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.

The risk profiles of pregnancy-related cerebral venous thrombosis: a retrospective study in a comprehensive hospital.

OBJECTIVES: To investigate the risk factors and underlying causes of pregnancy-related cerebral venous thrombosis (PCVT). METHODS: A retrospective cohort of 16 patients diagnosed with CVT during pregnancy and postpartum (within six weeks after delivery) in a comprehensive hospital in China between 2009 and 2022 were carefully reviewed, focusing on demographic, clinical, and etiological characteristics, especially underlying causes. We matched 16 PCVT patients with 64 pregnant and puerperal women without PCVT to explore risk factors and clinical susceptibility to PCVT. RESULTS: PCVT occurred commonly during the first trimester (43.75%) and the puerperium (37.5%). The frequency of anemia, thrombocytosis and thrombocytopenia during pregnancy, dehydration, and pre-pregnancy anemia was significantly higher in women with PCVT than in those without PCVT (P < 0.05). Among the 16 patients, five were diagnosed with antiphospholipid syndrome and one was diagnosed with systemic lupus erythematosus. Three patients had distinct protein S deficiency and one had protein C deficiency. Whole Exome Sequencing (WES) was performed for five patients and revealed likely pathogenic mutations associated with CVT, including heterozygous PROC c.1218G > A (p. Met406Ile), heterozygous PROS1 c.301C > T (p. Arg101Cys), composite heterozygous mutation in the F8 gene (c.144-1259C > T; c.6724G > A (p. Val2242Met)) and homozygous MTHFR c.677C > T (p. Ala222Val). CONCLUSIONS: The occurrence of anemia, thrombocytopenia and thrombocytosis during pregnancy, dehydration and pre-pregnancy anemia suggested a greater susceptibility to PCVT. For confirmed PCVT patients, autoimmune diseases, hereditary thrombophilia, and hematological disorders were common causes. Screening for potential etiologies should be paid more attention, as it has implications for treatment and long-term management.

Postinfectious purpura fulminans: A case report. / Púrpura fulminante postinfecciosa: a propósito de un caso.

Acquired postinfectious purpura fulminans is a rare, acute, and severe disease characterized by skin necrosis associated with disseminated intravascular coagulation (DIC) in the absence of active infection or previous coagulation disorders. It mainly affects the pediatric population and, in 90% of cases, it is preceded by an infectious process. The pathophysiological mechanism is a transient autoantibody-mediated protein S deficiency that favors a hypercoagulable state. Here we describe the case of a previously healthy 8-year-old boy with purpuric skin lesions typical of purpura fulminans associated with DIC in the absence of sepsis. A transient plasma protein S deficiency was confirmed. He required replacement therapy with fresh frozen plasma and anticoagulation; he had a favorable course. Protein S activity remained decreased for 2 months.

La púrpura fulminante adquirida postinfecciosa es una entidad aguda y grave, poco frecuente, caracterizada por necrosis cutánea asociada a coagulopatía intravascular diseminada (CID), en ausencia de infección activa o alteraciones previas de la coagulación. Afecta fundamentalmente a la población pediátrica y, en el 90 % de los casos, está precedida por un proceso infeccioso. El mecanismo fisiopatológico es un déficit transitorio de proteína S mediado por autoanticuerpos que favorece un estado de hipercoagulabilidad. Se presenta el caso de un varón de 8 años previamente sano, con lesiones cutáneas purpúricas características de púrpura fulminante asociada a CID en ausencia de sepsis. Se constató deficiencia plasmática transitoria de proteína S. Requirió tratamiento sustitutivo con plasma fresco congelado y anticoagulación; la evolución fue favorable. La actividad de la proteína S permaneció disminuida durante 2 meses.

Púrpura fulminante postinfecciosa: a propósito de un caso / Postinfectious purpura fulminans: A case report

La púrpura fulminante adquirida postinfecciosa es una entidad aguda y grave, poco frecuente, caracterizada por necrosis cutánea asociada a coagulopatía intravascular diseminada (CID), en ausencia de infección activa o alteraciones previas de la coagulación. Afecta fundamentalmente a la población pediátrica y, en el 90 % de los casos, está precedida por un proceso infeccioso. El mecanismo fisiopatológico es un déficit transitorio de proteína S mediado por autoanticuerpos que favorece un estado de hipercoagulabilidad. Se presenta el caso de un varón de 8 años previamente sano, con lesiones cutáneas purpúricas características de púrpura fulminante asociada a CID en ausencia de sepsis. Se constató deficiencia plasmática transitoria de proteína S. Requirió tratamiento sustitutivo con plasma fresco congelado y anticoagulación; la evolución fue favorable. La actividad de la proteína S permaneció disminuida durante 2 meses.

Acquired postinfectious purpura fulminans is a rare, acute, and severe disease characterized by skin necrosis associated with disseminated intravascular coagulation (DIC) in the absence of active infection or previous coagulation disorders. It mainly affects the pediatric population and, in 90% of cases, it is preceded by an infectious process. The pathophysiological mechanism is a transient autoantibodymediated protein S deficiency that favors a hypercoagulable state. Here we describe the case of a previously healthy 8-year-old boy with purpuric skin lesions typical of purpura fulminans associated with DIC in the absence of sepsis. A transient plasma protein S deficiency was confirmed. He required replacement therapy with fresh frozen plasma and anticoagulation; he had a favorable course. Protein S activity remained decreased for 2 months.

Anetodermia primaria: un marcador cutáneo de estados protrombóticos / Primary anetoderma: A cutaneous marker of prothrombotic states

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Púrpura retiforme asociada a déficit de proteína S / Retiform Purpura Associated With Protein S Deficiency

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Central retinal vein prethrombosis as an initial manifestation of protein S deficiency

CONTEXTO: Trombose venosa retiniana é mais comum em pessoas idosas e freqüentemente está associada com doença vascular sistêmica. Uma causa sistêmica rara é a deficiência de proteína S. RELATO DE CASO: Um caso de paciente branca, de 21 anos, com pré-trombose de veia central da retina associada à deficiência isolada de proteína S é descrito. Ela apresentou súbito embaçamento visual e escotoma central em olho esquerdo. Terapia cumarínica foi iniciada e completa remissão dos achados oftalmoscópicos foi observada. Este caso mostra que deficiência de proteína S deve ser um fator que deve ser considerado em casos de oclusão venosa retiniana, particularmente em pacientes jovens.

Ischemic stroke in children: a study of the associated alterations

Acidente vascular cerebral Isquêmico (AVCI) na infância é relativamente raro, de conhecimento ainda obscuro, e com etiologia multifatorial. Pode causar grave impacto na criança e ser a primeira manifestação de doença sistêmica. O subdiagnóstico ainda é comum e são praticamente inexistentes as pesquisas sobre o assunto no nosso meio. Desordens protrombóticas têm sido descritas como importantes fatores causais do evento isquêmico na infância. Foram estudados 46 pacientes de zero a 18 anos, com diagnóstico de AVCI, no período de março/2002 a setembro/2003. Exames laboratoriais, incluindo proteínas de coagulação e ecocardiograma foram realizados. AVCI neonatal ocorreu em 35% dos casos. Crise focal e hemiparesia foram os sintomas iniciais mais freqüentes; 40% dos casos apresentaram patologia prévia. Anormalidades nas proteínas S e C ocorreram em 22% e 17% da amostra. Alterações associadas, principalmente as que geram um estado hipercoagulável, indicam que mais de um fator de risco pode causar essa doença na infância.

Trombosis del seno venoso cerebral en gestante con síndrome de Job / Cerebral venous sinus thrombosis in a pregnant woman with Job’s syndrome

La trombosis de seno venoso cerebral es una enfermedad infrecuente. La gestación es un factor de riesgo importante para su desarrollo. Se presenta el caso de una paciente con síndrome de Job y déficit de proteína C y S que presentó una trombosis del seno venoso cerebral y una fístula dural a las 36 semanas de gestación. A pesar de la heparinización, que es el tratamiento de elección, fue necesaria la terminación de la gestación para eliminar la situación protrombótica, y la embolización de la fístula dural para obtener la remisión total de la sintomatología neurológica (AU)

Cerebral venous sinus thrombosis is uncommon. Pregnancy is a major risk factor for the development of this entity. We report the case of a patient with Job’s syndrome and protein C and S deficiency who developed cerebral venous sinus thrombosis and dural fistula at 36 weeks’ gestation. After heparinization, the treatment of choice, pregnancy termination to eliminate the prothrombotic status and embolization of the dural fistula were required to obtain complete remission of the neurological symptoms (AU)

Deficiencia de proteína S / Protein S deficiency

Apresenta-se caso de Síndrome Hereditária de Hiper-coagulabilidade sanguínea causada por deficiência de proteína S. O diagnóstico foi sugerido pela anamnese e confirmado por dosagens quantitativas das proteínas S, C e antitrombina III. A paciente apresentava episódios trombo-embólicos recorrentes incluindo trombose venosa profunda, embolia pulmonar e trombose mesentérica. As dosagens plasmáticas demonstraram diminuiçäo da atividade de proteína S, corroborando hipótese de Síndrome de Hiper-coagulabilidade. Objetiva-se chamar a atençäo dos médicos em geral para os casos de trombose venosa profunda e embolia pulmonar recorrente, especialmente aqueles que envolvem membros de uma mesma família, que podem estar associadas aos estados de hiper-coagulabilidade sanguínea