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Currently, limited information is available in the literature regarding the relationships between PROC mutations and clinical features in Chinese individuals. We aimed to characterize severe congenital Protein C deficiency in 22 unrelated Chinese families in a tertiary hospital by analyzing its clinical manifestation, associated risk factors, and gene mutations. We measured protein C activity and antigen levels for all participants, screened them for mutations in the PROC gene, and analyzed the clinical features of each family to identify commonalities and differences. The analysis revealed a total of 75 individuals with PCD and 16 different PROC mutations, including 12 missense mutations and 4 deletion mutations. Among them, 11 who were compound heterozygotes or homozygotes for mutations tended to develop symptoms at a younger age without any clear triggers. In contrast, the remaining 64 individuals who were heterozygotes for mutations often had clear triggers for their symptoms and experienced a milder course of the disease. It is worth noting that the mutation c.565C > T occurred most frequently, being identified in 8 out of 22 families (36%). Our team also reported five novel mutations, including c.742-744delAAG, c.383G > A, c.997G > A, c.1318C > T, and c.833T > C mutations. The identification of five novel mutations adds to the richness of the Human Genome Database. Asymptomatic heterozygotes are not uncommon, and they are prone to develop symptoms with obvious triggers. The evidence presented strongly suggest that asymptomatic individuals with family history of protein C deficiency can benefit from mutational analysis of PROC gene., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Protein C deficiency is a rare blood disorder that increases the risk of thromboembolism, resulting in deep vein thrombosis, pulmonary embolisms and strokes. Segmental testicular infarction is also a rare condition with unclear aetiology. This case presents a man in his 50s with protein C deficiency who developed a segmental testicular infarction. The patient was managed conservatively, without surgical intervention. He was monitored with serial ultrasound, which demonstrated progression from normal testis to segmental infarction and eventually resolution. The case highlights that protein C deficiency can cause testicular infarction, and a multidisciplinary approach can help avoid unnecessary surgery with excellent outcomes. Segmental infarction should be considered in patients with pre-existing thrombophilias after excluding malignancy and infection. Conservative management with repeat ultrasonography and follow-up can be appropriate in such cases., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

The number of reports on genetic predisposition to pediatric thrombosis is increasing. The risk of thrombosis in childhood varies according to patient age, and the contribution of genetic predisposition also differs. The term early-onset thrombophilia, which occurs until the age of 20 years in patients with genetic diagnosis, was defined. Then, the registry in Japan was established. Further, publications were reviewed comprehensively, and results revealed the genetic and clinical characteristics of patients. Less than 60% of patients presented with protein C (PC) deficiency, and over half of them had PC-gene monoallelic variants. The number of patients with protein S or antithrombin deficiency increased with age. None of them were aged between 6 and 8 years. PC-Tottori and protein S-Tokushima, which are high-frequency and low-risk variants in Japanese, contributed to the development of thrombosis. However, PC-Tottori did not affect the development of severe PC deficiency. One exceptional de novo PC-deficient variant was identified in 32 EOT families, and thrombosis developed concurrently in three pairs of mothers-newborns. Appropriate EOT screening tests targeting PC deficiency are required to prevent maternal and neonatal thromboses.

Protein C (PC) is a vitamin K-dependent zymogen synthesized in the liver that plays a major role in regulating the coagulation pathway. Upon interaction with the thrombin-thrombomodulin complex, PC is converted to its active form, activated PC (APC). APC complexes with protein S and regulates thrombin generation by the inactivation of Factors Va and VIIIa. The role of PC as a key regulator of the coagulation process is highlighted in the deficiency state, in which heterozygous deficiency of PC predisposes to an increased risk of venous thromboembolism (VTE), while in the homozygous deficiency state, potentially fatal complications in the fetus including purpura fulminans and disseminated intravascular coagulation (DIC) can occur. Protein C is often measured with other factors such as protein S and antithrombin as a screen in the investigation of VTE. The chromogenic PC assay, the protocol described in this chapter, quantitates the amount of functional PC in the plasma using an activator of PC with the degree of color change proportional to the amount of PC present in the sample. Other methods, including functional clotting-based assays and antigenic assays, are available; however, protocols for these assays will not be provided in this chapter., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Thrombophilia causes thrombosis after kidney transplantation (KT). Protein C deficiency is a rare form of hereditary thrombophilia. To our knowledge, there are few reports on KT for patients with protein C deficiency, and there are no reports of KT in patients with protein C deficiency administered with activated protein C concentrate., Method: Here we reported the case of a patient with protein C deficiency who underwent KT without the occurrence of any fresh thrombosis after administration of an activated protein C concentrate. The patients was a 49-year-old woman diagnosed with immunoglobulin A nephropathy at 20 years of age. During pregnancy, she experienced deep vein thrombosis of the lower extremities and pulmonary embolism for which she was started on warfarin. After a thorough examination, the patient was diagnosed with protein C deficiency. The patient had end-stage kidney disease and received a preemptive living donor kidney transplant from her mother., Results: To prevent thrombosis, we switched from oral warfarin to continuous heparin 7 days before surgery. Heparin was discontinued 6 hours before surgery, and continuous activated protein C concentrate was administered 12 hours before surgery. Heparin administration was resumed 6 hours after the surgery. Warfarin administration was restarted 3 days after the surgery, and heparin was discontinued 11 days post-surgery. The surgery was performed without complications. After the KT, the patient's renal function steadily improved, and no fresh thrombosis were observed., Conclusions: Thrombosis can cause graft loss and pulmonary embolism, thus appropriate administration of activated protein C concentrate may help prevent thrombosis., (Copyright © 2022 Elsevier Inc. All rights reserved.)

This study investigated patients with thrombophilia and current peripartum management practices based on national surveillance in Japan. Between 2014 and 2018, antithrombin (AT), protein C (PC) and protein S (PS) deficiency were observed in 84, 67, and 443 pregnancies, respectively, with incidence rates among total deliveries at 0.012%, 0.009%, and 0.061%. The percentage of institutions that measured both antigens and AT, PC, and PS activity for the diagnosis of thrombophilia was 50.2%, and 46.9% of institutions did not perform gene analysis. Prophylactic anticoagulation therapy was used in the ante- and postpartum management of patients with AT deficiency at 67.1% and 66.3% of institutions, most commonly with 10,000 units of unfractionated heparin. Ante- and postpartum management of PC and PS deficiency was performed at 75.3% and 67.1% of institutions. Approximately half of the institutions performed peripartum prophylactic AT supplementation for AT deficiency. Low trough AT activity before supplementation was most commonly 50 ≤  < 70%, and the highest AT supplementation was 1500 ≤  < 3000 units. The number of pregnancies with AT, PC and PS deficiency might be as many as 29, 23 and 151 every year in Japan if complete answers were provided., (© 2022. Japanese Society of Hematology.)

Severe congenital protein C deficiency (SCPCD) is rare and there is currently substantial variation in the management of this condition. A joint project by three Scientific and Standardization Committees of the ISTH: Plasma Coagulation Inhibitors, Pediatric/Neonatal Thrombosis and Hemostasis, and Women's Health Issues in Thrombosis and Hemostasis, was developed to review the current evidence and help guide on diagnosis and management of SCPCD. We provide a summary of the clinical presentations, differential diagnoses, appropriate investigations to confirm the diagnosis, approaches for management of the acute situation, and options for long-term management including subsequent pregnancies. We finally provide a set of recommendations to help in this regard., (© 2022 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Homozygous protein C deficiency is a rare hypercoagulability disorder. This study describes the ocular manifestations and the genetic background in a family with two affected children. This is a retrospective review of ophthalmic examinations, investigations, genetic testing, and blood work-up of two children with homozygous protein C deficiency from a single family. A family with a positive history of consanguineous marriage was found to have two affected children with homozygous protein C deficiency. Abnormal visual behavior was the presenting symptom. Both children had bilateral total tractional retinal detachments at presentation. Skin manifestations included episodes of discoloration and bruising. Laboratory work-up revealed absent protein C activity. Genetic testing confirmed the presence of a homozygous pathogenic mutation in protein C gene (NM&#95;000312.3: c.1297G>A: p.Gly433Ser). Homozygous protein C deficiency should be considered in the differential diagnosis of early-onset tractional retinal detachment in infancy. Although rare, the ophthalmologist may be the first to encounter the condition, and treatment with protein C replacement or anticoagulants may be life-saving. Examination under anesthesia with fluorescein angiography and laser treatment early in life may be warranted to preserve vision. [ Ophthalmic Surg Lasers Imaging Retina . 2022;53:293-296. ].

Significance: Protein C deficiency is a thrombophilic condition that increases the risk of venous and arterial thrombi, the latter of which can cause transient monocular vision loss. In cases of recurrent transient monocular vision loss, in which the typical stroke workup has been unrevealing, investigation for hypercoagulable states is warranted., Purpose: This study reports a case of transient monocular vision loss secondary to protein C deficiency in a patient with no known personal or family history of venous thromboembolism and highlights the eye care provider's role in helping with diagnosis of this condition., Case Report: A 59-year-old woman presented with recurrent transient monocular vision loss of the right eye. Her history was remarkable for suffering an ischemic stroke with hemorrhagic conversion shortly after experiencing episodes of transient monocular vision loss. These episodes initially waned but recurred 3 months later. Extensive workup at the time of recurrence of her visual symptoms was unrevealing. Given the timing of her visual symptoms and history of stroke, her presentation was suggestive of transient ischemic attacks. Her previous extensive workup and chronicity of symptoms did not necessitate emergent evaluation. However, additional workup for hypercoagulable conditions was initiated. The testing revealed protein C deficiency, which prompted initiation of oral anticoagulants for stroke prophylaxis., Conclusions: Transient monocular vision loss is a symptom commonly encountered by eye care providers, which necessitates emergent evaluation to reduce stroke risk if the symptom appears vascular in origin. Testing for hypercoagulable conditions is indicated in patients demonstrating recurrent transient monocular vision loss, even if there is no known personal or family history of venous thromboembolism. Eye care providers need to be aware of this association between hypercoagulable conditions and transient vision loss to aid in prompt diagnosis and treatment with the goal of preventing stroke and permanent vision loss., Competing Interests: Conflict of Interest Disclosure: KAM is a consultant and speaker for RVL Pharmaceuticals and Osmotica Pharmaceuticals, which have no relation to this manuscript., (Copyright © 2021 American Academy of Optometry.)

Plasma protein-C is a natural anticoagulant that inactivates factors Va and VIIIa. Familial protein C deficiency is inherited as an autosomal dominant disorder. The homozygous or compound heterozygous type may present early as purpura fulminant, while the heterozygous type can present as thromboembolism later in life. Presented in this report is a case of a 21-year-old female patient with protein-C deficiency, confirmed by thrombophilia investigations. She experienced recurrent deep vein thrombosis and cerebral sinus thrombosis due to thrombotic occlusion. She had a family history of deep vein thrombosis. Hence, high-risk cases should be seriously considered for long term anticoagulation therapy. The utility versus futility of thrombophilia testing in a particular situation is discussed to address and ensure safe practice among patients with thromboembolism.

Background: Severe protein C deficiency is a rare and inherited cause of thrombophilia in neonates. Protein C acts as an anticoagulant, and its deficiency results in vascular thrombosis. Herein, we report a case of protein C deficiency with a homozygous pathogenic variant in a term neonate, with good outcomes after proper treatment., Case Presentation: A four-day-old male newborn was transferred to the Seoul National University Hospital on account of dark red to black skin lesions. He was born full-term with an average birth weight without perinatal problems. There were no abnormal findings in the prenatal tests, including intrauterine sonography. The first skin lesion was observed on his right toes and rapidly progressed to proximal areas, such as the lower legs, left arm, and buttock. Under the impression of thromboembolism or vasculitis, we performed a coagulopathy workup, which revealed a high D-dimer level of 23.05 μg/ml. A skin biopsy showed fibrin clots in most capillaries, and his protein C activity level was below 10%, from which we diagnosed protein C deficiency. On postnatal day 6, he experienced an apnea event with desaturation and an abnormal right pupillary light reflex. Brain computed tomography showed multifocal patchy intracranial hemorrhage and intraventricular hemorrhage with an old ischemic lesion. Ophthalmic examination revealed bilateral retinal traction detachments with retinal folds. Protein C concentrate replacement therapy was added to previous treatments including steroids, prostaglandin E1, and anticoagulation. After replacement therapy, there were no new skin lesions, and the previous lesions recovered with scarring. Although there were no new brain hemorrhagic infarctions, there was ongoing ischemic tissue loss, which required further rehabilitation. Ophthalmic surgical interventions were performed to treat the bilateral retinal traction detachments with retinal folds. Molecular analysis revealed a homozygous pathogenic variant in the PROC gene., Conclusion: Severe protein C deficiency can manifest as a fatal coagulopathy in any organ. Early diagnosis and proper treatment, including protein C concentrate replacement, may improve outcomes without serious sequelae., (© 2021. The Author(s).)

Portal vein thrombosis (PVT) is a rare but severe condition. Several risk factors predispose to PVT. However, it remains unclear to which degree thrombophilia contributes to the risk of PVT and whether PVT patients should be routinely referred for thrombophilia testing. The aim of the present study was to investigate the prevalence of thrombophilia in PVT patients to clarify the relevance of thrombophilia testing in PVT patients. Clinical data and results from thrombophilia investigations were systematically obtained from all PVT patients referred to Centre for Hemophilia and Thrombosis, Aarhus University Hospital, Denmark for thrombophilia testing between 1 st of January 2010 and 31 st of December 2018 ( n  = 93). The investigated thrombophilias included factor V Leiden and prothrombin G20210A mutations, deficiency of protein S, protein C and antithrombin, antiphospholipid syndrome, and increased levels of factor VIII. The prevalence of thrombophilia was compared to healthy controls obtained from previously published data on thrombophilia distribution in cohorts of the Western European adult general population. Comparing PVT patients with healthy controls, significantly increased odds of presence of lupus anticoagulant (crude odds ratio (OR) 6.2, 95% confidence interval (CI) 1.8-20.6) were found, whereas no significantly increased odds of inherited thrombophilia were demonstrated. In conclusion, routine testing for inherited thrombophilia in PVT patients does not seem indicated. However, PVT patients should still be tested for antiphospholipid antibodies because patients meeting the criteria for antiphospholipid syndrome preferentially should receive vitamin K antagonists as anticoagulant therapy.

Pregnant women presenting to the ED with abdominal pain or vomiting are likely to be evaluated for problems with the pregnancy. Although pregnancy-related pathology is common, patients may have intra-abdominal pathology that requires prompt evaluation and possible surgical intervention.

Background: Homozygous protein C (PC) deficiency is a potentially fatal disease with ocular blinding presentation or sequela., Case Presentation: A 5 month-old boy was presented for evaluation of leukocoria. He had a history of frequent bruises and PC deficiency, treated with warfarin. His intraocular pressure was normal. In the left eye leukoma with anterior segment dysgenesis, shallow anterior chamber, and cataract were observed. Fundus was not visible. B-scan revealed a closed funnel retinal detachment. His right eye had a normal anterior segment and a thin retina with anomalous retinal vascular branching at equator and peripheral retina. A fibrovascular tuft on the optic nerve head with induced traction on superior arcade was visible. Total loss of a and b wave of both were appreciated in electroretinography (ERG). Fluorescein angiography (FA) showed very severe leakage at the junction of the vascularized and non-vascularized retina and optic nerve head. Favorable outcome was achieved with lasering of avascular retina in the right eye., Conclusion: The potential for protein C deficiency should be assessed in all infants with leukocoria, anterior segment dysgenesis, retinal detachment and retinal dysplasia. Early diagnosis could save the child's life and vision.

Inherited protein C (PC) deficiency increases risk of venous thromboembolism (VTE) by 5 to 10-fold in thrombosis-prone families; however, heterozygous PC deficiency alone does not determine that a subject has thrombophilia. Protein C deficient subjects, who lack additional inherited risk factors such as factor V Leiden or have no major acquired risk factors, may not suffer from VTE. In addition, PC deficiency may be acquired, often due to vitamin K antagonist treatment or liver disease. In contrast, homozygous or compound heterozygous PC deficiencies are rare and serious disorders, and affected infants are often in families with no history of PC deficiency or thrombosis. Laboratories commonly use the chromogenic PC assay to diagnose deficiency. Chromogenic assay is recommended due to its good specificity, but this assay fails to detect the rare type 2b deficiency where the defect is due to poor interaction with calcium ions, phospholipid, protein S, and factor Va and factor VIIIa. The clotting-based assay of PC is capable of detecting type 2b deficiency but it has reduced specificity. Importantly, PC level varies with age, adult reference ranges cannot be applied to babies or children and levels may not reach those of adults even in adolescence. Pre-analytical variables in the specimen affect measurement of PC, and can be assay-dependent; for example, a partially clotted sample will have falsely raised PC level by chromogenic assay but reduced level by clotting-based assay. Direct oral anticoagulants falsely raise PC level in the clotting-based assay but the standard chromogenic assay is unaffected., (© 2020 International Society on Thrombosis and Haemostasis.)

Thrombophilia increases the risk of venous thrombosis, but is rarely responsible for aortic thrombosis. Aortic mural thrombus (AMT) may be associated with a protein C deficiency. However, it is necessary to determine whether the protein C deficiency is congenital/hereditary or secondary/acquired (consumption of protein C during the process of thrombus formation). This study describes a 77-year-old Japanese woman with incidentally diagnosed AMT, who had a protein C deficiency (activity 54%, antigen 42%). Sequencing of the protein C gene revealed a heterozygous mutation of c.1268delG, p.Gly423Valfs ＊ 82 in exon 9, indicating a congenital protein C deficiency. These findings indicate that very late onset AMT can occur in an adult with congenital protein C deficiency.

We describe a term infant who experienced recurrent apnea associated with intracranial hemorrhage and later, developed colonic perforation. Plasma protein C activity was below detectable limits and a heterozygous PROC mutation was identified. Neonatal colonic perforation is rare, and this case report highlights the importance of considering congenital Protein C deficiency.

Protein C (PC) deficiency is a heritable or acquired risk factor for thrombophilia, with presentations varying from asymptomatic to venous thromboembolism to neonatal purpura fulminans, a life-threatening disorder. Hereditary PC deficiency is caused by mutation in the PC ( PROC ) gene located on chromosome 2q14.3. Heterozygous and acquired PC deficiencies are more common than homozygous deficiency. The recommended initial laboratory test measures PC activity using either clot-based or chromogenic methods. There are numerous potential interferences in PC activity testing that may result in either false-positive (falsely low activity) or false-negative (falsely normal or elevated activity) results. In the present review, we discuss common clinical presentations; laboratory testing, with a focus on potential assay interferences; treatment options; and prognosis in patients with PC deficiency.

Background and Objectives: Thrombophilia might increase the risk of suffering from obstetric complications by adversely affecting the normal placental vascular function. Our aim was to study the distributions of five thrombosis-associated genetic variants: factor V Leiden, prothrombin G20210A, -675 4G/5G PAI-1, 10034C/T gamma fibrinogen and 7872C/T factor XI and the frequencies of the deficiencies of protein C, S and antithrombin in Argentinian patients with recurrent pregnancy loss (RPL) and, therefore, to analyse their association with the risk and timing of RPL and the risk of suffering other vascular obstetric pathologies., Patients and Methods: We performed a case-control study that included 247 patients with idiopathic RPL (cases), 107 fertile controls and 224 subjects from general population (reference group). Cases were stratified according to the gestational time of the losses (early RPL, n = 89; late losses, n = 158; foetal losses, n = 107) and according to the type of vascular obstetric pathologies., Results: No differences were found in the distribution of the genetic variants among RPL group vs. control/reference group (p >.05). Similarly, no differences were observed in their distributions when analysing RPL patients stratified according to gestational times or vascular obstetric pathologies (p >.05), except for the factor V Leiden carriage in patients with foetal growth retardation vs. controls (11.8%, 4/34 vs. 1.9%, 2/107; p = .04) (OR = 7.11 [1.24-40.93], p = .03)., Conclusions: Factor V Leiden might have a significant impact on certain obstetric pathologies such as foetal growth retardation. The genetic variants, 10034C/T gamma fibrinogen and 7872C/T factor XI, associated with thromboembolic disease, would not have an impact on PRE., (Copyright © 2018 Elsevier España, S.L.U. All rights reserved.)

A thrombophilic disorder is a hereditary or acquired condition that increases the risk of thrombosis. The most common hereditary thrombophilias that predispose to venous thrombosis in the Caucasian population are the heterozygous forms of the factor V Leiden and prothrombin G20210A mutation that are generally detected by direct DNA genotyping. Immunologic antigen assays and chromogenic or clot-based activity assays are used to identify deficiencies in the natural coagulation inhibitors antithrombin, protein C and protein S. Because pre-analytical errors and acquired causes of low antithrombin, protein C or protein S levels are considerably more common than hereditary deficiencies, all potential conditions that may lower activity levels of the natural coagulation inhibitors (e.g. concomitant liver disease, pregnancy, anticoagulant therapy) must be considered and excluded before the diagnosis of an inhibitor deficiency can be made. To avoid misclassification, the diagnosis should not be made based on a single abnormal test result. Thus, repetitive testing when the patient is not on anticoagulant therapy is mandatory to confirm the diagnosis. Screening for antiphospholipid syndrome (APS) comprises testing for lupus anticoagulants (LAs) and the presence of IgG or IgM antibodies directed against phospholipids and phospholipid-binding proteins such as β-2-glycoprotein-I. A combination of clot-based assays has been recommended to demonstrate LA activity, whereas solid-phase immunoassays allow the detection of anti-cardiolipin and anti-β-2-glycoprotein-I antibodies. The diagnosis of APS requires the persistence of antiphospholipid antibodies for at least 12 weeks together with thrombotic and/or obstetric features of APS., Competing Interests: Prof. Dr. B. Linnemann received honoraria and/or travel reimbursements over the last three years for lectures and consultancy work related to the topic of this article from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer and Siemens Healthcare.Priv.-Doz. Dr. C. Hart received honoraria and/or travel reimbursements over the last three years for lectures and consultancy work related to the topic of this article from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer and Leo Pharma., (Georg Thieme Verlag KG Stuttgart · New York.)

Abstarct: OBJECTIVE: The diagnosis of neonatal-onset protein C (PC) deficiency is challenging. This study aimed to establish the neonatal screening of heritable PC deficiency in Japan., Study Design: We determined the changes in plasma activity levels of PC and protein S (PS) in healthy neonates, and studied newborn patients with PROC mutation in the Japanese registry., Result: Physiological PC and PS levels increased with wide range. The PC/PS-activity ratios converged after birth. The PC/PS-activity ratios of 19 patients with biallelic mutations, but not, 9 with monoallelic mutation, were lower than those of 13 without mutation. The logistic regression analyses established a formula including two significant variables of PC activity (cut-off < 10%, odds ratio = 30.0) and PC/PS-activity ratio (cut-off < 0.35, odds ratio = 22.7), with 93% sensitivity and 44% specificity for determining patients with mutation(s)., Conclusion: The PC/PS-activity ratio is an effective parameter for the genetic screening of neonatal-onset PC-deficiency in Japanese population.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a potentially correctable cause of secondary pulmonary hypertension. Surgical treatment remains the primary treatment for patients with CTEPH. Pulmonary thromboendarterectomy (PEA) with deep hypothermic circulatory arrest is the standard and recommended surgical technique for the treatment of these patients. The prevalence of CTEPH after an acute pulmonary thromboembolism (PTE) has been found in various studies to be between 0.6 and 8.8%. Mortality rates in elective PEA cases with CTEPH are reported to be between 1.9 and 4.5%. We report on a 50-year-old female patient with combined inherited thrombophilia, including protein C and protein S deficiencies, who was diagnosed with CTEPH and was successfully treated with pulmonary thromboendarterectomy.

Introduction: To investigate the thrombotic tendency in patients with systemic lupus erythematosus (SLE) by evaluating congenital and acquired abnormalities with an increased risk of thrombosis., Patients and Methods: A total of 53 patients with SLE were included in the study. Fifty-three healthy controls paired by age and sex were assessed. Anticardiolipin antibodies (aCL), anti β2 glycoprotein (aβ2GP), lupus anticoagulant (LAC), protein C (PC), protein S (PS), antithrombin (AT), acquired activated protein C, and homocysteinemia were evaluated. Comparisons for categorical variables were analyzed by Chi 2 and student tests., Results: The patients were all female and had a mean age of 30.6 years (16/58). The healthy controls were all female and their mean age was 30.8 years (17/56). Five patients (9.4%) developed venous thrombosis during the 24 months of follow-up. The antiphospholipid antibodies were positive in 17 patients (32.1%) and negative in all healthy controls (P=0.01). PS deficiency was noted in 17 patients (32.1%) and in 5 controls (P=0.004). Hyperhomocysteinemia was noted in 16 patients (30.2%) versus 3 controls (5.6%) (P=0.002). Test for PC deficiency and acquired activated protein C showed no significant difference between the two groups. No AT deficiency was found in the patients. The study of clinical and biological correlations based on the presence and absence of thrombophilic parameters concluded to a significant association between Protein C deficit and thrombosis (P=0.02) and acquired activated protein C resistance and thrombosis (P=0.04). There was no significant association between the APL and thrombosis., Conclusion: Thrombophilic abnormalities were significantly more frequent in lupus patients than in healthy controls. Thrombotic events were significantly associated with PC deficit and acquired protein C resistance. There was no correlation between antiphospholipid antibodies and thrombosis., (Copyright © 2018. Published by Elsevier Masson SAS.)

Objective: Budd-Chiari syndrome (BCS) is a life-threatening hepatic disease characterized by hepatic venous obstruction at the level of hepatic vein, hepatic venules, or inferior vena cava. No evidence reported the relationship between the endothelial progenitor cells and the deficiency of factor V Leiden and protein C in patients with primary Budd-Chiari syndrome., Patients and Methods: We recruited participants between June 2014 and July 2015. For primary BCS group, 28 patients were collected. 20 patients were included in the NAFLD group. Another 73 healthy participants were recruited into the control group. None of the patients and participants had received interventional therapy or had undergone surgery prior to being recruited. Levels and functions of endothelial progenitor cells (EPCs) were examined. The factor V Leiden mutation, protein C deficiency and protein S deficiency were evaluated. Finally, the relationship between the levels and function of endothelial progenitor cells and factor V Leiden and protein C deficiency in patients with primary Budd-Chiari syndrome was analyzed., Results: The results showed that no significant differences were found between the BCS (and NAFLD) and control group considering age, sex, BMI, smoking (p>0.05 for variables). However, significant differences were observed in TG, TC, HDL-C, white blood cells, hemoglobin, ALT, AST, ALP, γ-GT, total bilirubin, and albumin (p<0.05 for variables). Compared with the healthy participants, significant downregulation was found in BCS and NAFLD patients regarding CD34+/CD45-, late outgrowth endothelial cells (OECs) colonies, OECs proliferation, and OECs tubulogenesis (p<0.001 for variables). Among the 28 BCS patients, factor V Leiden mutation (n=10, 35.71%, OR 12.67, 95% CI 5.24-27.93) and hereditary protein C deficiency (n=4, 14.29%, OR 7.48, 95% CI 2.02-21.43) were more prevalent than those in the control group. These results suggested that factor V Leiden mutation and protein C deficiency were major risk factors for BCS. Finally, we demonstrated that factor V Leiden and protein C deficiency may negatively regulate the OECs levels and functions in BCS patients., Conclusions: It's important to improve the OECs levels and functions, and to prevent the deficiency of factor V Leiden and protein C in the treatment of BCS.

Background: Hereditary thrombophilia (HT) is a genetic predisposition to thrombosis. Asian mutation spectrum of HT is different from Western ones. We investigated the incidence and clinical characteristics of HT in Korean patients with unprovoked venous thromboembolism (VTE)., Methods: Among 369 consecutive patients with thromboembolic event who underwent thrombophilia tests, we enrolled 222 patients diagnosed with unprovoked VTE. The presence of HT was confirmed by DNA sequencing of the genes that cause deficits in natural anticoagulants (NAs). Median follow-up duration was 40±38 months., Results: Among the 222 patients with unprovoked VTE, 66 (29.7%) demonstrated decreased NA level, and 33 (14.9%) were finally confirmed to have HT in a genetic molecular test. Antithrombin III deficiency (6.3%) was most frequently detected, followed by protein C deficiency (5.4%), protein S deficiency (1.8%), and dysplasminogenemia (1.4%). The HT group was significantly younger (37 [32-50] vs. 52 [43-65] years; P < 0.001) and had a higher proportion of male (69.7% vs. 47%; P = 0.013), more previous VTE events (57.6% vs. 31.7%; P = 0.004), and a greater family history of VTE (43.8% vs. 1.9%; P < 0.001) than the non-HT group. Age <45 years and a family history of VTE were independent predictors for unprovoked VTE with HT (odds ratio, 9.435 [2.45-36.35]; P = 0.001 and 92.667 [14.95-574.29]; P < 0.001)., Conclusions: About 15% of patients with unprovoked VTE had HT. A positive family history of VTE and age <45 years were independent predictors for unprovoked VTE caused by HT.

Congenital thrombophilia which is characterized by deficiencies in proteins such as antithrombin (AT), protein C (PC) and protein S (PS), is a major cause of venous thromboembolism (VTE). A total of 130 patients with VTE were evaluated for congenital thrombophilia based on the activity of AT, PC, or PS. Fifteen VTE patients with congenital AT deficiency (11.5 %), 16 with congenital PC deficiency (12.3 %) and eight with congenital PS deficiency (6.2 %) were diagnosed using DNA analysis. The frequency of congenital AT deficiency was significantly higher in subjects with pregnancy-related and idiopathic VTE than in those with VTE due to other causes, and congenital PC and PS deficiency were frequently associated with idiopathic VTE. Among the groups examined, the plasma levels of AT were the lowest in subjects with pregnancy-related VTE. Although our findings may have been influenced by some unintentional bias, congenital thrombophilia is nevertheless a major cause of VTE in pregnant patients as well as in young or middle-aged patients without any underlying diseases.

Genetic risk factors predispose to thrombophilia and play the most important etiopathogenic role in venous thromboembolism (VTE) in people younger than 50 years old. At least one inherited risk factor could be found in about half of the cases with a first episode of idiopathic VTE.Roughly, genetic risk factors are classified into two main categories: loss of function mutations (such as deficiencies of antithrombin, protein C, protein S) and gain of function mutations, (such as prothrombin mutation G20210A, factor V Leiden). A revolutionary contribution to the genetic background of VTE was brought by the achievements of the genome-wide association studies which analyze the association of a huge number of polymorphisms in large sample size.Hereditary thrombophilia testing should be done only in selected cases. The detection of hereditary thrombophilia has impact on the management of the anticoagulation in children with purpura fulminans, pregnant women at risk of VTE and may be useful in the assessment of the risk for recurrent thrombosis in patients presenting an episode of VTE at a young age (<40 years) and in cases with positive family history regarding thrombosis.

Despite advances in the treatment of chronic renal failure, vascular access remains the weakest link in renal replacement therapy (RRT) and the leading cause of morbidity in patients on hemodialysis We report the case of a young female patient with chronic renal insufficiency secondary to vascular nephropathy on periodic hemodialysis and whose vascular capital was early exhausted due to iterative thromboses in arteriovenous fistulas and failure in peritoneal dialysis. Protein C deficiency was objectified. The patient underwent tunneled hemodialysis catheter insertion at the level of the right atrium via a right anterolateral thoracotomy with cannulation of the inferior vena cava, with poor functional outcome after three months of use. Since then she has been dialyzed using puncture of the external jugular veins., Competing Interests: Les auteurs ne déclarent aucun conflit d'interêt.

A 32year-old female presenting with right lower quadrant pain was found to have caecal varices. Extensive work-up revealed underlying protein C deficiency., (Copyright © 2016 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.)

Objective: To investigate the molecular etiology of protein C (PC) deficiency. Methods: Routine diagnosis and genetic analysis were performed on four probands with PC deficiency. Results: ①Case 1, female, 40 years old, diagnosed of deep vein thrombosis in left lower limb. PC activity (PC∶C) was 48%, PS activity (PS∶C) was 26.3%, AT activity (AT∶C) was 75.6%. Genetic analysis discovered heterozygous mutation C5156T on promoter of PC gene, together with heterozygous mutation A6578T on Exon2 of PC gene. After anticoagulant, thrombolysis and filter implantation therapies, the patient went home with improvement. ②Case 2, female, 32 years old, diagnosed of deep vein thrombosis in both lower limb, ischemia in both lower and upper limb, and skin infection in both lower limb. PC∶C 27%, PS∶C 22.9%, AT∶C 86.7%. Genetic analysis identified heterozygous mutation C5156T, together with heterozygous mutation A5045T on promoter of PC gene. After anticoagulant and anti-infection therapy, the patient died of respiratory failure, septic shock and DIC. ③Case 3, female, 28 years old, diagnosed of vein thrombosis in right iliac and femoral vein. PC∶C 58%, PS∶C 57.3% , AT∶C 80.8%. Genetic analysis disclosed heterozygous mutation C4867T on promoter of PC gene, AGA 12702-12704del or 12705-12707del on Exon7, the latter one lead to Arg192 or 193del. Heterozygous mutation G15240A on Exon9 was also found. After anticoagulant, thrombolysis and filter implantation therapies, the patient went home with improvement. ④Case 4, male, 30 years old, diagnosed of vein thrombosis in right iliac and femoral vein. PC∶C 50%, PS∶C 75.0%, AT∶C 89.1%. Genetic analysis found homozygous mutation C4867T and G4880A on promoter of PC gene, heterozygous mutation A5045T on promoter and heterozygous mutation T6589C on Exon2. After anticoagulant, thrombolysis and filter implantation therapies, the patient went home with improvement. ⑤ Polymorphism analysis revealed that heterozygous mutation C4867T, homozygous mutation G4880A, and heterozygous mutation C5156T were polymorphism sites of PC gene. Conclusions: Polymorphism sites (G4880A, C4867T, C5156T), missense mutation A5045T, A6578T, G15240A, and deletion mutation AGA12702-12704del, 12705-12707del may be related to deficiency of PC. Missense mutation A5045T, A6578T, G15240A, and deletion mutation AGA12702-12704, 12705-12707del were first reported worldwide.

Introduction: Venous thromboembolic disease is a multifactorial, frequently recurrent pathology, whose treatment is based on anticoagulation. As part of the etiological investigation, screening for an inherited thrombophilia is framed by French guidelines published in 2009. The aim of the study is to assess the contribution of inherited thrombophilias testing in common practice., Method: This is a retrospective single-center observational study. Over a period of a year, all records of patients who were screened for a hereditary thrombophilia were analyzed. The conformity of the indication of hereditary thrombophilia workup in balance with the guidelines, its completeness and therapeutic impact were studied., Results: Of the 494 records analyzed, 225 were related to venous thromboembolism. Among them, there were 162 pulmonary embolisms or deep vein thrombosis of the lower limbs. In this subgroup, 57 % of records complied with guidelines and 69 % were complete. Thirty-four thrombophilias were highlighted: 4 protein S deficiencies, 1 protein C deficiency, 4 combined deficiencies, 17 factor V Leiden mutations and 8 factor II G20210A mutations. For one patient, hereditary thrombophilia diagnosis had profoundly changed the curative therapeutic approach., Conclusion: Adherence to French guidelines remains limited. In clinical practice, diagnosis of hereditary thrombophilia has little impact on the curative therapeutic approach in venous thromboembolic disease., (Copyright © 2016 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Portal vein thrombosis is considered a vaso-occlusive process that can appear during the course of hepatosplenic Schistosoma mansoni, but may result from impaired portal blood flow or be associated with acquired or inherited thrombophilic factors. Here, we report the case of a 67-year-old woman who developed thrombocytopenia as a result of hypersplenism. Following the diagnosis of hepatosplenic schistosomiasis, portal vein thrombosis was detected by ultrasound examination, while haematological tests revealed low levels of protein C (43.3%) and high levels of factor VIII (183.1%). The pathogenesis of portal vein thrombosis remains unclear in some patients with S. mansoni. We recommend, therefore, that early clinical and haemostatic investigations are done to evaluate risk of portal vein thrombosis and hence avoid further complications.

Many subjects carrying inherited thrombophilic defects will never experience venous thromboembolism (VTE) while other individuals developed recurrent VTE with no known additional risk factors. High levels of circulating microparticles (MP) have been associated with increased risk of VTE in patients with factor V Leiden and prothrombin G20210A mutation, suggesting a possible contribution of MP in the hypercoagulability of mild genetic thrombophilia. The role of MP as additional risk factor of VTE in carriers of natural clotting inhibitors defects (severe thrombophilia) has never been assessed. Plasma levels of annexin V-MP, endothelial-derived MP (EMP), platelet-derived MP (PMP), tissue factor-bearing MP (TF+) and the MP procoagulant activity (PPL) were measured in 132 carriers of natural anticoagulant deficiencies (25 antithrombin, 63 protein C and 64 protein S defect) and in 132 age and gender-matched healthy controls. Carriers of natural anticoagulant deficiencies, overall and separately considered, presented with higher median levels of annexin V-MP, EMP, PMP, TF+MP and PPL activity than healthy controls (p< 0.001, < 0.001, < 0.01, 0.025 and 0.03, respectively). Symptomatic carriers with a previous episode of VTE had significantly higher median levels of annexin-V MP than those without VTE (p=0.027). Carriers with high levels of annexin V-MP, EMP and PMP had an adjusted OR for VTE of 3.36 (95% CI, 1.59 to 7.11), 9.26 (95% CI, 3.55 to 24.1) and 2.72 (95%CI, 1.16 to 6.38), respectively. Elevated levels of circulating MP can play a role in carriers of mild and severe inherited thrombophilia. The clinical implications of this association remain to be defined.