Low-dose Immune Tolerance Induction in Hemophilia: A Single-Center Experience.

INTRODUCTION: The development of inhibitors against factors VIII/IX is the most serious complication in hemophilia. The best treatment strategy for inhibitor eradication is immune tolerance induction (ITI). The aim of this study was to evaluate patients treated with low-dose ITI at a single center with limited resources. MATERIALS AND METHODS: In total, 29 (8.05%) of 360 hemophilia A patients exhibited inhibitors. The data from hemophilia patients with inhibitors undergoing ITI between 1999 and 2017 were collected and analyzed. RESULTS: Seventeen ITIs administered to 15 hemophilia A patients with inhibitors were analyzed, and the data from 13 ITIs conducted in 12 patients were evaluated. The median age at ITI onset was 10 years (range: 1.25 to 52 y). The maximum inhibitor titer before ITI was 30 Bethesda Units (BU) (range: 4.48 to 135), and the median inhibitor titer was 1.25 BU (range: 0 to 5.6) at the onset of ITI. The median time interval between the inhibitor development and ITI onset was 60 months (range: 7 to 264 mo). The median inhibitor titer during ITI was 3.4 BU (range: 0 to 158.7). At the end of the treatment, 4 of the 12 patients (33.3%) exhibited a complete response, 4 (33.3%) had partial responses (with continuing ITI), and 4 (33.3%) exhibited ITI failure. CONCLUSIONS: Treatment of hemophilia patients with inhibitors is challenging, and ITI is the best treatment method; however, a high-dose daily ITI regimen cannot be given to every patient in every country due to its high cost. Our results show that low-dose ITI may be a choice for selected patients with inhibitors.

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...

Retrospective analysis of 1,226 Chinese patients with haemophilia in a single medical centre.

Haemophilia A (HA) and B (HB) are X-linked congenital disorders caused by deficiencies of Factor VIII and FIX. Being the world's most populous country, China potentially has a large population of haemophilia patients. During the last decade, no studies have been published regarding the clinical information of haemophilia in China. A retrospective study was conducted in patients with HA and HB referred to Tianjin Haemophilia Centre between 2002 and 2012. We identified 1,226 males with haemophilia (1,019 HA and 207 HB). The results revealed that activate partial thromboplastin time was negatively correlated plasma factor level of person with haemophilia. Our data did not offer sufficient evidence of any relationship existed between disease severity and risk or site of haemorrhage. There was a trend toward a higher inhibitor incidence induced by plasma-derived factor VIII products, than by recombinant FVIII (rFVIII) alone. It seemed that second generation of rFVIII more likely developed inhibitor, and first generation of rFVIII was nevertheless more closely connected to high-titer inhibitor. We found that delay in diagnosis and blood-borne infections were significantly reduced, while the joint deformity rate did not decrease despite the wide variety of products to choose from in this decade. The development of inhibitor still remains a major challenge in replacement therapy in haemophilia.

Successful immune tolerance induction with high-dose coagulation factor VIII and intravenous immunoglobulins in a patient with congenital hemophilia and high-titer inhibitor of coagulation factor VIII despite unfavorable prognosis for the therapy.

BACKGROUND: The production of factor VIII (FVIII) inhibitors is a serious problem of replacement therapy with FVIII concentrates in hemophiliacs. It affects 10-20% patients and leads to an increased risk of severe bleeding and its complications. Immune tolerance induction (ITI) is considered the appropriate treatment in such cases, despite different regimens without clearly defined effectiveness. ITI eradicates FVIII inhibitors and allows retreatment with FVIII concentrates in 70% of patients. CASE REPORT: The case of a patient with congenital hemophilia A in whom allo-antibodies against FVIII were identified in a high titer at the age of 5 after 70 exposures to human plasma FVIII concentrates is presented. A spontaneous decrease in inhibitor titer to 14 BU/ml within 6 months after the termination of FVIII administration allowed ITI, consisting of FVIII in high doses and intravenous immunoglobulins. Cessation of bleeding during the treatment was achieved with recombinant activated FVII (rFVIIa). ITI lasted for 22 months and, despite the high inhibitor titer at the start of ITI suggesting poor outcome, it led to eradication of the inhibitor. The prophylactic replacement therapy with FVIII was restarted and since then no signs of FVIII inhibitor have been observed. CONCLUSIONS: ITI with high-dose FVIII, intravenous immunoglobulins, and rFVIIa is a beneficial treatment option for hemophiliac A patients with high-titer FVIII inhibitor.

Lower doses of rFVIIa therapy are safe and effective for surgical interventions in patients with severe FXI deficiency and inhibitors.

Severe FXI deficiency is a rare injury-related bleeding disorder. In patients with FXI inhibitors, surgeries may be treated using recombinant activated factor VII; however, treatment safety is a major concern and the best dosing regimen as well as mode of administration is still to be defined. We describe four patients with severe factor XI deficiency and inhibitors to FXI, undergoing eight (four major) surgical procedures treated with continuous infusion of rFVIIa. Following acute MI that evolved after surgery of our first patient, all other patients were treated with low-dose bolus rFVIIa followed by low-dose continuous infusion of rFVIIa. Haemostasis was successfully achieved and no further thrombotic complications occurred. To support our clinical results ex-vivo thromboelastography studies were performed, demonstrating the differences of clot formation and lysis between patients with FXI deficiency and healthy controls and suggesting that low-dose rFVIIa corrects coagulation similarly to high-dose rFVIIa in FXI deficiency. Recombinant FVIIa at low doses may effectively induce haemostasis and seems to be a safe treatment mode in patients with FXI deficiency and inhibitors undergoing surgeries.

Concomitant infusion of low doses of rFVIIa and FEIBA in haemophilia patients with inhibitors.

Patients with severe haemophilia A and an inhibitor may become refractory to FEIBA and/or recombinant factor VIIa (rFVIIa). Sequential therapy with both products has been reported in such patients. In this pilot study, we examined the safety and efficacy of combined rFVIIa and FEIBA therapy in patients with haemophilia A and inhibitors during bleeding episodes. We also tried to evaluate whether thrombin generation (TG), by various mixtures of these agents, can serve as a guide for tailoring therapy. TG was measured in plasma taken from eight haemophilia A patients. Increasing concentrations of rFVIIa, FEIBA or both were added ex vivo to the plasmas, and TG was induced by recalcification. Since low concentrations of rFVIIa and FEIBA had either an additive or a synergistic effect in all patients, the lowest combination, yielding TG comparable or lower than TG achieved with either FEIBA 100 U kg(-1) or rFVIIa 160 microg kg(-1) alone, was selected for the treatment of bleeding episodes. Five patients with a high titre of an inhibitor (8-1300 BU), including one previously refractory to infusions of rFVIIa at doses up to 400 microg kg(-1) X4 daily, were treated with combinations of 30-70 microg kg(-1) rFVIIa and 20-30 U kg(-1) FEIBA during a total number of 400 bleeding episodes with excellent haemostatic effect. No adverse events and no DIC were observed following these infusions. Concomitant infusion of low-dose rFVIIa and low-dose FEIBA, seems to be safe, efficacious and economical in patients refractory to rFVIIa and probably other haemophilia A patients with an inhibitor.

Effect of rFVIIa dose and time to treatment on patients with haemophilia and inhibitors: analysis of HemoRec registry data from the Czech Republic.

Identifying haemophilia patients with inhibitors for clinical trials is difficult due to the limited number of patients available. Registries are therefore being established as an additional means of data collection. The aim of this study was to investigate the effect of different recombinant activated factor VII (rFVIIa; NovoSeven dose ranges and dosing schedules on the incidence of re-bleeding in haemophilia patients with inhibitors. In this retrospective, uncontrolled study, data on the bleeding patterns of adult haemophilia patients with high responding inhibitors were analysed. Only data from the Czech Republic, obtained by the HemoRec registry, were used. This study analysed 'real-life' clinical data and focused on the collection of the same parameters in different patients: time from bleeding onset to first injection, effect of first injection, number of re-bleedings, total number of injections and total amount of haemostatic drug used. Fifteen patients met the inclusion criteria and were included into the study (128 bleeding episodes). Patients treated within 2 h of bleeding onset experienced less re-bleeding than patients treated after 2 h of bleeding onset (5.2% vs. 13.7%, respectively). In addition, patients who were treated after 2 h of bleeding onset experienced fewer re-bleedings when high-dose rFVIIa was used (15.8% and 0%; <120 microg kg(-1) and >250 microg kg(-1), respectively). Initial high-dose rFVIIa was also associated with a decline in total rFVIIa consumption. This registry has provided a unique insight into the bleeding patterns of inhibitor patients, highlighting the importance of early treatment initiation and appropriate starting dose.

Side-effects and venous access issues with immune tolerance therapy.

Immune tolerance therapy (ITT) is the most effective approach to eradicate inhibitors in patients with haemophilia who develop high-titre inhibitors. Yet ITT is associated with many adverse side-effects. Rarely, adverse side-effects arise from the various factor concentrates that patients on ITT receive or from adjuvant immunosuppressive agents used during ITT. Most adverse side-effects of ITT are related to the need for frequent and repetitive venous access, which often results in the need for central venous access devices (CVAD). These devices greatly facilitate the ability to give repeated doses of factor concentrates to patients and are particularly useful in young children who often have small and poorly functioning peripheral veins. These devices can become infected, can malfunction or can lead to venous thrombosis. These complications, although rarely causing mortality, may lead to significant morbidity including the need to have the devices removed and new ones inserted. As well, such CVAD complications may lead to reduced effectiveness of ITT through interruptions in ITT.

Single-dose (270 microg kg(-1)) recombinant activated factor VII for the treatment and prevention of bleeds in haemophilia A patients with inhibitors: experience from seven European haemophilia centres.

Several studies have suggested that recombinant factor VIIa (rFVIIa) is effective and safe at doses >90 microg kg(-1). In March 2007, the European Medicines Agency approved the use of single-dose rFVIIa 270 microg kg(-1) for the treatment of mild-to-moderate bleeds in haemophilia patients with inhibitors. The aim of this study was to describe the use of single-dose rFVIIa in a real-life setting. In November 2007, seven haemophilia specialists from five European countries convened to share and discuss their experiences with the single-dose rFVIIa regimen within haemophilia A. Case histories of eight patients were discussed in this retrospective study. Six adult and two paediatric patients (age range, 19 months-40 years) were treated with single-dose rFVIIa for a variety of target-joint bleeding, other bleeds and bleeding prevention. Treatment was successful in all the eight cases, with most patients requiring one dose to achieve bleeding resolution. No thrombotic or other safety concerns were raised by single-dose rFVIIa treatment. All patients and physicians preferred single-dose rFVIIa treatment to multiple injections; key benefits of single-dose rFVIIa treatment reported by patients and physicians included improved quality of life, greater convenience and ease of administration, improved compliance, faster control of bleeding, less injection-related pain and faster pain relief. In the patients reported here, single-dose rFVIIa 270 microg kg(-1) appears to be an effective and safe haemostatic treatment that improves the quality of life and convenience of treatment for patients. Such treatment might be of particular benefit for patients with difficult venous access or needle phobia.

Home treatment with bypassing products in inhibitor patients: a 7.5-year experience.

The advantages of early treatment of bleeds include minimizing the damage caused by the haemorrhage as well as offering increased convenience and time saved for the patient. The objectives of this prospective, single-centre study were to evaluate the efficacy, safety and feasibility of long-term home treatment with bypassing product in inhibitor patients. Since May 2000, 10 haemophilia A patients with high-titre inhibitors have been included in the study. Nine patients were treated with activated prothrombin complex concentrate (aPCC; factor eight inhibitor bypassing activity, FEIBA; Baxter AG, Vienna, Austria) and one patient with both aPCC and recombinant activated factor VII (rFVIIa; NovoSeven; NovoNordisk A/S, Bagsvaerd, Denmark). A total of 1008 infusions of aPCC and 17 infusions of rFVIIa were given in a home treatment setting. The numbers include 448 infusions of aPCC and 10 infusions of rFVIIa given as prophylactic treatment. During the 7.5 years of follow-up, the patients experienced 431 bleeds. Five hundred and sixty infusions of aPCC and seven infusions of rFVIIa were given to treat these bleeds. Haemostasis was rated as effective in 88% (372/424) and partially effective in 10% (43/424) of the bleeds after a mean number of 1.3 injections. The number of treatments rated as effective was comparable for muscle (90%), joint (85%) and mucocutaneous (86%) bleeds. The safety of the treatment was very good. Only two mild adverse events were reported in total. No thrombotic adverse event has been observed. In conclusion, home treatment with bypassing agents in inhibitor patients is feasible, effective and safe in a long-term perspective.

Factor VIII recovery after a single infusion of recalibrated ReFacto in 14 severe haemophilia A patients.

A recent multicentre collaborative study showed higher estimates of ReFacto potency when assayed with ReFacto Laboratory Standard(TM) (RLS) in comparison when standards consisting of full-length factor VIII (FVIII) were used. The RLS was hence recalibrated, leading to a 20% increase in the amount of ReFacto per vial without change in the labelled potency. The primary objective of this study was to determine the incremental and in vivo recovery of the recalibrated ReFacto in patients with severe haemophilia A. Fourteen male severe haemophilia A patients (FVIII < 1 IU dL(-1)) with a cumulative previous exposure days to any FVIII product >150 were administered an intravenous infusion 50 +/- 5 IU kg(-1) of ReFacto over a 5-min period. Blood samples were collected before infusion and after 15, 30 and 60 min. FVIII clotting activity (FVIII:C) was assessed in a central laboratory by the chromogenic substrate assay. After ReFacto infusion, peak FVIII:C was obtained within 15 min for 10 patients and within 30 min for the remaining four. Mean FVIII:C at peak was 117.7 +/- 17.3 IU dL(-1). Mean incremental recovery was 2.22 +/- 0.27 IU dL(-1) per IU kg(-1) while mean in vivo recovery was 105.9 +/- 14.6%. One patient reported three mild adverse events rated as 'unrelated' to the study drug. FVIII recovery after recalibrated ReFacto infusion falls within the expected range and is similar to the values reported for other FVIII concentrates.

Surgery in patients with hemophilia and inhibitors: a review of the Norwegian experience with FEIBA.

Surgical interventions in patients with hemophilia and inhibitors have often been postponed as long as possible due to difficulties in maintaining intra- and postoperative hemostatic control. Nonactivated and activated prothrombin complex concentrates have been successful in controlling acute bleeding in patients with inhibitors and have been useful in the surgical setting. At the Rikshospitalet-Radiumhospitalet University Hospital in Oslo, Norway, 17 minor and seven major surgical procedures were performed in nine patients with congenital hemophilia A and two patients with acquired hemophilia. Patients are generally treated according to the following dosing regimen, with changes made on a case-by-case basis: a preoperative loading dose of 100 U/kg of Factor Eight Inhibitor Bypassing Activity, Anti-Inhibitor Coagulant Complex, Vapor Heated (FEIBA; Baxter AG, Vienna, Austria), followed by 200 U/kg per day for 3 days. The dose is then tapered to 150 U/kg per day and subsequently to 100 U/kg per day. Hemostatic control was attained in all cases and only 1 major adverse event was observed. A 69-year-old patient experienced a non-ST-elevation myocardial infarction 3 days after undergoing a sigmoidectomy. He continued on FEIBA therapy and was stabilized with nitrates, opioid analgesia, and diuretics without clinical signs of heart failure.

Targeting coagulation factor XII provides protection from pathological thrombosis in cerebral ischemia without interfering with hemostasis.

Formation of fibrin is critical for limiting blood loss at a site of blood vessel injury (hemostasis), but may also contribute to vascular thrombosis. Hereditary deficiency of factor XII (FXII), the protease that triggers the intrinsic pathway of coagulation in vitro, is not associated with spontaneous or excessive injury-related bleeding, indicating FXII is not required for hemostasis. We demonstrate that deficiency or inhibition of FXII protects mice from ischemic brain injury. After transient middle cerebral artery occlusion, the volume of infarcted brain in FXII-deficient and FXII inhibitor-treated mice was substantially less than in wild-type controls, without an increase in infarct-associated hemorrhage. Targeting FXII reduced fibrin formation in ischemic vessels, and reconstitution of FXII-deficient mice with human FXII restored fibrin deposition. Mice deficient in the FXII substrate factor XI were similarly protected from vessel-occluding fibrin formation, suggesting that FXII contributes to pathologic clotting through the intrinsic pathway. These data demonstrate that some processes involved in pathologic thrombus formation are distinct from those required for normal hemostasis. As FXII appears to be instrumental in pathologic fibrin formation but dispensable for hemostasis, FXII inhibition may offer a selective and safe strategy for preventing stroke and other thromboembolic diseases.

Are hemostasis and thrombosis two sides of the same coin?

Factor XII (FXII), a clotting enzyme that can initiate coagulation in vitro, has long been considered dispensable for normal blood clotting in vivo because hereditary deficiencies in FXII are not associated with spontaneous or excessive bleeding. However, new studies show that mice lacking FXII are protected against arterial thrombosis (obstructive clot formation) and stroke. Thus, FXII could be a unique drug target that could be blocked to prevent thrombosis without the side effect of increased bleeding.