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.

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.

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.

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.

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.

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.

APA scoring system: a novel predictive model based on risk factors of pregnancy loss for recurrent spontaneous abortion patients.

The aim of this study was to analyse the risk factors of pregnancy loss of patients with recurrent spontaneous abortion (RSA) and develop a scoring system to predict RSA. Clinical data of 242 cases, with RSA who were treated at Fujian Provincial Maternity and Children's Hospital, were selected. The factors of pregnancy loss for RSA patients were evaluated by univariate and multivariate analyses. There were 242 RSA patients, of whom 34 (14.0%) developed pregnancy loss. A multivariate analysis showed the following adverse risk factors for RSA: antinuclear antibody spectrum, protein s deficiency and antiphospholipid antibodies. The pregnancy loss rates of antinuclear antibody spectrum group, protein S deficiency group and antiphospholipid antibodies group were 25.0%, 22.5% and 19.4%, respectively. Each of these factors contributed 1 point to the risk score. The pregnancy loss rates were 6.3%, 24.6%, 50% for the low-, intermediate- and high-risk categories, respectively (p < .001). The area under the receiver operating characteristic curve for the score of RSA was .733. Our findings suggest that this validated and simple scoring system could accurately predict the risk of pregnancy loss of RSA patients. The score might be helpful in the selection of risk-adapted interventions to decrease the incidence. Impact StatementWhat is already known on this subject? The live birth rate increases to 80%-90% after anticoagulant and/or immunosuppressive treatment in patients with RSA. However, there is still a high rate of re-abortion even after active treatment.What do the results of this study add? Antinuclear antibody spectrum, protein s deficiency and antiphospholipid antibodies were independent risk factors for pregnancy loss. A novel predictive model based on these factors was then established and validated.What are the implications of these findings for clinical practice and/or further research? The newly developed score might be helpful in the selection of risk-adapted interventions to decrease the incidence. For patients in the intermediate-risk and high-risk groups, we should conduct more targeted studies and formulate corresponding therapies to improve the success rate of treatment.

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.

Protein S Deficiency with Recurrent Deep Vein Thrombosis and Post Thrombotic Syndrome: A Case Report.

Protein S is a vitamin K-dependent protein that acts as a break in secondary hemostasis by inactivating activated factor V and activated factor VIII. We report a case of a 40 years old male who had the first episode of deep vein thrombosis of the left lower limb 10 years back, which despite treatment, reoccurred 3 months later in the bilateral lower limb. Thrombophilic screening showed severe protein S deficiency. The patient then developed deep vein thrombosis of both upper limbs. The patient was advised to place an inferior vena cava filter, which he denied. The patient is now presenting with multiple episodes of post-thrombotic syndrome. Such attacks are treated with elastic compression stockings, rivaroxaban, and morphine. However, despite medication, the pain has not yet subsided. Hence, even though protein S deficiency is the rare cause of deep vein thrombosis when recurrent should be considered despite its rare occurrence. Keywords: deep vein thrombosis; protein S deficiency; rivaroxaban.

A Case of a Pediatric Patient With Protein S Heerlen Polymorphism and Deep Venous Thrombosis.

Hereditary protein S (PS) deficiency is a rare autosomal dominant disorder with increased risk of venous thromboembolism. The PS Heerlen polymorphism at codon 501 of the PROS1 gene is considered a variant of uncertain significance. It has since been shown that PS Heerlen has a reduced half-life, resulting in reduced levels of free PS. We report a case of an adolescent female with May Thurner syndrome and heterozygous PS Heerlen mutation resulting in a mild PS deficiency and venous thromboembolism. With this nonmodifiable risk factor, the patient received prolonged anticoagulation with strong consideration for lifelong prophylaxis.

Resolution of possible acquired protein S deficiency after viral suppression in HIV infection.

Current literature suggests an increased risk of venous thromboembolism (VTE) in people living with HIV (PLWH) with poorly controlled viraemia and immunodeficiency. VTE treatment guidelines do not specifically address anticoagulation management in PLWH. We report a case of a 33-year-old woman diagnosed with an unprovoked pulmonary embolism (PE) and deemed protein S deficient. Three years later, she was diagnosed with AIDS. Antiretroviral therapy (ART) was promptly initiated with viral suppression and immune reconstitution within 12 months. Eight years after her initial PE, the patient self-discontinued warfarin. Multiple repeat protein S values were normal. ART without anticoagulation has continued for 3 years with no thrombotic events. This case describes a patient with VTE presumably secondary to undiagnosed HIV with possible consequent acquired protein S deficiency. Additional research is needed to understand the characteristics of PLWH with VTE who may warrant long-term anticoagulation as opposed to shorter courses.