Antithrombin deficiency caused by SERPINC1 gene mutation in white matter lesions: A case report.

RATIONALE: White matter lesions (WMLs) are structural changes in the brain that manifest as demyelination in the central nervous system pathologically. Vasogenic WMLs are the most prevalent type, primarily associated with advanced age and cerebrovascular risk factors. Conversely, immunogenic WMLs, typified by multiple sclerosis (MS), are more frequently observed in younger patients. It is crucial to distinguish between these 2 etiologies. Furthermore, in cases where multiple individuals exhibit WMLs within 1 family, genetic testing may offer a significant diagnostic perspective. PATIENT CONCERNS: A 25-year-old male presented to the Department of Neurology with recurrent headaches. He was healthy previously and the neurological examination was negative. Brain magnetic resonance imaging (MRI) showed widespread white matter hyperintensity lesions surrounding the ventricles and subcortical regions on T2-weighted and T2 fluid-attenuated inversion recovery images, mimicking immunogenic disease-MS. DIAGNOSES: The patient was diagnosed with a patent foramen ovale, which could explain his headache syndrome. Genetic testing unveiled a previously unidentified missense mutation in the SERPINC1 gene in the patient and his father. The specific abnormal laboratory finding was a reduction in antithrombin III activity, and the decrease may serve as the underlying cause for the presence of multiple intracranial WMLs observed in both the patient and his father. INTERVENTIONS: The patient received percutaneous patent foramen ovale closure surgery and took antiplatelet drug recommended by cardiologists and was followed up for 1 month and 6 months after operation. OUTCOMES: While the lesions on MRI remain unchanging during follow-up, the patient reported a significant relief in headaches compared to the initial presentation. LESSONS: This case introduces a novel perspective on the etiology of cerebral WMLs, suggesting that hereditary antithrombin deficiency (ATD) could contribute to altered blood composition and may serve as an underlying cause in certain individuals with asymptomatic WMLs.

Successful treatment of a massive sinus thrombosis in a Chinese woman with antithrombin III deficiency: a case report and review of the literature.

: The incidence of antithrombin III (AT III) deficiency is very rare. The most common complication of AT III deficiency is deep venous thrombosis, which causes a low incidence of intracranial sinus thrombosis. We presented a 31-year-old Chinese woman patient who had a family history of AT III deficiency admitted to our hospital. She had a history of pulmonary embolism. She took rivaroxaban for a long time to prevent thrombosis. After giving birth, she stopped taking the medication for half a year and suffered from drug withdrawal symptoms. Four months after drug withdrawal, she suddenly fell into a coma. After diagnosis, it was found to be caused by a subarachnoid hemorrhage. Finally, she was diagnosed with sagittal and transverse sinus thrombosis. After treatment with mechanical thrombectomy, she fully recovered. In sum, we concluded that mechanical thrombectomy was efficient for AT III deficiency and treating thrombosis.

Management of antithrombin deficiency: an update for clinicians.

Introduction. Antithrombin is a serpin that inhibits multiple procoagulant serine proteases and acts as an endogenous anticoagulant. Thus, congenital antithrombin deficiency constitutes a major thrombophilic state, the most severe so far. Areas covered. In the present work, we globally review the biology, genetics, diagnosis, and management of congenital antithrombin deficiency, and also discuss puzzling questions and future perspectives regarding this severe inherited thrombophilia. Expert opinion. Although this disorder exerts high clinical heterogeneity, many carriers will need careful and long-term anticoagulation and/or thromboprophylaxis, especially in high-risk situations, such as surgery and pregnancy. Notably, antithrombin concentrates constitute a considerable arsenal for both treatment and prevention of acute venous thrombosis in subjects with antithrombin deficiency. Current evidences are based almost exclusively on retrospective case series, so an integrated functional, biochemical and molecular characterization will be of clinical relevance and guide hematologists' personalized decisions.

Antithrombin Debrecen (p.Leu205Pro) - Clinical and molecular characterization of a novel mutation associated with severe thrombotic tendency.

INTRODUCTION: Hereditary antithrombin (AT) deficiency is a rare thrombophilic disorder with heterogeneous genetic background and various clinical presentations. In this study we identified a novel AT mutation. Genotype-phenotype correlations, molecular characteristics and thrombotic manifestations of the mutation were investigated. MATERIALS AND METHODS: Thirty-one members of a single family were included. Clinical data was collected regarding thrombotic history. The mutation was identified by direct sequencing of the SERPINC1 gene. HEK293 cells were transfected with wild type and mutant SERPINC1 plasmids. Western blotting, ELISA and functional amidolytic assay were used to detect wild type and mutant AT. After double immunostaining, confocal laser scanning microscopy was used to localize mutant AT in the cells. Molecular modeling was carried out to study the structural-functional consequences of the mutation. RESULTS: Unprovoked venous thrombotic events at early age, fatal first episodes and recurrences were observed in the affected individuals. The median AT activity was 59%. Genetic analysis revealed heterozygous form of the novel mutation p.Leu205Pro (AT Debrecen). The mutant AT was expressed and synthesized in HEK293 cells but only a small amount was secreted. The majority was trapped intracellularly in the trans­Golgi and 26S proteasome. The mutation is suspected to cause considerable structural distortion of the protein. The low specific activity of the mutant AT suggested functional abnormality. CONCLUSIONS: AT Debrecen was associated with very severe thrombotic tendency. The mutation led to misfolded AT, impaired secretion and altered function. Detailed clinical and molecular characterization of a pathogenic mutation might provide valuable information for individualized management.

A case that illustrates the challenges of managing pregnant patients with antithrombin deficiency: More questions than answers.

Using an illustrative case of a patient with antithrombin (AT) deficiency who developed a recurrent venous thromboembolism (VTE) in pregnancy despite therapeutic low-molecular-weight heparin (LMWH), we highlight what is known in the literature and address areas of controversy through a series of questions around the case. The questions we address include the role of anti-Xa monitoring for patients with past VTE on antepartum LMWH, what treatment regimen is recommended for pregnant patients who develop a recurrent VTE while on therapeutic anticoagulation, the role of antepartum AT concentrate prophylaxis, and the management of labor/delivery, epidural anesthesia and postpartum anticoagulation. We also describe practical considerations for use of AT concentrate, including teaching our patient to self-infuse AT concentrate at home with support of a hemophilia treatment center (HTC), and the direct and indirect costs of AT concentrate for secondary prophylaxis.

Management of hereditary antithrombin deficiency in pregnancy.

Antithrombin (AT) deficiency is a high-risk thrombophilia and a rare condition. Despite full anticoagulation during pregnancy and the postpartum period, women with AT deficiency may still be vulnerable to developing venous thromboembolism (VTE), including fatal events. There is limited guidance on the management of AT deficiency in pregnancy, including the role of AT concentrates. Following a comprehensive review of the state of the art with respect to recommendations and guidelines, our expert panel in maternal-fetal medicine, hematology and basic science reached consensus on key issues in the recognition and management of AT deficiency in pregnancy. This paper summarizes the state of the art and summarizes what we believe are best practices with special emphasis on a multidisciplinary approach involving obstetrics and hematology in the care of women with AT deficiency.

A complex genomic abnormality found in a patient with antithrombin deficiency and autoimmune disease-like symptoms.

Hereditary antithrombin (AT) deficiency is an autosomal dominant thrombophilic disorder caused by SERPINC1 abnormality. In the present study, we analyzed SERPINC1 in a Japanese patient with AT deficiency and autoimmune disease-like symptoms. Direct sequencing and multiplex ligation-dependent probe amplification revealed that the patient was hemizygous for the entire SERPINC1 deletion. Single nucleotide polymorphism genotyping, gene dose measurement, and long-range polymerase chain reaction (PCR) followed by mapping PCR and direct sequencing of the long-range PCR products revealed that the patient had an approximately 111-kb gene deletion from exon 2 of ZBTB37 to intron 5 of RC3H1, including the entire SERPINC1 in chromosome 1. We also found a 7-bp insertion of an unknown origin in the breakpoint, which may be a combination of three parts with a few base-pair microhomologies, resulting from a replication-based process known as 'fork stalling and template switching'. Because RC3H1, which encodes the protein roquin is involved in the repression of self-immune responses, the autoimmune disease-like symptoms of the patient may have resulted from this gene defect. In conclusion, we identified an entire SERPINC1 deletion together with a large deletion of RC3H1 in an AT-deficient patient with autoimmune disease-like symptoms.

Recurrent ischemic cerebrovascular events in a patient with type I antithrombin deficiency caused by 9788 G>A splice site mutation: a case report.

Type I antithrombin deficiency is an autosomal dominant disorder associated with high risk for venous thromboembolism. Data on the association between antithrombin deficiency and arterial thromboembolism are inconsistent. We report here the case of AT deficiency in a 43-year-old man free of cardiovascular risk factors who experienced venous thromboembolism and ischemic stroke followed by two transient ischemic attacks after interruption of oral anticoagulation due to colonoscopy. DNA sequencing of the antithrombin gene revealed heterozygosity for the previously reported substitution G to A at nucleotide position 9788 in intervening sequence four. To our knowledge, this report is the first to show that this genetic abnormality can be associated with recurrent cerebrovascular ischemic events.

Two concurrent chromosomal aberrations involving interstitial deletion in 1q24.2q25.2 and inverted duplication and deletion in 10q26 in a patient with stroke associated with antithrombin deficiency and a patent foramen ovale.

Advanced high-throughput molecular cytogenetic analysis has enabled the identification of small chromosomal rearrangements, and two or more concurrently occurring chromosomal rearrangements have been identified using this technique. A girl with severe psychomotor developmental delay associated with an uncertain abnormality (detected by conventional karyotyping) in chromosome 10q had a sudden stroke at the age of 35 months. Laboratory and radiographic examinations revealed antithrombin (AT) deficiency and a patent foramen ovale (PFO). Two concurrent chromosomal aberrations, inverted duplication and deletion in the 10q26 region and a microdeletion in the 1q24.2q25.2 region including the AT gene (SERPINC1), were identified by microarray-based comparative genomic hybridization analysis. Both chromosomal aberrations were found to be of paternal origin. This study described the concurrence of chromosomal rearrangements involving two chromosomes, and estimated the frequency of two or more chromosomal aberrations as 2-4%.

Testing for inherited thrombophilias in arterial stroke: can it cause more harm than good?

BACKGROUND AND PURPOSE: Despite a paucity of evidence supporting a true association of ischemic stroke and the inherited thrombophilias, it is common practice for many neurologists to order these tests as part of the work-up of ischemic stroke, especially in young patients. Treatment with oral anticoagulation is often used in patients with positive results for the inherited thrombophilias. METHODS: We reviewed the literature focusing on case-control studies of the 5 most commonly inherited disorders of coagulation: protein C deficiency, protein S deficiency, antithrombin deficiency, and the factor V Leiden and prothrombin gene mutations in patients with stroke. We also analyzed the available data on stroke patients with inherited thrombophilia and patent foramen ovale. RESULTS: Multiple case-control studies have not convincingly shown an association of the inherited thrombophilias with ischemic stroke, even in young patients and patients with patent foramen ovale. CONCLUSIONS: If there is an association between the inherited thrombophilias and arterial stroke, then it is a weak one, likely enhanced by other prothrombotic risk factors. The consequences of ordering these tests and attributing causality to an arterial event can result in significant costs to the health care system and pose a potential risk to patients, because this may lead to inappropriate use of long-term oral anticoagulants, exposing patients to harm without a clearly defined benefit.

Usefulness of antithrombin deficiency phenotypes for risk assessment of venous thromboembolism: type I deficiency as a strong risk factor for venous thromboembolism.

Inherited antithrombin deficiency, an established risk factor for venous thromboembolism (VTE), can be classified into type I (quantitative deficiency) or type II (qualitative deficiency). In the present study, we assessed the VTE risk associated with the phenotypes of antithrombin deficiency in patients admitted to our hospital. We found that patients with type I deficiency (n = 21) had more VTE events and earlier onset of VTE than those with type II deficiency (n = 10). The VTE-free survival analysis showed that the risk for VTE in patients with type I deficiency was sevenfold greater than that in patients with type II deficiency (hazard ratio: 7.3; 95% confidence interval: 1.9-12.2; P = 0.0009). The prevalence of type I deficiency in the VTE group (5.6%, 6/108) was higher than that in the general population (0.04%, 2/4,517) (odds ratio: 132.8; 95% confidence interval: 26.5-666.1; P < 0.0001). However, the prevalence of type II deficiency was not different between the VTE group and the general population. Our study indicated that the risk for VTE in patients with type I deficiency was much higher than that in patients with type II deficiency. Thus, simple phenotypic classification of antithrombin deficiency is useful for assessment of VTE risk in Japanese.

Simultaneous thromboses of double coronary arteries in a young male with antithrombin III deficiency.

In most acute ST-segment elevation myocardial infarction, a single culprit vessel is often found; however, multivessel occlusion, although uncommon, can occur and usually with a poor prognosis, including mortality. We reported a 22-year-old young male who presented to our emergency department because of chest pain after exercise. On physical examination, the cardiac auscultation revealed gallop rhythm without murmur, and the pulmonary auscultation revealed minimal basal moist rales. Other physical examinations were unremarkable. Twelve-lead electrocardiography showed normal sinus rhythm with rate of 96 beats per minute, hyperacute T wave in V1 to V6 and II, III, aVF with reciprocal change in lead I, aVL. He underwent immediate coronary angiography that revealed simultaneous total occlusion of proximal portion of right coronary artery and left anterior descending coronary artery. Successful percutaneous coronary intervention with angioplasty was performed with optimal angiographic result. Although simultaneous total occlusion of double coronary arteries is a rare condition, especially in young group with antithrombin III deficiency, percutaneous coronary intervention and long-term anticoagulant agent are still one of the standard treatments, but the operator should be aware of the hemodynamic change and the importance of mechanical support.

Multiple isolated sinus dural arteriovenous fistulas associated with antithrombin III deficiency--case report--.

A 55-year-old man presented with a rare case of multiple isolated sinus dural arteriovenous fistulas (AVFs) associated with antithrombin (AT) III deficiency manifesting as sudden onset of headache and gait disturbance. Increased arterial shunting flow had caused intraventricular hemorrhage after incomplete repeated transarterial embolization procedures for dural AVFs. Multiple isolated sinus dural AVFs were located in the anterior superior sagittal sinus (SSS) and transverse sinus, which were completely embolized by direct packing of the isolated sinuses via the SSS. The development of dural AVF is complicated and associated with a number of factors, such as congenital abnormality, head trauma, craniotomy, radiation, hematological abnormality, and sinus thrombosis. Hematological abnormality is a risk factor of sinus thrombosis. In the present case, the multiple isolated sinus dural AVFs might have resulted from the aggravation of multiple dural AVFs and the coagulative tendency due to AT III deficiency. Direct sinus packing should be considered if transvenous catheterization is difficult or fails.