The Role of Race and Ethnicity in the Clinical Outcomes of Severe Hemophilia A Patients with Inhibitors.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1163-1163 ◽  
Author(s):  
Rebecca Kruse-Jarres ◽  
Nick M. Pajewski ◽  
Cindy A. Leissinger
Keyword(s):  
African American ◽  
African Americans ◽  
Immune Tolerance ◽  
Race And Ethnicity ◽  
Hemophilia A ◽  
Bleeding Complications ◽  
P Value ◽  
Severe Hemophilia ◽  
Inhibitor Development ◽  
History Of

Abstract Background: Repeatedly, it has been observed that inhibitors to factor VIII are more frequent in African American (AA) and Hispanic (H) patients with severe congenital hemophilia A than in Caucasian (C) patients. Large retrospective reviews have shown that the mortality rates between African American and Caucasian patients with hemophilia have been similar, although non-whites had significantly more bleeding complications, need for hospitalizations and joint limitations. One possible explanation suggested that whites were more likely to receive aggressive treatment strategies such as home infusion. In none of the above reviews were patients stratified by inhibitor status. Few non-white patients have been included in large studies of inhibitor development and natural history. The purpose of this study was to evaluate the impact of race and ethnicity on the clinical characteristics and outcomes of inhibitors in patients with severe hemophilia A. Methods: This is a retrospective review of the repository database of the Hemophilia and Thrombosis Research Society (HTRS). Due to skewed distributions, non-parametric Kruskal-Wallis tests were used to test for racial differences. Results: The HTRS database captured data from 658 hemophilia patients since January 2000. Within the HTRS registry, there were 562 patients with severe hemophilia A: 68.1% (n=383) Caucasian, 21.0% (n=118) African American, and 10.9% (n=61) Hispanic. In comparison to Caucasians, Hispanics had a higher age at hemophilia diagnosis (p-value <0.01), while there was not a significant difference with African-Americans (p-value =0.53). Amongst those subjects with a prior history of inhibitors, African-Americans and Hispanics had a higher family history of inhibitor development: 13.7% of C, 26.3% of AA (pwhite = 0.02), and 41.2% of H (pwhite = <0.01). In patients with a history of inhibitors, Caucasians reported the lowest prevalence of a history of Intracranial Hemorrhage (ICH): 15.8% of C, 29.8% of AA (pwhite = 0.03), and 20.6% of H (pwhite = 0.52). African-Americans reported the lowest rate of receiving ITT (64.9%), followed 76.5% in Hispanics and 84.9% in Caucasians. African-Americans also had the lowest success rate of ITT, 30.4% as compared to 35.3% in Hispanics and 60.3% in Caucasians. In comparison to African-Americans, Caucasians did not have a significantly higher rate of unrestricted function (p=0.13), while the rate was significantly higher in Hispanics (p=0.02). Conclusion: While the HTRS database did not assess overall bleeding complications, it did show a significantly higher incidence of ICH in African-Americans versus Caucasian inhibitor patients, which could not be confirmed in non-inhibitor patients. It also appears, that fewer African-Americans and Hispanics are receiving immune tolerance therapy and that they have a lower success rate than Caucasians. However, there were insufficient patients studied to reach statistically significant conclusions. Hispanics did report significantly higher level of function. However, the HTRS survey does not use a very intricate, detailed tool to assess function. The above data proposes further investigation of bleeding risk across race/ethnicity in inhibitor vs. non-inhibitor populations. It also prompts us to look at larger databases to assess use and outcome of immune tolerance across races. Thirdly, it poses the question, whether there is a racial/ethnic difference in functional status and whether there could be variation in severity and outcome of bleeds.

Influence of the type of factor VIII concentrate on the incidence of factor VIII inhibitors in previously untreated patients with severe hemophilia A

Blood ◽  
2006 ◽  
Vol 107 (1) ◽  
pp. 46-51 ◽  
Author(s):  
Jenny Goudemand ◽  
Chantal Rothschild ◽  
Virginie Demiguel ◽  
Christine Vinciguerrat ◽  
Thierry Lambert ◽  
...  
Keyword(s):  
Factor Viii ◽  
Immune Tolerance ◽  
Hemophilia A ◽  
Tolerance Induction ◽  
Adjusted Relative Risk ◽  
Severe Hemophilia ◽  
Immune Tolerance Induction ◽  
Inhibitor Development ◽  
End Point ◽  
History Of

Abstract Inhibitor development is the major treatment complication in children with severe hemophilia A. It is not clear whether the risk of inhibitors is higher with recombinant factor VIII or with plasma-derived factor VIII. We used multivariate analysis to compare 2 cohorts of previously untreated patients (PUPs) with severe hemophilia A: 62 patients treated with the same brand of high-purity plasma-derived FVIII (pFVIII) containing von Willebrand factor (VWF) and 86 patients treated with full-length recombinant FVIII (rFVIII). In addition to the usual end points (all inhibitors, high inhibitors), we also examined a third end point (high inhibitors and/or immune tolerance induction). The risk of inhibitor development was higher in patients treated with rFVIII than in patients treated with pFVIII, regardless of other risk factors (F8 genotype; nonwhite origin; history of inhibitors in patients with a family history of hemophilia; age at first FVIII infusion). The adjusted relative risk (RRa) for inhibitor development with rFVIII versus pFVIII was 2.4 (all inhibitors), 2.6 (high inhibitors), and 3.2 (high inhibitors and/or immune tolerance induction), respectively, depending on the end point (above). The pathophysiology of this large effect must be understood in order to improve the characteristics of recombinant products and to reduce the incidence of inhibitors to FVIII.

Who Gets Inhibitors? Predicting Inhibitory Antibodies in Children with Severe Hemophilia A.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1158-1158
Author(s):  
Petra C. ter Avest ◽  
Kathelijn Fischer ◽  
Elena Santagostino ◽  
Marijke H. van den Berg ◽  
Johanna G. van der Bom
Keyword(s):  
Family History ◽  
High Risk ◽  
Risk Score ◽  
Hemophilia A ◽  
Positive Family History ◽  
Treatment Strategies ◽  
Intensive Treatment ◽  
Severe Hemophilia ◽  
Inhibitor Development ◽  
History Of

Abstract Background. Replacement therapy in severe hemophilia A patients is complicated by formation of inhibitors in around 25% of children. Identification of patients at the highest risk may help to tailor personalized treatment strategies. Objectives. To develop a scoring system that may be used to identify patients at the highest risk of inhibitor development at first treatment. Methods. We used the data from a retrospective multicentre cohort study (the Canal cohort) of patients with severe hemophilia A (factor VIII (FVIII)less than 0.01 IU/ml), born 1990–2000, followed at least until their 50th exposure day. Presence of inhibitor was defined as twice a positive inhibitor titer and a decreased FVIII recovery. Based on the coefficients of a logistic regression model, a weighted risk-score was developed. Shrinkage of regression coefficients was used to control for overfitting. The discriminative ability of the risk-score was expressed as the area under the curve (AUC) of a receiver operating characteristic curve. Results. Out of the 366 patients from the Canal cohort, 284 children were selected of whom 78 developed an inhibitor (27%). Logistic regression analysis revealed 3 independent risk factors for inhibitor development: positive family history, intensive treatment (at least 5 consecutive days) at the first FVIII exposure, and high risk FVIII gene mutations. Table 1 presents odds ratios of the uni- and multivariate analyses, and the risk score. The AUC for the risk-score was 0,724. Table 2 shows that the model is able to separate high and low risk patients from patients with an intermediate risk of 25%. Conclusions. The risk score includes positive family history of inhibitors, high risk factor VIII gene mutation and intensive treatment at first FVIII exposure. This risk score can recognize patients with a doubled risk for inhibitor development and may be used to guide inhibitor preventive treatment strategies. Table 1. Uni- and Multivariate analysis and risk-score. OR (CI), Univariate OR (CI), Multivariate p-value Risk-Score CI = confidence interval 95% Positive Family History of Inhibitors 4.0 (1.7–9.4) 3.0 (1.2–7.7) ,022 3 High risk FVIII Gene Mutation 3.6 (1.8–7.2) 3.7 (1.8–7.9) ,001 4 Intensive Treatment at 1st FVIII exposure 6.8 (3.6–12.9) 7.2 (3.4–15.1) ,000 6 Table 2. Calibration of the risk-score. Model Total n° patients Predicted n° Inhibitors Observed n° Inhibitors Positive Predictive Value Negative Predictive Value LR= Low Risk, MR= Medium Risk, HR= High risk LR:0 72 7 6 0,34 0,92 MR:3–4 153 39 38 0,25 0,69 HR: >4 59 32 34 0,58 0,80

Increased Prevalence of Inhibitors in Mexican-Hispanic Patients with Severe Hemophilia A Enrolled in the Universal Data Collection Project.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3488-3488 ◽  
Author(s):  
Shannon Carpenter ◽  
J. Michael Soucie ◽  
Sophia Sterner ◽  
Rodney J Presley
Keyword(s):  
African Americans ◽  
Data Collection ◽  
Factor Viii ◽  
Hemophilia A ◽  
Conflicts Of Interest ◽  
Treatment Center ◽  
Hispanic Population ◽  
Severe Hemophilia ◽  
Inhibitor Development ◽  
Insurance Type

Abstract Abstract 3488 Poster Board III-425 Neutralizing inhibitor formation occurs in up to 20-30% of patients with severe factor VIII deficiency, leading to significantly increased morbidity in affected individuals. It has been well-established that patients of African descent have a higher prevalence of inhibitor development. [Oldenburg, J et al. Semin Hematol, 2004] The Hispanic population also has been assumed to have an increase in inhibitor development when compared with Caucasians. The study presented here is the first to definitively demonstrate an increased prevalence of inhibitors in the Hispanic population. We compared inhibitor prevalence among various racial and ethnic groups in a cross-sectional analysis of 6198 males with severe hemophilia A that participated in the Universal Data Collection project sponsored by the Centers for Disease Control and Prevention. We used logistic regression analysis to control for potential confounding variables including age, insurance type (as a proxy for access to care and socio-economic status), age at first bleed, age at diagnosis and use of prophylaxis. The included table shows those variables that were determined to be independently predictive of inhibitors. We assigned Mexican derivation to participants who labeled themselves as Hispanic and who were born either in Mexico, in states bordering Mexico or in states with large Mexican populations as established by Census data. The prevalence of high titer inhibitors in the Mexican-Hispanic population was 26.3% compared to 16.4% for Caucasian patients [OR 1.5, 95% CI 1.1, 1.9], and 26.8% for African-Americans. The underlying cause of increased inhibitor prevalence in these populations is still unknown, though a recent study in African-Americans demonstrated wild-type factors unique from commercially available product. [Viel KR, et al. Inhibitor of Factor VIII in Black Patients with Hemophilia. N Engl J Med, 2009] Further investigation of this phenomenon in the Mexican-Hispanic population, as well as the potential impact of differing immune responses, is warranted. Multivariate analysis of ethnicity and other variables found to be independently predictive of a prevalent inhibitor Characteristic Odds Ratio 95% CI Race/Ethnicity African-American 1.5 1.2 - 1.9 Mexican Hispanic 1.5 1.1 - 1.9 Hispanic 1.2 0.9 - 1.7 Other 1.2 0.9 - 1.6 White Ref Age* (years) <2 4.2 3.0 - 5.9 2-5 6.4 5.1 - 8.0 6-10 2.8 2.2 - 3.5 11-18 1.7 1.4 – 2.1 >18 Ref Insurance type Medicare 1.8 1.4 - 2.3 Medicaid 1.3 1.1 - 1.5 State program 1.1 0.6 - 1.9 TRICARE 1.0 0.4 - 2.1 Other 0.8 0.6 - 1.2 Uninsured 1.6 1.0 - 2.4 Commercial Ref Prophylaxis Yes 0.6 0.5 - 0.7 No Ref * Age with inhibitor or last UDC visit if no inhibitor The authors wish to acknowledge the contributions of the Hemophilia Treatment Center Network Investigators in the completion of this study. Disclosures: No relevant conflicts of interest to declare.

French Previously Untreated Patients with Severe Hemophilia A after Exposure to Recombinant Factor VIII : Incidence of Inhibitor and Evaluation of Immune Tolerance

1998 ◽  
Vol 80 (11) ◽  
pp. 779-783 ◽  
Author(s):  
Y. Laurian ◽  
E. P. Satre ◽  
A. Borel Derlon ◽  
H. Chambost ◽  
P. Moreau ◽  
...  
Keyword(s):  
Factor Viii ◽  
Immune Tolerance ◽  
Hemophilia A ◽  
High Titer ◽  
Recombinant Factor Viii ◽  
High Dose ◽  
Severe Hemophilia ◽  
Inhibitor Development ◽  
Intron 22 Inversion ◽  
Median Period

SummaryFifty French previously untreated patients with severe hemophilia A (factor VIII <1%), treated with only one brand of recombinant factor VIII (rFVIII), were evaluated for inhibitor development, assessment of risk factors and outcome of immune tolerance regimen. The median period on study was 32 months (range 9-74) since the first injection of rFVIII. Fourteen patients (28%) developed an inhibitor, four of whom (8%) with a high titer (≥10 BU). All inhibitor patients but one continued to receive rFVIII either for on-demand treatment or for immune tolerance regimen (ITR). Among these patients, inhibitor was transient in 2 (4%), became undetectable in 6 and was still present in 6. The prevalence of inhibitor was 12%. Presence of intron 22 inversion was found to be a risk factor for inhibitor development. Immune tolerance was difficult to achieve in our series despite a follow-up period of 16 to 30 months: immune tolerance was complete in only one out of the 3 patients undergoing low dose ITR and in one out of the 5 patients with high dose ITR.

Mild / Moderate Hemophilia A with Factor VIII Inhibitors (MHAI): Results of a French and Belgian Survey.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3088-3088
Author(s):  
Roseline d’Oiron ◽  
Jean Maurice Lavergne ◽  
Jenny Goudemand ◽  
Annie Borel-Derlon ◽  
Claude Guerois ◽  
...  
Keyword(s):  
Factor Viii ◽  
Immune Tolerance ◽  
Baseline Level ◽  
Hemophilia A ◽  
Immunosuppressive Agents ◽  
Specific Treatment ◽  
Cumulative Exposure ◽  
Anamnestic Response ◽  
Inhibitor Development ◽  
History Of

Abstract The development of anti-factor VIII inhibitors in mild/moderate hemophilia A (MHA) patients was described as an uncommon event. The largest cohort reported so far included 26 MHAI patients (Hay et al, 1998) and with other anecdotic reports underlined a special pattern of the bleeding reminiscent of acquired hemophilia, a generally poor response to immune tolerance protocol compared to severe patients, and potential factors contributing to a high-risk of inhibitor development such as the FVIII genotype, family related factors and intense substitutive therapy. The optimal therapeutic strategy in MAHI remains unknown. A retrospective data collection was therefore conducted. To date 45 MHAI patients from 29 french and belgian centers were included, with a median FVIII:C baseline level of 0.08 IU/ml (1–28). More than a half of the cases were detected within the last 4 years (y) for a total study period of 20 y. The median age for MHA diagnosis, first FVIII treatment and inhibitor disclosure was respectively 5-y (0 to 73-y),10.5-y (0 to 73-y) and 22.5-y (1 month to 81-y). One splice and 22 different missense mutations were identified for 34 patients (8 already described including 5 with inhibitor, and 15 new). Before the inhibitor appearance, patients received plasma derived (13) or recombinant (12) products only, or both (20). The median number of cumulative exposure days before inhibitor diagnosis was 29 (3–150). History of intense substitutive therapy (≥4 consecutive days or prophylactic treatment every other day for ≥8 days) was observed in 35 (77%) patients, and history of intracranial bleeding in 6/45 (13%). The median maximum historical titer was 6.6 UB (0.5 – 288). In 19 out of 45 (42%) patients FVIII:C baseline level was less than 0.01 IU/ml, while decreased but still detectable (0.01 IU/ml or higher) in 16 (35%), stable in 4 (9%), and unknown in the 6 others. No specific treatment to eradicate the inhibitor was used in 24 patients, while 19 received either an immune tolerance protocol (14 patients, including 6 with combined immunosuppressive drugs), either immunosuppressive agents alone (5 patients); specific treatment was unknown in 2. Apart 2 deaths unrelated to MHA and 3 unknown outcomes, the inhibitor disappeared for 30 patients with a median of 8 months, persisted as a plateau in 2, and was still decreasing in 7 after a median follow-up of 5 months. Anamnestic response defined as an increase of at least 30 % of the inhibitor titer after FVIII or aPCC concentrates was observed in 17 out of the 29 (65%) patients that were rechallenged, but none after recombinant factor VIIa (Novoseven®) or DDAVP. When an anamnestic response occured the median delay for inhibitor eradication increased from 3 to 11 months. This survey underlines: i) that MAHI is not rare, but likely better recognized nowadays, ii) the need for systematic inhibitor assessment after substitutive therapy in MHA, iii) the role of FVIII genotype, intense treatment and possibly inracranial bleeds as contributing factors for inhibitor development, iv) how treatment of bleeds in MHA have to be carefully discussed to limit the risk of respectively appearance or anamnestic response in patients without or with inhibitors.

Successful Orthotopic Liver Transplantation in Severe Hemophilia A with High Responding Inhibitor.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3968-3968
Author(s):  
Robert Chen ◽  
Seligman Paul ◽  
Justin Call ◽  
Brenda Riske ◽  
Ruth Ann Kirschman ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Factor Viii ◽  
Orthotopic Liver Transplantation ◽  
Immune Tolerance ◽  
Hemophilia A ◽  
White Male ◽  
Factor Vii ◽  
Severe Hemophilia ◽  
Factor Viii Activity ◽  
History Of

Abstract Orthotopic liver transplantation (OLT) is an effective treatment for both hepatitis C associated cirrhosis, hepatocellular carcinoma, and hemophilia A. Factor VIII activity usually increases into the normal range. Only a few patients with hemophilia complicated by an inhibitor have undergone OLT with both successful outcomes and uncontrolled bleeding being reported. We report early results of OLT in a middle-aged white male severe hemophilia A patient with a history of a high responding inhibitor (historical high - 70 Bethesda units) who had been on immune tolerance for greater than 10 years prior to transplant. A regimen of 40 u/kg of Factor VIII three times per week successfully suppressed inhibitor titers to less than 2 Bethesda units in the previous years. Hand surgery was managed with Factor VII infusions in the year prior to OLT with good results. At the time of transplantation, his inhibitor titer was 0.7 B.U. Due to his history of non-linear kinetics with factor VIII infusion, (5% of a dose remaining at 24 hours), frequent bolus dosing during surgery was employed. He received 10,500 units (116 units/kg) prior to the incision with smaller doses repeated every 2–4 hours. During the operation and the 24 hr immediately post op he required another 27,300 units (300 units/kg) of factor VIII infusion to maintain activity between 61–122%. On post op day 1 he required 46 units/kg to keep activity between 60.2–108%. On post op day 2 he required 35 units/kg to keep activity between 36.8–68.4%. His immunosuppresion included tacrolimus, mycophenolate, and solumedrol taper of 120 mg on day 2, 80 mg on day 3, 40 mg on day 4, and 20 mg day 5. From day 6 to day 8, his total bilirubin increased to 15 and his requirement for Factor VIII also increased to 70 units/kg daily for 3 days to keep his activity between 33.1% to 71.2%. His immunosuppression was increased because of possible acute rejection and solumedrol 500 mg IV was given daily for 3 days. On day 9 his requirement for factor decreased to 11.6 units/kg daily for 4 additional days. Solumedrol was tapered off to prednisone 10 mg po daily. On day 13 post operation, Factor VIII replacement was stopped and his activity was 56.8%, which gradually rose to 81% on day 25. We conclude: Orthotopic liver transplantation was successful in a hemophilia A inhibitor patient on long term immune tolerance. Factor VIII production by the transplanted liver suppressed the inhibitor and normalized Factor VIII activity up to 4 weeks post transplant. Close follow-up will be required.

Congenital Bleeding Disorders

Hematology ◽  
2003 ◽  
Vol 2003 (1) ◽  
pp. 559-574 ◽  
Author(s):  
Margaret E. Rick ◽  
Christopher E. Walsh ◽  
Nigel S. Key
Keyword(s):  
Gene Transfer ◽  
Immune Tolerance ◽  
Hemophilia A ◽  
Tolerance Induction ◽  
Von Willebrand Disease ◽  
Bleeding Disorders ◽  
Immune Tolerance Induction ◽  
Inhibitor Development ◽  
History Of ◽  
Von Willebrand

Abstract Both clinical and basic problems related to the congenital bleeding disorders continue to confront hematologists. On the forefront are efforts to bring genetic correction of the more common bleeding disorders such as hemophilia A to the clinic in a safe and accessible manner. A second issue, particularly for patients with hemophilia, is the development of inhibitors—questions of how they arise and how to prevent and treat these problems that confound otherwise very successful replacement therapy and allow patients to maintain normal lifestyles. A third issue is the continuing question of diagnosis and management of von Willebrand disease, the most common congenital bleeding disorder, especially in individuals who have borderline laboratory values, but have a history of clinical bleeding. In Section I, Dr. Christopher Walsh discusses general principles of effective gene transfer for the hemophilias, specific information about viral vectors and non-viral gene transfer, and alternative target tissues for factor VIII and factor IX production. He highlights information about the immune response to gene transfer and reviews data from the hemophilia gene transfer trials to date. The future prospects for newer methods of therapy such as RNA repair and the use of gene-modified circulating endothelial progenitors are presented as possible alternatives to the more traditional gene therapy approaches. In Section II, Dr. Nigel Key focuses on inhibitor development in patients with hemophilia A. He reviews the progress in our understanding of the risk factors and presents newer information about the immunobiology of inhibitor development. He discusses the natural history of these inhibitors and the screening, laboratory diagnosis, and treatment, including the use of different modalities for the treatment of acute bleeding episodes. Dr. Key also presents information about the eradication of inhibitors by immune tolerance induction and reviews recent information from the international registries regarding the status and success of immune tolerance induction. In Section III, Dr. Margaret Rick discusses the diagnosis, classification, and management of von Willebrand disease. Attention is given to the difficulty of diagnosis in patients with mild bleeding histories and borderline laboratory test results for von Willebrand factor. She presents the value of different laboratory assays for both diagnosis and classification, and she relates the classification of von Willebrand disease to the choice of treatment and to the known genetic mutations. Practical issues of diagnosis and treatment, including clinical cases, will be presented.

Use of Arsenic Trioxide in Acute Promyelocytic Leukemia Leads to Cardiotoxicity in African-American Patients.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 896-896 ◽  
Author(s):  
Sandip P. Patel ◽  
Elihu H. Estey
Keyword(s):  
African American ◽  
African Americans ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Promyelocytic Leukemia ◽  
P Value ◽  
Qtc Interval ◽  
Cardiac Side Effects ◽  
Qtc Interval Prolongation ◽  
History Of

Abstract Arsenic trioxide (ATO) is an effective therapy for acute promyelocytic leukemia (APL), but cardiac side effects have been described. We reviewed the charts of all 77 patients given ATO at M.D. Anderson from 1998 to present. Our objectives were to: (1) identify patients at relatively high risk of developing arrhythmias after receiving ATO and (2) evaluate the sensitivity and specificity of the electrocardiographic QTc interval in predicting subsequent arrhythmias. The median age of the patients was 54 years. 5% were African-American. 70% received ATO for treatment of APL, 18% for myelodysplastic syndrome, and 12% for other hematological malignancies. The dose of ATO was 0.15 mg/kg daily for 60 days. If, after this time, response was observed ATO was given for an additional 6 months, on a 2 weeks on, 2 weeks off schedule. The dose was lowered from 0.15 mg/kg in the event of acute toxicity, however the African-American patients discussed below were on the standard 0.15 mg/kg dose when they experienced arrhythmias. Arrhythmias were observed in 4 of the 77 patients (5%, exact 95% CI 1– 13%). Of these 4 patients, 2 developed ventricular tachycardia and 2 atrial tachycardia. In 3 of the 4 patients, these arrhythmias led to discontinuation of ATO and its replacement by mylotarg. Three of the 4 African-Americans given ATO developed arrhythmias vs. only 1/73 non African-Americans (Fisher exact p value, 0.002). The patients who developed arrhythmias were younger (median age = 32) than those who did not (median age = 57) and had no history of cardiac disease, electrolyte abnormalities, or use of medications that would alter their response to ATO relative to the other patients. African-Americans tended to be younger than non African-Americans: 3/4 were age &lt; 40 vs. 19/73 non African-Americans. However, since the incidence of arrhythmias in patients age &lt; 40 was 3/3 for African-Americans vs. 0/19 for others (p= 0.0006), it seems that race, not age, is the principal predictor of arrhythmias. Similarly, although all 4 African-Americans had APL vs. 50/73 others, the respective incidence of arrhythmias in African-American APL patients was 3/4 vs. 1/50 in non African-American APL patients (p = 0.0006). Furthermore, arrhythmias were seen on average 8 days after ATO induction in the 3 African-Americans, while the Caucasian patient did not develop arrhythmias until 45 days after ATO induction. Although all patients were on weekly to bimonthly ECG monitoring, QTc interval prolongation (&gt; 430 ms) was not observed in the patients who developed serious cardiac arrhythmias. None of the 3 patients with QTc prolongation had a documented arrhythmia. Thus, QTc monitoring had zero sensitivity and zero specificity for eventual arrhythmia development. Despite uncertainty as to mechanism, physicians should be aware that ATO may cause arrhythmias in young African Americans. Our data also calls into question the value of QTc monitoring, at least in patients given ATO.

Immune Tolerance Induction in 28 Children with Hemophilia Awith Inhibitors.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1046-1046
Author(s):  
Michael U. Callaghan ◽  
Indira Warrier ◽  
Madhvi Rajpurkar ◽  
Jeanne Lusher
Keyword(s):  
Immune Tolerance ◽  
Hemophilia A ◽  
Tolerance Induction ◽  
Hemophilia B ◽  
Recurrent Infections ◽  
Severe Hemophilia ◽  
Central Venous ◽  
Immune Tolerance Induction ◽  
Inhibitor Development ◽  
Peak Titer

Abstract Aim: To study the characteristics, treatment, and outcome of patients with hemophilia with inhibitors who have undergone immune tolerance induction (ITI) at the Children’s Hospital of Michigan over the past 14 years. Methods: In compliance with local IRB regulations, patient charts and laboratory databases were reviewed and salient data extracted. 28 boys underwent 29 attempts at immune tolerance induction. Results: Hemophilia A 26 boys with severe hemophilia A with inhibitors underwent 27 trials of ITI. In this cohort of 26 patients the average age at which patients developed an inhibitor was 22 months and the average age at start of ITI was 5 years 4 months (range 2 months to 17 years 5 months). The average number of exposure days prior to inhibitor development was 10 (1–47). The average time between development of an inhibitor and initiation of ITI was 43 months, with no difference between those who successfully completed ITI and those who did not. Six patients had low titer inhibitors (0.8–6.5 BU) and successfully completed ITI using a modified low dose ITI regimen of factor infusions 3–7 times per week. 20 of the patients with high titer inhibitors (6.4–1280 BU) were treated with daily infusions of 50–200 units/kg/d of factor VIII (FVIII) products. For ITI, 4 patients received high purity plasma derived FVIII (PD-FVIII) and 21 received recombinant FVIII (rFVIII) and one received both. In patients who became tolerized to FVIII, the average time to achieve an inhibitor titer of 0 Bethesda Units (BU) was 211 days. In those who were unable to achieve tolerance, the average length of the trial was 263 days. 21 of the ITI trials employed a central venous catheter and in 5 patients ITI was stopped after removal of the line because of recurrent infections. 14 boys received FEIBA, rFVIIa, or porcine FVIII for bleeding episodes during ITI; 8 of them failed ITI and one is still on therapy. Seven trials of ITI were in Caucasian patients (26 %), 17 in African American (AA) (63 %), and 3 in Middle Eastern patients (11 %). 19 patients achieved complete tolerance (73 %), 6 patients failed (23 %), one failed twice, and one patient continues on therapy. All but 2 patients who successfully completed ITI went on prophylaxis with FVIII. All patients who successfully completed ITI have maintained tolerance with a mean follow-up of 101 months (range 7–168). Table I: Hemophilia A Failed ITI Successful ITI *One still ongoing Number of trials* 7 (23 %) 19 (73 %) African Americans 7 (41 %) 10 (59 %) Non-AA 0 10 (100 %) Historical Peak Titer (mean) 345 BU 47 BU Titer at Start of ITI (mean) 62 BU 5 BU Peak Titer on ITI (mean) 168 BU 46 BU Age at inhibitor development (mean) 26 months 12 months ITI with PD-FVIII 1 4 ITI with rFVIII 7 15 Hemophilia B During this time period, 2 boys with severe hemophilia B underwent ITI. Both had severe allergic reactions at the time of inhibitor development; both underwent desensitization successfully but both failed ITI. Both started ITI with plasma derived factor nine at age 15 months. One developed nephrotic syndrome while on ITI. Conclusions: Most patients with Hemophilia A were able to achieve and maintain tolerance (73%). Higher titer inhibitors, hemophilia B, younger age at development of inhibitor, AA race and treatment of bleeds with bypass agents or porcine factor while on ITI were risk factors for ITI failures. Loss of central venous access with recurrent infections was also a common reason for ITI failure.

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