Recombinant porcine sequence factor VIII (rpFVIII) for acquired haemophilia A: practical clinical experience of its use in seven patients.

INTRODUCTION: A recombinant porcine factor VIII B-domain-deleted product (rpFVIII; OBIZUR, Baxalta Incorporated, Deerfield, IL 60015, USA) was recently approved for treatment of bleeding episodes in adults with acquired haemophilia A (AHA) in the United States. To date, no clinical experience outside the registration study has been reported. AIM: To describe early clinical experience using rpFVIII for AHA. METHODS: A retrospective chart review of seven patients with AHA treated with rpFVIII at four institutions from November 2014 to October 2015. RESULTS: The time to diagnosis of AHA ranged from 5 days to 6 weeks. Six major and one other bleed were treated with rpFVIII following unsatisfactory bypassing agent (BPA) therapy. Good haemostatic efficacy was seen in five of seven cases. rpFVIII loading doses of 100 (n = 6) or 200 U kg-1 (n = 1) increased FVIII activity from <1 to 9% at baseline to 109-650% within 0.25-7 h in six of seven cases. Subsequent median doses ranged from 30 to 100 U kg-1 for 3-26 days. No rpFVIII-related adverse events were reported. Three patients survived with inhibitor eradication, one with persistent inhibitor, two died with inhibitors present and one was discharged and later died from unrelated causes. CONCLUSIONS: rpFVIII showed good haemostatic efficacy with no recurrences in most cases, with consumption substantially less than in the registration study. Treatment decisions were based on FVIII activity levels and clinical assessment. The ability to titrate rpFVIII dose using FVIII activity was considered advantageous compared with BPA therapy. Notable delays in diagnosis were observed.

Radionuclide synovectomy/synoviorthesis (RS) in patients with bleeding disorders: A review of patient and procedure demographics and functional outcomes in the ATHNdataset.

INTRODUCTION: Radionuclide synovectomy/synoviorthesis (RS) to manage proliferative synovitis in persons with bleeding disorders has been utilized for decades; however, aggregate US results are limited. AIM: To determine the prevalence of RS utilization, patient and procedure related demographics and functional outcomes in United States haemophilia treatment centres (HTCs). The ATHNdataset includes US patients with bleeding disorders who have authorized the sharing of their demographic and clinical information for research. METHODS: We performed a multi-institutional, observational cohort study utilizing this dataset through 2010. Cases treated with RS procedure were compared to controls within the dataset. Standard template for data collection included patient and procedure related demographics as well as functional outcomes including range of motion (ROM) of the affected joint. Normative age- and sex-matched control ROM was obtained from published data. RESULTS: In the ATHNdataset there were 19 539 control-patients and 196 case-patients treated with RS. Patients with severe haemophilia were more likely to have had RS compared to those with mild/moderate haemophilia, although the proportion of RS performed was similar between severe HA and HB. Inhibitory antibodies, HIV and hepatitis C infection were significantly more common in cases. There were 362 RS procedures captured with 94 cases having >1 RS procedures. CONCLUSIONS: Right-sided joint procedures were more prevalent than left-sided procedures. Overall, case-patients had worse joint ROM compared to control-patients and published normative values. Geographically, there was regional variation in RS utilization, as the Southeast region had the largest percent of case-patients.

The impact of the economic downturn and health care reform on treatment decisions for haemophilia A: patient, caregiver and health care provider perspectives.

Little is known about the impact of the recent US economic downturn and health care reform on patient, caregiver and health care provider (HCP) decision-making for haemophilia A. To explore the impact of the recent economic downturn and perceived impact of health care reform on haemophilia A treatment decisions from patient, caregiver and HCP perspectives. Patients/caregivers and HCPs completed a self-administered survey in 2011. Survey participants were asked about demographics, the impact of the recent economic downturn and health care reform provisions on their treatment decisions. Seventy three of the 134 (54%) patients/caregivers and 39 of 48 (81%) HCPs indicated that the economic downturn negatively impacted haemophilia care. Seventy of the 73 negatively impacted patients made financially related treatment modifications, including delaying/cancelling routine health care visit, skipping doses and/or skipping filling prescription. Treatment modifications made by HCPs included delaying elective surgery, switching from higher to lower priced product, switching from recombinant to plasma-derived products and delaying prophylaxis. Health care reform was generally perceived as positive. Due to the elimination of lifetime caps, 30 of 134 patients (22%) and 28 of 48 HCPs (58%) indicated that they will make treatment modifications by initiating prophylaxis or scheduling routine appointment/surgery sooner. Both patients/caregivers and HCPs reported that the economic downturn had a negative impact on haemophilia A treatment. Suboptimal treatment modifications were made due to the economic downturn. Health care reform, especially the elimination of lifetime caps, was perceived as positive for haemophilia A treatment and as a potential avenue for contributing to more optimal treatment behaviours.

Healthcare resource utilization among haemophilia A patients in the United States.

Advances in therapy have improved life expectancy and quality of life of patients with haemophilia A. Due to the chronic and complex management of this disease, particularly, the development of inhibitors, little is known about their health resource utilization in the real-life setting over time. The aim was to assess the distribution and trend of healthcare resource utilization among US haemophilia A patients with and without inhibitors. The MarketScan® Database, was queried to identify individuals with ≥1 year continuous enrolment, two medical diagnoses of haemophilia A and claims for factor VIII or bypassing agent (to infer inhibitor status) during 2001-2007. Haemophilia-related cost was estimated from inpatient, outpatient and pharmacy claims. Annual cost differences were assessed by age and over a 4-year period for those with continuous enrolment. Among 51 million covered lives, 1044 haemophilia patients were identified, of whom 981 (94%; mean age = 21.2 years) did not have an inhibitor. The median haemophilia-related cost for these patients was $63,935 per patient per year. When normalized by weight, annual cost was stable (no statistically significant differences) among 312 non-inhibitor patients (mean age = 21.8 years) with 4-year continuous data. While there was a wide distribution of haemophilia-related cost among the 63 individuals with an inhibitor (mean age = 15.4 years), only 0.6% of the total haemophilia patients had costs exceeding $1 million per patient per year. This study indicated that most haemophilia A patients were inhibitor-free with relatively stable annual costs over time. There was a wide distribution of haemophilia-related cost for inhibitor patients, while the proportion of patients who incurred extreme high cost was low.

Pilot dose-finding and safety study of bivalirudin in infants <6 months of age with thrombosis.

BACKGROUND: Thrombosis is not uncommon in children with serious medical conditions. Unfractionated heparin, the most commonly used anticoagulant in the acute management of thrombosis, has significant pharmacologic limitations, especially in infants. Newer anticoagulants have improved properties relative to heparin, and this may enhance the outcome in children. OBJECTIVE: To determine dosing, and to assess the safety and efficacy of bivairudin for infants with thrombosis. METHODS: Infants <6 months old were chosen for this pilot study as they may most benefit from a direct thrombin inhibitor because of their physiologically low antithrombin levels. This was an open label, dose-finding and safety study. Patients received one of three bolus doses and one of two initial infusion doses with subsequent dosing adjusted utilizing the activated partial thromboplastin time. Safety was assessed by specific bleeding endpoints. Efficacy was determined by reassessing the initial imaging study at 48-72 h and by measurement of molecular markers of thrombin generation. RESULTS: Sixteen patients completed the study. All three bolus doses resulted in therapeutic anticoagulation, as did both initial infusion doses. A dose-response effect was noted for the continuous infusion but not the bolus dosing. Two patients met the study criteria for major bleeding, both with gross hematuria, which resolved with a reduction in the bivalirudin infusion rate. In terms of efficacy, 37.5% of patients had complete or partial resolution of their thrombosis by 48-72 h. There was a significant decrease in all three molecular markers of thrombin generation. CONCLUSION: This study demonstrates the potential utility of bivalirudin in the pediatric population.

Characterization of the anti-factor VIII immunoglobulin profile in patients with hemophilia A by use of a fluorescence-based immunoassay.

BACKGROUND: The development of neutralizing antibodies, referred to as inhibitors, against factor VIII is a major complication associated with FVIII infusion therapy for the treatment of hemophilia A (HA). Previous studies have shown that a subset of HA patients and a low percentage of healthy individuals harbor non-neutralizing anti-FVIII antibodies that do not elicit the clinical manifestations associated with inhibitor development. OBJECTIVE: To assess HA patients' anti-FVIII antibody profiles as potential predictors of clinical outcomes. METHODS: A fluorescence immunoassay (FLI) was used to detect anti-FVIII antibodies in 491 samples from 371 HA patients. RESULTS: Assessments of antibody profiles showed that the presence of anti-FVIII IgG1 , IgG2 or IgG4 correlated qualitatively and quantitatively with the presence of an FVIII inhibitor as determined with the Nijmegen-Bethesda assay (NBA). Forty-eight patients with a negative inhibitor history contributed serial samples to the study, including seven patients who had negative NBA titers initially and later converted to being NBA-positive. The FLI detected anti-FVIII IgG1 in five of those seven patients prior to their conversion to NBA-positive. Five of 15 serial-sample patients who had a negative inhibitor history and had anti-FVIII IgG1 later developed an inhibitor, as compared with two of 33 patients with a negative inhibitor history without anti-FVIII IgG1 . CONCLUSIONS: These data provide a rationale for future studies designed both to monitor the dynamics of anti-FVIII antibody profiles in HA patients as a potential predictor of future inhibitor development and to assess the value of the anti-FVIII FLI as a supplement to traditional inhibitor testing.

Acute immune (idiopathic) thrombocytopenic purpura in childhood.

Acute immune (idiopathic) thrombocytopenic purpura (ITP) in childhood is most commonly a self-limiting condition with unexplained onset and resolution. In cases of severe thrombocytopenia, or situations where the condition persists beyond 6 months, treatment may be required to minimize the danger of life-threatening intracranial hemorrhage. Nonsurgical treatment options include corticosteroids, intravenous gammaglobulin (i.v.Ig), or anti-D. Specific indications, benefits, and limitations of these modalities are discussed, with recommendations for future directions in therapy.

Treatment options for chronic immune (idiopathic) thrombocytopenia purpura in children.

Immune (idiopathic) thrombocytopenic purpura (ITP) in children is usually acute and self-limiting, but may become chronic in 10% to 30% of patients. Salient issues in the treatment of childhood chronic ITP (cITP) include the following: the choice of immunomodulatory agent; the child's desire for unrestricted physical activity; interventions to avoid or defer splenectomy; and, finally, choosing when (and how) to perform splenectomy. Treatment for children with cITP during childhood usually is extrapolated from that for acute ITP. Treatment with pooled intravenous immunoglobulin (IVIg) and anti-D immunoglobulin often gives an acute response followed by a predictable decay of platelet count. Corticosteroids usually lead to a platelet increase; however, the associated adverse effects of chronic usage are generally unsatisfactory for most children and adolescents. With pulsed, high-dose corticosteroids, a durable platelet response is the exception, not the rule. More aggressive immunosuppression is usually reserved for patients who are symptomatic and refractory to the above treatments, Including splenectomy. Although the estimated success rate ranges from 70% to 90%, the long-term outcome of splenectomy in children with cITP in not well described. In addition, the risk of fatal postsplenectomy infections is significant. A familiar initial strategy among pediatric hematologists thus involves deferral of splenectomy with the reasonable possibility of spontaneous recovery. Corticosteroids, anti-D, and IVIg are effective, temporizing medical alternatives to splenectomy in treating cITP in children. Quality-of-life measurements in children with cITP may help to stimulate the development of new approaches.

Treatment of acute immune thrombocytopenic purpura.

Medical history, physical examination, and laboratory testing are essential to arriving at the diagnosis of acute immune thrombocytopenic purpura (ITP). A history of recent viral illness occurs in about half of the pediatric patients who present with acute symptoms of ITP. The physical examination is normal except for purpura; a complete blood cell count with a differential white blood cell count can be used to confirm the diagnosis of acute ITP. Treatment decisions for acute ITP remain controversial. Treatment generally is designed to prevent life-threatening complications, such as intracranial hemorrhage, and may include single or combination therapy with corticosteroids, intravenous immunoglobulin (IVIg), anti-D, and splenectomy. Corticosteroids are inexpensive and offer an alluring option, especially in the recent era of cost-containment. The often slow platelet response and the potentially severe adverse effects of corticosteroid therapy are frequently a deterrent. IVIg usually leads to a rapid rise in platelet count; however, IVIg is very expensive and adverse effects associated with its infusion are common and sometimes troublesome. The role of anti-D in acute ITP is still evolving. It is similar to IVIg in platelet response and is considerably less expensive. Some degree of hemolysis, the main adverse reaction with anti-D, is inevitable due to the binding of anti-D antibody to Rh-positive erythrocytes. However, most cases of hemolysis do not require medical intervention. Splenectomy is reserved for refractory thrombocytopenia with life-threatening hemorrhage in acute ITP or after recurrent severe thrombocytopenia in chronic ITP. Other immunomodulatory therapies are also discussed.

Hemophilia therapy innovation: development of an advanced category recombinant factor VIII by a plasma/albumin-free method. Proceedings of a Special Symposium at the XIXth Congress of the International Society on Thrombosis and Haemostasis, July 12-18, 2003, Birmingham, UK.

Replacement therapy for hemophilia A has evolved from the early use of whole blood, citrated plasma, and cryoprecipitate, to purified factor VIII (FVIII) concentrates, first derived from plasma, then produced by recombinant DNA technology. Recombinant FVIII (rFVIII) concentrates have provided improved safety for patients with hemophilia A since they significantly reduce the risk of transmission of blood-borne infections. Nevertheless, human- or animal-derived plasma proteins are still included at some step in preparation of all previously licensed rFVIII, thereby introducing the potential for transmission of human or animal pathogens. Anti-hemophilic factor (recombinant), plasma/albumin-free method (rAHF-PFM), a novel advanced category rFVIII produced without the addition of human or animal plasma proteins, has been developed with the goal of providing the greatest possible margin of safety to hemophilia patients. This report, based on a symposium of the XIXth International Society on Thrombosis and Haemostasis Congress, provides an overview of the rAHF-PFM development program as well as current findings from the global clinical evaluation of rAHF-PFM in pediatric and adult previously treated patients.

Clinical manifestations of the prothrombin G20210A mutation in children: a pediatric coagulation consortium study.

The prothrombin G20210A mutation is a common risk factor for thrombosis which increases the risk of deep vein thrombosis, stroke, and fetal loss. There are few publications of its clinical manifestations in children. Our objective was to determine the clinical manifestations of the prothrombin mutation in children. Via survey of pediatric hematologists, we collected data on children with thrombosis and the prothrombin mutation. Thirty-eight patients with a thrombotic event were identified as having the prothrombin mutation. Children with arterial thrombosis were younger, less than half had additional risk factors present at the time of the event, and had a high frequency of central nervous system thrombosis. Children with venous thrombosis were older, almost always had additional risk factors present, and had thrombosis occur most often in the extremities, although there were also a significant number of events in the central venous and cerebral circulation. There was a striking predilection for central nervous system events as 30% of all the events and 67% of the arterial events occurred there. In all, 14/38 children (37%) had central nervous system thrombosis. Unlike factor V Leiden and deficiencies of proteins C and S which cause venous thromboembolism, the prothrombin mutation in children is often associated with arterial thrombosis and with central nervous system events. In children with the prothrombin mutation and venous thrombosis, other risk factors are usually present. Therefore, children with arterial or venous thrombosis of any location should be evaluated for the presence of the prothrombin mutation.

A detailed analysis of charges for hematopoietic stem cell transplantation at a children's hospital.

We analyzed hospital charges for pediatric hematopoietic stem cell transplantation (HSCT) to understand better the medical origin of these charges. Forty-nine patients undergoing HSCT at Kosair Children's Hospital between January 1992 and August 1995 had hospital charges analyzed by cost center, donor type and clinical outcome. Thirty-three autologous, two syngeneic and 14 allogeneic transplants were performed. Twenty-four transplants were performed for hematological malignancies, 22 for solid tumors, and three for non-malignant diseases. Pharmaceutical charges comprised the largest single component of total hospital charges (THC), accounting for 38.9%. Room charges were the next largest group at 33.7% of THC. Other cost centers, in order of magnitude, were central supply (7.9%), transfusion services (7.5%), laboratory (5.8%), microbiology (3.6%), miscellaneous (1.9%), and radiology (1.4%). Within the pharmaceutical cost center, colony-stimulating factors comprised the largest single item, making up 18% of total pharmacy charges and 7% of THC. Antibiotics were the second largest component, at 16% of pharmacy charges and 6% of THC. Patients transferred to the intensive care unit (ICU) had charges 68% greater than non-ICU patients. Allogeneic transplant patients had THC 35% greater than autologous transplant patients, but also a four-fold greater chance of becoming an ICU patient. THC for non-ICU allogeneic transplant patients were 18% greater than for autologous non-ICU patients. THC for allogeneic ICU patients were 21% greater than for autologous ICU patients. Patients who died of transplant-related toxicity prior to day 100 had THC 83% greater than those who survived beyond day 100. This is the first published comprehensive and detailed analysis of charges associated with hematopoietic stem cell transplantation. With increased emphasis on the provision of cost-effective care in both Europe and the USA, medical practices must be examined with the goal of reducing inefficiencies while preserving quality of care. Understanding the genesis of charges in expensive procedures such as stem cell transplantation is an initial step in cost containment.

Calcified thrombus in the right atrium: a rare complication of long-term parenteral nutrition in a child.

A 5-year-old boy with short-bowel syndrome who receives home parenteral nutrition developed a calcified thrombus that involved the inferior vena cava (IVC) and the right atrium. Symptoms included 3 to 4 months of intermittent fever and 2 months of vague chest pain. Blood could not be aspirated from the IVC catheter and an IVC contrast study demonstrated the calcified thrombus. The intracardiac portion of the mass was removed surgically, but the IVC mass could not be completely excised. The boy developed a pericardial effusion 6 weeks after surgery. He was treated for this and 6 months after the initial surgery the patient was asymptomatic.

Evaluation of bleeding and thrombotic events during long-term use of romiplostim in patients with chronic immune thrombocytopenia (ITP).

BACKGROUND: Romiplostim is a peptibody protein that raises platelet counts during long-term treatment of patients with chronic immune thrombocytopenia (ITP). Clinical outcomes related to increased platelet counts include a reduced risk of bleeding and a potential risk of thrombosis. OBJECTIVE: To evaluate bleeding and thrombotic events occurring in chronic ITP patients during two phase 3, randomized, placebo-controlled, 24-week studies of romiplostim and during subsequent treatment in an open-label extension study. PATIENTS/METHODS: In the phase 3 trials, 125 patients were randomized to romiplostim or placebo; romiplostim dose was adjusted to maintain platelet counts of 50-200 x 10(9) L(-1). Patients who completed the phase 3 trials could enroll in the extension study in which all patients received romiplostim. RESULTS: In the phase 3 trials, a significantly greater percentage of patients treated with placebo (34%) had bleeding adverse events of moderate or greater severity than did patients treated with romiplostim (15%, P = 0.018). In the extension study, the incidence of bleeding adverse events of moderate or greater severity decreased from 23% of patients in the first 24 weeks to 12% after 24-48 weeks, remaining < or = 6% thereafter. The exposure-adjusted incidence of thrombotic events was 0.1 per 100 patient-weeks in the phase 3 studies, and 0.08 per 100 patient-weeks in the extension study where patients received romiplostim for up to 144 additional weeks. CONCLUSIONS: The incidence and severity of bleeding was decreased in chronic ITP patients treated with romiplostim compared with placebo, and the incidence of thrombotic events was not different between the two groups.