As trombofilias na perda gestacional de repetição: uma revisão de prevalência e condutas / Thrombophilias in recurrent pregnancy loss: a review of prevalence and conduct

Objetivo: Discutir o papel das trombofilias na perda gestacional de repetição, com foco em prevalência/associação dessas patologias com perdas de repetição e seu tratamento, por meio de resultados de ensaios clínicos, revisões sistemáticas e metanálises. Métodos: Trata-se de uma revisão não sistemática de artigos publi- cados nas bases eletrônicas PubMed, Cochrane e SciELO nos últimos cinco anos, utilizando os seguintes descritores: "recurrent pregnancy loss", "recurrent abortion", "habitual abortion", "thrombophilia", "antiphospholipid syndrome" e "treatment". Resultados: A maioria dos estudos relatou forte associação entre os anticorpos antifosfolípides específicos e a síndrome do anticorpo antifosfolípide com perda gestacional de repetição. Mulheres portadoras da mutação do fator V de Leiden, mutação do gene da protrombina e deficiência de proteína S apresentaram alto risco de perda gestacional de repetição em uma grande revisão sistemática. Estudos recentes demonstraram taxas de prevalência das trombofilias hereditárias e da síndrome do anticorpo antifosfolípide, em mulheres com perda gestacional de repetição, semelhantes às da população em geral. Os estudos atuais endossam o uso da heparina associada à aspirina em mulheres com síndrome do anticorpo antifosfolípide, com aumento da taxa de nascidos vivos, mas sem diferença em re- lação às complicações obstétricas. Conclusão: Apesar de novos estudos demons- trarem que a prevalência das trombofilias hereditárias e adquiridas em mulheres com perda gestacional de repetição é semelhante à da população em geral, reco- menda-se a pesquisa rotineira de síndrome do anticorpo antifosfolípide nessas pacientes. O uso de aspirina em baixas doses associada à heparina é a intervenção farmacológica de primeira linha para a prevenção de perda gestacional de repeti- ção em pacientes com síndrome do anticorpo antifosfolípide.

Objective: To discuss the role of thrombophilias in recurrent pregnancy loss, focu- sing on the prevalence/association of these pathologies with recurrent abortion and treatment, through results of clinical trials, systematic reviews and meta-analyses. Methods: This is a non-systematic review of articles published in electronic databa- ses PubMed, Cochrane, SciELO in the last five years, using the following descriptors: "recurrent pregnancy loss", "recurrent abortion", "habitual abortion", "thrombophilia", "antiphospholipid syndrome", and "treatment". Results: Most studies have reported a strong association between specific antiphospholipid antibodies and antiphospho- lipid antibody syndrome with recurrent pregnancy loss. Women carrying the factor V Leiden mutation, prothrombin gene mutation, and protein S deficiency were shown to be at high risk of recurrent pregnancy loss in a large systematic review. Recent studies have shown prevalence rates of hereditary thrombophilias and antiphospholipid antibody syndrome, in women with re- current pregnancy loss, similar to those of the general po- pulation. Current studies endorse the use of heparin plus aspirin in women with antiphospholipid antibody syndrome, with an increase in live birth rate, but with no difference in obstetric complications. Conclusion: Although new studies demonstrate that the prevalence of hereditary and acquired thrombophilias in women with recurrent pregnancy loss is si- milar to that of the general population, routine investigation of antiphospholipid antibody syndrome in these patients is recommended. The use of low-dose aspirin plus heparin is the first-line pharmacological intervention for the prevention of recurrent pregnancy loss in patients with antiphospholipid antibody syndrome.

Asymptomatic type B right atrial thrombus in a case with protein S deficiency.

Thirty seven year old asymptomatic male underwent routine medical examination which revealed an abnormal mass in the right atrium. Family history was not suggestive of any cardiac or malignant disease. Detailed investigation detected defi ciency of protein S, which is a vitamin K dependent protein and a cofactor for activated protein C mediated cleavage of factor Va and VIIIa. The defi ciency of protein S predisposes to venous thrombosis. Further investigation revealed that it was an organized calcifi ed thrombus in right atrium occupying almost whole of the cavity. Various approaches including surgical excision, thrombolysis and anticoagulation has been used to manage such thrombosis. However therapeutic approach is still a question of debate. Atriotomy and excision of mass was done using cardiopulmonary bypass.

Portal-Splenic-Mesenteric Venous Thrombosis in a Patients with Protein S Deficiency due to Novel PROS1 Gene Mutation / 대한소화기학회지

Protein S (PS), a vitamin K-dependent glycoprotein, performs an important role in the anticoagulation cascade as a cofactor of protein C. Because of the presence of a pseudogene and two different forms of PS in the plasma, protein S deficiency (PSD) is one of the most difficult thrombophilias to study and a rare blood disorder associated with an increased risk of thrombosis. We describe a unusual case of previously healthy 37-year-old man diagnosed with portal-splenic-mesenteric vein thrombosis secondary to PSD. The patient was admitted to the hospital due to continuous nonspecific abdominal pain and nausea. Abdominal computed tomography revealed acute venous thrombosis from inferior mesenteric vein to left portal vein via splenic vein, and laboratory test revealed decreased PS antigen level and PS functional activity. Conventional polymerase chain reaction and direct DNA sequencing analysis of the PROS1 gene demonstrated duplication of the 166th base in exon 2 resulting in frame-shift mutation (p.Arg56Lysfs*10) which is the first description of the new PROS1 gene mutation to our knowledge. Results from other studies suggest that the inherited PSD due to a PROS1 gene mutation may cause venous thrombosis in a healthy young man without any known predisposing factor.

Deficiencia de proteínas C y S: marcadores de riesgo trombótico / Deficiency of proteins C and S: trombotic risk markers

Desde hace varios siglos se conoce que los defectos de la coagulación causan enfermedades hemorrágicas, pero el estudio de su contraparte, las enfermedades trombóticas, se ha desarrollado con mayor profundidad hace solo algunas décadas. Son estos trastornos del sistema de la coagulación los que constituyen una de las causas más comunes de muerte en el mundo de hoy donde cada año mueren alrededor de 2 millones de personas por trombosis, ya sea arterial o venosa. Además, se consideran una fuente importante de morbilidad en las personas que las padecen y sobreviven. Los estados de hipercoagulabilidad o trombofilias son condiciones clínicas que afectan a una serie de pacientes con tendencia anormal a presentar eventos trombóticos. La deficiencia de proteína C (PC) y proteína S (PS) constituyen causas de trombofilias congénitas o adquiridas que predisponen a la aparición de trastornos tromboembólicos, pérdidas recurrentes de embarazos, trombosis venosas recurrentes, entre otros. Su diagnóstico es de gran importancia porque permite realizar profilaxis para evitar el riesgo de recurrencia e informa sobre la posibilidad de un estado de portador en cualquier otro miembro de la familia

For several centuries it has been known that coagulation defects cause hemorrhagic disease, but the study of its counterpart, thrombotic diseases, has been developed in more depth just a few decades ago. These disorders of coagulation system are one of the most common causes of death in the world today, where about two million people die every year from thrombosis, either arterial or venous. They are also considered an important source of morbidity in people who suffer it and survive. Hypercoagulable state or thrombophilia are clinical conditions that affect a number of patients with abnormal tendency to thrombotic events. Deficiency of protein C (PC) and protein S (PS) are causes of congenital or acquired thrombophilias that predispose to thromboembolic disorders, recurrent pregnancy loss, recurrent venous thrombosis, among others. Its diagnosis is very important it provides tools for its prophylaxis in order to reduce the risk of recurrence and the possibility of identify a carrier state in any other family member

Protein S deficiency in a case of superor sagital vein thrombosis.

Cortical vein thrombosis (CVT) is rare and is most common in the third decade of life. Cerebral venous thrombosis may be due to a variety of pathologic conditions like deficiencies of protein S (PS), antithrombin III, protein C, factor V Leiden, prothrombin gene mutations and hyperhomocysteinemia. Protein S is a vitamin K-dependent anticoagulant present in plasma and prevent thrombosis in association with protein C. Lack of it results in venous thromboembolism (VTE) rarely causing thrombosis of cerebral venous sinuses. Our patient is a 35-year-old male who presented with focal seizures. MRI brain showed venous infarcts, and MR venogram showed extensive thrombosis of superior sagittal sinus. Later work up for hypercoagulable state showed significant Protein S deficiency.

Protein C and protein S: Causative factor for developing a hemorrhagic infarct in a HbE/Beta thalassemia child.

A 10-yr-old HbE/Beta thalassemia child who developed subacute to chronic occipitotemporal hemorrhagic infarct with smaller chronic infarct with gliotic changes in the left frontal periventricular white matter. Genetic tests showed that patient was positive for HbE and IVS1-5 mutation and was negative for thrombogenic mutations. Hemorrhagic infarct was confirmed by magnetic resonance imaging study. Antigenic levels of Protein C and Protein S were low. Based on these outcomes, it was concluded that Protein C and Protein S deficiency were the causative factor for developing hemorrhagic infarct in the HbE/ Beta thalassemia patient.

Deficiencies in proteins C and S in a patient with idiopathic portal hypertension accompanied by portal vein thrombosis / 대한간학회지

Portal vein thrombosis (PVT) is an uncommon cause of presinusoidal portal hypertension. Among various hepatoportal disorders, noncirrhotic portal hypertension conditions such as idiopathic portal hypertension (IPH) are considered to have a close relation with PVT. PVT is known to have several predisposing conditions, including infection, malignancies, and coagulation disorders. There is growing interest and recognition that deficiencies in proteins C and S are associated with a hypercoagulable state. These deficiencies are regarded as key factors of systemic hypercoagulability and recurrent venous thromboembolism. We report the case of a 19-year-old male diagnosed as IPH with PVT and combined deficiencies in proteins C and S.

Extrahepatic portal hypertension due to familial protein S deficiency.

Portal vein thrombosis (PVT) is a common cause of portal hypertension in children. A majority of children with PVT of unknown etiology have functional Protein C deficiency or abnormally elevated levels of anti-cardiolipin antibodies. We report an 8 years old Indian girl with portal cavernoma due to hereditary Protein S deficiency. We documented familial deficiency of Protein S in 2 asymptomatic siblings suggesting that this deficiency is the primary cause of portal vein thrombosis.

Tuberous sclerosis with portal vein thrombosis, protein C and S deficiency.

A 29-year-old lady with a bad obstetric history and portal vein thrombosis, presented to the Skin OPD for facial lesions. On examination, angiofibromas on face, shagreen patch and periungual fibromas were observed. She also had dental pits and a retinal hamartoma. Investigations revealed hamartomas in the brain and kidney. Hematological work-up showed protein C and S deficiency with Factor V Leiden positivity. Except for the cutaneous symptoms, the patient did not have any clinical manifestations in other organs affected by tuberous sclerosis. A similar association of tuberous sclerosis with protein C deficiency has been reported in only one case in literature.

Celiac Artery Thrombosis and Splenic Infarction in a Patient with Protein S Deficiency / 대한소화기학회지

Protein S deficiency is a rare blood disorder associated with an increased risk of thrombosis. Only a few cases of arterial thrombosis of digestive tract have been noted. We report a case of celiac arterial thrombosis and splenic infarction in 46-year-old male with protein S deficiency. Abdominal computed tomography and angiography revealed thrombotic obstruction of the proximal celiac and common hepatic artery with splenic infarction. His total and free antigen of protein S were normal, however, the activity of protein S was low. Percutaneous transluminal angioplasty was performed to revascularise celiac and common hepatic artery.

Hemiconvulsion, hemiplegia, epilepsy syndrome and inherited protein S deficiency.

A nine-year-old Nepalese girl developed hemiconvulsion, hemiplegia, epilepsy syndrome (HHE syndrome) after an episode of right-sided focal status epilepticus following acute gastroenteritis. She had left middle cerebral artery (MCA) territory infracts due to inherited protein S deficiency.

Protein S deficiency is common in a healthy Thai population.

Currently, venous thromboembolism is a growing menace in Asians, approaching to that of Western countries. The most common genetic mutations causing thrombosis in Caucasians are factor V Leiden and prothrombin mutation. However both are very rare in Asians. On the other hand, natural anticoagulant protein (protein S, protein C and antithrombin) deficiencies are more common in Asian than in Western thrombotic patients. The prevalence of these deficiencies is very low in healthy Caucasians (0.02-0.3%). It is possible that the prevalence is higher in an Asian general population. However there have been very few prevalence studies to prove this hypothesis. Protein S deficiency was found in 3.7% (13/352, 95% confident interval 1.72-5.66) healthy Thais. Seven of them were type III deficiency. Similar to previous studies, total and free protein S levels were lower in females, but positively and negatively correlated with age, respectively. In contrast, one protein C deficiency (0.27%, 1/370) and no antithrombin deficiency (0/206) were detectable in our population. Furthermore, the authors found that antithrombin was significantly lower in women and there was a positive correlation between protein C activity and age. In conclusion, protein S deficiency is more common in Thais than in Caucasians. This result remains to be confirmed by a large population-based study.

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.

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.

Analgesia de parto em paciente portadora de deficiência de proteína S: relato de caso / Labor analgesia in protein S deficient patient: case report

JUSTIFICATIVA E OBJETIVOS: Na deficiência de proteína S, uma glicoproteína com atividade anticoagulante, o risco de eventos tromboembólicos está aumentado. O objetivo deste relato é abordar o manuseio anestésico em paciente obstétrica portadora desta deficiência. RELATO DO CASO: Paciente com deficiência de proteína S, com 25 semanas de gestação, apresentou os seguintes resultados de exames: INR = 0,9, TTPA = 32 s (controle 25,6), proteína S = 35 por cento (normal = 70 por cento a 130 por cento). Nos dois últimos trimestres de gravidez, fez uso de até 12000 U de heparina, cada 8 horas. Com 38 semanas, foi internada em trabalho de parto. Decorridas 8 horas da interrupção da heparina, já com TTPA 25,8 s (controle 27,8 s), realizou-se anestesia peridural injetando-se 6 ml de bupivacaína a 0,2 por cento e fentanil (20 µg), seguido de infusão contínua. O tempo de infusão foi de 5 horas com dose total de 40 mg de bupivacaína. Não houve intercorrências e, 1 hora após a retirada do cateter, foi reiniciada heparina, por via subcutânea, 10.000 UI, a cada 12 horas. A mãe e o recém-nascido evoluíram bem, recebendo alta no terceiro dia do pós-parto. CONCLUSÕES: Grávidas com deficiência de proteína S devem receber anticoagulantes com o objetivo de manter o TTPA 2 vezes o valor controle. A heparina, por não atravessar a barreira placentária, é o anticoagulante de eleição em obstetrícia. O bloqueio pode ser realizado respeitando um tempo mínimo entre 4 a 6 horas entre a última dose de heparina e a realização da punção lombar, desde que os exames apresentem parâmetros de normalidade. Entretanto, nestes casos, a analgesia peridural pode auxiliar na profilaxia de eventos tromboembólicos.

BACKGROUND AND OBJECTIVES: Deficiency in protein S, which is a glycoprotein with anticoagulant activity, increases the risk for thromboembolic events. This report aimed at addressing anesthetic management of protein S deficient obstetric patient. CASE REPORT: Protein S deficient patient, at 25 weeks gestation, presented the following lab results: INR = 0.9, TTPA = 32 s (control 25.6), protein S = 35% (normal = 70% to 130%). In the last three gestation quarters she has received up to 12,000 IU heparin every 8 hours. With 38 weeks, she was admitted in labor. After 8 uninterrupted heparin hours, already with TTPA of 25.8 s (control 27.8 s) epidural anesthesia was induced with 6 ml of 0.2% bupivacaine and fentanyl (20 µg), followed by continuous infusion. Infusion time was 5 hours with total 40 mg bupivacaine dose. There have been no intercurrences and 1 hour after catheter removal, subcutaneous 10,000 IU heparin were restarted at 12-hour intervals. Patient and neonate evolved well and were discharged 3 days later. CONCLUSIONS: Protein S deficient pregnant patients should receive anticoagulants to maintain TTPA twice the control value. Heparin, for not crossing placental barrier, is the anticoagulant of choice in obstetrics. Blockade may be induced respecting a minimum period of 4 to 6 hours between last heparin dose and lumbar puncture, provided lab tests are within normal ranges. In these cases, however, epidural analgesia may help in preventing thromboembolic events.

JUSTIFICATIVA Y OBJETIVOS: En la deficiencia de proteína S, una glucoproteína con actividad anticoagulante, el riesgo de eventos tromboembólicos está aumentado. El objetivo de este relato es abordar el manoseo anestésico en paciente obstétrica portadora de esta deficiencia. RELATO DE CASO: Paciente con deficiencia de proteína S, con 25 semanas de gestación, presentó los siguientes resultados de exámenes: INR = 0,9, TTPA = 32 s (control 25,6), proteína S = 35% (normal = 70% a 130%). En los dos últimos trimestres de embarazo, hizo uso de hasta 12000 U de heparina, cada 8 horas. Con 38 semanas, fue internada en trabajo de parto. Pasadas 8 horas de la interrupción de la heparina, y ya con TTPA 25,8 s (control 27,8 s), se realizó anestesia peridural con inyección de 6 ml de bupivacaína a 0,2% y fentanil (20 µg), seguido de infusión continua. EL tiempo de infusión fue de 5 horas con dosis total de 40 mg de bupivacaína. No hubo intercurrencias y, 1 hora después de la retirada del catéter, fue reiniciada heparina, por vía subcutánea, 10.000 UI, a cada 12 horas. La madre y el recién nacido evoluyeron bien, recibiendo alta en el tercero día del pos-parto. CONCLUSIONES: Embarazadas con deficiencia de proteína S deben recibir anticoagulantes con el objetivo de mantener el TTPA 2 veces el valor control. La heparina, por no atravesar a barrera placentaria, es el anticoagulante de elección en obstetricia. El bloqueo puede ser realizado respetando un tiempo mínimo entre cuatro a seis horas entre a última dosis de heparina y la realización de la punción lumbar, desde que los exámenes presenten parámetros de normalidad. Entretanto, en estos casos, la analgesia peridural puede auxiliar en la profilaxis de eventos tromboembólicos.

Endovascular Management of Iliofemoral Deep Venous Thrombosis due to Iliac Vein Compression Syndrome in Patients with Protein C and/or S Deficiency

The purpose of this study was to evaluate the early outcome of endovascular management in patients with iliofemoral deep venous thrombosis (DVT) due to iliac vein compression syndrome (IVCS) and protein C and/or S deficiency. Between September 2000 and January 2003, catheter-directed thrombolysis was performed in 11 patients with a diagnosis of acute iliofemoral DVT: 7 with protein C and/or S deficiency and 4 without protein C and/or S deficiency. After thrombolysis, the diagnosis of IVCS was confirmed in 6 patients: 4 with protein C and/or S deficiency and 2 without protein C and/or S deficiency. Further intervention consisted of angioplasty and stent placement was performed. Four patients with IVCS and protein C and/or S deficiency were included in this study. The immediate technical and clinical success rates were 100% in all 4 patients. There were no complications or clinically detectable pulmonary emboli. This initial experience suggests that endovascular management of iliofemoral DVT due to IVCS in patients with protein C and/or S deficiency is safe and effective.

Venous thrombosis: prevalence of prothrombotic defects in north Indian population.

431 patients with thrombosis of different venous system were evaluated for underlying acquired and inherited prothrombotic states. Associated acquired risk factors were observed to be present in 28.7% patients and possible inherited in 32.3%, in the rest, no cause could be identified. Major acquired risk factors included coexistence of liver disease (12.2%), oral contraceptives (4.1%), puerperium (2.5%), malignancy (2.3%) and lupus anticoagulant (2%). Low levels of protein C were detected in 21.1% and of which 11.3% were attributed to acquired factors. Protein S deficiency was found in 19.0% and of these 10.4% cases were associated with acquired risk factors. Antithrombin III (AT III) deficiency was detected in 6.4% of patients, of which 4.8% were secondary to acquired factors. In the rest, deficiency of protein C, protein S and AT III were attributed to inherited factors as no associated acquired risk factor was present. Activated protein C resistance (APC-R) was present in 12.5% cases.

Functional protein C and anti-cardiolipin antibody in children with portal vein thrombosis.

BACKGROUND: Portal vein thrombosis (PVT) is a common cause of portal hypertension in children from developing countries. Deficiencies of proteins C and S and elevated anticardiolipin antibody (aCL) levels have been shown to predispose to venous thrombosis. We studied these factors in children with idiopathic PVT. METHODS: 19 children with PVT (mean [SD] age 5.7 [2.1] y; 15 boys) were studied; all had had variceal bleeding, and had PVT on ultrasonography. Functional protein C activity was measured using a clotting assay; if it was normal, a clotting assay for functional protein S activity was performed. IgG aCL levels were measured in all sera using an in-house standardized solid-phase ELISA. RESULTS: Protein C functional activity ranged from 4% to 109%. Eight children had activity below 70%, the lower cut-off of the normal range. Protein S assay, done in 10 of the 11 children with normal protein C activity levels, was normal (above the cut-off level of 65% of the normal range). IgG aCL levels were abnormally elevated (>mean + 2SD of 16 healthy control children) in nine children; of these, three had associated protein C deficiency. Thus, of the 19 children with idiopathic PVT, 14 had abnormality in one or more tests. CONCLUSION: A majority of children with PVT of unknown etiology have functional protein C deficiency or abnormally elevated levels of aCL antibodies.