Development of inhibitory antibodies to coagulation factor VIII (fVIII) is the primary obstacle to the treatment of hemophilia A in the developed world. This adverse reaction occurs in 20-30% of persons with severe hemophilia A treated with fVIII-replacement products and is characterized by the development of a humoral and neutralizing immune response to fVIII. Patients with inhibitory anti-fVIII antibodies are treated with bypassing agents including recombinant factor VIIa (rfVIIa). However, some patients display poor hemostatic response to bypass therapy and improved treatment options are needed. Recently, we demonstrated that fVIII inhibitors display widely variable kinetics of inhibition that correlate with their respective target epitopes. Thus, it was hypothesized that for antibodies that display slow rates of inhibition, supplementation of rfVIIa with fVIII would result in improved thrombin generation and be predictive of clinical responses to this novel treatment regimen. In order to test this hypothesis, 10 murine monoclonal antibodies (MAbs) with non-overlapping epitopes spanning fVIII, differential inhibition titers, and inhibition kinetics were studied using a thrombin generation assay. Of the 3 MAbs with high inhibitory titers, only the one with fast and complete (classically defined as "type I") kinetics displayed significant inhibition of thrombin generation with no improvement upon supplementation of rfVIIa with fVIII. The other two MAbs that displayed incomplete (classically defined as "type II") inhibition did not suppress the potentiation of thrombin generation by fVIII. All antibodies that did not completely inhibit fVIII activity demonstrated potentiation of thrombin generation by the addition of fVIII as compared to rfVIIa alone. In conclusion, fVIII alone or in combination with rfVIIa corrects the thrombin generation defect produced by the majority of anti-fVIII MAbs better than single agent rfVIIa. Therefore, combined fVIII/rfVIIa therapy may provide better hemostatic control than current therapy in some patients with anti-fVIII inhibitors.
Introduction: Haemophilia A is an X-linked recessive bleeding disorder that primarily affects males. Emerging data support evidence for increased bleeding in female haemophilia A carriers despite factor VIII activity within the normal range.
Aim: Data regarding the effect of increased bleeding on health-related quality of life (HR-QOL) in haemophilia A carriers is sparse. We tested the hypothesis that haemophilia A carriers have reduced HR-QOL related to bleeding symptoms.
Methods: We conducted a cross-sectional study at Vanderbilt University. Case subjects were obligate or genetically verified haemophilia A carriers age 18 to 60 years. Control subjects were mothers of children with cancer who receive care at the Vanderbilt pediatric hematology-oncology clinic. Trained interviewers administered the Rand 36-Item Health Survey 1.0, a validated questionnaire evaluating eight health concepts that may affect HR-QOL, to each study participant. Mann-Whitney U tests were used to compare median scores for the eight health domains between the case and control groups.
Result: Forty-two haemophilia A carriers and 36 control subjects were included in analyses. Haemophilia A carriers had significantly lower median scores for the domains of “Pain” (73.75 versus 90; p= 0.02) and “General health” (75 versus 85; p= 0.01) compared to control subjects.
Conclusion: Haemophilia A carriers in our study demonstrated significantly lower median scores on the Rand 36-item Health Survey 1.0 in the domains of “Pain” and “General Health” compared to women in the control group. Our findings highlight the need for further investigation of the effect of bleeding on HR-QOL in this population.
by
Maria Elisa Mancuso;
Johnny Mahlangu;
Robert Sidonio Jr;
Peter Trask;
Marianne Uguen;
Tiffany Chang;
Midori Shima;
Guy Young;
Johannes Oldenburg;
Sylvia von Mackensen
Introduction
Persons with haemophilia A (PwHA) with factor (F)VIII inhibitors, including children, have impaired health‐related quality of life (HRQoL). The HAVEN 2 study (NCT027955767) of paediatric PwHA with FVIII inhibitors demonstrated that subcutaneous emicizumab prophylaxis resulted in low annualizedbleed rates.
Aim
We assessed the impact of emicizumab prophylaxis on the HRQoL of children and their caregivers participating in HAVEN 2.
Methods
Children aged 8‐11 years self‐reported HRQoL using the Haemophilia‐Specific Quality of Life Assessment Instrument for Children and Adolescents Short Form (Haemo‐QoL SF II). Caregivers of children aged 0‐11 years completed the Adapted Inhibitor‐Specific Quality of Life Assessment with Aspects of Caregiver Burden. All scores were transformed to a 0‐100 scale, where lower scores reflect a better HRQoL. The number of missed days from school/day care and hospitalizations was also recorded.
Results
In HAVEN 2 (n = 88), the median age was 6.5 years (range: 1‐15 years); 85 participants were aged < 12 years and included in this analysis, and 34 participants were aged 8‐11 years, thereby eligible to complete the Haemo‐QoL SF II questionnaire. The mean (standard deviation, n) baseline Haemo‐QoL SF II ‘Total’ score was 30.2 (14.9, 30), indicating moderate impairment; with emicizumab, mean score decreased by −9.62 (7.73, 17) points to 23.0 (13.93, 20) by Week 49. The most improved domains were ‘Sports & School’ and ‘Physical Health’. Caregivers reported similar improvements.
Conclusion
Prophylactic emicizumab is accompanied by substantial and sustained improvements in HRQoL of paediatric PwHA with FVIII inhibitors and their caregivers.
by
Rachael F. Grace;
Jenny M. Despotovic;
Carolyn Bennett;
James B. Bussel;
Michelle Neier;
Cindy Neunert;
Shelley E. Crary;
Yves D. Pastore;
Robert J. Klaassen;
Jennifer A. Rothman;
Kerry Hege;
Vicky R. Breakey;
Melissa J. Rose;
Kristen A. Shimano;
George R. Buchanan;
Amy Geddis;
Kristina M. Haley;
Adonis Lorenzana;
Alexis Thompson;
Michael Jeng;
Ellis J. Neufeld;
Travis Brown;
Peter W. Forbes;
Michele P. Lambert
Immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder which presents with isolated thrombocytopenia and risk of hemorrhage. While most children with ITP promptly recover with or without drug therapy, ITP is persistent or chronic in others. When needed, how to select second-line therapies is not clear. ICON1, conducted within the Pediatric ITP Consortium of North America (ICON), is a prospective, observational, longitudinal cohort study of 120 children from 21 centers starting second-line treatments for ITP which examined treatment decisions. Treating physicians reported reasons for selecting therapies, ranking the top three. In a propensity weighted model, the most important factors were patient/parental preference (53%) and treatment-related factors: side effect profile (58%), long-term toxicity (54%), ease of administration (46%), possibility of remission (45%), and perceived efficacy (30%). Physician, health system, and clinical factors rarely influenced decision-making. Patient/parent preferences were selected as reasons more often in chronic ITP (85.7%) than in newly diagnosed (0%) or persistent ITP (14.3%, P =.003). Splenectomy and rituximab were chosen for the possibility of inducing long-term remission (P <.001). Oral agents, such as eltrombopag and immunosuppressants, were chosen for ease of administration and expected adherence (P <.001). Physicians chose rituximab in patients with lower expected adherence (P =.017). Treatment choice showed some physician and treatment center bias. This study illustrates the complexity and many factors involved in decision-making in selecting second-line ITP treatments, given the absence of comparative trials. It highlights shared decision-making and the need for well-conducted, comparative effectiveness studies to allow for informed discussion between patients and clinicians.
Introduction:
In the network of U.S. comprehensive haemophilia treatment centres (HTCs), von Willebrand disease (VWD) is the most common bleeding disorder other than haemophilia. Estimates of the size and characteristics of the VWD population receiving treatment are useful for healthcare planning.
Aim:
Estimate the prevalence and incidence of VWD among males and females receiving care at U.S. HTCs (HTC-treated prevalence and incidence).
Methods:
During the period 2012–2019, de-identified surveillance data were collected on all VWD patients who visited an HTC including year of birth, sex, race, Hispanic ethnicity, VWD type, and laboratory findings and used to calculate period HTC-treated prevalence by VWD type and sex. Data from patients born 1995–1999 were used to estimate HTC-treated incidence rates.
Results:
During the period, 24,238 patients with a diagnosis of VWD attended HTCs; for 23,479 (96.9%), VWD type was reported or could be assigned. Age-adjusted HTC-treated prevalence was 8.6 cases/100,000 (7.2/100,000 for Type 1, 1.2/100,000 for Type 2 and 1.7/million for Type 3) and was twice as high in women as men (4.8 vs. 2.4 cases/100,000) for Type 1 and similar by sex for Type 2 and Type 3. HTC-treated Type 1 incidence increased over the period, averaging nearly threefold higher for women than men (26.2 vs. 9.9/100,000 live births). Sex differences were less for Type 2 (2.2 vs. 1.4 cases/100,000 births) and slight in Type 3.
Conclusion:
Prevalence and incidence of HTC-treated VWD differ by sex and type and are likely strongly influenced by differences in rates of diagnosis.
Summary
Objective
The pathogenicity of anti-human fVIII monoclonal antibodies (MAbs) was tested in a murine bleeding model.
Methods
MAbs were injected into the tail veins of hemophilia A mice to a peak plasma concentration of 60 nM, followed by injection of human B domain-deleted factor VIII (fVIII) at 180 U/kg, producing peak plasma concentrations of ∼2 nM. At 2 hours, blood loss following a 4 mm tail snip was measured. The following MAbs were tested: 1) 4A4, a type I anti-A2 fVIII inhibitor, 2) I54 and 1B5, classical type I anti-C2 inhibitors, 3) 2-77 and B45, non-classical type II anti-C2 inhibitors, and 4) 2-117, a non-classical anti-C2 MAb with inhibitory activity less than 0.4 Bethesda Units/mg IgG.
Results
All MAbs except 2-117 produced similar amounts of blood loss that were significantly greater than control mice injected with fVIII alone. Increasing the dose of fVIII to 360 U/kg overcame the bleeding diathesis produced by the type II MAbs 2-77 and B45, but not the type I antibodies, 4A4, I54, and 1B5. These results were consistent with the in vitro Bethesda assay in which 4A4 completely inhibited both 1 U/ml and 3 U/ml fVIII, while there was 40% residual activity at saturating concentrations of 2-77 at either concentration of fVIII.
Conclusions
For patients with an inhibitor response dominated by non-classical anti-C2 antibodies both the in vivo and in vitro results suggest that treatment with high-dose fVIII rather than bypassing agents may be warranted.