The role of point-of-Care Musculoskeletal Ultrasound for Routine Joint evaluation and management in the Hemophilia Clinic - A Real World Experience.

BACKGROUND: The use of musculoskeletal ultrasound (MSKUS) for point-of-care (POC) evaluation of hemophilic arthropathy is growing rapidly. However, the extent to which MSKUS influences clinical treatment decisions is unknown. METHODS: We conducted a three-year, prospective, multi-center study at three hemophilia treatment centers in the United States to evaluate the utilization of POC-MSKUS for routine clinical decision-making in adult persons with hemophilic arthropathy. Bilateral elbows, knees and ankles were assessed clinically [Hemophilia Joint Health Score (HJHS)] and with POC-MSKUS by the Joint TissueActivity and Damage Exam (JADE) protocol at baseline and approximately annually for two additional times. Treatment decisions, including physical therapy (PT) and "medical" (joint injections/aspirations, referrals to orthopedics, changes/adjustments of hemostatic plans, and use of oral anti-inflammatory medications) were recorded in relation to POC-MSKUS. RESULTS: Forty-four persons [median age 37 years (IQR 29, 51)], mostly with severe Hemophilia A on clotting factor prophylaxis, completed 129 visits, yielding 792 joint exams by POC-MSKUS and HJHS [median at baseline 27 (IQR 18, 42)] over a median follow up of 584 days (range: 363 to 1072). Among 157 management decisions, 70% were related to PT plans (n = 110) and 30% were "medical". Point-of-care MSKUS influenced 47/110 (43%) PT plans, mostly informing treatment of specific arthropathic joints (45/47 plans) in patients with high HJHS. Physical therapy plans influenced by POC-MSKUS directed more manual therapy/therapeutic exercises, while plans based on physical exam were focused more on global exercises and wellness. Treatment decisions were mostly based on the identification of specific musculoskeletal abnormalities visualized by POC-MSKUS. Of note 20/47 (43%) POC-MSKUS plans included de-escalation strategies, thereby reducing exercise intensity, mostly for joint instability and subclinical hemarthroses. Point-of-care MSKUS also informed 68% (32/47) of "medical" decisions, surprisingly mostly for injections/aspirations and referrals to orthopedics, and not for adjustments of hemostatic treatment. Although not formally studied, ultrasound images were used frequently for patient education. CONCLUSION: Routine joint evaluations with POC-MSKUS resulted in few changes regarding medical management decisions but had a profound effect on the formulation of PT plans. Based on these findings, new studies are essential to determine the benefit of MSKUS-informed management plans on joint health outcomes.

Alternative therapies for the management of inhibitors.

The development of inhibitors to factor VIII (FVIII) or factor IX (FIX) remains a major treatment complication encountered in the treatment of haemophilia. Not all patients with even the same severity and genotype develop inhibitors suggesting an underlying mechanism of tolerance against FVIII- or FIX-related immunity. One mechanism may be central tolerance observed in patients in whom the FVIII mutation enables some production of the protein. The other is a peripheral tolerance mechanism which may be evident in patients with null mutation. Recently, recombinant porcine FVIII (rpFVIII, Obixur, OBI-1, BAX801) has been developed for the haemostatic treatment of both congenital haemophilia with inhibitor (CHAWI) and acquired haemophilia A (AHA). In 28 subjects with AHA with life-/limb-threatening bleeding, rpFVIII reduced or stopped bleeding in all patients within 24 h. The cross-reactivity of anti-human FVIII antibodies to rpFVIII remains around 30-50%. Recently, new therapeutics based on the quite novel concepts have been developed and clinical studies are ongoing. These are humanized asymmetric antibody mimicking FVIIIa function by maintaining a suitable interaction between FIXa and FX (Emicizumab, ACE910), and small interfering RNAs (siRNA, ALN-AT3) suppress liver production of AT through post-transcriptional gene silencing and a humanized anti-TFPI monoclonal antibody (Concizumab). Their main advantages are longer half-life, subcutaneous applicability and efficacy irrespective of the presence of inhibitors which will make it easier to initiate more effective treatment especially early childhood.

Inhibitor recurrence after immune tolerance induction: a multicenter retrospective cohort study.

BACKGROUND: Immune tolerance induction (ITI) in patients with congenital hemophilia A is successful in up to 70%. Although there is growing understanding of predictors of response to ITI, the probability and predictors of inhibitor recurrence after successful ITI are not well understood. OBJECTIVES: To determine the association of clinical characteristics, particularly adherence to factor VIII (FVIII) prophylaxis after ITI, with inhibitor recurrence in patients with hemophilia A who were considered tolerant after ITI. METHODS: In this multicenter retrospective cohort study, 64 subjects with FVIII level < 2% who were considered successfully tolerant after ITI were analyzed to estimate the cumulative probability of inhibitor recurrence using the Kaplan-Meier method. The association of clinical characteristics with inhibitor recurrence was assessed using logistic regression. RESULTS: A recurrent inhibitor titer ≥ 0.6 BU mL(-1) occurred at least once in 19 (29.7%) and more than once in 12 (18.8%). The probability of any recurrent inhibitor at 1 and 5 years was 12.8% and 32.5%, respectively. Having a recurrent inhibitor was associated with having received immune modulation during ITI (odds ratio [OR] 3.8, 95% confidence interval [CI] 1.2-22.4) and FVIII recovery of < 85% at the end of ITI (OR 2.6, 95% CI 1.3-5.9) but was not associated with adherence to post-ITI prophylactic FVIII infusion (OR 0.5, 95% CI 0.06-4.3). CONCLUSIONS: The use of immune modulation therapy during ITI and lower FVIII recovery at the end of ITI appear to be associated with an increased risk of inhibitor recurrence after successful ITI. Adherence to post-ITI prophylactic FVIII infusions is not a major determinant of recurrence.

US Guidelines for immune tolerance induction in patients with haemophilia a and inhibitors.

INTRODUCTION: The development of anti-factor VIII (FVIII) antibodies (inhibitors) is the most serious treatment-related complication in patients with hemophilia A, rendering standard replacement therapy ineffective, heightening the risk for uncontrollable bleeding and morbidity, decreasing quality of life, and increasing healthcare costs. AIM: Formulate evidence-based guidelines for optimizing immune tolerance induction (ITI) in patients with hemophilia A and inhibitors. METHODS: Results from the International ITI study and other available evidence were used to develop guidelines for ITI. RESULTS: Predictors of ITI success were identified and recommendations made for ITI with regard to candidates, timing, product, regimen, monitoring, defining success, concurrent immunomodulation, duration of treatment, and bleed management before and during ITI. CONCLUSION: Evidence-based recommendations to guide treatment decisions may increase the likelihood of successful inhibitor eradication and the induction of FVIII tolerance in patients with hemophilia A who develop inhibitory antibodies.

Presentation and management of acute coronary syndromes among adult persons with haemophilia: results of an international, retrospective, 10-year survey.

Sparse data are available on presentation and management of acute coronary syndromes (ACS), including unstable angina and non-ST- and ST-elevation myocardial infarction, among persons with haemophilia (PWH). The aim of this study was to determine demographics, bleeding disorder characteristics, cardiovascular risk factors (CRFs), interventions, haemostatic protocol, revascularization outcomes and complications among PWH with ACS. Members of an international consortium comprising >2000 adult PWH retrospectively completed case report forms for episodes of ACS in a >10-year follow-up period (2003-2013). Twenty ACS episodes occurred among 19 patients [rate, 0.8% (95% CI 0.4, 1.2)]. Seven patients (37%) were aged <50 years; 10 (53%) had ≥3 CRFs. In 5/20 episodes (25%), the initial ACS management protocol was altered because of the bleeding disorder. None of the eight patients with severe haemophilia underwent coronary artery bypass grafting (CABG), compared with 54.5% of patients with non-severe disease (P = 0.02). Revascularization with percutaneous coronary intervention (PCI) or CABG was rated successful in 13/13 cases, with no excessive bleeding during initial management. During chronic exposure to antiplatelet agents, secondary haemophilia prophylaxis was more prevalent in patients with severe haemophilia compared with non-severe haemophilia (85.7% vs. 30%, P = 0.05). No ACS-related deaths occurred during initial management, but one patient with severe haemophilia A died of undetermined cause 36 months after the ACS event while on aspirin therapy. ACS occurs even among relatively younger PWH, typically in association with multiple CRFs. Revascularization with PCI/CABG is feasible, and antiplatelet agents plus secondary prophylaxis appears to be well tolerated in selected PWH with ACS.

Efficacy and safety of OBI-1, an antihaemophilic factor VIII (recombinant), porcine sequence, in subjects with acquired haemophilia A.

Acquired haemophilia A (AHA) is a rare bleeding disorder caused by autoantibodies against human factor VIII (hFVIII). OBI-1 is an investigational, B-domain deleted, recombinant FVIII, porcine sequence, with low cross-reactivity to anti-hFVIII antibodies. Efficacy can be monitored with FVIII activity levels in addition to clinical assessments. This prospective, open label, phase 2/3 study was designed to evaluate the efficacy of OBI-1 treatment for bleeding episodes in subjects with AHA. After an initial dose of 200 U kg(-1) , OBI-1 was titrated to maintain target FVIII activity levels, in correlation with clinical assessments, throughout the treatment phase. All 28 subjects with AHA had a positive response to OBI-1 treatment 24 h after initiation despite inhibition of FVIII activity levels immediately after infusion in 10 subjects with baseline anti-porcine FVIII inhibitors. Control of the qualifying bleed was ultimately achieved in 24 of 28 subjects. No related serious adverse events, thrombotic events, allergic reactions or thrombocytopaenia occurred. The results of this study indicate that OBI-1 is safe and effective in treating bleeding episodes in subjects with AHA. The ability to safely and effectively titrate dosing based on FVIII activity levels in this study demonstrates that OBI-1 fulfils the unmet medical need to monitor the key coagulation parameter in AHA patients.

Rituximab for treatment of inhibitors in haemophilia A. A Phase II study.

The development of antibodies against infused factor VIII (FVIII) in patients with haemophilia A is a serious complication leading to poorly controlled bleeding and increased morbidity. No treatment has been proven to reduce high titre antibodies in patients who fail immune tolerance induction or are not candidates for it. The Rituximab for the Treatment of Inhibitors in Congenital Hemophilia A (RICH) study was a phase II trial to assess whether rituximab can reduce anamnestic FVIII antibody (inhibitor) titres. Male subjects with severe congenital haemophilia A and an inhibitor titre ≥5 Bethesda Units/ml (BU) following a FVIII challenge infusion received rituximab 375 mg/m² weekly for weeks 1 through 4. Post-rituximab inhibitor titres were measured monthly from week 6 through week 22 to assess treatment response. Of 16 subjects who received at least one dose of rituximab, three (18.8%) met the criteria for a major response, defined as a fall in inhibitor titre to <5 BU, persisting after FVIII re-challenge. One subject had a minor response, defined as a fall in inhibitor titre to <5 BU, increasing to 5-10 BU after FVIII re-challenge, but <50% of the original peak inhibitor titre. Rituximab is useful in lowering inhibitor levels in patients, but its effect as a solo treatment strategy is modest. Future studies are indicated to determine the role of rituximab as an adjunctive therapy in immune tolerisation strategies.

Prevalence and risk factors for hypertension in hemophilia.

Hypertension (HTN) is a major risk factor for intracranial hemorrhage. We, therefore, investigated the prevalence, treatment, and control of HTN in adult patients with hemophilia (PWH). PWH≥18 years (n=458) from 3 geographically different cohorts in the United States were evaluated retrospectively for HTN and risk factors. Results were compared with the nationally representative sample provided by the contemporary National Health and Nutrition Examination Survey (NHANES). PWH had a significantly higher prevalence of HTN compared with NHANES. Overall, the prevalence of HTN was 49.1% in PWH compared with 31.7% in NHANES. At ages 18 to 44, 45 to 64, 65 to 74, and ≥75 years, the prevalence of HTN for PWH was 31.8%, 72.6%, 89.7%, and 100.0% compared with 12.5%, 41.2%, 64.1%, and 71.7% in NHANES, respectively. Of treated hypertensive PWH, only 27.1% were controlled, compared with 47.7% in NHANES (all P<0.05). Age, body mass index, diabetes mellitus, and renal function were independently associated with HTN. Among patients with moderate or severe hemophilia there was a trend (≈1.5-fold) for higher odds of having HTN compared with patients with mild hemophilia. On the basis of these results, new care models for adult PWH and further studies for the causes of HTN in hemophilia are recommended.

Inhibitors: our greatest challenge. Can we minimize the incidence?

Development of alloantibodies against infused factor VIII (FVIII) is the most significant complication of haemophilia care today. Antibodies inactivate the procoagulant activity of FVIII and inhibit patients' response to replacement therapy. As inhibitors tend to develop early in the course of FVIII treatment, the challenge is to bring patients through the critical early phase of FVIII exposure without inhibitor development as the subsequent risk is much lower. Disease severity, major FVIII gene defects, family history and non-Caucasian race are major risk factors for inhibitor development. Other variables thought to play a role in inhibitor formation include age at first treatment, intensity of early treatment, use of prophylaxis and product choice [especially recombinant vs. plasma-derived von Willebrand factor (VWF)-containing concentrates]. As these treatment-related variables are modifiable, they provide opportunity to minimize inhibitor incidence at the clinical level. At present, most data regarding inhibitor development derive from retrospective studies, registry reviews, small case series and uncontrolled studies. Findings have often been conflicting, which precludes drawing definitive conclusions. Nevertheless, some clarity is beginning to emerge. Intensity of early treatment appears to be a stronger risk factor for inhibitor development than timing of first treatment. Controlled early antigen presentation via prophylaxis looks promising, particularly in conjunction with strategies to avoid immunological danger signals, but the timing of introduction and optimal regimen are not yet known. Several reports suggest that plasma-derived VWF-containing FVIII concentrates are less immunogenic than recombinant or VWF-free plasma-derived concentrates, but this is awaiting confirmation in the ongoing prospective Survey of Inhibitors in Plasma-Product Exposed Toddlers study.

Management of bleeding disorders in the elderly.

We are entering a new phase in the management of patients with bleeding disorders such as haemophilia. This is the result of the positive effects that disease management strategies have had on patient longevity over the last 10-15 years. A greater number of individuals are entering middle- to old-age and, as a result, we face a new era of having to manage haemophiliac patients at risk of, or suffering from, age-related diseases. We can clearly learn from the experiences of geriatricians who have made many advances in the management of chronic disorders such as cardiovascular diseases and osteoporosis. However, the hypocoagulable state brings challenges of its own and it is important that we communicate our experiences so that the shared information can help drive improved levels of care and better clinical outcomes. In this article we look at factors that have impacted the life expectancy of patients with haemophilia over the last few decades, and we also review some of the early literature relating to cardiovascular risk management and the treatment of osteoporosis.

Outcomes of mentored, grant-funded fellowship training in haemostasis /thrombosis: findings from a nested case-control survey study.

Successful strategies by which to effectively recruit and retain academic subspecialists in benign haematology have not been established. To evaluate the effectiveness of a grant-funded, mentored fellowship with respect to retention and early career goals in haemostasis/thrombosis, we sought to compare outcomes for graduates of a grant-funded, mentored fellowship training programme in haemostasis/thrombosis [the National Hemophilia Foundation (NHF)-Baxter Clinical Fellowship Award] during conventional haematology/oncology fellowship training (cases), vs. their training peers who were graduates of conventional haematology/oncology fellowship training alone (controls), via a nested case-control survey study. Survey response rate was 85% (11/13) for cases and 90% (9/10) for controls. All respondents had pursued careers in academic haematology/oncology. Median (range) percent time spent in benign haematology postfellowship was 98% (70-100%) for cases vs. 0% (0-20%) for controls. Time spent in research was significantly greater among cases than controls (median 80% [range: 42-90%] vs. 55% [10-80%], respectively; P = 0.01). By years 3-4 postfellowship, median annual number of peer-reviewed publications was higher for cases than controls (3.5 vs. 1.0; P = 0.01). Cases were also more successful in grant funding (including K-awards). These data suggest that a grant-funded, mentored fellowship training programme in haemostasis/thrombosis may be superior to conventional haematology/oncology fellowship training alone with respect to outcomes of retention in clinical care/research, early-career grant funding and publication productivity.

Inhibitor development and successful immune tolerance in an HIV-infected patient with haemophilia A and after immune reconstitution with HAART.

This is the case of a 28-year-old man with severe congenital haemophilia A, who had a relatively mild bleeding course during early childhood, with limited factor VIII (FVIII) exposure. He was infected with HIV before the age of 7 years, and demonstrated profound immunodeficiency from childhood, with very low CD4+ cell counts for more than a decade. Following initiation of highly active anti-retroviral therapy (HAART) and gradually increasing CD4+ cells, he presented for the first time with a high-titre inhibitor at age 26, despite over 1000 previous FVIII exposures. Subsequently, his inhibitor was successfully eradicated with a standard immune tolerance protocol. It is likely that the effects of chronic HIV infection on T-lymphocyte pathways, and the partial immune reconstitution resulting from HAART, led to this patient's unusual inhibitor course. Such a case serves to augment knowledge gained in animal studies about the immunobiology of FVIII inhibitors.