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.

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.

Incidence of factor VIII inhibitors throughout life in severe hemophilia A in the United Kingdom

Blood ◽  
2011 ◽  
Vol 117 (23) ◽  
pp. 6367-6370 ◽  
Author(s):  
Charles R.M. Hay ◽  
Ben Palmer ◽  
Elizabeth Chalmers ◽  
Ri Liesner ◽  
Rhona Maclean ◽  
...  
Keyword(s):  
United Kingdom ◽  
Factor Viii ◽  
Hemophilia A ◽  
Interquartile Range ◽  
Severe Hemophilia ◽  
The United Kingdom ◽  
Potential Risk Factors ◽  
History Of ◽  
Previously Treated Patients ◽  
Adjusted Incidence

Abstract The age-adjusted incidence of new factor VIII inhibitors was analyzed in all United Kingdom patients with severe hemophilia A between 1990 and 2009. Three hundred fifteen new inhibitors were reported to the National Hemophilia Database in 2528 patients with severe hemophilia who were followed up for a median (interquartile range) of 12 (4-19) years. One hundred sixty (51%) of these arose in patients ≥ 5 years of age after a median (interquartile range) of 6 (4-11) years' follow-up. The incidence of new inhibitors was 64.29 per 1000 treatment-years in patients < 5 years of age and 5.31 per 1000 treatment-years at age 10-49 years, rising significantly (P = .01) to 10.49 per 1000 treatment-years in patients more than 60 years of age. Factor VIII inhibitors arise in patients with hemophilia A throughout life with a bimodal risk, being greatest in early childhood and in old age. HIV was associated with significantly fewer new inhibitors. The inhibitor incidence rate ratio in HIV-seropositive patients was 0.32 times that observed in HIV-seronegative patients (P < .001). Further study is required to explore the natural history of later-onset factor VIII inhibitors and to investigate other potential risk factors for inhibitor development in previously treated patients.

scholarly journals Postpartum Acquired Hemophilia: A Rare Cause of Postpartum Hemorrhage

2013 ◽  
Vol 2013 ◽  
pp. 1-2 ◽  
Author(s):  
Srikanth Seethala ◽  
Sumit Gaur ◽  
Elizabeth Enderton ◽  
Javier Corral
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Factor Vii ◽  
Normal Vaginal Delivery ◽  
Factor Viii Inhibitor ◽  
Activity Levels ◽  
Factor Viii Activity ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Viii Inhibitor

A 36-year-old female started having postpartum vaginal bleeding after normal vaginal delivery. She underwent hysterectomy for persistent bleeding and was referred to our institution. An elevation of PTT and normal PT made us suspect postpartum acquired hemophilia (PAH), and it was confirmed by low factor VIII activity levels and an elevated factor VIII inhibitor. Hemostasis was achieved with recombinant factor VII concentrates and desmopressin, and factor eradication was achieved with cytoxan, methylprednisolone, and plasmapheresis.

Efficacy and Safety of Secondary Prophylactic Versus On-Demand Sucrose-Formulated Recombinant Factor VIII Treatment in Adults with Severe Hemophilia A: Results from a 13-Month Crossover Study

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 516-516 ◽  
Author(s):  
Peter Collins ◽  
Albert Faradji ◽  
Massimo Morfini ◽  
Monika Maas Enriquez ◽  
Eduard Gorina ◽  
...  
Keyword(s):  
Health Economics ◽  
Factor Viii ◽  
Crossover Study ◽  
Hemophilia A ◽  
Recombinant Factor Viii ◽  
Severe Hemophilia ◽  
Joint Function ◽  
On Demand ◽  
History Of ◽  
Male Patients

Abstract Many of the physical, psychosocial, and financial difficulties associated with severe hemophilia can be attributed to the effects of recurrent joint bleeds and chronic arthropathy. Regimens for clotting factor replacement treatment for hemophilia include prophylactic and on-demand therapy. A study in pediatric male patients with severe hemophilia A showed that prophylactic treatment with sucrose-formulated recombinant factor VIII (rFVIII-FS) resulted in prevention of joint damage and a decrease in the frequency of joint and other bleeds compared with on-demand therapy (Manco-Johnson MJ, et al. N Engl J Med.2007;357:535). A clinical trial was conducted in adult patients with severe hemophilia A and history of frequent bleeding to evaluate the effect of secondary rFVIII-FS prophylaxis on the number of joint bleeds after switching from on-demand rFVIII-FS therapy. Secondary study objectives were to compare these treatment strategies with regard to joint function, number of all bleeds, health-related quality of life, health economics, and safety. Male patients who were aged 30–45 years, had a negative inhibitor status, had a history of FVIII treatment (&gt;100 exposure days), and were using on-demand FVIII treatment before the study were eligible to participate in this prospective 13-month crossover study. During the first 6 months, all patients received on-demand rFVIII-FS treatment. Patients were then switched to prophylactic rFVIII-FS treatment (20–40 IU/kg 3 times per wk at a stable dose as determined by investigators based on the patient’s bleeding history) for the remaining 7 months, with the first month constituting a washout/stabilization run-in period. Patients were monitored throughout the 13 months for bleeds and health-economics parameters and were evaluated by the Gilbert score (joint function) and the Haemo-QoL questionnaire at baseline and at the end of the on-demand (at 6 mo) and prophylactic (at 13 mo) treatment periods. A total of 20 patients from 9 international sites participated in the study. Patients received a mean dose of 31 IU/kg/wk during the on-demand period, which increased to 86 IU/kg/wk during the prophylaxis period. Although 16/20 patients already had 1 to 4 target joints, mean (±SD) numbers of joint and total bleeds per patient significantly decreased during the prophylaxis period (1.5±2.1 and 1.9±3.3, respectively) compared with the on-demand period (18.5±11.6 and 23.7±13.3; P&lt;0.001 for both). Mean (±SD) total Gilbert scores indicated better joint function at the end of prophylaxis (19.8±11.7) vs on-demand (25.3±11.7; P&lt;0.001) treatment. During this short observation period, there was no statistically significant difference between treatments in the pharmacoeconomic variables assessed (days off work, general practitioner visits, and hospitalization days) or in the mean total Haemo-QoL score, although patients reported significantly fewer restrictions at work or school by the end of the prophylaxis period compared with the end of the on-demand period (P=0.016). There was a trend toward improved patient activity levels with prophylaxis. Similar numbers of patients reported adverse events (AEs) during on-demand (n=9, 45.0%) and prophylactic (n=10, 52.6%) treatment; AEs occurring in 2 patients (dysgeusia and headache) were considered treatment related. Serious AEs were reported by 1 patient during each treatment; neither serious AE was related to treatment. No de novo inhibitor development was observed during either treatment. In summary, prophylaxis with rFVIII-FS was well tolerated and reduced the frequency of joint and other bleeds compared with on-demand treatment in previously treated adults with severe hemophilia A and target joints.

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.

scholarly journals First manifestation of severe haemophilia: acute flaccid paralysis due to spinal cord contusion with subdural hemorrhage

2018 ◽  
Vol 5 (2) ◽  
pp. 657
Author(s):  
Nigam P. Narain ◽  
Bhupendra Narain ◽  
Md. Nasim Ahmed ◽  
Mampy Das
Keyword(s):  
Family History ◽  
Factor Viii ◽  
Hemophilia A ◽  
Lower Limbs ◽  
Flaccid Paralysis ◽  
Subdural Hemorrhage ◽  
Severe Hemophilia ◽  
Intracranial Hemorrhages ◽  
Coagulation Profile ◽  
History Of

Hemophilia A and hemophilia B are the most common and serious congenital coagulation factor deficiencies. Intracranial hemorrhages occur in 3-10%. Spinal epidural hematomas are rare. Even with severe hemophilia, only 90% have evidence of increased bleeding by 1 year of age. Only 2% of neonates with hemophilia sustain intracranial hemorrhages. Here we describe a case of a 5-month old boy with positive family history of hemophilia A on his maternal side who was admitted to the hospital because of retention of urine and decreased movement in both lower limbs following history of fall from height (approximately 2 feet high), two days prior to admission. Physical examination showed no skin lesion or hematoma. Neurological examination showed the infant in frog like posture with flaccid paralysis of both lower limbs without loss of sensation. There was associated bladder involvement with a Phantom hernia on the right side of his abdomen. MRI Spine revealed cord contusion in D4-D9 segment with spinal subdural hemorrhage. Coagulation profile was abnormal with a prolonged Activated plasma thromboplastin time. Factor VIII assay revealed a level of 1%. Treatment was conservative, and the infant was given factor VIII replacement. There was remarkable improvement within weeks. Thus, spinal hematomas being rare should still be considered and ruled out for prompt management of cases of suspected hemophilia. This case highlights the importance of a thorough family history which led to the ultimate diagnosis of severe Hemophilia A by coagulation profile and neuroimaging and further confirmed by factor VIII assay.

scholarly journals The factor VIII treatment history of non‐severe hemophilia A

2020 ◽  
Vol 18 (12) ◽  
pp. 3203-3210
Author(s):  
Amal Abdi ◽  
Fabienne R. Kloosterman ◽  
Corien L. Eckhardt ◽  
Christoph Male ◽  
Giancarlo Castaman ◽  
...  
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Severe Hemophilia ◽  
Treatment History ◽  
History Of

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.

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.

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