Anticoagulação no paciente oncologico / Anticoagulation in the oncologic patient

A doença neoplásica associa-se a um aumento da incidência de eventos tromboembólicos. Os fatores associados a esses fenômenos englobam não apenas o estado pró-trombótico associado ao câncer, mas também os efeitos colaterais dos quimioterápicos, além da imobilidade associada a algumas situações, como intervenções cirúrgicas, por exemplo. De acordo com a American Cancer Society (ACS), que desenvolveu a mais recente diretriz sobre profilaxia e tratamento da TVP em pacientes oncológicos, somando os fatores de risco já existentes aos fatores intrínsecos dos pacientes oncológicos, esses pacientes são, quase sempre, classificados como de alto risco. A simplicidade de administração oral sem necessidade de monitorização laboratorial torna os novos anticoagulantes orais uma alternativa atrativa para a prevenção e o manejo de eventos tromboembólicos em pacientes oncológicos. Subgrupos de estudos maiores demonstram a eficácia e segurança dessa classe de fármacos nesse grupo de pacientes, porém, mais estudos estão sendo conduzidos, a fim de responder com mais clareza a esta questão. O estado pró-trombótico promovido pela doença neoplásica acarreta maior risco de fenômenos embólicos em pacientes oncológicos com fibrilação atrial (FA). Não existem recomendações específicas para terapia antitrombótica para pacientes com FA e câncer. Não há evidência que essa população apresente risco aumentado de acidente vascular cerebral embólico em comparação com os pacientes com FA sem neoplasia associada. Os pacientes portadores de FA e câncer concomitantemente são mais idosos do que os pacientes portadores apenas de FA. Ainda existem muitas controvérsias com relação à anticoagulação no paciente oncológico. Novos estudos com foco nessa temá- tica contribuirão muito para o manejo mais homogêneo e embasado nessa população

Neoplastic disease is associated with an increase in the incidence of thromboembolic events. Factors associated with these phenomena include not only the prothrombotic state associated with cancer, but also the side effects of chemotherapy, and the immobility associated with certain situations, such as surgical interventions. According to the American Cancer Society (ACS), which produced the latest guidelines on prophylaxis and treatment of DVT in cancer patients, adding the existing risk factors to the intrinsic factors of cancer patients, these patients are almost always classified as high risk. The simplicity of oral administration, without the need for laboratory monitoring, makes the new oral anticoagulants an attractive alternative in the prevention and management of thromboembolic events in cancer patients. Subgroups of larger studies demonstrate the efficacy and safety of this class of drugs in this group of patients. However, further studies are being conducted in order to answer this question more clearly. The prothrombotic state promoted by the neoplastic disease presents a higher risk of embolic phenomena in cancer patients with atrial fibrillation (AF). There are no specific recommendations for antithrombotic therapy in patients with AF and cancer. There is no evidence that this population presents an increased risk of embolic cerebrovascular event compared to patients with AF without associated neoplasia. It is known that cancer patients with concomitant cancer and AF are older than non-cancer patients. There is still much controversy regarding anticoagulation in cancer patients. New studies focusing on this theme will contribute to a more homogeneous and grounded management of this population

Terapia anticoagulante nas valvopatias / Anticoagulant therapy in valvulopathies

As valvopatias, especialmente na presença da fibrilação atrial (FA), aumentam o risco de eventos tromboembólicos que, além de modificar a história natural da doença, têm impacto significativo na sobrevida e na qualidade de vida dos pacientes. Além do envelhecimento da população mundial, com o consequente número crescente de pacientes com fibrilação atrial, há cada vez mais associações de valvopatias com a doença arterial coronariana (DAC). Nesse grupo de pacientes para os quais há indicação emergencial ou eletiva de intervenção coronariana percutânea (ICP) com implante de stents, serão prescritos antiplaquetários e anticoagulantes ao menos nos primeiros meses pós-ICP. A prevenção do tromboembolismo (TE) com anticoagulantes, como a varfarina ou com os anticoagulantes orais diretos (AOD), é recomendada na maioria das diretrizes. O emprego dos escores CHADS2-VASc e HAS-BLED são úteis para a quantificação dos riscos TE e hemorrágicos

Valvulopathies, especially in the presence of atrial fibrillation (AF), increase the risk of thromboembolic events, which in addition to modifying the natural history of the disease; have a significant impact on survival and quality of life of patients. In addition to the aging of the world's population, with a consequent increase in the number of patients with atrial fibrillation, there are increasing cases of associations of valvular diseases with coronary artery disease (CAD). In this group of patients, in whom there is an emergency or elective indication for percutaneous coronary intervention (PCI) with the implantation of stents, antiplatelet and anticoagulant therapies will be prescribed, at least in the first months after PCI. The prevention of thromboembolic events (TE) with anticoagulants, such as warfarin, or with direct oral anticoagulants (DAOCs), is recommended in most of the Guidelines. The use of the CHADS2-VASc and HAS-BLED scores are useful in the quantification of TE and hemorrhagic risks

A Case of Acquired Factor V Deficiency after Percutaneous Coronary Intervention / 대한내과학회지

Acquired factor V deficiency is extremely rare. Here we report the case of an 88-year-old female patient who presented with hematochezia 1 month after undergoing percutaneous coronary intervention. Her laboratory results showed an extremely prolonged prothrombin time and an activated partial thromboplastin time, but neither improved after fresh frozen plasma transfusion. She was finally diagnosed with acquired factor V deficiency and successfully treated with an immunosuppressant.

Intervenção em dispositivos cardíacos eletrônicos implantáveis sob uso de anticoagulante oral: experiência inicial / Intervention in cardiac implantable electronic devices in use of oral anticoagulant: initial experience

O manejo de dispositivos cardíacos eletrônicos implantáveis em portadores de arritmias atriais ou outras condições que demandem uso crônico de anticoagulante oral sempre gerou grande conflito nas cirurgias. Este trabalho traz a experiência da realização de intervenções com dispositivos cardíacos eletrônicos implantáveis em serviço especializado em arritmias cardíacas, apresentando resultados similares aos da literatura e que devem mudar paradigmas. Método: Realizamos intervenções desde implante de marcapassos monocamerais até upgrade para marcapassos/ cardiodesfibriladores multissítio em usuários de anticoagulantes orais, incluindo varfarina e os novos anticoagulantes orais ou de ação direta (dabigatrana, rivaroxabana e apixabana). As intervenções foram realizadas por médicos experientes e todos os pacientes foram reexaminados 15 dias após a cirurgia para retirada dos pontos e revisão clínica e do dispositivo. Resultados: Os procedimentos foramrealizados em 20 pacientes, em 5 dos quais foi mantido o uso de anticoagulantes de ação direta. A ocorrência de hematoma na loja se deu em 3 pacientes (INR de 3,4 e 2,63 e outro com apixabana) e todos tiveram boa evolução após conduta expectante sem retirada do anticoagulante oral, com reabsorção completa 30 dias depois.Naqueles em uso de varfarina, o INR médio foi de 2,85, sendo o menor de 2 e o maior, de 4,14. Em nossa série decasos conseguimos reproduzir dados do estudo BRUISE, que demonstrou diferença significativa na ocorrência dehematoma quando se adotou estratégia de intervenção realizando ponte com heparina. Em nossa série, 3 pacientesapresentaram hematoma, sem necessidade de intervenção (somente acompanhamento clínico) e sem aumentar o tempo de internação. Nossa série de casos incluiu os anticoagulantes de ação direta disponíveis no mercado.Conclusão: Este trabalho traz dados similares aos dos grandes estudos...

The management of implantable electronic cardiac devices in patients with atrial arrhythmias or other conditions that require the chronic use of oral anticoagulants has always generated great controversy in surgery. This study reports the experience of performing interventions with implantable electronic cardiac devices in specialized cardiac arrhythmia services with similar results to literature data, which must surely change paradigms. Method: We performed interventions ranging from single-chamber pacemaker implant to upgrade to multisite pacemakers/cardiodefibrillator in patients receiving oral anticoagulants including warfarin and the new oral or direct action anticoagulants (dabigatran, rivaroxaban and apixaban). Experienced surgeons performed the interventions. All of the patients were reexamined 15 days after the surgery to remove stiches,for clinical and device evaluation. Results: We performed procedures in 20 patients; in 5 of them direct oralanticoagulants were maintained. Significant hematomas were observed in 3 patients (INR of 3.4 and 2.63 andanother with apixaban), and all of them had good outcomes after a watchful waiting while maintaining the oralanticoagulant, with complete reabsorption after thirty days. In patients receiving warfarin, mean INR was 2.85, the lowest was 2.0 and the highest 4.14. In our series of cases we reproduced data from BRUISE study, which showed a significant difference in the occurrence of hematoma when the intervention strategy included a “bridge”with heparin. In our series, 3 patients had hematoma, but did not require an intervention (only clinical follow-up)and there was no increase in the length of stay. We used direct action anticoagulants available in the market.Conclusion: Our study provides similar data to major studies...

Hemorragia masiva con riesgo mortal por activación de inhibidores de la coagulación posterior a cirugía ortognática. Un reporte de caso / Massive hemorrhage with mortal risk by activation of inhibitors in orthognatic surgery. A case report

La corrección de las desarmonías dentofaciales mediante osteotomías de los huesos maxilares se denomina cirugía ortognática, y es una práctica muy común dentro de la cirugía máxilofacial. Son técnicas que se encuentran perfectamente protocolizadas y a las que se llega después de una preparación ortodóncica previa, en la gran mayoría de los casos. Las complicaciones transoperatorias o postoperatorias son un riesgo inherente en cualquier cirugía, y entre las más problemáticas se encuentras las hemorragias postoperatorias, que pueden originarse por hipertensión, ligaduras de vasos no adecuadas, fístulas arteriovenosas, entre otras. Se reporta el caso de un paciente de 18 años de edad, que fue sometido a cirugía ortognática bimaxilar, él cuál una semana después presentó sangrado masivo a través de la boca, y epistaxis de aproximadamente 3.5 litros. Se describe el manejo de la emergencia y el diagnóstico establecido por hematología de anticuerpos contra los factores de coagulación. (AU)

Correction of Dentofacial Deformities by easy bone osteotomies called orthognathic surgery. It is a common practice in maxillofacial surgery, are techniques that are perfectly notarized and arriving after a previous orthodontic preparation in the vast majority of cases.The intraoperative and postoperative complications are a risk inherent in any surgery, among the most problematic are the postoperative hemorragias, which can be caused by hypertension, ligatures unsuitable vessels, arteriovenous fistulas, among others.In this article the case of a patient of eighteen who underwent bimaxillary orthognathic surgery and eight days after massive bleeding develops through mouth and epistaxis approximately 3.5 liters occurs.In this case report described the emergency management and diagnosis established by two physicians hematologists inhibitors against coagulation factors. (AU)

A cross-sectional survey of coagulation factor VIII inhibitor in children with hemophilia A / 中华儿科杂志

<p><b>OBJECTIVE</b>To study the current situation of coagulation factor VIII (FVIII) inhibitor development in children with hemophilia A (HA) through a cross-sectional survey, and to explore the risk factors of inhibitor development in order to provide evidence for further prevention and management strategies.</p><p><b>METHOD</b>The clinical data of outpatients with hemophilia A in Beijing Children's Hospital seen from November 2012 to May 2013 were collected, FVIII inhibitor was screened and analyzed its risk factors.</p><p><b>RESULT</b>A total of 102 HA children were enrolled, 5 were mild cases, 32 were moderate, and 65 were severe cases; the median age on enrollment was 55.5 (3.0-200.0) months:19(18.6%) of patients had inhibitors and 9 (8.8%) had low-titer inhibitors, 10 (9.8%) had high-titer inhibitors. Receiving FVIII treatment for life-threatening bleeding (P = 0.03) ,OR 4.10 (95%CI:1.17-14.32) was a risk factor for inhibitor generation and patients within 20 exposure days have more chances of inhibitor development (P = 0.04) ,OR 3.32 (95%CI:1.02-10.86) . High and intense FVIII exposure within short term was the risk factor for high titer inhibitor development (P = 0.01) ,OR 5.25 (95%CI:1.45-21.92) .</p><p><b>CONCLUSION</b>Intense FVIII exposure for severe hemorrhage was the risk factor of inhibitors development especially of high titer inhibitors.</p>

A Case of Acquired Factor V Deficiency Treated with Corticosteroids and Cyclophosphamide / 대한내과학회지

Acquired factor V deficiency is a rare bleeding disorder, the severity of which ranges from mild to fatal. There are various suggested treatments, including transfusion of fresh frozen plasma (FFP) or platelets, plasmapheresis and immunosuppressive therapy. We encountered a case of idiopathic acquired factor V deficiency with fatal retroperitoneal bleeding treated with steroid and cyclophosphamide.

A Case of Acquired Factor V Deficiency Treated with Corticosteroids and Cyclophosphamide / 대한내과학회지

Acquired factor V deficiency is a rare bleeding disorder, the severity of which ranges from mild to fatal. There are various suggested treatments, including transfusion of fresh frozen plasma (FFP) or platelets, plasmapheresis and immunosuppressive therapy. We encountered a case of idiopathic acquired factor V deficiency with fatal retroperitoneal bleeding treated with steroid and cyclophosphamide.

Screening and analysis of coagulation factor VIII inhibitor in patients with hemophilia A / 中国实验血液学杂志

In order to detect coagulation factor VIII (FVIII) inhibitor in patients with severe hemophilia A (HA) and preliminarily study the genetic mutation in patients with inhibitor positive. Totally 58 patients with HA (FVIII: C < 1%) were enrolled. FVIII: C activity was measured by one-stage coagulation assay. FVIII inhibitor was screened by using APTT method and FVIII inhibitor in screened positive patients with HA was quantitatively analyzed by using Bethesda method. Using genomic DNA as template, 12, 14, 16 exons of FVIII in screened positive patients were amplified, and the mutations of amplified products were detected by direct sequencing. The results indicated that the FVIII inhibitor could be detected in 4 patients (6.9%) from 58 HA patients, no gene mutations in 12, 14, 16 exons of FVIII were found. It is concluded that the positive rate of FVIII inhibitor in HA patients is lower than that reported in literature. The causes of inhibitor production needs to further investigate.

Comparative Measurement of FVIII Inhibitors in Hemophilia A Patients Using ELISA and the Bethesda Assay / 대한진단검사의학회지

Factor VIII inhibitors are produced during or after coagulation factor VIII (FVIII) therapy in hemophilia A patients. These inhibitors are usually detected by a modified Bethesda assay or an enzymelinked immunosorbent assay (ELISA). In this study, we used the Bethesda assay to determine the incidence of FVIII inhibitors in 75 fresh plasma samples obtained from 50 hemophilia A patients, and then used ELISA and the Bethesda assay to determine the titres of these inhibitors after the samples had been frozen and thawed. The samples from the screening Bethesda assay were centrifuged and stored at -70degrees C in accordance with the assay guidelines. Subsequently, these samples were thawed and analyzed using ELISA and the Bethesda assay. The incidence of inhibitors in hemophilia A patients was 20.0%. Among the 35 inhibitor-positive samples identified in the screening Bethesda assay, 16 were positive in ELISA while only 4 were positive in the repeated Bethesda assay. In this study, the ELISA technique showed a higher sensitivity than the Bethesda assay in the detection of FVIII inhibitors in samples that were subjected to freezing and thawing procedures; this was because the Bethesda assay could not identify the FVIII inhibitors that were degraded after freezing and thawing.

Protein Z in beta-thalassemia major adult patients and risk of thrombosis

Recent studies have suggested an association between protein Z [PZ] deficiency and thrombosis. Profound haemostatic changes have been observed in patients with beta-thalassemia major with a higher incidence than normal of Ihromboembolic events, so our present study was carried to asses the role of PZ in hypercoagulable state in beta-thalassemia major with other coagulation factors inhibitors [protein C and S] and to compare the splenectomized versus non-splenectomized patients regarding the risk of thrombosis. The study included 44 patients with beta-thalassemia major [22 splenectomized and 22 non-splenectomized], their age ranged from 20-32 years. All were recruited from hematology department of Kaser ALAini hospital. Fifteen healthy subjects who were age and sex matched were included as controls. Complete blood picture, liver function tests, serum ferritin, PZ antigen, PC and PS activity and FDPs were measured for all participants. Study showed significant reduction of PZ antigen together with reduced PC and PS activity in thalassemic patients compared to controls [p<0.001], FDPs was higher in both thalassemic groups compared with control group [p<0.001]. The reduction of PZ antigen, PC and PS activity was more significant in splenectomized patients compared to non-splenectomized patients together with higher FDPs [All p values <0.001]. An inverse correlation between FDPs and PZ antigen, FDPs and PC and PS activity were detected. Reduced PZ antigen together with PC and PS activity may be a contributing factor for hypercoagulable state in thalassemia major. Splenectomized patients are at higher risk of thrombosis

Evaluación de inhibidores fisiológicos de la coagulación en pacientes diabéticos tipo 2 / Evaluation about coagulation physiological inhibitors in type 2 diabetic patients

La diabetes mellitus está asociada a disturbios en la hemostasis que pueden contribuir al desarrollo de enfermedad vascular diabética. El objetivo de este trabajo fue estudiar la coagulación en una población diabética de Uruguay y compararla con una población de referencia normal. Se trabajó con 100 pacientes diabéticos tipo 2, de ambos sexos (49 mujeres y 51 hombres), con edades comprendidas entre 42 y 79 años, y una población control representada por 130 individuos aparentemente sanos (73 mujeres y 57 hombres) cuyas edades oscilaron entre 37 y 78 años, los que fueron tomados como referencia. Se realizaron las determinaciones de tiempo de protrombina (TP), fibrinógeno (Fib), proteína C (PC), proteína S (PS), antitrombina III (ATIII) e inhibidor del activador de plasminógeno (PAI) en plasma citratado. El TP y el Fib se realizaron por nefelometría, la PC, ATIII y PAI se midieron cromogénicamente y la PS se determinó por coagulometría. Se encontró que los inhibidores fisiológicos de la coagulación PS y ATIII son significativamente menores en la población diabética, en tanto que los factores procoagulantes Fib y PAI son significativamente mayores, comparados con la población de referencia. De los hallazgos precedentes se confirma una tendencia a un disbalance hemostático que contribuiría al estado protrombótico que acompaña a un alto porcentaje de la población diabética.

Diabetes mellitus is associated with disturbances in hemostasis, which may contribute to the development of diabetic vascular disease. Coagulation tests were performed both in diabetic patients and healthy individuals in Uruguay. The results obtained were compared. Diabetic patients were 100, with ages between 42 and 79 years, 49 females and 51 males. Reference population were 130 healthy individuals between 37 and 78 years, 73 females and 57 males. Prothrombin time (PT), fibrinogen( Fib), protein C (PC), protein S (PS), antithrombin III (ATIII) and plasminogen activator inhibitor (PAI) were measured on citrated plasma. PT and Fib were determined nephelometrically, PC, ATIII y PAI were measured cromogenically and PS was determined by coagulometry. Coagulation physiological inhibitors outcomes such as PS and ATIII showed significantly lower levels in the diabetic patient than in the healthy person, and at the same time, Fib and PAI, which are procoagulant factors, have significantly higher concentrations in the diabetic patient than in the healthy person. These findings permit to assess that an impaired haemostatic balance is present in the diabetic population, which may contribute to the hypercoagulability that accompanies a high percentage of these patients.

Inhibición del crecimiento tumoral en ratones induciendo coagulación selectiva de los vasos tumorales / Inhibition of tumor growth in mice by selective coagulation of tumors vessels

El presente estudio se basó en el hecho de que el factor tisular (TF), la proteína humana inductora de la coagulación es el principal disparador de la coagulación sanguínea. El objetivo de este trabajo fue demostrar en un modelo animal la factibilidad de tratar tumores sólidos humanos activando la coagulación e inhibiendo el crecimiento tumoral mediante infarto del mismo. Demostrar que el factor tisular truncado(tTF) recupera su capacidad inductora de la coagulación In vitro como In vivo y que fusionado al péptido RGD (tTF-RGD) en su carbono terminal hace blanco en marcadores de la angiogenesis presentes en el endotelio vascular tumoral no así en tejidos normales, como un novedoso abordaje en cáncer. Utilizando para la investigación dos líneas tumorales humanas (M21 y CCL-185) xenotransplantadas cada una en grupos de 24 ratones cada vez y distribuidos en grupos de 8 cada uno para las terapias con tTF-RGD, tTF y solución salina, respectivamente; En conclusión este trabajo muestra por primera vez que la caracterización específica del tTF-RGD en su carbono terminal le permite activar la coagulación selectiva, trombosis e infarto del tejido tumoral, inhibiendo en 100% el crecimiento de tumores humanos en ratones y sin efectos adversos significativos...

Inhibidor adquirido del factor VIII en paciente no hemofílico. Caso clínico - actualización / Acquired factor VIII inhibitors in a non-hemophilic patient. Case report

Se presenta el caso clínico de una paciente joven que instala un síndrome hemorragíparo secundario a un déficit adquirido de la coagulación provocado por la aparición deanticuerpos antifactor VIII. El interés de la presente comunicación radica en que si bien la aparición de inhibidores de la coagulación en pacientes no hemofílicos es un fenómeno raro, se trata de un cuadro grave que puede determinar la muerte del paciente, por lo que es de capital importancia realizar un diagnóstico y tratamiento precoz, así como definir si constituye un trastorno primario o, por el contrario, responde a la existencia de una enfermedad subyacente que el clínico debe diagnosticar. Se realiza una descripción fisiopatológica a fin de facilitar la comprensión de los pasos que permiten arribar al diagnóstico así como una actualización de las herramientas terapéuticas disponibles.

Natural inhibitors of coagulation and markers of coagulation activation: the hypercoagulable state in sickle cell disease

This study was designed to clarify abnormalities of the natural coagulation inhibitors and of the markers of thrombin generation in patients with homozygous sickle cell disease [HbSS] in the steady-state, and to evaluate their role in the contribution of the increased thrombotic risk in these patients that could result in new therapeutic interventions. This study was carried out on 50 subjects. They were divided into two groups. Group [A] included 30 patients with homozygous sickle cell disease [HbSS]. Group [B] included 20 apparently healthy age- and sex-matched control subjects; with normal baseline hematologic parameters and haemoglobin electrophoresis as well as no apparent increased thrombotic risk. All patients were tested during steady-state phase with no symptoms or signs of crises or infection for at least 8 weeks and had not had any blood transfusion during the preceding two weeks. They were not on medications other than folic acid 5mg tablets. HbSS was diagnosed by family studies and haemoglobin electrophoresis on cellulose-acetate at pH 8.6. Both patients and control groups were subjected to initial laboratory investigations including complete blood count [CBC], bleeding time [BT], prothrombin time [PT] and INR, activated partial thromboplastin time [aPTT] and haemoglobin electrophoresis. Then, both groups were tested for: [1] Natural coagulation inhibitors including Protein C [antigen and activity], Protein S [total and free levels], Antithrombin-III activity, Heparin cofactor II level, and Tissue factor pathway inhibitor [TFPI] and [2] Markers of coagulation activation; Prothrombin fragments 12 [Fl.2] and Thrombin-antithrombin complex [TAT]. HbSS patients had significantly higher leukocytic count [x 10 [3]/cmm] than control subjects [10.4 +/- 2.8 compared to 6.2 +/- 2.4, p < 0.01]. There was no significant difference between both groups regarding platelet count, bleeding time, prothrombin time [and INR] and activated partial prothrombin time. HbSS patients had significantly lower values than the control group regarding the level of protein C antigen, protein C activity, protein S total and protein S free as well as heparin cofactor TI [p < 0.001, each]. Although FIbSS had lower antithrombin-III activity and tissue factor pathway inhibitor than the control group, the difference was not significant. On the other hand, markers of coagulation activation [namely prothrombin fragments 1.2 and thrombin-antithrombin complex] were significantly higher in HbSS patients compared to the control group [p < 0.001, each]. Comparative studies showed no significant correlation between the level of haemoglobin SS and any of the studied coagulation inhibitors or markers of activation. These data shows that steady state SCD is associated with significant reduced level and/or function of the majority of naturally occurring anticoagulants as well as increased markers of thrombin generation denoting a state of chronic hypercoagulability with increased thrombotic and vasoocclusive tendency. Such changes might justify the prophylactic use of low dose coumadin and/or antiplatelet drugs in HbSS

Treatment of patients with haemophilia and inhibitory antibodies.

The development of inhibitory antibodies is a complication which arise in approximately 10% of patients with haemophilia A. The underlying genetic mutation is the single most important predisposing cause, although other risk factors have been identified. Periodic screening for inhibitors is a vital aspect of haemophilia care. The consequences of inhibitor development are very significant in terms of morbidity and cost. Several agents are now available for control of bleeding, but these are often very expensive. The most useful agents include recombinant activated factor VII, prothrombin complex concentrates and porcine factor VIII. It is possible to suppress antibody production with immune tolerance, which is successful in approximately 85% of cases and relapse is rare.