Isolated gastric varices associated with antiphospholipid syndrome and protein S deficiency: a case report and review of the literature.

The mortality rate of gastric varices bleeding can reach 20% within 6 weeks. Isolated gastric varices (IGVs) refer to gastric varices without esophageal varices and typically arise as a common complication of left portal hypertension. Although IGVs commonly form in the setting of splenic vein occlusion, the combination of antiphospholipid syndrome and protein S deficiency leading to splenic vein occlusion is rare. We herein present a case of a 28-year-old woman with intermittent epigastric pain and melena. She was diagnosed with antiphospholipid syndrome based on the triad of pregnancy morbidity, unexplained venous occlusion, and positive lupus anticoagulant. Laparoscopic splenectomy and pericardial devascularization were performed for the treatment of IGVs. During the 6-month postoperative follow-up, repeated endoscopy and contrast-enhanced computed tomography revealed disappearance of the IGVs. This is the first description of splenic vein occlusion associated with both antiphospholipid syndrome and protein S deficiency. We also provide a review of the etiology, clinical manifestations, diagnosis, and treatment methods of IGVs.

The Protein S Erlangen Mutation PROS1c.1904T>C (F635S) Suppresses Secretion.

BACKGROUND: The recently identified PROS1 mutation Protein S Erlangen c.1904T>C, resulting in amino acid exchange F635S, is associated with severe quantitative protein S (PS) deficiency and clinical thrombosis. It was hypothesized that this deficiency is due to a secretion defect [1]. This report aims to further elucidate the potential secretion defect of PS Erlangen. METHODS: Coding sequences (CDS) of wild type (WT) PROS1 (encoding PS) and mutated PROS1c.1904T>C (encoding PSF635S) were cloned in front of the CDS of green fluorescent protein (GFP), and the respective plasmids were introduced into HEK293T cells. PROS1-GFP and PROS1c.1904T>C-GFP expressing HEK293T cell lines were analyzed by confocal laser scanning microscopy and western blot for cellular proteins and proteins secreted to the growth medium. RESULTS: Western blot analysis revealed a significantly reduced secretion of PSF635S compared to WT PS. This observation was confirmed by the detection of mutant PSF635S-GFP fusion exclusively in the endoplasmic reticulum (ER), while PS-GFP passed through the entire secretory pathway, as indicated by the localization within both the ER and Golgi apparatus. CONCLUSIONS: The Protein S Erlangen mutation results in type I PS deficiency caused by a secretion defect.

Outcomes of venous thromboembolism in patients with inherited thrombophilia treated with direct oral anticoagulants: insights from the RIETE registry.

While direct oral anticoagulants (DOACs) are frequently used to treat venous thromboembolism (VTE), the outcomes of patients with inherited thrombophilia (IT) receiving DOACs for VTE remain understudied. We used data from the international RIETE registry to compare the rates of VTE recurrences, major bleeding, and mortality during anticoagulant treatment in VTE patients with and without IT, grouped by the use of DOACs or standard anticoagulant therapy. Among 103,818 enrolled patients, 21,089 (20.3%) were tested for IT, of whom 8422 (39.9%) tested positive: Protein C deficiency 294, Protein S deficiency 726, Antithrombin deficiency 240, Factor V Leiden 2248, Prothrombin gene mutation 1434, combined IT 3480. Overall, 14,189 RIETE patients (6.2% with IT) received DOACs, and 89,629 standard anticoagulation (8.4% with IT), mostly with heparins followed by vitamin K antagonists. Proportions of patients receiving DOACs did not differ between IT-positive and IT-negative patients. Rates of VTE recurrence on anticoagulant treatment were highest in patients with AT deficiency (P < 0.01). Rates of on-treatment major bleeding and all-cause mortality were lowest among patients with Factor V Leiden (FVL) or PT G20210A mutations, compared with patients who tested negative. Patients with IT who received DOACs had lower rates of major bleeding than those receiving standard anticoagulation. Excluding FVL and Protein S deficiency, patients with IT had lower rates of VTE recurrence with DOACs than with standard anticoagulation. DOACs are equally safe and effective in VTE patients with IT, with lower bleeding rates than those on standard anticoagulation.

Lessons from an elderly patient with pulmonary embolism caused by protein S deficiency: a case report.

BACKGROUND: Lower limb deep vein thrombosis (DVT) concurrent with pulmonary embolism (PE) is perilous, particularly in the elderly, exhibiting heterogeneity with thrombophilia mutations. Tailored treatment is essential, yet sudden deaths complicate causative factor elucidation. This report emphasizes genetic testing necessity in PE patients with thrombophilia indicators, facilitating cause identification, personalized treatment guidance, and family education. CASE PRESENTATION: This study details a 75-year-old Chinese woman with DVT and PE, where genetic testing identified thrombophilia, guiding personalized treatment decisions. RESULTS: Upon admission, the patient, after over 10 days of bed rest, presented chest tightness, shortness of breath, and unilateral leg swelling. Diagnostic measures revealed DVT and a substantial PE. Genetic testing identified a PROS1 gene C200A>C mutation, reducing protein S activity. Following 2 weeks of anticoagulation and inferior vena cava filter insertion, the patient, discharged, initiated lifelong anticoagulant therapy. A 1-year follow-up showed no recurrent thrombotic events. Family members carrying the mutation received informed and educational interventions. CONCLUSION: Genetic testing for thrombophilic predisposition post-PE is crucial, elucidating etiology, guiding individualized treatment, and playing a pivotal role in family education.

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.

The clinical and genetic landscape of early-onset thrombophilia in Japan.

OBJECTIVES: To determine the optimal management for early-onset thrombophilia (EOT), the genetic and clinical features of protein C (PC)-, protein S (PS)-, or antithrombin (AT)-deficient patients of ≤20 years of age were studied in Japan. METHODS/RESULTS: Clinical and genetic information of all genetically diagnosed cases was collected through the prospective, retrospective study, and literature review. One-hundred-one patients had PC (n = 55), PS (n = 29), or AT deficiency (n = 18). One overlapping case had PC- and PS-monoallelic variant. Fifty-five PC-deficient patients (54%) had 26 monoallelic or 29 biallelic variant(s), and 29 (29%) PS-deficient patients had 20 monoallelic or nine biallelic variant(s). None of the patients had AT-biallelic variants. The frequent low-risk allele p.K193del (PC-Tottori) was found in five patients with monoallelic (19%) but not 29 with biallelic variant(s). The most common low-risk allele p.K196E (PS-Tokushima) was found in five with monoallelic (25%) and six with biallelic variant(s) (67%). One exceptional de novo PC variant was found in 32 families with EOT. Only five parents had a history of thromboembolism. Thrombosis concurrently developed in three mother-newborn pairs (two PC deficiency and one AT deficiency). The prospective cohort revealed the outcomes of 35 patients: three deaths with PC deficiency and 20 complication-free survivors. Neurological complications were more frequently found in patients with PC-biallelic variants than those with PC-, PS-, or AT-monoallelic variants (73% vs. 24%, p = .019). CONCLUSIONS: We demonstrate the need for elective screening for EOT targeting PC deficiency in Japan. Early prenatal diagnosis of PC deficiency in mother-infant pairs may prevent perinatal thrombosis in them.

A Rare Case with Pulmonary Embolism and Literature Review.

BACKGROUND: Pulmonary embolism is rare in children, and most of them have high-risk factors, such as antiphospholipid syndrome, intravenous catheterization, fracture bed rest, etc. For children with pulmonary embolism without clear inducement, hereditary thrombophilia should be considered. Genetic protein S deficiency (PSD) is a kind of thrombophilia, which is caused by the mutation of PROS 1 gene, resulting in an increased tendency to thrombosis. METHODS: The diagnosis of the two cases was made after detecting based on Thrombophilia screening and Sanger sequencing in clinical laboratory. RESULTS: Sanger sequencing found that case 2 and case 1 genotypes were the same, case 1 sister and grandfather carried c.200a>c (p.e67a) mutation, and case 1 aunt and grandmother did not carry PROS1 gene mutation. Case 1 received anticoagulation therapy for 3 months, and case 2 also received anticoagulation therapy for 3 months. During the 1 year follow-up, no new thrombotic events and no adverse reactions such as bleeding were observed in both patients. CONCLUSIONS: For children with pulmonary embolism without clear risk factors, PSD should be considered, and protein S activity should be tested before receiving anticoagulant drugs.

Protein C and protein S deficiencies are associated with increased risk of deep vein thrombosis in pregnant women using oral contraceptives.

BACKGROUND: Oral contraceptives are commonly taken by women and are known to increase the risk of venous thromboembolism (VTE). OBJECTIVE: The aim of this study was to investigate the association between oral contraceptive use and natural anticoagulants, that is, protein C (PC), protein S (PS), and antithrombin in pregnant women with deep vein thrombosis (DVT). MATERIALS AND METHODS: This case-control study was conducted on 330 pregnant women, that is, cases 165 (who used oral contraceptives) and controls 165 (who did not use oral contraceptives). The levels of PC, PS, and antithrombin were measured and compared between the two groups. The use of different types of oral contraceptives and their association with DVT and PC and PS were also analyzed. RESULTS: The study found that women with DVT had significantly lower levels of PC and PS compared with controls ( P  < 0.001). However, no significant difference was found in the levels of AT. Among the different types of oral contraceptives, first-generation progestin pills including Ethynodiol Diacetate, Norethindrone Acetate, Norethynodrel, and second-generation oral contraceptives (Lynestrenol, Levonorgestrel and Norgestrel) were not found to be associated with lower levels of PC and AT while Desogestrel, Norgestimate, and Gestodene (third-generation) were associated with lower levels of PS. CONCLUSION: This study suggests that the use of contraceptives, particularly those containing Desogestrel, Norgestimate, and Gestodene, may be associated with a higher risk of thrombosis because of the associated lower levels of PS. Monitoring anticoagulant levels is crucial in preventing DVT in this population.

As trombofilias na perda gestacional de repetição: uma revisão de prevalência e condutas / Thrombophilias in recurrent pregnancy loss: a review of prevalence and conduct

Objetivo: Discutir o papel das trombofilias na perda gestacional de repetição, com foco em prevalência/associação dessas patologias com perdas de repetição e seu tratamento, por meio de resultados de ensaios clínicos, revisões sistemáticas e metanálises. Métodos: Trata-se de uma revisão não sistemática de artigos publi- cados nas bases eletrônicas PubMed, Cochrane e SciELO nos últimos cinco anos, utilizando os seguintes descritores: "recurrent pregnancy loss", "recurrent abortion", "habitual abortion", "thrombophilia", "antiphospholipid syndrome" e "treatment". Resultados: A maioria dos estudos relatou forte associação entre os anticorpos antifosfolípides específicos e a síndrome do anticorpo antifosfolípide com perda gestacional de repetição. Mulheres portadoras da mutação do fator V de Leiden, mutação do gene da protrombina e deficiência de proteína S apresentaram alto risco de perda gestacional de repetição em uma grande revisão sistemática. Estudos recentes demonstraram taxas de prevalência das trombofilias hereditárias e da síndrome do anticorpo antifosfolípide, em mulheres com perda gestacional de repetição, semelhantes às da população em geral. Os estudos atuais endossam o uso da heparina associada à aspirina em mulheres com síndrome do anticorpo antifosfolípide, com aumento da taxa de nascidos vivos, mas sem diferença em re- lação às complicações obstétricas. Conclusão: Apesar de novos estudos demons- trarem que a prevalência das trombofilias hereditárias e adquiridas em mulheres com perda gestacional de repetição é semelhante à da população em geral, reco- menda-se a pesquisa rotineira de síndrome do anticorpo antifosfolípide nessas pacientes. O uso de aspirina em baixas doses associada à heparina é a intervenção farmacológica de primeira linha para a prevenção de perda gestacional de repeti- ção em pacientes com síndrome do anticorpo antifosfolípide.

Objective: To discuss the role of thrombophilias in recurrent pregnancy loss, focu- sing on the prevalence/association of these pathologies with recurrent abortion and treatment, through results of clinical trials, systematic reviews and meta-analyses. Methods: This is a non-systematic review of articles published in electronic databa- ses PubMed, Cochrane, SciELO in the last five years, using the following descriptors: "recurrent pregnancy loss", "recurrent abortion", "habitual abortion", "thrombophilia", "antiphospholipid syndrome", and "treatment". Results: Most studies have reported a strong association between specific antiphospholipid antibodies and antiphospho- lipid antibody syndrome with recurrent pregnancy loss. Women carrying the factor V Leiden mutation, prothrombin gene mutation, and protein S deficiency were shown to be at high risk of recurrent pregnancy loss in a large systematic review. Recent studies have shown prevalence rates of hereditary thrombophilias and antiphospholipid antibody syndrome, in women with re- current pregnancy loss, similar to those of the general po- pulation. Current studies endorse the use of heparin plus aspirin in women with antiphospholipid antibody syndrome, with an increase in live birth rate, but with no difference in obstetric complications. Conclusion: Although new studies demonstrate that the prevalence of hereditary and acquired thrombophilias in women with recurrent pregnancy loss is si- milar to that of the general population, routine investigation of antiphospholipid antibody syndrome in these patients is recommended. The use of low-dose aspirin plus heparin is the first-line pharmacological intervention for the prevention of recurrent pregnancy loss in patients with antiphospholipid antibody syndrome.

[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.

PROS1 variant c.1574C>T p.Ala525Val causes portal vein thrombosis with protein S deficiency.

BACKGROUND: Protein S (PS) is a vitamin K-dependent plasma glycoprotein, and the deficiency of PS increases the risk of venous thromboembolism (VTE). PS deficiency has been found in 1.5-7% of selected groups of thrombophilic patients. However, the reported PS deficiency patients with portal vein thrombosis are scarce. CASE REPORT AND RESULTS: Our case described a 60-year-old male patient presented portal vein thrombosis with protein S deficiency. Imaging findings of the patient revealed extensive thrombosis involving the portal vein and superior mesenteric vein. His medical history revealed lower extremity venous thrombosis 10 years ago. The level of PS activity was greatly reduced (14%, reference: 55-130%). Acquired thrombophilia caused by antiphospholipid syndrome, hyperhomocysteinemia, or malignancy were excluded. Whole exome sequencing revealed a heterozygous missense variation c.1574C>T, p.Ala525Val in the PROS1 gene. The in-silico analysis of the variant was performed by SIFT and PolyPhen-2. The results showed that the variant is a pathogenic and likely pathogenic variation respectively (SIFT, -3.404; PolyPhen-2, 0.892), the amino acid substitution A525V is presumed to result in unstable PS protein which is degraded intracellularly. Mutation site of the proband and his family members was validated by Sanger sequencing. CONCLUSION: According to the clinical manifestation, imaging findings, protein S level, and the genetic results, a diagnosis of portal vein thrombosis with PS deficiency was made. To the best of our knowledge, our case is the second reported PS deficiency patient caused by PROS1 c.1574C>T, p.Ala525Val variant in Asia, and the case is also the only reported case with PROS1 c.1574C>T, p.Ala525Val variant presents portal vein thrombosis.

Combination Treatment of Balloon Pulmonary Angioplasty and Direct Oral Anticoagulant in a Patient with Chronic Thromboembolic Pulmonary Hypertension Complicated by Protein S Deficiency.

Introduction: Chronic thromboembolic pulmonary hypertension (CTEPH) is a phenotype of pulmonary hypertension due to chronic and multiple organized thrombus. The therapeutic strategy for patients with CTEPH and comorbid protein S deficiency remains unknown due to its rarity. Case: We encountered a 49-year-old male patient with CTEPH and concomitant mild protein S deficiency (type III). We could successfully perform balloon pulmonary angioplasty without any major complications, including thromboembolism and bleeding, followed by standard-dose oral anticoagulation therapy instead of warfarin. Conclusion: A currently established standard therapeutic strategy for CTEPH, including pulmonary angioplasty, may be safe and effective even in patients with concomitant inherent coagulation abnormalities.

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.

Spinal Cord Infarction in an Adolescent with Protein S Deficiency: A Case Report and Literature Review.

Protein S deficiency causes spinal cord infarction in rare cases. We herein report the first case of severe cervicothoracic cord infarction in an adolescent with protein S deficiency. A 16-year-old boy presented with neck pain, four-limb paralysis, and numbness. Magnetic resonance imaging revealed spinal artery infarction in the C4 to Th4 area. Protein S antigen and activity were decreased. The patient was diagnosed with protein S deficiency-associated cervicothoracic cord infarction, which was treated with anticoagulation. Protein S deficiency should be considered as a potential cause of spinal cord infarction in young healthy patients and should be appropriately treated with anticoagulation.

Dysregulation of Protein S in COVID-19.

Coronavirus Disease 2019 (COVID-19) has been widely associated with increased thrombotic risk, with many different proposed mechanisms. One such mechanism is acquired deficiency of protein S (PS), a plasma protein that regulates coagulation and inflammatory processes, including complement activation and efferocytosis. Acquired PS deficiency is common in patients with severe viral infections and has been reported in multiple studies of COVID-19. This deficiency may be caused by consumption, degradation, or clearance of the protein, by decreased synthesis, or by binding of PS to other plasma proteins, which block its anticoagulant activity. Here, we review the functions of PS, the evidence of acquired PS deficiency in COVID-19 patients, the potential mechanisms of PS deficiency, and the evidence that those mechanisms may be occurring in COVID-19.

Benefits and risks of low molecular weight heparin use on reproductive outcomes: A retrospective cohort study.

OBJECTIVE: Low molecular weight heparin (LMWH) has been given to reproductive-age women with various indications. This study aims to assess the benefits and risks of such use. MATERIALS AND METHODS: We retrospectively reviewed data (n = 204) between Jan 2016 and May 2019. Logistic regression analysis was conducted to evaluate the correlation between indications and reproductive outcomes. RESULTS: LMWH use had higher odds of live birth in women less than 30 years of age (OR: 4.98; 95% CI = 1.13-21.98; p = 0.034) and with protein S deficiency (OR: 3.90; 95% CI = 1.77-8.59; p = 0.001). For the subgroup of recurrent pregnant loss, LMWH use was only advantageous to women with protein S deficiency (OR: 2.45; 95%:1.01-5.97; p = 0.048). Risks such as preterm delivery, small-for-gestational-age, placental abruption, antepartum/postpartum hemorrhage were not significantly increased among subgroups. Women treated with LMWH and who had successful live births (n = 171) had a slightly increased risk of postpartum hemorrhage compared to controls (n = 8058) during this period in our institution (2.9% vs 1.2%, p < 0.001). CONCLUSION: LMWH administration produces a higher chance of live-birth to women younger than 30 years of age or with protein S deficiency. However, risk of postpartum hemorrhage is increased.

Protein S: a Central Regulator of Blood Coagulation.

BACKGROUND: Protein S is a central regulator of coagulation as it critically participates in down-regulation of both extrinsic and intrinsic pathways of the coagulation cascade. In this review, we aim to provide an update on protein S and its anticoagulant functions as a central hemostatic regulator. METHODS: Electronic databases including, Google, Google Scholar, PMC, PubMed, Science Direct, and Scopus were rigorously searched using the terms protein S, hemostasis, natural anticoagulants, regulators of coagulation, and coagulation inhibitors for the completion of this descriptive review. RESULTS: Literature review shows that protein S is a potent cofactor for activated protein C (APC) in the regulation of the intrinsic pathway and a cofactor for tissue factor pathway inhibitor (TFPI) in the regulation of the extrinsic pathway. The strong association between protein S deficiency either hereditary or acquired and increased risk for venous thrombosis indicates the important and central role of protein S in controlling the initiation and propagation phase of coagulation cascade and that protein S is an important determinant for optimal activity of both APC and TFPI in coagulation regulation. CONCLUSIONS: Available evidence suggests that the role of protein S in the down-regulation of blood coagulation is mainly mediated through its high affinity binding to negatively charged phospholipid surfaces. This high affinity binding to negatively charged phospholipids helps bring the anticoagulant proteins to the membranes, resulting in efficient and targeted regulation of coagulation. In the shade of current COVID-19 pandemic, protein S deficiency has been found to be a leading cause of thrombotic complications associated with COVID-19.

An Atypical Case of Idiopathic Purpura Fulminans.

Idiopathic purpura fulminans (PF) is rare but has been reported in pediatric patients, commonly following infections. We present a case of a 5-year-old boy, heterozygous for factor V Leiden, with no history of recent infections, who presented with PF secondary to acquired protein S deficiency. Despite initial supportive treatment, the patient required surgical fasciotomy and extensive skin grafts. The protein S level normalized 4 months following the presentation. In this context, an autoimmune component with transient anti-protein S antibodies was believed to be involved. This case report highlights the course of idiopathic PF due to noninfectious acquired protein S deficiency.

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.