The factor VIII treatment history of non‐severe hemophilia A: COMMENT. Joint damage in adult patients with mild or moderate hemophilia A evaluated with the HEAD‐US system

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.

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Animal Testing of Retroviral-Mediated Gene Therapy for Factor VIII Deficiency

Thrombosis and Haemostasis ◽

10.1055/s-0037-1615880 ◽

1999 ◽

Vol 82 (08) ◽

pp. 555-561 ◽

Cited By ~ 31

Author(s):

Douglas Jolly ◽

Judith Greengard

Keyword(s):

Gene Therapy ◽

Factor Viii ◽

Hemophilia A ◽

Joint Damage ◽

Coagulation Factor ◽

The United States ◽

Severe Hemophilia ◽

Factor Viii Gene ◽

Bleeding Episodes

IntroductionHemophilia A results from the plasma deficiency of factor VIII, a gene carried on the X chromosome. Bleeding results from a lack of coagulation factor VIII, a large and complex protein that circulates in complex with its carrier, von Willebrand factor (vWF).1 Severe hemophilia A (<1% of normal circulating levels) is associated with a high degree of mortality, due to spontaneous and trauma-induced, life-threatening and crippling bleeding episodes.2 Current treatment in the United States consists of infusion of plasma-derived or recombinant factor VIII in response to bleeding episodes.3 Such treatment fails to prevent cumulative joint damage, a major cause of hemophilia-associated morbidity.4 Availability of prophylactic treatment, which would reduce the number and severity of bleeding episodes and, consequently, would limit such joint damage, is limited by cost and the problems associated with repeated venous access. Other problems are associated with frequent replacement treatment, including the dangers of transmission of blood-borne infections derived from plasma used as a source of factor VIII or tissue culture or formulation components. These dangers are reduced, but not eliminated, by current manufacturing techniques. Furthermore, approximately 1 in 5 patients with severe hemophilia treated with recombinant or plasma-derived factor VIII develop inhibitory humoral immune responses. In some cases, new inhibitors have developed, apparently in response to unnatural modifications introduced during manufacture or purification.5 Gene therapy could circumvent most of these difficulties. In theory, a single injection of a vector encoding the factor VIII gene could provide constant plasma levels of factor in the long term. However, long-term expression after gene transfer of a systemically expressed protein in higher mammals has seldom been described. In some cases, a vector that appeared promising in a rodent model has not worked well in larger animals, for example, due to a massive immune response not seen in the rodent.6 An excellent review of early efforts at factor VIII gene therapy appeared in an earlier volume of this series.7 A summary of results from various in vivo experiments is shown in Table 1. This chapter will focus on results pertaining to studies using vectors based on murine retroviruses, including our own work.

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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 ◽

10.1182/blood.v112.11.516.516 ◽

2008 ◽

Vol 112 (11) ◽

pp. 516-516 ◽

Cited By ~ 2

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 (>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<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<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.

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Low dose long-acting factor VIII prophylaxis in pediatric and young adult patients with hemophilia A: Short-term single-center experience from a developing country

10.25259/jhas_13_2021 ◽

2021 ◽

Vol 0 ◽

pp. 1-6

Author(s):

Shailendra Prasad Verma ◽

Anil Kumar Tripathi ◽

Geeta Suri Sharma ◽

Nidhish Kumar ◽

Rashmi Kushwaha

Keyword(s):

Young Adult ◽

Adverse Events ◽

Factor Viii ◽

Low Dose ◽

Hemophilia A ◽

Adult Patients ◽

Severe Hemophilia ◽

Emergency Visits ◽

Episodic Treatment ◽

Long Acting

Objectives: High dose factor prophylaxis in hemophilia has been proven to prevent joint bleeds in the western world effectively. We look for a cost-effective and feasible way for Indian patients to reduce the dose and frequency of factor infusion. Data on prophylaxis with a low dose, long-acting factor infusion twice a week dosing schedule is limited. The purpose was to study the efficacy and safety of long-acting factor VIII (Eloctate) for secondary/ tertiary prophylaxis in pediatric and young adult patients with moderate and severe hemophilia A. Materials and Methods: Thirty-eight patients with moderate and severe hemophilia A with an age range from 1 to 25 years were included in the study. During the initial 4 months, they received therapeutic doses of ELOCTATE (Factor VIII with Fc Fusion Protein) on an episodic basis after a clinical bleed. In the next 4 months, they received prophylactic intravenous ELOCTATE at the dose of 20 units/kg body weight twice a week. Annual bleeding rates (ABR), school absenteeism, emergency visits, joint scores, and adverse events were compared during both periods. Results: The total number of joint bleeds during the episodic treatment and prophylaxis period was 608 and 67, respectively. ABR was 47.9 during the episodic treatment period and 5.3 during prophylaxis showing an 88.9% reduction in joint bleeds. School/college absenteeism and emergency visits were significantly reduced during prophylaxis. No significant adverse events were noted during prophylaxis. Conclusion: Low dose, twice a week, and long-acting recombinant factor VIII-Fc (Eloctate) prophylaxis can be a reasonable options for patients with hemophilia A in developing countries.

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Early Prophylaxis Provides Continued Joint Protection in Severe Hemophilia A: Results of the Joint Outcome Continuation Study

Blood ◽

10.1182/blood-2018-99-117413 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 382-382 ◽

Cited By ~ 3

Author(s):

Beth Boulden Warren ◽

Dianne Thornhill ◽

Jill Stein ◽

Michael Fadell ◽

Sharon Funk ◽

...

Keyword(s):

Soft Tissue ◽

Factor Viii ◽

Board Of Directors ◽

Research Funding ◽

Hemophilia A ◽

Joint Damage ◽

Severe Hemophilia ◽

Advisory Committees ◽

Episodic Treatment ◽

Bayer Healthcare

Abstract Background: The Joint Outcome Study (JOS) was a randomized controlled trial showing that, in severe hemophilia A, prophylactic factor VIII every other day starting prior to age 30 months leads to better joint outcomes at age 6 years than enhanced episodic treatment with factor VIII for bleeding1. After conclusion of the JOS, all participants were encouraged to continue on, or to transition to, prophylaxis. Here we describe the results of the Joint Outcome Continuation Study (JOS-C), which followed the participants of the JOS to age 18 years. Methods: All participants of the JOS were eligible for the JOS-C. MRIs of 6 index joints (right and left ankles, knees, and elbows), index joint physical exam scores using the Colorado Haemophilia Paediatric Joint Physical Examination Scale2 , estimates of joint bleeding episodes, and surgery information were collected. The primary endpoint, as in the initial JOS analysis, was evidence of hemophilia-related osteochondral joint damage on MRI, scored using the extended MRI scale3. Results: Of the 65 previous participants of the JOS, 37 gave informed consent for the JOS-C study, including 18 initially randomized to prophylaxis prior to age 30 months ("early prophylaxis"), and 19 initially randomized to enhanced episodic treatment who started prophylaxis at a mean age of 7.5 years (median 6.1, range 2.7-17.1, "delayed prophylaxis"). All initially on prophylaxis in the JOS continued on prophylaxis through the JOS-C. One participant (early prophylaxis arm) failed to complete an MRI, and four others (2 early and 2 delayed prophylaxis) had their MRIs excluded for technical reasons. Four participants (3 early prophylaxis and 1 delayed prophylaxis) developed high titer inhibitors during or shortly after the JOS and were analyzed separately. Osteochondral joint damage was defined as evidence of osteochondral damage on MRI or a need for joint surgery. The relative risk of osteochondral damage in those on delayed prophylaxis as compared to those on early prophylaxis was 6.5 (95% CI 1.3, 33.6; p=0.029). At age 18, 67% of those on early prophylaxis, and only 24% of those on delayed prophylaxis had zero index joints with osteochondral damage (Figure 1). Twenty-five percent of early prophylaxis and 47% of delayed prophylaxis participants had osteochondral damage to more than one joint. Most participants had some soft tissue changes on MRI, defined as effusion, synovial hypertrophy, or hemosiderin deposition. There was no difference in risk of soft tissue damage between initial treatment groups (p=0.48). Osteochondral damage scores were available for 3 patients with inhibitors: two with refractory inhibitors had osteochondral changes on at least one joint, and one with an inhibitor that tolerized within 3 months had no osteochondral damage. Total physical exam scores were also higher in the delayed prophylaxis arm (mean 22.6, standard deviation (SD) 15.5) than in the early prophylaxis arm (mean 16.2, SD 10.5), but this difference was not statistically significant (p=0.19). Conclusion: The JOS-C demonstrates that, in severe hemophilia A, initiation of prophylaxis prior to age 30 months provides continued protection against joint damage throughout childhood. Those who started on prophylaxis later in childhood had higher risk of joint damage at age 18. Initiation of factor VIII prophylaxis in the toddler years is critical to preventing osteochondral joint damage and should not be delayed. ReferencesManco-Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med. 2007;357(6):535-544.Hacker MR, Funk SM, Manco-Johnson MJ. The Colorado Haemophilia Paediatric Joint Physical Examination Scale: normal values and interrater reliability. Haemophilia. 2007;13(1):71-78.Hong W, Raunig D, Lundin B. SPINART study: validation of the extended magnetic resonance imaging scale for evaluation of joint status in adult patients with severe haemophilia A using baseline data. Haemophilia. 2016;22(6):e519-e526. Figure 1: Percentage of participants with zero joints with osteochondral damage at JOS exit (age 6 years) and JOS-C exit (age 18 years), excluding participants with inhibitors. Disclosures Warren: Bayer Healthcare: Research Funding; HTRS/Novo Nordisk: Research Funding; Bayer Hemophilia Awards Program Fellowship Project Award: Research Funding; CSL Behring Heimburger Award: Research Funding. Shapiro:Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Prometic Life Sciences: Consultancy, Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Research Funding; Kedrion Biopharma: Consultancy, Research Funding; Bio Products Laboratory: Consultancy; Bioverativ, a Sanofi Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Healthcare: Other: International Network of Pediatric Hemophilia; Sangamo Biosciences: Consultancy; Octapharma: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; OPKO: Research Funding; BioMarin: Research Funding. Recht:Shire: Research Funding; Biogen: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Membership on an entity's Board of Directors or advisory committees. Manco-Johnson:Bayer AG: Honoraria, Research Funding; Novo Nordisk: Honoraria; Biogentek: Honoraria; CSL Behring: Honoraria; Baxalta, now part of Shire: Honoraria.

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

International Journal of Contemporary Pediatrics ◽

10.18203/2349-3291.ijcp20180575 ◽

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.

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

Blood ◽

10.1182/blood.v110.11.3968.3968 ◽

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.

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