Research Studies

Per Dr. Schulman, the JGP enabled him to dedicate time to hemophilia research, and more importantly, demonstrated to his department that what he is doing is extremely important to external funding sources. Dr. Schulman has never been formally involved with a Hemophilia Treatment Center, however, his institution has an entire division of hemostasis and thrombosis with clinical and research activity. As a note in proof, I would like to add that the generous support of the NHF has also been instrumental in helping me to establish a viable career path as a physician-scientist focused on the biology and treatment of disorders of hemostasis. Recognition by the NHF with this award has helped me to secure additional protected time and institutional commitment to continue along this career path at Beth Israel Deaconess Medical Center.  I wanted to thank the NHF again, the award has helped me to gain recognition and commitment from my home institution that I expect will eventually enable me to launch an independent career with a focus on bleeding disorders.

This study will evaluate hemophilia treatment center (HTC) services provided to women with hemophilia A or B (Factor VIII or Factor IX level [ 50%). The American Thrombosis and Hemostasis Network (ATHN) maintains a confidential national database for patients with bleeding and clotting disorders. Utilizing this existing ATHNdataset, the study will analyze the effect of gender on the delivery of comprehensive care in patients with hemophilia A and B. The project will focus on how gender impacts three specific components of care: identification of patients with factor VIII or IX deficiency, inclusion of patients in the comprehensive care model, and monitoring of joint bleeding as a key component of comprehensive care provided by HTCs. Demonstrating gender-based disparities in comprehensive care would provide evidence for making changes to improve the clinical care provided to women with hemophilia. This study will add to the knowledge regarding the care of women with hemophilia, helping to inform future studies of this under-researched population.

Background:

Congenital afibrinogenemia is an autosomal recessive bleeding disorder referring to the total absence of fibrinogen measured by an antigenic assay. The commonest manifestation of the disease is bleeding from mucosal surfaces, however musculoskeletal bleeding, gynecologic and obstetric complications, spontaneous bleeding, bleeding after minor trauma and during interventional procedures or thromboembolic episodes.

Objective:

We hereby report the only case of this disorder in Slovakia with a successful perioperative management of hemostasis during revision total hip arthroplasty.Method and results: Preoperatively, the patient received fibrinogen concentrate in the dose of 75mg/kg, this dose increased the level of fibrinogen after 2 hours to corresponding 170mg/dL. During surgery, the patient received fibrinogen concentrate in the dose of 25mg/kg. The patient was administered an intraoperative transfusions because of blood loss. Twenty-four hours after surgery, the fibrinogen concentrate was applied in the patient at the dose 37.5 mg/kg every 8 hours. One day after surgery, we administered fibrinogen concentrate at the dose of 37.5 mg/kg every 12 hours with a targeted level of fibrinogen in the interval of 130-150mg/dL. We continued to reduce the dose of fibrinogen concentrate. The patient was discharged safely at 12th day after surgery with level of fibrinogen above 50mg/dL. The administration of fibrinogen concentrate was combined with low molecular weight heparin.

Conclusion:

Our results in this patient with congenital afibrinogenemia who underwent the successful repeated total left hip arthroplasty reaffirm the recommendation to tailor treatment to ensure a hemostasis balance between the replacement of clotting factor (fibrinogen concentrate) and thromboprophylaxis.

Background:

Many hemophilia treatment centers (HTCs) have a comprehensive care clinic in which a variety of providers see patients with bleeding disorders. Registered dental hygienists (RDHs) are, in some cases, a part of the comprehensive care clinic due to an access to dental care issue for those with bleeding disorders. The RDH may educate patients with bleeding disorders about oral health and act as a liaison between the patients’ hematologist and dentist.

Objective:

To determine if HTC nurses who work with RDHs are more confident in addressing patients’ oral health than nurses who do not. Methods: HTC nurses in the United States were sent a 10-item survey to evaluate presence of a RDH within the HTC, oral health related services provided to patients, and level of confidence and knowledge in discussing oral health with patients. IRB approval was obtained prior to data collection.

Results:

Response rate=49.7%. 45% of nurses that responded stated their HTC employs a RDH (n=31). There were not statistically significant differences in confidence levels between nurses working with a RDH versus those that do not. Data revealed that RDHs help patients find access to dental care, educate patients on oral health, and act as a liaison between the hematologist and the patient’s dentist. 19.4% of nurses that do not have a RDH do not help patients find access to dental care. Nurses that worked more often were more likely to help patients find access to dental care (p=0.01) and more confident in the relationship between oral health and bleeding disorders (p=0.001) and in discussing oral health with patients (p=0.002).

Conclusions:

Although there were no statistically significant differences in the two groups of nurses when measuring confidence, knowledge, and services provided, the study shed light into what services RDHs are providing within the comprehensive care setting. Due to the many complications patients with bleeding disorders can face during treatment, it would be beneficial to have a specialized oral health care provider incorporated into the HTC team to educate patients on preventing oral disease. This model of an RDH as a part of the comprehensive care clinic could translate into additional career opportunities for the RDH.

Objective:

N9-GP is a glycoPEGylated recombinant factor-IX (rFIX) product that provides approximately two times incremental recovery, five times half-life, and 10 times area under the plasma concentration-time curve compared with standard rFIX. Phase 3 single-dose (40 IU/kg) in adults showed incremental recovery 2.34 %/IU/kg and 17% mean FIX activity at 7 days. This analysis investigates N9-GP 40 IU/kg as a single-dose on-demand (OD) treatment for hemophilia B, focusing on predictors of a second dose.

Methods:

In the paradigm™2 pivotal trial of previously treated adult/adolescent patients (≤2% FIX), the FDA requested that a group receive OD treatment prior to US enrollment into prophylaxis. This case-by-case analysis evaluated OD treatment in relationship to bleed type/pattern and prestudy treatment regimen. Hemostatic efficacy was reported by patients on a 4-point scale.

Summary:

Fifteen patients were enrolled for OD treatment (13 severe, two moderate); 13 were previously treated OD and two with prophylaxis. Overall, 14/15 patients experienced 143 bleeds during 26 weeks, of which 120 (84%) in 13 patients were treated with one dose. Seven patients (five severe, two moderate) treated all bleeds (62) with one dose (36 ‘excellent’ and 26 ‘good’ response). The other seven patients, described below, experienced 58 bleeds (72%) treated with one dose (seven ‘excellent’, 49 ‘good’, one ‘moderate’, one not reported); their other 23 bleeds (28%) required ≥2 doses (17 ‘good’, six ‘moderate’). Two of these seven had 4/11 (36%) recurrent target joints (TJ) bleeds/rebleeds treated with additional doses. An 18-year-old previously treating with plasma-derived FIX (pdFIX), 76 IU/kg/bleed, had three right elbow TJ bleeds in two months treated with one, five, and two doses. A 27-year-old previously on prophylaxis (pdFIX 100 IU/kg every 3 days and 100 IU/kg/bleed) had two bleeds in a right ankle TJ in 2 weeks treated with two doses (including one for early rebleeding) and six doses prior to withdrawing from the study. Another four patients with bleeds requiring multiple doses had been historically treated with multiple high FIX doses (IU/kg x doses per bleed: 60×2, 80×2, 80×2, and 81×3) with prescribed dosing of 120, 160, 160, and 243 IU/kg/bleed; they reported 63 bleeds, of which 45 (71%) were treated with a single 40-IU/kg dose, 17 with two, and one with four doses. Average N9-GP dosing was 44.0, 74.7, 97.9, and 52.8 IU/kg/bleed (63%, 53%, 39%, and 78% reduction in FIX use per episode). The last patient was treated prestudy with 10 IU/kg/bleed had seven bleeds (six treated with one dose, mean 46.8 IU/kg/bleed).

Conclusions:

N9-GP 40 IU/kg was effective as a single-dose OD bleed treatment (84%). Additional dose(s) for some bleeds were associated with recurrent TJ bleeds in patients not on prophylaxis or patients previously taking multiple high doses for bleeding.

Background:

Inherited factor X deficiency is an autosomal recessive bleeding disorder with an estimated occurrence rate of 1:1,000,000¹. Historically, bleeding symptoms have been treated with topical therapies, antifibrinolytic agents, fresh frozen plasma (FFP) or plasma-derived FIX concentrates (PCCs). In 2015, the first factor X (FX) concentrate was approved in the U.S.

Objective:

This organization was interested in reviewing clinical outcomes such as perceived pain and unplanned hospitalizations of adults and children with FX disease currently being treated in the home with Coagadex®. METHODS: This organization conducted a retrospective review of a population of seven adult and pediatric patients. Patients were surveyed for pain, bleeding episodes, hospitalizations/ ER visits, dosing parameters and administration methods pre/post initiation of FX therapy. There were 3 children, 12 years old and under and four adults. Ages ranged from 5-60 years old with the average age of 27.9. There were five males and two females. The average length of treatment was 6.4 months. One patient was naïve, six converted from other therapies. Dose ranges administered by caregivers or self-infusion were 750 -2800 IU (26-61 IU/Kg). One patient was on-demand and six were administering prophylaxis therapy.

Results:

There were two converted prophylaxis patients reported pain with PCC’s and none with FX; one on-demand naïve patient stated his pain was markedly improved with prn administration of FX; four converted prophylaxis patients with no prior pain history reported no changes in pain on FX therapy. For on-demand patients treating bleeding episodes, three reported a decrease in the number of bleeding episodes, three were unchanged and one reported one additional bleeding episode. A total of ten hospitalizations or emergency room visits were reported during the six months prior to initiation of FX treatment and only one in the six months following initiation of treatment.

Conclusion:

Early recognition and home treatment with FX concentrate allows for prompt resolution of bleeding symptoms, decreased pain and decreased hospitalization or emergency room visits. Further investigation is needed to determine cost-savings for decreased hospitalization/ ER visits.References:Brown, D.L. & Kouides, P.A. (2008). Diagnosis and treatment of Inherited Factor X deficiency. Haemophilia. (14). 1176-1182. Retrieved from: https://www.hemophilia.org/sites/default/files/document/files/DiagnosisAndTreatmentOfInheritedFact…

Klaus Bonazza received his Ph.D. in chemistry from Vienna University of Technology. He is currently a postdoctoral researcher at Boston Children's Hospital and appointed at Harvard Medical School, mentored by Dr. Timothy Springer. His field of interest is the ultra-large concatemeric protein von Willebrand factor (VWF), which accounts for the adaptability of hemostasis to different flow conditions in the blood vessels.

At moderate, physiological flow VWF has a packed, "bird nest's" shape whereas strong elongational flow conditions, occurring downstream of vascular restrictions or injuries, induce a transition to a threat-like, elongated state. On top of this overall unpacking, tensile forces, which are exerted on the chain and transmitted by its A1 domain, cause local conformational changes which activate binding of thrombocyte receptor Glycoprotein Ib (GPIbα) to initiate coagulation. With his JGP fellowship award, Dr. Bonazza will pioneer a new method to obtain structural insights into force dependent VWF unpacking, A1 deformation and GPIbα binding based on hydrogendeuterium exchange under elongational flow conditions.