Immune tolerance induction in 31 children with haemophilia A: is ITI less successful in African Americans?

Inhibitor development continues to be a major problem in the treatment of haemophilia. Immune tolerance induction (ITI) continues to be the most effective approach to managing this complication. This study reviews the practice and outcome of ITI at a single centre over a 17-year period. All 31 inhibitor patients have haemophilia A. Two patients with haemophilia A underwent two trials of ITI and a third patient underwent three trials of ITI for a total of 35 courses of ITI in these 31 patients. Most patients had high responding inhibitors, 22 of 31. Seventy-one percent of haemophilia patients achieved tolerance. Courses of ITI in African American (AA) patients with haemophilia A were much less likely to achieve tolerance compared with non-AAs, 57.9% and 92% (P = 0.04) respectively. Most trials of ITI were carried out with recombinant products (25 of 35). While ITI continues to be an effective therapy for patients with inhibitors, it is less effective in AA patients, and patients with higher inhibitor titres. In this refractory group of patients, new approaches are needed.

Inhibitors in factor IX deficiency a report of the ISTH-SSC international FIX inhibitor registry (1997-2006).

Haemophilia B is an X-linked disorder resulting in coagulation factor IX deficiency. Patients with severe deficiency (<1% factor IX activity) may have significant bleeding complications similar to patients with haemophilia A or factor VIII deficiency. The development of inhibitory antibodies to the missing coagulation factor is a major complication in patients with haemophilia. While the incidence of inhibitors in patients with haemophilia A is higher than that in haemophilia B, the occurrence of allergic and or anaphylactic reactions with the development of inhibitors is unique to haemophilia B patients. Since haemophilia B is a rare bleeding disorder and the incidence of inhibitors is an even rarer entity, a registry was established by Dr Indira Warrier under the auspices of the FVIII/FIX subcommittee of the International Society of Thrombosis and Haemostasis, to gather information on the occurrence and characteristics of patients with inhibitors and also the incidence of allergic and anaphylactic reactions in this group of patients. This is the first report from this registry and helps us to gather some insight on haemophilia B patients with inhibitors and complications related to inhibitor development and difficulties with immune tolerance.

Use of intravenous gamma globulin in children and adolescents with idiopathic thrombocytopenic purpura and other immune thrombocytopenias.

Approximately 85 to 90 percent of cases of idiopathic thrombocytopenic purpura (ITP) in children are of the acute, self-limited variety that generally occurs after a viral infection. The remaining 10 to 15 percent of children with this disorder have the chronic (autoimmune) type of ITP. For these patients, splenectomy is often the recommended treatment if severe bleeding occurs and platelet counts remain below 40,000/mm3. However, splenectomy has associated risks and the response to this surgery cannot always be predicted. Intravenous gamma globulin (IVIG) has proven useful as an alternative to splenectomy, especially in children who are considered too young for splenectomy or in those in whom there is no response to splenectomy. It should be noted that booster shots are frequently required and the patient's ITP may become refractory. IVIG may also be useful in preparing a child with ITP for splenectomy and in treating children or adolescents with ITP who have central nervous system or other serious hemorrhages. Although IVIG is not always effective in raising the platelet count, it does provide a very useful alternative method of treating this disorder.

Intravenous gamma globulin treatment for chronic idiopathic thrombocytopenic purpura in children.

Six children, five to 16 years of age, with the chronic, autoimmune form of idiopathic thrombocytopenic purpura were given intravenous gamma globulin (Gamimune, Cutter Biological, Berkeley, California) in a dose of 400 mg/kg per day for five consecutive days as six-hour infusions. Two of the six children had undergone splenectomy but the other four had not. Three of six children had a good or excellent response to the first five-day course of intravenous gamma globulin. The peak platelet count occurred within 12 days of the start of therapy in all. All three have required booster doses of intravenous gamma globulin to maintain platelet counts at a safe level. All children had marked increases in serum IgG following intravenous gamma globulin, except one who had undergone splenectomy and who had chronic idiopathic thrombocytopenic purpura with high baseline levels of immunoglobulin G (IgG). The significance of the observed increase in platelet-associated IgG during treatment is not clear. No untoward reactions necessitating cessation of therapy were encountered during this study. Our short-term observations in six children with chronic idiopathic thrombocytopenic purpura indicate that high-dose intravenous gamma globulin is an effective form of treatment for certain children with this condition.

Hemophilia A.

Over the past few years considerable progress has been made in elucidating the molecular genetics of hemophilia A, in carrier detection and prenatal diagnosis, and in the production of safer clotting factor concentrates. Recombinant FVIII, shown to be safe and effective in ongoing prelicensure clinical trials that began in the spring of 1987, should soon be licensed and commercially available. There is now considerable interest in beginning prophylactic therapy regimens at 1 or 2 years of age, in an attempt to prevent chronic joint disease and other complications of serious bleeding episodes. The possibility of gene insertion therapy for persons with hemophilia now seems to be a realistic one--perhaps achievable in the 1990s. Although many problems remain--major problems resulting from HIV, HCV, and HBV infections; how to deal with existing musculoskeletal problems; how to pay for the higher-priced new technologies; high titer inhibitors; just to name a few--the many recent scientific advances and their clinical applications make this an exciting time. This is truly, as indicated in the title of the proceedings of the XIX Congress of the World Federation of Hemophilia, a new decade of hopes and challenges.

Development of anaphylactic shock in haemophilia B patients with inhibitors.

The development of inhibitor antibody is a serious complication of haemophilia in young children. The incidence of factor IX (FIX) inhibitors in haemophilia B patients is five- to 10-times less common (1.5-3%) than the incidence of FVIII inhibitors in haemophilia A (15-30%). Inhibitors are commonly associated with the total absence of FIX antigen due to total deletions or other major derangements of the FIX gene. Unlike those with haemophilia A, patients with haemophilia B often experience anaphylactic reactions to FIX concentrates at the time of inhibitor development. Although the reasons for anaphylaxis at the time of inhibitor development are not yet clear, several hypotheses can be considered. One relates to the smaller molecular size of FIX compared with FVIII. With a molecular size of 55000, FIX diffuses into extravascular spaces more readily. Secondly, since the normal plasma FIX concentration is much higher compared with FVIII (5 microg/ml versus 0.1 microg/ml), haemophilia B patients are exposed to higher amounts of exogenous protein when a standard dose of 40-80 units/kg FIX is used. The routine exposure of haemophilia B patients to such large amounts of exogenous protein without any endogenous FIX antigen may contribute to the development of hypersensitivity. A third reason to consider is the absence of tolerance. Whether the lack of tolerance is due to the total absence of any FIX antigen or co-deletion of neighbouring genes that modulate the immune system is unknown. Management of bleeding in patients with inhibitors and anaphylaxis is complicated because the only readily available products for treatment are the FIX-containing prothrombin complex concentrates or activated prothrombin complex concentrates, the very same products that induce anaphylaxis. Recently, recombinant activated factor VII (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark) has been used effectively in several of these children, but in the USA rFVIIa is only available on a compassionate basis for the treatment of life- or limb-threatening bleeding. Eradication of the inhibitor by immune tolerance induction (ITI) has only been minimally successful in haemophilia B patients with inhibitors and anaphylaxis. Despite initial successful desensitization, the majority of these patients have had recurrent allergic reactions to FIX requiring administration of antihistamines and steroids. Recently, the development of nephrotic syndrome has been reported as a serious complication of ITI in these patients. Since inhibitor antibody is seen in association with complete gene deletions or major derangements of the FIX gene, it may be possible to select those patients with the highest risk for close monitoring during the early period of treatment by obtaining molecular diagnosis at the time of presentation.

Paraplegia after lumbar puncture. In an infant with previously undiagnosed hemophilia A. Treatment and peri-operative considerations.

We report a 3-month-old infant who became paraplegic from an epidural hematoma caused by a diagnostic lumbar puncture for work-up of sepsis. The differential diagnosis of the cause of paraplegia was epidural hematoma formation versus spinal abscess. Hemophilia A was diagnosed when coagulation studies were discovered to be abnormal, and non-contrast CT scan revealed an epidural mass with spinal cord displacement. The coagulopathy was rapidly corrected preoperatively with an infusion of cryoprecipitate. A medially limited bilateral T8-L4 laminectomy allowed complete evacuation of the hematoma with maximum preservation of normal bone tissue, but no clinical improvement resulted. Coagulopathy should be highly suspect in an infant who becomes paraplegic after lumbar puncture. The coagulopathy may be rapidly corrected with deficient factor replacement, allowing major spinal surgery to be performed safely.

Plasma and albumin-free recombinant factor VIII: pharmacokinetics, efficacy and safety in previously treated pediatric patients.

BACKGROUND: The pharmacokinetics of factor VIII replacement therapy in preschool previously treated patients (PTPs) with hemophilia A have not been well characterized. OBJECTIVES: To assess the pharmacokinetics, efficacy and safety of a plasma-free recombinant FVIII concentrate, ADVATE [Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method, rAHF-PFM], in children < 6 years of age with severe hemophilia. PATIENTS/METHODS: Fifty-two boys, one girl, mean (+/- SD) age 3.1 +/- 1.5 years and >or= 50 days of prior FVIII exposure, were enrolled in a prospective study of ADVATE rAHF-PFM at 23 centers. RESULTS: The mean terminal phase half-life (t(1/2)) was 9.88 +/- 1.89 h, and the mean adjusted in vivo recovery (IVR) was 1.90 +/- 0.43 IU dL(-1) (IU kg(-1))(-1). Over the 1-6-year age range, t(1/2) of rAHF-PFM increased by 0.40 h year(-1). IVR increased by 0.095IU dL(-1)(IU kg(-1))(-1) (kg m(-2))(-1) in relation to body mass index (BMI). Patients primarily received prophylaxis. Median (range) annual joint bleeds were 0.0 (0.0-5.8), 0.0 (0.0-6.1) and 14.2 (0.0-34.5) for standard prophylaxis, modified prophylaxis and on-demand treatment, respectively. Bleeds were managed in 90% (319/354) of episodes with one or two rAHF-PFM infusions; response was rated excellent/good in 93.8% of episodes. Over a median 156 exposure days, no FVIII inhibitors were detected and no related severe adverse events or unusual non-serious adverse events were seen. CONCLUSIONS: Children < 6 years of age appear to have shorter FVIII t(1/2) and lower IVR values than older subjects. However, these parameters increased with age (t(1/2)) and BMI (adjusted IVR), respectively. rAHF-PFM was clinically effective and well tolerated, with no signs of increased immunogenicity in previously treated young children with hemophilia A.

Management of haemophilia B patients with inhibitors and anaphylaxis.

The development of inhibitor antibodies is a serious complication of haemophilia in young children. Occurrence of anaphylaxis at the time of inhibitor development is a recently described complication unique to haemophilia B. Management of these inhibitor patients with allergy is complicated due to the absence of any readily available products for treatment of acute bleeding episodes. Clinical experience suggests that recombinant activated factor VII is the most appropriate and logical treatment for acute bleeding episodes in these patients. From the limited information available regarding immune tolerance induction (ITI) in these patients, it appears that ITI regimens have been only minimally successful and are associated with a high rate of complication (nephrotic syndrome).

Factor IX antibody and immune tolerance.

Prevalence of FIX inhibitor is ten times lower than factor VIII inhibitor. FIX inhibitor patients pose major challenges for treatment because of the simultaneous occurrence of severe allergy to FIX at the time of inhibitor development. Immune tolerance induction in haemophilia B inhibitor patients with allergy to FIX is complicated due to the development of nephrotic syndrome. Moreover, response to ITI usually is poor.

Anaphylaxis in patients with hemophilia.

Anaphylactic reactions are rare emergencies observed in hemophilia patients. In hemophilia (B) (HB) patients they typically occur coincident with the development of an inhibitor. It is important to be aware of the possibility of such reactions, and the patient's family should be educated at the time of initial diagnosis and discussion. Because these reactions typically occur within the first 10 to 20 treatment courses, the first few infusions should be given in a hospital/clinic setting equipped to manage such emergencies. Obtaining the exact genotype may identify the HB patients at risk for this complication. When immune tolerance induction (ITI) is attempted in patients with HB inhibitors and anaphylaxis, the physician should be vigilant in detecting proteinuria.

Congenital thrombocytopenias.

Congenital thrombocytopenias are rare bleeding disorders but must be included in the differential diagnosis when investigating a young infant with chronic thrombocytopenia. Several of these syndromes have associated defects of immune, renal, or skeletal systems in addition to thrombocytopenia. These can be categorized into two groups depending on the presence or absence of bone marrow hypoplasia. The majority of these disorders are associated with a mild bleeding tendency and thus may be missed until the affected individuals experience excessive postoperative or posttraumatic hemorrhage. In adults, this entity must be considered when evaluating a patient with thrombocytopenia who is unresponsive to the medical management of immune thrombocytopenia. Other than platelet transfusion, no specific therapy is available for these disorders. A test dose of desmopressin may be attempted in a nonbleeding patient (to see if it will shorten the bleeding time) prior to using it for treatment of a bleeding episode or surgical prophylaxis. Bone marrow transplantation may prove curative in a select group of thrombocytopenic syndromes.

Intravenous gammaglobulin (Gaminume) for treatment of chronic idiopathic thrombocytopenic purpura (ITP): a two-year follow-up.

Thirteen subjects 5-20 years of age with the chronic, autoimmune form of idiopathic thrombocytopenic purpura (ITP) were given intravenous gammaglobulin (Gamimune; Cutter Biological, Berkeley, CA) in a dose of 400 mg/kg per day for 5 consecutive days. Two of the 13 children had undergone splenectomy; the other 11 had not. Eight of these 13 children had also received corticosteroid therapy with no sustained increase in platelet counts. Six of 13 children had a good or excellent response to the first 5 day course of gammaglobulin therapy, and one had a fair response. The peak platelet count occurred within 7 days of the start of therapy except in one patient, whose platelet count peaked on day 12. Six of seven patients who initially responded to Gamimune required booster doses to maintain platelet counts at a safe level. All children had marked increases in serum IgG following Gamimune except one (who had undergone splenectomy for chronic ITP), who had high baseline levels of immunoglobulin G (IgG). No untoward reactions necessitating cessation of therapy were encountered during this study. The most common side effect observed was headache. During the first year of follow-up after Gamimune, three of seven initial responders became refractory to Gamimune therapy. Two of these three refractory subjects later underwent splenectomy with excellent response. The third refractory patient who was splenectomized prior to gammaglobulin therapy had spontaneous remission of his ITP 5 months after the last dose of Gamimune. Three of the four other initial responders have continued to do well and have maintained platelet counts above 40,000/mm3 (one without booster). The fourth subject dropped out of the study. Thus our observations indicate that Gamimune is an effective form of treatment for some children with chronic ITP, and can be considered as an alternative to splenectomy or as a potential therapeutic modality in those who have failed to respond to splenectomy.

Retrovir therapy in hemophilic children with symptomatic human immunodeficiency virus infection: efficacy and toxicity.

In desperation, we have used retrovir in five hemophilic children (10-16 years old) over the past 22 months. All had presented with various clinical manifestations of acquired-immune-deficiency-syndrome (AIDS)-related complex or AIDS. Our decision to treat with retrovir was based on clinical manifestations and very low numbers of CD4 cells (less than 200). The most common clinical presentation was recurrent oral moniliasis. Other significant findings included recurrent herpes zoster, thrombocytopenia, growth failure, and biliary tract infection. Initially, all five children received the full adult dosage of retrovir (200 mg q 4 h x 6 doses/day). This dosage had to be reduced in four children because of toxicity. The most commonly observed toxic side effects were anemia and neutropenia. Alanine aminotransferase (ALT) levels rose to 4-10 times the upper limit of normal in four of five children. One was on concomitant ketokonazole prior to the rise in ALT level. Myalgia and headache were reported by two patients. Improvement in clinical and immunological status was observed in all children initially. After 12-18 months of retrovir therapy, infectious complications secondary to prolonged neutropenia were seen in these immunocompromized children. However, compared to historic controls, these children have had fairly stable disease. We feel that all hemophilic children with symptomatic human immunodeficiency virus infection should be offered this drug, even though the optimal dosage for children is not yet established.

The spectrum of Evans' syndrome.

Eleven patients (10 boys, one girl) with Evans' syndrome with a median follow up time of 8.0 years were evaluated retrospectively. Six patients had either persistent hepatosplenomegaly or generalised lymphadenopathy, or both. In five patients, an increase in lymph node and/or spleen size was observed during the exacerbations of cytopenias. Seven patients had quantitative serum immunoglobulin abnormalities at the time of presentation. There were associated systemic manifestations in nine patients. Various forms of treatment were used with mixed results. Four patients died from sepsis and haemorrhage; four had complete recovery--two after splenectomy. These findings show that Evans' syndrome is a heterogeneous disorder with significant morbidity and mortality. High incidence of quantitative serum immunoglobulin abnormalities, lymphoid hyperplasia, and associated systemic manifestations suggest that Evans' syndrome may represent a stage of a more broad spectrum, generalised immune dysregulation.

Immune tolerance induction in the treatment of paediatric haemophilia A patients with factor VIII inhibitors.

The development of an inhibitor to transfused factor VIII (FVIII) is a serious treatment-related problem in haemophiliac children. The management of patients with high titre FVIII inhibitors is difficult, and immune tolerance induction (ITI) is the only method available for the eradication of these inhibitors. The results of the ITI regimen used at the Children's Hospital of Michigan Haemophilia Treatment Center are described and discussed. ITI was attempted in 14 children with severe haemophilia A (13 high responders, one low responder), with daily doses of FVIII alone. FVIII dosage was chosen according to the patient's historical peak inhibitor titre. ITI included three phases; induction phase, dose reduction phase and maintenance phase. During the first phase, the starting dose was 50 or 100 U kg-1 d-1; during the second phase the FVIII dosage was reduced gradually to 25 U kg-1 every other day according to the inhibitor titre, FVIII recovery and/or half-life study. In the third (maintenance) phase, the children received either prophylactic therapy or episodic therapy for 12 months. The inhibitor elimination was defined as the time taken to achieve a negative inhibitor assay with no anamnestic response and normal FVIII recovery and/or normal half-life. Immune tolerance was achieved in 11 of 14 patients (79%) patients within a median time of 6 months; two children are still on therapy, three failed ITI. We observed either failure or prolongation of immune tolerance if the historical peak titre or the maximum titre during ITI was >200 BU. The success rate of our low dose ITI regimen is not different from that reported by other investigators and the inhibitor elimination time is similar to some of the studies reported previously.

Cardiac rhythm abnormalities during intravenous immunoglobulin G infusion for treatment of thrombocytopenia.

PURPOSE: Several side effects of intravenous immunoglobulin G (IVIG) therapy are known, but it has never been reported to be associated with cardiac rhythm abnormalities other than sinus tachycardia. PATIENTS AND METHODS: We describe the development of cardiac dysrhythmias during intravenous immunoglobulin G infusion in two children with thrombocytopenia. One of the patients had a history of supraventricular tachycardia, and the other had evidence suggestive of preexisting long QT syndrome. CONCLUSION: Cardiac rhythm abnormalities may be exacerbated in individuals with preexisting cardiac problems by IVIG infusion, and such patients should be monitored closely during IVIG administration.

The overall effectiveness of prophylaxis in severe haemophilia.

The aim of this retrospective review was to assess the overall effectiveness of prophylaxis when compared with on-demand treatment of haemophilic patients. Twenty-five children (22 with severe haemophilia A and three with severe haemophilia B) were evaluated. Five haemophilia A patients received primary prophylaxis (instituted before the onset of any joint bleed) while the other 17 haemophilia A and all three haemophilia B patients were on secondary prophylaxis. We compared factor usage, number of bleeding episodes, emergency room (ER) visits and hospitalizations while on prophylaxis to those while on demand therapy. All subjects were male, the median age at time of review was 11.4 years and at start of prophylaxis was 4.5 years. Thirteen of the 25 patients (52%) required indwelling venous catheters for access, seven of these had one or more (one-six) episodes of line sepsis. Haemophilia A patients received an average of 23.8 U kg(-1) (20-30 U kg(-1)) of recombinant factor VIII three times a week while haemophilia B patients received 50 U kg(-1) recombinant FIX twice weekly. There was a significant reduction in the mean number of major bleeds on prophylaxis from 15.5 to 1.9 per year and a significant decrease in target joints, ER visits and hospitalizations. Although factor usage per year was higher on prophylaxis, there was an overall reduction in number of bleeds and resultant decrease in hospitalizations and ER visits. By preventing new target joints, prophylaxis can lead to reduction in long-term morbidity and a better quality of life despite increased central lines and higher factor usage.