Incidence and features of thrombosis in children with inherited antithrombin deficiency.

Pediatric thromboembolism (≤18 years) is very rare (0.07-0.14/10,000/year) but may be more prevalent in children with severe thrombophilia (protein C, protein S or antithrombin deficiency). The aim of this study was to define the prevalence and clinical characteristics of pediatric thrombosis in subjects with inherited antithrombin deficiency. Our observational retrospective multicentric study from two countries recruited 968 patients of any age from 441 unrelated families with genetically, biochemically and functionally characterized antithrombin deficiency. Seventy-three subjects (7.5%) developed thrombosis before 19 years of age. Two high-risk periods for thrombosis were identified: adolescence (12-18 years, n=49) with thrombus localization (lower limb deep venous thrombosis or pulmonary embolism) and triggering factors common to adults (oral contraceptives, surgery or pregnancy); and the neonatal period (<30 days, n=15) with idiopathic thrombosis at unusual sites. The clinical evaluation of pediatric thrombosis in subjects with antithrombin deficiency revealed: i) a high prevalence of cerebral sinovenous thrombosis (n=13, 17.8%), mainly at young age (8 neonates and 4 children <6 years); ii) severe outcome with fatality in six cases (3 neonates, two of them homozygous for p.Leu131Phe). The majority of subjects (76.7%) carried quantitative type I deficiency. This retrospective analysis includes the largest cohort of subjects with inherited antithrombin deficiency so far and provides strong evidence for an increased risk of pediatric thrombosis associated with this thrombophilia (300-fold compared with the general population: 0.41%/year vs 0.0014%/year, respectively). Our results support testing for antithrombin deficiency in children of affected families, particularly in case of type I deficiency.

The prevalence and clinical manifestation of hereditary thrombophilia in Korean patients with unprovoked venous thromboembolisms.

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.

[Phenotypic and genetic analysis of two pedigrees affected with hereditary antithrombin deficiency].

OBJECTIVE: To explore the phenotype, genotype and molecular mechanism for two pedigrees affected with hereditary antithrombin (AT) deficiency. METHODS: Clinical diagnosis was validated by assaying of coagulation parameters including prothrombin time, activated partial thromboplastin time, thrombin time, fibrinogen, antithrombin activity (AT:A) and specific antigen (AT:Ag), protein C activity, as well as protein S activity. To detect potential mutations in the probands, all exons, exon-intron boundaries and the 3', 5' untranslated regions were amplified by PCR and subjected to direct sequencing. Suspected mutation was confirmed by reverse sequencing and silver staining. The effect of mutations on the AT protein was analyzed with bioinformatics software. RESULTS: The AT:Ag of pedigree 1 was normal, but its AT:A has reduced to 30%. A heterozygous c.235C>T mutation in exon 2 causing p.Arg47Cys, in addition with two single nucleotide polymorphisms (c.981G>A, c.1011G>A) in exon 5 were identified in the patient. His four children, except for the elder daughter, were heterozygous for the mutations. The plasma levels of AT:A and AT:Ag in proband 2 have decreased to 39% and 103 mg/L, respectively. A heterozygous deletion (g.5890-5892delCTT) leading to loss of p.Phe121 was also detected in his father. Bioinformatic analysis suggested that the missense mutation Arg47Cys can affect the functions of AT protein. Meanwhile, lacking of Phe121 will result in loss of hydrogen bonds with Ala124, Lys125 and the cation π interactions with Lys125, Arg47, which may jepordize the stability of the protein. CONCLUSION: The proband 1 had type II AT deficiency, while proband 2 had type I AT deficiency. The p.Arg47Cys and g.5890-5892delCTT mutations of the AT gene are significantly correlated with the levels of AT in the two probands, respectively.

A new case of successful outcome of pregnancy in a carrier of homozygous type II (L99F) antithrombin deficiency.

Inherited antithrombin deficiency is associated with an increased risk of venous thromboembolism. There is no consensus about pregnancy management in antithrombin deficiency patients because there are very few cases published in the literature. We report a successful pregnancy in a 32-year-old female carrier of a homozygous type II (L99F) antithrombin deficiency who developed a spontaneous deep vein thrombosis at the age of 27 years.

Prevention, management and extent of adverse pregnancy outcomes in women with hereditary antithrombin deficiency.

Antithrombin (AT) deficiency is a rare hereditary thrombophilia with a mean prevalence of 0.02 % in the general population, associated with a more than ten-fold increased risk of venous thromboembolism (VTE). Within this multicenter retrospective clinical analysis, female patients with inherited AT deficiency were evaluated concerning the type of inheritance and extent of AT deficiency, medical treatment during pregnancy and postpartally, VTE risk as well as maternal and neonatal outcome. Statistical analysis was performed with SPPS for Windows (19.0). A total of 18 pregnancies in 7 patients were evaluated, including 11 healthy newborns ≥37th gestational weeks (gw), one small for gestational age premature infant (25th gw), two late-pregnancy losses (21st and 28th gw) and four early miscarriages. Despite low molecular weight heparin (LMWH) administration, three VTE occurred during pregnancy and one postpartally. Several adverse pregnancy outcomes occurred including fetal and neonatal death, as well as severe maternal neurologic disorders occurred. Patients with substitution of AT during pregnancy in addition to LMWH showed the best maternal and neonatal outcome. Close monitoring with appropriate anticoagulant treatment including surveillance of AT levels might help to optimize maternal and fetal outcome in patients with hereditary AT deficiency.

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.

[Hemostatic disorders in liver disease]. / Anomaliile hemostazei in suferintele hepatice.

Hemorrhagic complications are common in patients with liver diseases and contribute to the morbidity and mortality associated to this condition. The liver plays a central role in the hemostatic process as here all clotting factors and their inhibitors are synthetized. Liver damage is commonly associated with variable impairment of hemostasis due to multiple causes: decreased synthesis of clotting and inhibitor factors, decreased clearance of activated factors, hyperfibrinolysis, accelerated intravascular coagulation, quantitative and qualitative platelet defects. Their clinical implications remain to be elucidated, so further studies addressing this issue are needed.

Inherited antithrombin deficiency: a review.

Antithrombin (AT) is a potent inactivator of thrombin and factor Xa and the major inhibitor of blood coagulation. Inherited AT deficiencies are uncommon, with prevalences in the general population between 1 in 500 and 1 in 5000. They are either quantitative (type I) or qualitative (type II). Type II is subdivided into the more common, but less thrombogenic, type IIb deficiency caused by a defect in the heparin-binding region of AT and the less common, but more thrombophilic, type IIa variant caused by mutations in the thrombin-binding site. A pleiotropic type IIc deficiency also exists. In the evaluation of a thrombophilic individual, a functional AT assay (AT activity) should be used and the diagnosis of AT deficiency only established after acquired causes have been ruled out and repeat AT testing on an additional sample has been performed. A subsequent antigenic AT assay result leads to differentiation between type I and type II deficiency. Further specialized tests help subclassify the type II deficiencies, but this is typically not carried out for clinical purposes, even though it might be helpful to assess thrombosis risk. AT deficiency is associated with an increased risk for venous thromboembolism (VTE) and pregnancy loss. The association with arterial thrombosis is only weak. VTE prophylaxis and treatment management will be discussed in this article and existing treatment guidelines presented. The lack of data surrounding the use of AT concentrates and the resulting ambiguity as to when to use such concentrates will be discussed.

Pregnancy and thrombophilia.

The physiological changes that occur during pregnancy create a hypercoagulable milieu. This hypercoagulable state is thought to be protective, especially at the time of labor, preventing excessive hemorrhage. The presence of hereditary or acquired causes of thrombophilia during pregnancy tilts the balance in favor of unwanted venous thromboembolism and adverse pregnancy outcomes due to vascular uteroplacental insufficiency. These adverse pregnancy outcomes include recurrent pregnancy losses, intrauterine fetal death, intrauterine growth retardation, preeclampsia and placental abruption. Much of the current data with regards to the association of the different thrombophilias and pregnancy-related complications are based on retrospectively designed studies. This lack of randomization, in-homogeneity of patient populations, varying case definitions, selection biases and inadequately matched control populations, have given rise to conflicting data with regard to screening for, and treatment of, pregnant women with suspected thrombophilias. The limited data that we have support the use of anticoagulant drugs for the prevention of pregnancy-related complications in the setting of thrombophilia. Heparin and low-molecular-weight heparins are the anticoagulant drugs of choice as they do not cross the placental barrier and, hence, do not cause fetal anticoagulation or teratogenicity. Warfarin can be used from the 12th week of gestation onwards but is preferably reserved for the postpartum period.

Estudio diagnóstico de trombofilia en pacientes jóvenes con ictus / Diagnosis of thrombophilia in young people with ictus

La mayoría de los ictus aparecen en personas de más de 50 años y asociados a factores de riesgo cardiovascular. Sin embargo, los ocurridos en pacientes jóvenes, no siempre se justifican con la arterioesclerosis, por lo que se buscan otras etiologías como las trombofilias. Los objetivos del estudio fueron 1.-Conocer la prevalencia de trombofilias y/o estados de hipercoagulabilidad en pacientes jóvenes ingresados por ictus en un hospital de tercer nivel. 2.-Conocer con qué frecuencia se realizan estudios de trombofilia en dichos pacientes. 3.-Cuáles son las características de este tipo de pacientes. Para ello se realizó un estudio descriptivo y retrospectivo, revisando las historias clínicas de todos los pacientes ingresados en el Hospital Clínico Universitario Lozano Blesa" (Zaragoza) durante el año 2004 con diagnóstico de ictus en paciente joven. Se registraron características, antecedentes de interés y estudios de trombofilia/s realizados. Se revisaron 64 pacientes, 32 de ellos fueron isquémicos. En 16 se solicitó algún tipo de estudio de trombofilia. En el estudio de trombofilia plasmática la alteración más frecuente fue el déficit de Antitrombina III, seguido de resistencia al factor V de Leiden. En el estudio de trombofilia genéticas la mutación de la Metiltetrahilrofolatorreductasa (IMTHFR), todos heterocigotos, fue el hallazgo más frecuente. Los parámetros estudiados en inmunología fueron variables e inconstantes. Conclusiones: 1.-Los estudios de trombofilias se solicitaron en menor número de lo que sería recomendable 2.-Las peticiones de estudio no son uniformes para los distintos tipos de trombofilias, siendo los estudios plasmáticos los más solicitados (AU)

Most ictus appear in people over 50 and are associated with cardiovascular risk factors. Nevertheless, those that occur in young patients are not always caused by arteriosclerosis, so other etiologies such as thrombophilias are sought. The objectives of this study were: 1.-To find out the prevalence of thrombophilias and/or states of hypercoagulation in young patients admitted for ictus in a tertiary hospital. 2.-To find out the frequency with which thrombophilia studies are carried out in such patients. 3.-To find out the characteristics of these patients. To do so, a descriptive and retrospective study was carried out, reviewing the clinical histories of all the patients admitted to the Hospital Cllnico Universitario "Lozano Blesa" (Zaragoza) during the year 2004 with diagnoses of ictus in young patients. The characteristics, interesting antecedents and thrombophilia studies carried out were recorded. 64 patients were reviewed, 32 of them showed ischemia. In 16, some type of thrombophilia study was requested. In the study of plasmatic thrombophilia, the most common alteration was antithrombin III deficiency, followed by resistance to V Leyden factor. In the study of genetic thrombophilias, the mutation of Metiltetrahifrofolato reductase (MTHFR), in all cases heterozygotic, was the most frequent finding. The parameters studied in immunology were variable. Conclusions: 1.- Thrombophilia studies are requested less frequently than would be recommendable 2.-The requests for studies are not uniform for the different types of trombofilias, plasmatic studies being the most requested (AU)

hsp70, hsp32, and grp78 are increased in thermally injured skin with and without antithrombin(human) concentrate infusion.

An acquired deficiency of antithrombin (AT), an anti-inflammatory protein, develops in patients with thermal injuries. Skin thermotolerance is regulated by heat shock protein (hsp) genes. hsp70, hsp32, hsp27, and glucose-regulated protein78 (grp78) were studied in burned and unburned human skin to determine whether correction of the AT deficiency modulated the intensity of expression of these proteins. Fifty-four human skin samples were prepared by Western blot analysis: 11 unburned and 22 burned control skin samples and 7 unburned and 14 burned skin samples from patients treated with AT(Human), or AT(H). The intensity of hsp32 expression in burned AT(H)-treated skin (P < .001) and in burned control skin (P < .01) was significantly increased compared with unburned control skin. The intensity of expression of hsp70 was statistically significant in burned AT(H)-treated skin compared with unburned control skin (P < .02), as was that of grp78 (P < .01). Thermally injured skin with or without AT(H) treatment had an increased expression of hsp70, hsp32, and grp78 compared with unburned control skin.

deficiencia de la antitrombina III, la proteína C, la proteína S y resistencia a la proteina C activada en pacientes con trombosis venosa profunda

Objetivo. Establecer la frecuencia de la deficiencia de la antitrombina III (Ant III), proteina C, proteina S y de la resistencia a la proteina C activadas (RPCA) en pacientes con trombosis venosa profunda (TVP). diseño. Estudio prospectivo descriptivo desde julio de 1995 a julio de 1997. Lugar. salas de medicina interna y consulta de anticoagulación del Hospital San Vicente de Paúl. Pacientes. Se estudiaron 17 pacientes menores de 45 años con TVP confirmada por dúplex o pletismografía venosa. Los criterios de exclusión fueron: ser mayor de 45 años, tener síndrome nefrótico o hepatopatía, o estar anticoagulado. Intervención. Se hizo medición cuantitativa de la antitrombina III (valor de referencia (VR): 88-131 por ciento), la proteina C (VR: 66-129 por ciento) y la proteina S (VR: 61.9-145.3 por ciento). La RPCA se determinó por la medición del tiempo de coagulación en el plasma en la respuesta a la proteina C activada. El APTT se determinó en presencia y ausencia de la proteina C activada. El resultado se expresó como una razón entre dos tiempos de coagulación (APTT/APTT2) y se consideró la presencia si dicha razón era menor o igual a 2. Resultados. La edad prometio fue de 32.05 años. El 70.5 por ciento fueron mujeres. La frecuencia de la deficiencia de la ant III y de la proteína C en 17 pacientes fue de 5.88 por ciento. En 16 pacientes la frecuencia de la deficiencia de la proteina S fue de 6.25 por ciento y de la RPCA 37.5 por ciento. Conclusiones. La RPCA fue la causa más comín de trombofilina en los pacientes estudiados. Las frecuencias de las deficiencias de estas proteínas y la RPCA concordaron con lo publicado en la literatura. En nuestro medio se deberian estudiar los pacientes para trombofilia heredada si la TVP ocurre en personasd menores de 45 años, especialmente la RPCA