Recombinant factor VIII Fc fusion protein for immune tolerance induction in patients with severe haemophilia A with inhibitors-A retrospective analysis.

INTRODUCTION: Immune tolerance induction (ITI) is the gold standard for eradication of factor VIII inhibitors in severe haemophilia A; however, it usually requires treatment for extended periods with associated high burden on patients and healthcare resources. AIM: Review outcomes of ITI with recombinant factor VIII Fc fusion protein (rFVIIIFc) in patients with severe haemophilia A and high-titre inhibitors. METHODS: Multicentre retrospective chart review of severe haemophilia A patients treated with rFVIIIFc for ITI. RESULTS: Of 19 patients, 7 were first-time ITI and 12 were rescue ITI. Of 7 first-time patients, 6 had at least 1 high-risk feature for ITI failure. Four of 7 first-time patients were tolerized in a median of 7.8 months. The remaining 3 patients continue on rFVIIIFc ITI. Of 12 rescue patients, 7 initially achieved a negative Bethesda titre (≤0.6) in a median of 3.3 months, 1 had a decrease in Bethesda titre and continues on rFVIIIFc ITI and 4 have not demonstrated a decrease in Bethesda titre. Of these 4, 3 continue on rFVIIIFc ITI and 1 switched to bypass therapy alone. Two initially responsive patients transitioned to other factors due to recurrence. Overall, 16 of 19 patients remain on rFVIIIFc (prophylaxis or ITI). For those still undergoing ITI, longer follow-up is needed to determine final outcomes. No adverse events reported. CONCLUSIONS: Recombinant factor VIII Fc fusion protein demonstrated rapid time to tolerization in high-risk first-time ITI patients. For rescue ITI, rFVIIIFc showed therapeutic benefit in some patients who previously failed ITI with other products. These findings highlight the need to further evaluate the use of rFVIIIFc for ITI.

Current prescription of prophylactic factor infusions and perceived adherence for children and adolescents with haemophilia: a survey of haemophilia healthcare professionals in the United States.

The primary goal of prophylaxis in patients with severe haemophilia is to convert the phenotype from severe to moderate and to prevent the development of chronic arthropathy. Prior studies have demonstrated that prophylaxis decreases episodes of joint bleeds and chronic arthropathy. Effectiveness depends on prescription of prophylaxis and adherence to the prescribed regimen. The aim of this study was to determine if prescription of prophylaxis for children with haemophilia and perceptions of adherence to prophylaxis have changed since publication of the Joint Outcome Study (JOS). A questionnaire was sent, in electronic and written formats, to health professionals who provide care to children with haemophilia at US haemophilia treatment centres (HTCs). The response rate was 56 of 128 (44%) of the targeted HTCs. There were a few missing data and denominators are provided. All responses agreed with the results of the JOS and 30/55 (55%) reported the JOS increased their prescription of prophylaxis. Nineteen of 56 (34%) physicians or HTC staff reported that they had not prescribed prophylaxis within the last year due to concerns about adherence, and 19/56 (34%) reported they had stopped prophylaxis due to concerns about adherence within the last year. Predicted adherence decreased with increasing age. Prescription of prophylaxis appears to be increasing since publication of the JOS. Strategies to improve adherence may increase the likelihood of physician prescription of prophylaxis and make prophylaxis easier to implement for individual patients, thereby improving the clinical outcome of children and adults with haemophilia.

Transition of care for pediatric and adult patients with venous thromboembolism: A National Quality Improvement Project from the American Thrombosis and Hemostasis Network (ATHN).

BACKGROUND: Transition of care (TOC) for management of anticoagulation from inpatient to outpatient setting for patients with acute venous thromboembolism (VTE) poses serious safety concerns. We implemented a national quality improvement educational initiative to address this issue. METHODS: Pediatric and adult patients admitted for their first VTE were prospectively enrolled at 16 centers from January 2016 to December 2018. Patient demographics, VTE diagnosis, risk factors, and treatment characteristics were collected. There were two phases: pre-intervention (PI) and quality intervention (QI). The PI phase assessed the quality and patient understanding and satisfaction of anticoagulation instructions given at hospital discharge and adherence to these instructions via a patient and/or caregiver feedback questionnaire (PFQ) and a patient knowledge questionnaire (PKQ) at 30 days. The QI phase provided patient and/or caregiver enhanced education regarding anticoagulation therapy and VTE at hospital discharge using a comprehensive discharge instruction module and a phone call follow-up at one week. Patient and/or caregiver knowledge at 7 and 30 days was assessed with the same PFQ and PKQ and compared to the PI baseline measures. RESULTS: Of the 409 study patients, 210 (51%) were adults, 218 (53%) females, and 316 (77%) White. Deep vein thrombosis (62.8%) and pulmonary embolism (47.9%) were the most common VTE in children and adults, respectively. Day 30 PFQ scores were significantly higher in the QI phase compared to the PI phase by 11% (p < 0.01). Day 30 PKQ demonstrated enhanced teaching (93.7% vs. 83.5%, p-value 0.004) and disease recognition (89.6% vs. 84.6% p = 0.03) in the QI phase than the PI phase. CONCLUSION: Comprehensive VTE discharge instructions followed by a 1-week post-discharge phone call strengthen patient and caregiver knowledge, satisfaction of education given and care provided, and disease recognition.

Physicians' perceptions of adherence to prophylactic clotting factor infusions.

The objective of this study was to investigate whether paediatric Haemophilia Treatment Centre (HTC) physicians are concerned about poor adherence to prophylaxis and if such concerns decrease prescription of prophylaxis in patients with haemophilia. Fifty-nine HTC physicians completed a written survey based on self-report of individual practice. Fifty-one (86%) prescribed prophylaxis on a routine basis. Overall, 32 (54%) believed that 76-100% of the patients on prophylaxis infuse > or =80% of the recommended prophylaxis doses and 25 (42%) believed that 51-75% of the patients infuse > or =80% of the doses. Physicians utilize multi-modal methods to make this assessment. Forty-eight (81%) respondents identified that perceptions of patient non-adherence decrease their prescription of prophylaxis. In fact, 30% decided not to prescribe prophylaxis for individual patients within the last year secondary to concerns about non-adherence. Strategies should be developed to improve the implementation of prophylaxis.

Recombinant activated factor VIIa treatment for refractory hemorrhage in infants.

OBJECTIVE: Report clinical response to recombinant factor VIIa in a cohort of critically ill infants. STUDY DESIGN: We identified all infants who received factor VIIa in the Duke Neonatal Intensive Care Unit between January 2005 and July 2008. Hematological data and volume of blood transfusions before and after factor VIIa treatment were compared. The precipitating diagnosis for each factor VIIa use, and the ensuing clinical outcomes of bleeding, thrombosis and mortality were noted. RESULT: We identified 18 infants with median birth weight of 880 g and median gestational age of 26 weeks. One to six doses of factor VIIa (90 mcg kg(-1) per dose) were administered, with 13 (72%) infants receiving a single dose. Hemostasis was achieved in 13 (72%) of the infants. Prothrombin time and activated partial thromboplastin time significantly decreased following treatment with factor VIIa. Volume of plasma transfusions significantly decreased following treatment with factor VIIa (P=0.02). Thrombosis occurred in one (11%) infant. Six (33%) infants died within 72 h of treatment, and overall mortality was 10/18 (56%). CONCLUSION: Treatment with factor VIIa at doses of 90 mcg kg(-1) improved coagulation studies and decreased the need for plasma transfusions in a group of critically ill infants without significant risk. Factor VIIa may be an effective addition to current treatment modalities for refractory hemorrhage in infants.

The utility of the autohaemolysis test for children with congenital haemolytic anaemia.

Autohaemolysis testing can assist the evaluation of haemolytic anaemia, but involves a cumbersome assay that is difficult to perform accurately. Because this test persists in clinical practice without clear indications or guidelines, we retrospectively reviewed our experience with autohaemolysis testing for children with suspected congenital haemolytic anaemia. Over 12 years, autohaemolysis without glucose was elevated for 38 of 39 children with congenital spherocytosis, while glucose corrected or reduced autohaemolysis in 33 of these patients. Autohaemolysis was elevated only once among seven other cases (four with congenital nonspherocytic haemolytic anaemia and three normal siblings). In three cases of congenital spherocytosis with equivocal osmotic fragility, autohaemolysis was abnormal and corrected with glucose in two. In our experience, autohaemolysis testing was helpful diagnostically in only two of 54 cases, so has only limited utility as a routine test for children with suspected congenital haemolytic anaemia.

An infant with homozygous hemoglobin D-Iran.

Hemoglobin D-Iran (Hb D-Iran, beta 22 Glu-->Gln) is a beta-chain variant that was first described in 1973. Hb D-Iran in combination with normal Hb A (Hb D-Iran trait) is a benign condition. Hb D-Iran has also been described in combination with sickle hemoglobin and beta thalassemia, but never as a homozygous mutation. The authors describe a case of homozygous Hb D-Iran in an infant of Pakistani descent. The hematologic values, hemoglobin electrophoresis, peripheral blood smear, and clinical course to date suggest that homozygous Hb D-Iran is a relatively benign condition with mild microcytic anemia, poikilocytosis, and minimal hemolysis.