One Case].

Reduced protein S activity is one of the high-risk factors for venous thromboembolism.Hereditary protein S deficiency is an autosomal dominant disorder caused by mutations in the PROS1 gene.We reported a female patient with a mutation of c.292 G>T in exon 3 of the PROS1 gene,which was identified by sequencing.The genealogical analysis revealed that the mutation probably originated from the patient's mother.After searching against the PROS1 gene mutation database and the relevant literature,we confirmed that this mutation was reported for the first time internationally.

Cerebral venous sinus thrombosis and dural arteriovenous fistula associated with protein S deficiency: a case series study.

OBJECTIVE: To describe the characteristics of patients with cerebral venous sinus thrombosis (CVST) and dural arteriovenous fistula (AVF) associated with protein S (PS) deficiency. METHODS: We conducted a search of medical records in Hainan General Hospital from January 2000 to December 2020 for coexistence of CVST and dural AVF associated with PS deficiency and searched PubMed、Embase and Chinese biomedical databases (CBM) for all literature describing CVST and dural AVF with PS. We analyzed clinical characteristics, location, sequence of CVST and dural AVF, level of PS, therapeutic methods and prognosis. RESULTS: We presented 1 patient in our hospital's database combined CVST and dural AVF associated with PS, plus 5 cases reported in literature. The most common symptoms were headache, generalized seizure, disturbance of consciousness. The most frequent location of CVST was at internal cerebral vein, while transverse sinus, sigmoid sinus, parietal region in dural AVF. Two patients developed dural AVF several months or years after CVST. Clinical characteristics and level of PS were summarized. CONCLUSION: These findings alert physicians to consider PS deficiency in patients who suffer from CVST, especially those combined with dural AVF.

Combined preoperative plasma exchange and red blood cell exchange transfusion in a renal transplant patient with protein S deficiency and hemoglobin SC disease.

BACKGROUND: Protein S deficiency is associated with increased risk of venous thromboembolism, complicating the perioperative management of such patients. We present a patient with sickle cell disease (Hb SC genotype) and inherited protein S deficiency who underwent a living-donor renal transplant. To minimize thrombotic risk and sickle cell complications, both plasma exchange and red blood cell (RBC) exchange transfusion were performed pre-operatively. METHODS AND MATERIALS: Plasma exchange was utilized to increase protein S levels and to reduce the risk of post-operative venous thromboembolism, including allograft thrombosis, while RBC exchange was performed to reduce the risk of acute post-operative sickle cell disease complications. RESULTS: With the use of combined pre-operative plasma exchange and RBC exchange transfusion, this patient with protein S deficiency and Hb SC underwent a successful renal transplant without acute sickle cell complications or thrombotic complications. CONCLUSIONS: This case demonstrates the potential use of pre-operative plasma exchange in patients with protein S deficiency undergoing high thrombotic risk procedures.

Recurrent hematuria and painful necrotic purpura induced by acquired Protein S deficiency associated with monoclonal immunoglobulin.

Protein S deficiency is associated with an increased risk of thromboembolism, which may be caused by hereditary deficiency and several physiological and pathologic conditions, such as pregnancy, contraceptive use, liver diseases, inflammatory disease, and certain viruses infections. However, monoclonal immunoglobulin-mediated Protein S deficiency is rarely reported. Here we described a 49-year-old woman with a history of recurrent painful swelling in both lower extremities due to venous thrombosis for 7 years, accompanied by recurrent gross hematuria and multiple painful necrotic purpuras for 5 years, who was then diagnosed with acquired Protein S deficiency induced by the monoclonal immunoglobulin. Then she was successfully treated with rituximab combined with anticoagulation therapy. This case highlights the rare manifestations of Protein S deficiency and the influence of the monoclonal immunoglobulin produced by monoclonal B lymphocytes and monoclonal plasma cells on the activity of Protein S, which can be treated effectively with rituximab combined with anticoagulation therapy.

[Clinical guidance for the peripartum management of patients with hereditary thrombophilia].

Hereditary thrombophilia is a condition in which individuals are susceptible to the formation of thrombi due to a hereditary deficiency in the anticoagulant factors antithrombin (AT), protein C, or protein S. The recommendations for peripartum management are as follows: 1) For women with acute venous thromboembolism (VTE) during pregnancy, anticoagulant therapy with a therapeutic dose of unfractionated heparin (UFH) is recommended; 2) For women with a history of VTE, a prophylactic dose of UFH is suggested during pregnancy; 3) For those with AT deficiency, supplementation with an AT preparation in addition to UFH is suggested; 4) For women with no history of VTE, anticoagulant therapy during pregnancy is considered for each thrombophilia type; 5) When anticoagulant therapy consisting of a prophylactic dose of UFH is administered during pregnancy, injection is discontinued with the onset of labor pains in cases of vaginal delivery and 6 hours before the start of delivery in cases of planned delivery or cesarean section; 6) In cases of AT deficiency, regardless of the thrombophilia type, supplementation with AT before and after delivery is suggested; 7) For women with thrombophilia and a history of VTE and for those who receive anticoagulant therapy during pregnancy, postpartum anticoagulant therapy is recommended.

Lead thrombus under standard-dose edoxaban in a patient with normal to high creatinine clearance and protein S deficiency.

BACKGROUND: Non-vitamin K antagonist oral anticoagulants (NOACs) are as effective and safe as warfarin for thromboembolic prevention and treatment. The efficacy of NOACs lacks evidence from large and randomized studies in patients with inherited severe thrombophilia, including protein S deficiency. Further, some concerns still exist regarding the relative efficacy of edoxaban in preventing arterial thromboembolism in patients with normal to high creatinine clearance (CrCl). We present a case of a rare complication of lead thrombus under standard-dose edoxaban in a patient with protein S deficiency and supernormal renal function. CASE PRESENTATION: A 65-year-old man experienced persistent chest tightness and a high level of D-dimer. Chest computed tomography (CT) showed a lead thrombus at the superior vena cava. He had a medical history including, paroxysmal atrial fibrillation (PAf), sick sinus syndrome after permanent pacemaker implantation, and transient ischemic attack. He received standard-dose edoxaban (60 mg daily) after PAf was diagnosed. His estimated CrCl was 98.6-102.1 mL/min. However, protein S deficiency (22.8%; normal range: 55-130%) was diagnosed. After switching to dabigatran (150 mg twice daily) for 3 months, the chest CT showed lead thrombus resolution and no symptoms were seen during the follow-up period. CONCLUSIONS: This case was a rare complication of lead thrombus in a protein S deficient patient with normal renal function receiving standard-dose edoxaban. Edoxaban efficacy is uncertain in patients with protein S deficiency, and intracardiac devices also increase the risk of thromboembolic events.

Two Novel Variants in the Protein S Gene PROS1 Are Associated with Protein S Deficiency and Thrombophilia.

Protein S (PS) is an important anticoagulant. Its main function is to act as a non-enzymatical cofactor of activated protein C. PS deficiency is defined as low plasma levels of PS and/or loss of function associated with variable risk of venous thromboembolism (VTE). We report 2 novel variants in the PS gene (PROS1) which are associated with PS deficiency and severe thrombophilic diathesis in 2 patients. Patient 1 suffered from 3 VTE events, including a spontaneous VTE at the age of 19. Patient 2 suffered from 2 provoked VTE events. In both patients decreased plasma levels of PS antigen as well as decreased PS activity were found. Gene sequencing results showed a heterozygous deletion of 8 base pairs (c.938_945delTAAAATTT, p.Leu313Serfs13*) in exon 9 of the PROS1 gene in patient 1 and a missense variant (c.1613C>T, p.Ser538Phe) in patient 2. Due to the clinically proven history of recurrent VTE events in both patients, genetic testing of first-degree relatives is discussed.

Thrombophilic alterations, migraine, and vascular disease: results from a case-control study.

BACKGROUND: The association between thrombophilic alterations, migraine, and vascular events has been broadly investigated but not been completely clarified. METHODS: In this cross-sectional, case-control study, we included consecutive outpatients diagnosed with migraine referring to a tertiary headache center. Migraine patients were matched to headache-free control subjects. All participants were evaluated for free protein S anticoagulant, functional protein C anticoagulant, homocysteine, and antiphospholipid antibodies (aPLs). History of ischemic stroke (IS) or transient ischemic attack (TIA), coronary heart disease, and peripheral venous thrombosis was also ascertained. RESULTS: We included 329 migraine patients and 329 control subjects (mean age 41 years, 77% women in both groups). Among migraine patients, 239 (72.6%) had migraine without aura and 90 (27.4%) had migraine with aura. Migraine patients had more frequently arterial hypertension, hypercholesterolemia, history of IS or TIA and, peripheral venous thrombosis compared to control subjects, whereas we found no differences in diabetes mellitus, BMI, and coronary heart disease between the two groups. At least one thrombophilic alteration was detected in 107 (32.5%) migraine patients and in 74 (22.5%) control subjects (OR = 1.66, 95% CI 1.17-2.35, p = 0.004). We identified an association of migraine with aPL positivity (OR = 2.6, 95% CI 1.5-4.7, p = 0.001) and with free protein S deficiency (OR = 4.7, 95% CI 1.6-14.0, p = 0.002), whereas we found no differences in protein C deficiency, APCR, and hyperhomocysteinemia between the two groups. Furthermore, aPL positivity and free protein S deficiency were more common in migraine patients with and without aura than in control subjects. We found that in migraine patients, aPL positivity was associated with both IS or TIA (OR = 5.6, 95% CI 1.5-20.4, p = 0.009) and with coronary heart disease (OR = 27.6, 95% CI 1.4-531.1, p = 0.028), whereas free protein S deficiency was associated with IS or TIA only (OR = 14.3, 95% CI 2.8-74.4, p = 0.002). CONCLUSIONS: Our research documented a significative higher prevalence of aPL positivity and protein S deficiency in migraineurs than in controls. Data also showed an association between these alterations and some vascular thrombotic events in migraine patients. We can argue that thrombophilic disorders associated with migraine may contribute to the occurrence of vascular events.

Clinical guidance for peripartum management of patients with hereditary thrombophilia.

Hereditary thrombophilia is a condition in which individuals are susceptible to the formation of thrombi due to a hereditary deficiency in anticoagulant factors, antithrombin (AT), protein C (PC), or protein S (PS). Many Japanese thrombophilia patients have PS deficiency, especially PS p.K196E (also called as PS Tokushima), which is exclusive to the Japanese population, and thrombosis sometimes occurs during pregnancy. At present, no management guidelines for pregnancy and delivery in thrombophilia patients have been developed. The Study Group for Hereditary Thrombophilia, one of the research groups of blood coagulation abnormalities in the Research Program on Rare and Intractable Diseases supported with the Research Grants of the Ministry of Health, Labour and Welfare Science, has therefore developed this clinical guidance to provide healthcare workers with necessary information on safe pregnancy, parturition and neonatal management, adopting a format of responses to seven clinical questions (CQ). At the end of each answer, the corresponding Recommendation Level (A, B, C) is indicated.

A novel rare c.-39C>T mutation in the PROS1 5'UTR causing PS deficiency by creating a new upstream translation initiation codon.

Autosomal dominant inherited Protein S deficiency (PSD) (MIM 612336) is a rare disorder caused by rare mutations, mainly located in the coding sequence of the structural PROS1 gene, and associated with an increased risk of venous thromboembolism. To identify the molecular defect underlying PSD observed in an extended French pedigree with seven PSD affected members in whom no candidate deleterious PROS1 mutation was detected by Sanger sequencing of PROS1 exons and their flanking intronic regions or via an multiplex ligation-dependent probe amplification (MLPA) approach, a whole genome sequencing strategy was adopted. This led to the identification of a never reported C to T substitution at c.-39 from the natural ATG codon of the PROS1 gene that completely segregates with PSD in the whole family. This substitution ACG→ATG creates a new start codon upstream of the main ATG. We experimentally demonstrated in HeLa cells that the variant generates a novel overlapping upstream open reading frame (uORF) and inhibits the translation of the wild-type PS. This work describes the first example of 5'UTR PROS1 mutation causing PSD through the creation of an uORF, a mutation that is not predicted to be deleterious by standard annotation softwares, and emphasizes the need for better exploration of such type of non-coding variations in clinical genomics.

Validation and standardization of the ETP-based activated protein C resistance test for the clinical investigation of steroid contraceptives in women: an unmet clinical and regulatory need.

Background Regulatory bodies recommend the use of an assay based on the assessment of the endogenous thrombin potential (ETP) for the investigation of the activated protein C resistance (APCr) in the development of steroid contraceptives in women. However, the assays described in the literature are home-made and not standardized regarding the method, the reagents, the reference plasma and the quality controls. In the absence of any commercially available method, we aimed at validating the ETP-based APCr assay. Methods The validation was performed according to regulatory standards. The method targets a 90% inhibition of the ETP in healthy donors in the presence of APC compared to the same condition in the absence of APC. As a large-scale production of a pool of plasma from well-selected healthy donors is impossible, algorithms were applied to a commercial reference plasma to correlate with the selected pool. Results Repeatability and intermediate precision passed the acceptance criteria. The assay demonstrated a curvilinear dose response to protein S and APC concentrations (R2 > 0.99). Analysis of plasma samples from 47 healthy individuals (22 women not taking combined hormonal contraceptives [CHC], and 25 men not Factor V Leiden carriers) confirmed the validity of the test, with a mean inhibition percentage of 90%. Investigations in 15 women taking different contraceptives and in two subjects with Factor V Leiden confirmed the good sensitivity and performance of the assay. Conclusions This validation provides the pharmaceutical industry, the regulatory bodies and physicians with a reproducible, sensitive and validated gold-standard ETP-based APCr assay.

A novel mutation Gly222Arg in PROS1 causing protein S deficiency in a patient with pulmonary embolism.

BACKGROUND: Thrombophilia is becoming a more frequently reported disorder these years. Hereditary protein S deficiency is one of the anticoagulant deficiencies that eventually results in thrombophilia. CASE PRESENTATION: A 24-year-old male patient was suffering from unexplained thrombosis for the second time with a family history of deep venous thrombosis. Screening tests for anticoagulant proteins found the activity of protein S markedly lowered (5.0%). The patient was discharged after anticoagulation treatment. Four years later, the review still showed the activity of protein S in his plasma decreased (16.0%). Molecular genetic analysis revealed him homozygous for a missense mutation, c.664G>A, in the exon7 of PROS1. The mutation discovered here is the first mutation affecting the codon 222 of PROS1. This mutation results in the replacement of the glycine at the codon 222 of protein S with arginine, leading to a reduction of protein S function. CONCLUSIONS: The finding of this mutation may help with the understanding of the mechanism of protein S deficiency, especially in the Chinese population.

Ischemic Stroke with Protein S Deficiency Treated by Apixaban.

A 57-year-old man with atherosclerosis obliterans was admitted with sudden-onset sensory aphasia and right hemiparesis. Brain MRI revealed acute cerebral infarctions in the left temporal lobe and magnetic resonance angiography showed occlusion of the posterior branch of the left middle cerebral artery. Transesophageal echocardiography and ultrasonography respectively confirmed a patent foramen ovale and deep vein thrombosis in the bilateral femoral veins. Blood findings showed low protein S antigen, low protein S activity, and a missense mutation of the PROS 1 gene. The administration of apixaban 10 mg BID prevented ischemic stroke recurrence and decreased the deep vein thrombosis. These outcomes indicated that apixaban may be alternative to warfarin for the secondary prevention of ischemic stroke in a patient with a protein S deficiency.

[Hereditary protein S deficiency: survey results from a Chinese pedigree].

Objective: To investigate the clinical characteristics and gene mutation, and analyze the association between genotype and phenotype of hereditary protein S deficiency in a Chinese pedigree. Methods: Hereditary protein S deficiency was diagnosed in January 2016 in our hospital. A total of 26 family members were surveyed in this study. Blood samples and clinical data were collected from them, and mutations were identified by Sanger sequencing. Pathogenicity of gene mutations was predicted by protein function prediction software including SIFT, PolyPhen_2, nsSNPAnalyzer and MutPred2. Swiss Model (https://swissmodel.expasy.org/) was used to perform homology modeling of the tertiary structure of the protein S wild-type and mutant-type, and observe the impact of gene mutation on the tertiary structure of the protein. Results: Four out of 26 family members of 4 generations were clinically diagnosed with hereditary protein S deficiency. The proband presented with recurrent pulmonary embolism and venous thromboembolism of the lower extremities, and her uncle and mother had a history of venous thromboembolism. Sequencing revealed a mutation in the c.200A>C gene in the second exon of the PROS1 gene of proband and part of her families (Ⅱ2, Ⅱ6, Ⅲ4, Ⅳ2). The prediction results of this gene mutation performed by SIFT, PolyPhen_2, nsSNPAnalyzer, MutPred2 were all harmful. The results of Swiss-Model homology modeling showed that the 67th amino acid was mutated from glutamic acid to alanine because of this gene mutation. Conclusion: A gene mutation cDNA (c. 200A>T) is identified in a Chinese pedigree with hereditary protein S deficiency. This gene mutation may reduce protein S activity, which may cause recurrent pulmonary embolism and venous thromboembolism of the patients.

Risk Factors and Outcomes of Recurrent Pregnancy Loss in Japan.

AIM: To clarify the risk factors and pregnancy outcomes for each risk factor of recurrent pregnancy loss (RPL) in Japan. METHODS: Using a prospective RPL database collected from 16 facilities in Japan, the prevalence of risk factors for RPL, their treatments and pregnancy outcomes were examined. RESULTS: Of 6663 patients registered in our database, 5708 patients had RPL. All examinations for risk factors were performed for 1340 patients (23.5%). The prevalences of positive antiphospholipid antibodies (aPL), malformation of the uterus, thyroid dysfunction, parental karyotype abnormality, factor XII deficiency, protein S deficiency and unknown risk factors were 8.7%, 7.9%, 9.5%, 3.7%, 7.6%, 4.3% and 65.1%, respectively. Although factor XII deficiency and protein S deficiency are not recognized as risk factors for RPL in general, low-dose aspirin (LDA) or unfractionated heparin + LDA therapy improved live birth rates. In transiently aPL-positive patients, the live birth rate with LDA therapy was similar to that with heparin + LDA. For unknown risk factors of RPL, the live birth rate in normal fetal karyotype in the none treatment group was similar to that in all other treatments group (81.3% vs 86.0%). Of 5708 RPL patients, pregnancy outcomes were known for 2261 patients and 1697 patients (75.1%) had at least one live birth. CONCLUSION: The risk factors and pregnancy outcomes for each risk factor of RPL are useful for clinicians and patients. Factor XII deficiency and protein S deficiency may be risk factors of RPL.